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APRINCIPLESOF NEURALSCIENCESixth EditionEric R . Kande]John D. Koester 1Sarah H , Mack« Steven A'.’SiegelbaumMeGrawHillLPRINCIPLES OF NEUR AL SCIENCESixth EditionEdited byERIC R. KANDELJOHN D. KOESTERSARAH H. MACKSTEVEN A. SIEGELBAUMNew York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney TorontoKandel_FM.indd 5 20/01/21 9:04 AMCopyright © 2021 by McGraw Hill. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher.ISBN: 978-1-25-964224-1MHID: 1-25-964224-0The material in this eBook also appears in the print version of this title: ISBN: 978-1-25-964223-4,MHID: 1-25-964223-2.eBook conversion by codeMantraVersion 1.0All trademarks are trademarks of their respective owners. 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McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.http://www.mhprofessional.comSarah H. Mack1962–2020WE DEDICATE THIS SIXTH EDITION OF Principles of Neural Science to our dear friends and colleagues, Thomas M. Jessell and Sarah H. Mack. Sarah Mack, who contrib-uted to and directed the art pro-gram of Principles of Neural Science during her more than 30-year tenure, passed away on Octo-ber 2, 2020. She worked coura-geously and tirelessly to ensure that all the artwork for this edi-tion met her high standards and could be completed while she still had the strength to continue. After graduating from Williams College with honors in English literature in 1984, Sarah worked for five years in the field of social work, while taking courses at Columbia in studio art and computer graphics. She first con-tributed to the art program for the third edition of the book when she joined the Kandel lab as a graphic artist in 1989. Five years later, as the fourth edition went into the planning stage, Sarah, together with Jane Dodd as art editor, completely redesigned the art program, developing and converting hundreds of figures and introducing color. This monu-mental task required countless aesthetic decisions to develop a stylistic consistency for the various figure elements throughout the book. The result was a set of remarkably clear, didactic, and artistically pleasing diagrams and images. Sarah maintained and extended this high level of excellence as art editor of the fifth and sixth editions of the book. She has thus left an enduring mark on the thousands of students who over the years, as well as in years to come, have been introduced to neuro-science through her work. Sarah was a most remarkable and gifted artist, who developed a deep understanding and appreciation of neuroscience during the many years she contributed to the book. In addition to her artistic con-tributions to the figures, she also edited the associated text and legends for maximum clarity. Because her contributions extended far beyond the preparation of the figures, Sarah was made co-editor of the cur-rent edition of the book. Sarah also had an amazing ability to juggle huge numbers of negotiations with dozens of authors simultaneously, all the while gently, but firmly, steering them to a final set of elegantly instructive images. She did this with such a spirit of generosity that her interactions with the authors, even those she never met in person, developed into warm friendships. Over the past three editions, Sarah was the driving force that formed the basis for the aesthetic unifying vision running throughout the chapters of Principles. She will be greatly missed by us all.Kandel_FM.indd 7 20/01/21 9:04 AMTom Jessell was an extraor-dinary neuroscientist who made a series of pioneering contribu-tions to our understanding of spinal cord development, the sensory-motor circuit, and the control of movement. Tom had a deep encyclopedic knowledge and understanding of all that came within his sphere of inter-est. Equally at home discussing a long-forgotten scientific dis-covery, quoting Shakespeare by heart, or enthusing about 20th-century British or Italian Renaissance art, Tom was a bril-liant polymath.Tom’s interest in neuro-science began with his under-graduate studies of synaptic pharmacology at the University Thomas M. Jessell1951–2019of London, from which he graduated in 1973. He then joined Leslie Iversen’s laboratory at the Medical Research Council in Cambridge to pursue his PhD, where he investigated the mechanism by which the newly discovered neuropeptide substance P controls pain sensation. Tom made the pivotal observation that opioids inhibit transmission of pain sensation in the spinal cord by reducing substance P release. After receiving his doctoral degree in 1977, he continued to explore the role of substance P in pain processing as a postdoctoral fellow with Masa-nori Otsuka in Tokyo, solidifying his lifelong interest in spinal sensory mechanisms while managing to learn rudimentary Japanese. Tom then realized that deeper insights into spinal cord function might best be obtained through an understanding of neural development, prompt-ing him to pursue research on the formation of a classic synapse, the neuromuscular junction, in Gerry Fischbach’s30Direction (degrees)Firing rate (spikes/s)60 300DecodeddirectionNeuron 2activityNeuron 1activityNeuron 1activityNeuron 2activityNeuron 1activityNoiseNoise0 120 180 240 360Direction (degrees)60 300 0 120 180 240 36060 300Direction (degrees)more accurately determined. If the second neuron fires at 5 spikes per second, corresponding to a movement in either the 60° or 120° direction, the only movement direction that is consistent between the two neurons is 120° (Figure 39–4B). Thus, by recording from these two neurons simultaneously, the intended reach direction can be determined more accurately than by record-ing from one neuron. (However, two neurons do not necessarily provide a perfect estimate of the intended reach direction due to noise, as described next.)The second reason why decoding a movement from the activity of several neurons gives greater accu-racy is because a neuron’s activity level usually varies across repeated movements in the same direction. This variability is typically referred to as spiking “noise.” Let us say that due to spiking noise the first neuron fires at slightly less than 30 spikes per second and the second neuron fires at slightly more than 5 spikes per second (Figure 39–4C). Under these conditions, no sin-gle movement direction is consistent with the activity level of both neurons. Instead, a compromise must be made between the two neurons to determine a move-ment direction that is as consistent as possible with their activities. By extending this concept to more than two neurons, the movement direction can be decoded even more accurately as the number of neurons increases.Decoding Algorithms Estimate Intended Movements From Neural ActivityMovement decoders are a central component of BMIs. There are two types of BMI decoders: discrete and continuous (Figure 39–3C). A discrete decoder esti-mates one of several possible movement goals. Each of these movement goals could correspond to a letter on a keyboard. A discrete decoder solves a classifica-tion problem in statistics and can be applied to either preparation activity or execution activity. A continuous decoder estimates the moment-by-moment details of a movement trajectory. This is important, for exam-ple, for reaching around obstacles or turning a steer-ing wheel. A continuous decoder solves a regression problem in statistics and is usually applied to execu-tion activity rather than preparation activity because the moment-by-moment details of a movement can be more accurately estimated from execution activity (Chapter 34).Motor BMIs must produce movement trajecto-ries as accurately as possible to achieve the desired movement and typically use a continuous decoder to do this. In contrast, communication BMIs are con-cerned with enabling the individual to transmit infor-mation as rapidly as possible. Thus, the speed and accuracy with which movement goals (or keys on a keyboard) can be selected are of primary importance. Communication BMIs can use a discrete decoder to directly select a desired key on a keyboard or a con-tinuous decoder to continuously guide the cursor to the desired key, where only the key eventually struck actually contributes to information conveyance. This seemingly subtle distinction has implications that influence the type of neural activity required and therefore the brain area that is targeted, as well as the type of decoder that is used.Kandel-Ch39_0953-0974.indd 960 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 961Figure 39–5 Discrete decoding.A.Calibration phase. A population activity space is shown for two neurons, where each axis represents the firing rate of one neuron. On each trial (ie, movement repetition), the activity of the two neurons together defines one point in the population activity space. Each point is colored by the movement goal, which is known during the calibration phase. Decision bounda-ries (dashed lines) are determined by a statistical model to optimize discrimination among the movement goals. The decision boundaries define a region in the population activity space for each movement goal.B.Ongoing use phase. During this phase, the decision bounda-ries are fixed. If we record new neural activity (square) for which the movement goal is unknown, the movement goal is determined by the region in which the neural activity lies. In this case, the neural activity lies in the region corresponding to the leftward target, so the decoder would guess that the sub-ject intended to move to the leftward target.Neural decoding involves two phases: calibra-tion and ongoing use. In the calibration phase, the relationship between neural activity and movement is characterized by a statistical model. This can be achieved by recording neural activity while a para-lyzed person attempts to move, imagines moving, or passively observes movements of a computer cursor or robotic limb. Once the relationship has been defined, the statistical model can then be used to decode new observed neural activity (ongoing use phase). The goal during the ongoing use phase is to find the movement that is most consistent with the observed neural activity (Figure 39–4B,C).Discrete Decoders Estimate Movement GoalsWe first define a population activity space, where each axis represents the firing rate of one neuron. On each trial (ie, movement repetition), we can measure the fir-ing rate of each neuron during a specified period, and together they yield one point in the population activity space. Across many trials, involving multiple move-ment goals, there will be a scatter of points in the pop-ulation activity space. If the neural activity is related to the movement goal, then the points will be sepa-rated in the population activity space according to the movement goal (Figure 39–5A). During the calibration phase, decision boundaries that partition the population A Calibration phase B Ongoing use phase0 20 40200 040DownRightUpLeftDownRightUpLeftBoundariesmoved to optimizediscriminationBoundaries�xedNewactivityNeuron 1 (spikes/s)Neuron 2 (spikes/s)0 20 402040Neuron 1 (spikes/s)Neuron 2 (spikes/s)activity space into different regions are determined by a statistical model. Each region corresponds to one movement goal.During the ongoing use phase, we measure new neural activity for which the movement goal is unknown (Figure 39–5B). The decoded movement goal is determined by the region in which the neural activity lies. For example, if the neural activity lies within the region corresponding to the leftward target, then the discrete decoder would guess that the subject intended to move to the leftward target on that trial. It is possi-ble that the subject intended to move to the rightward target, even though the recorded activity lies within the region corresponding to the leftward target. In this case, the discrete decoder would incorrectly estimate the subject’s intended movement goal. Decoding accu-racy typically increases with an increasing number of simultaneously recorded neurons.Continuous Decoders Estimate Moment-by-Moment Details of MovementsArm position, velocity, acceleration, force, and other aspects of arm movement can be decoded using the methods described here with varying levels of accu-racy. For concreteness, we will discuss decoding move-ment velocity because it is one of the quantities most strongly reflected in the activity of motor cortical Kandel-Ch39_0953-0974.indd 961 14/12/20 9:44 AM962 Part V / Movementneurons and is the starting point for the design of most BMI systems.Consider a population of neurons whose level of activity indicates the movement velocity (ie, speed and direction). During the calibration phase, a “pushing vector” is determined for each neuron (Figure 39–6A). A pushingvector indicates how a neuron’s activity influ-ences movement velocity. Various continuous decoding algorithms differ in how they determine the push-ing vectors. One of the earliest decoding algorithms, the population vector algorithm (PVA), assigns each neuron’s pushing vector to point along the neuron’s preferred direction (see Figure 34–22A). A neuron’s preferred direction is defined as the direction of move-ment for which the neuron shows the highest level of activity (ie, peak of curves in Figure 39–4). Much of the pioneering work on BMIs used the PVA. However, the PVA does not take into account the properties of the spiking noise (ie, its variance and covariance across neurons), which influences the accuracy of the decoded movements. A more accurate decoder, the optimal lin-ear estimator (OLE), incorporates the properties of the spiking noise to determine the pushing vectors.During the ongoing use phase, the pushing vec-tors are each scaled by the number of spikes emitted by the corresponding neuron at each time step (Figure 39–6B). At each time step, the decoded movement is the vector sum of the scaled pushing vectors across all neurons. The decoded movement represents a change in position during one time step (ie, velocity). The BMI cursor (or limb) position (Figure 39–6C) is then updated according to the decoded movement.To further improve decoding accuracy, the esti-mation of velocity at each time step should take into account not only current neural activity (as illustrated in Figure 39–6), but also neural activity in the recent past. The rationale is that movement velocity (and other kinematic variables) changes gradually over time, and so neural activity in the recent past should Figure 39–6 (Opposite) Continuous decoding.A.During the calibration phase, a pushing vector is determined for each of 97 neurons. Each vector represents one neuron and indicates how one spike from that neuron drives a change in position per time step (ie, velocity). Thus, the units of the plot are millimeters per spike during one time step. Different neurons can have pushing vectors of different magnitudes and directions.B.During ongoing use, spikes are recorded from the same neurons as in panel A during movement execution. At each time step, the new length of an arrow is obtained by starting with its previous length in panel A and scaling it by the number of spikes produced by the neuron of the same color during that time step. If a neuron does not fire, there is no arrow for that neuron during that time step. The decoded movement (black arrow) is the vector sum of the scaled pushing vectors, repre-senting a change in position during one time step (ie, velocity). For a given neuron, the direction of its scaled pushing vectors is the same across all time steps. However, the magnitudes of the scaled pushing vectors can change from one time step to the next depending on the level of activity of that neuron.C.The decoded movements from panel B are used to update the position of a computer cursor (orange dot), robotic limb, or paralyzed limb at each time step.be informative about the movement velocity. This can be achieved by temporally smoothing the neural activity before applying a PVA or OLE or by using a Kalman filter to define a statistical model describing how movement velocity (or other kinematic variables) changes smoothly over time. With a Kalman filter, the estimated velocity is a combination of the scaled push-ing vectors at the current time step (as in Figure 39–6B) and the estimated velocity at the previous time step. Indeed, continuous decoding algorithms that take into account neural activity in the recent past have been shown to provide higher decoding accuracy than those that do not. The Kalman filter and its extensions are widely used in BMIs and among the most accurate continuous decoding algorithms available.Increases in Performance and Capabilities of Motor and Communication BMIs Enable Clinical TranslationPatients with paralysis wish to perform activities of daily living. For people with ALS or upper spinal cord injury who are unable to speak or to move their arms, the most desired tasks are often the ability to commu-nicate, to move a prosthetic (robotic) arm, or to move the paralyzed arm by stimulating the musculature. Having described how neural signals can be read out from motor areas of the brain and how these electrical signals can be decoded to arrive at BMI control signals, we now describe recent progress toward restoring these abilities.The majority of laboratory studies are carried out in able-bodied nonhuman primates, although paralysis is sometimes transiently induced in important control experiments. Three types of experimental paradigms are in broad use, differing in the exact way in which arm behavior is instructed and visual feedback is pro-vided during BMI calibration and ongoing use. Setting Kandel-Ch39_0953-0974.indd 962 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 963A Calibration phaseB Ongoing use phaseC Decoded cursor movements5 mm/spike5 mm5 mm0 ms 20 ms 40 ms 60 ms0–20 ms 20–40 ms 40–60 msNeuron 1Neuron 2Neuron 97Individual neuronpushing vectorsDecodedmovementNeuron 32 spikes1 spike2 spikes2 spikes4 spikes5 spikes1 spike2 spikes3 spikesKandel-Ch39_0953-0974.indd 963 14/12/20 9:44 AM964 Part V / MovementFigure 39–7 A communication brain–machine interface can control a computer cursor using a discrete decoder based on neural activity during the preparation epoch.A.After a monkey touched a central target (large yellow square) and fixated a central point (red +), a peripheral target (small yellow square) appeared and the monkey prepared to reach to it. Spike counts were taken during the preparation epoch and fed into a discrete decoder. The duration of the period in which spike counts are taken (ie, width of light blue shading) affects decoding performance and information transfer rate (ITR) (see panel B). Based on the spike counts (blue square), the discrete decoder guessed the target the monkey was preparing to reach to.B.Decoding accuracy (black) and information transfer rate (ITR, bits/s; red) are shown for different trial lengths and numbers of targets. Trial length was equal to the duration of the period in which spike counts were taken (varied during the experiment) plus 190 ms (fixed during the experiment). The latter provided time for visual information of the peripheral target to reach the premotor cortex (150 ms), plus the time to decode the target location from neural activity and render the decoded target location on the screen (40 ms). (Adapted, with permission, from Santhanam et al. 2006.)these differences aside, we focus below on how BMIs function and perform. We also highlight recent pilot clinical trials with people with paralysis.Subjects Can Type Messages Using Communication BMIsTo investigate how quickly and accurately a commu-nication BMI employing a discrete decoder and prepa-ration activity can operate, monkeys were trained to fixate and touch central targets and prepare to reach to a peripheral target that could appear at one of several different locations on a computer screen. Spikes were recorded using electrodes implanted in the premotor cortex. The number of spikes occurring during a par-ticular time window during the preparation epoch was used to predict where the monkey was preparing to reach (Figure 39–7A). If the decoded target matched the peripheral target, a liquid reward was provided to indicate a successful trial.By varying the duration of the period in which spike counts are taken and the number of possible tar-gets, it was possible to assess the speed and accuracy 2 targets30405060708090100Decoding accuracy (% correct)Neurons200 300 400 5004targets200 300 400 5008 targets200 300 400 500Trial length (ms)16 targets200 300 400 50001234567ITR (bps)Targetonset TimeDiscrete decoderA Experimental setup B Single-trial decoding accuracy decreases andITR increases as more target locations are usedDownRightUpLeftNeuron 1 (spikes/s)Neuron 2(spikes/s)of target selections (Figure 39–7B). Decoding accuracy tended to increase with the period in which spike counts are taken because spiking noise is more easily averaged out in longer periods.An important metric for efficient communication is information transfer rate (ITR), which measures how much information can be conveyed per unit time. A basic unit of information is a bit, which is specified by a binary value (0 or 1). For example, with three bits of information, one can specify which of 23 = 8 possible targets or keys to press. Thus, the metric for ITR is bits per second (bps). ITR increases with the period in which spike counts are taken, then declines. The reason is that ITR takes into account both how accu-rately and how quickly each target is selected. Beyond some point of diminishing returns of a longer period, accuracy fails to increase rapidly enough to overcome the slowdown in target-selection rate accompanying a longer period.Overall performance (ITR) increases with the num-ber of possible targets, despite a decrease in decoding accuracy, because each correct target selection conveys more information. Fast and accurate communication Kandel-Ch39_0953-0974.indd 964 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 965has been demonstrated in BMIs with this design based on a discrete decoder applied to preparatory activity. The ITR of this BMI is approximately 6.5 bps, which corresponds to approximately two to three targets per second with greater than 90% accuracy.Recent studies have also investigated how quickly and accurately a communication BMI employing a continuous decoder and execution activity can oper-ate. Two different types of continuous decoders were evaluated: a standard Kalman filter decoding move-ment velocity (V-KF) and a recalibrated feedback intention-trained Kalman filter (ReFIT-KF). The V-KF was calibrated using the neural activity recorded dur-ing actual arm movements (ie, open-loop control). The ReFIT-KF incorporated the closed-loop nature of BMIs into decoder calibration by assuming that the user desired to move the cursor straight to the target at each time step.To assess performance, both types of decoders were used in closed-loop BMI control (Figure 39–8A). Monkeys were required to move a computer cursor from a central location to eight peripheral locations and back. A gold standard for performance evaluation was established by having the monkeys also perform the same task using arm movements. The ReFIT-KF outperformed the V-KF in several ways: Cursor move-ments using ReFIT-KF were straighter, producing less movement away from a straight line to the target; cur-sor movements were faster, approaching the speed of arm movements (Figure 39–8B); and there were fewer (potentially frustrating) long trials.Given its performance benefits, the ReFIT-KF is being used in clinical trials by people with paralysis (Figure 39–8C). Spiking activity was recorded using a 96-channel electrode array implanted in the hand control area of the left motor cortex. Signals were fil-tered to extract action potentials and high-frequency local field potentials, which were decoded to provide “point-and-click” control of the BMI-controlled cursor. The subject was seated in front of a computer monitor and was asked, “How did you encourage your sons to practice music?” By attempting to move her right hand, the computer cursor moved across the screen and stopped over the desired letter. By attempting to squeeze her left hand, the letter beneath the cursor was selected, much like clicking a mouse button.BMI performance in the clinical trials was assessed by measuring the number of intended characters sub-jects were able to type (Figure 39–8D). Subjects were able to demonstrate that the letters they typed were intended by using the delete key to erase occasional mistakes. These clinical tests showed that it is possible to type at a rate of many words per minute using a BMI.Subjects Can Reach and Grasp Objects Using BMI-Directed Prosthetic ArmsPatients with paralysis would like to pick up objects, feed themselves, and generally interact physically with the world. Motor BMIs with prosthetic limbs aim to restore this lost motor functionality. As before, neural activity is decoded from the brain but is now routed to a robotic arm where the wrist is moved in three dimensions (x, y, and z) and the hand is moved in an additional dimension (grip angle, ranging from an open hand to a closed hand).In one test of a robotic arm, a patient with paralysis was able to use her neural activity to direct the robotic arm to reach out, grab a bottle of liquid, and bring it to her mouth (Figure 39–9). The three-dimensional reaches and gripping were slower and less accurate than natural arm and hand movements. Importantly, this demonstrated that the same BMI paradigm origi-nally developed with animals, including measuring and decoding signals from motor cortex, works in peo-ple even years after the onset of neural degeneration or the time of neural injury.BMI devices directing prosthetic arms and hands are now able to do more than just control three-dimensional movement or open and close the hand. They can also orient the hand and grasp, manipulate, and carry objects. A person with paralysis was able to move a prosthetic limb with 10 degrees of freedom to grasp objects of different shapes and sizes and move them from one place to another (Figure 39–10). Com-pletion times for grasping and moving objects were considerably slower than natural arm movements, but the results are encouraging. These studies illustrate the existing capabilities of prosthetic arms and also the potential for even greater capabilities in the future.Subjects Can Reach and Grasp Objects Using BMI-Directed Stimulation of Paralyzed ArmsAn alternative to using a robotic arm is to restore lost motor function to the biological arm. Arm paralysis results from the loss of neural signaling from the spinal cord and brain, but the muscles themselves are often still intact and can be made to contract by electrical stimulation. This capacity underlies functional electri-cal stimulation (FES), which sends electrical signals via internal or external electrodes to a set of muscle groups. By shaping and timing the electrical signals sent to the different muscle groups, FES is able to move the arm and hand in a coordinated fashion to pick up objects.Laboratory studies in monkeys have demon-strated that this basic approach is viable in principle. Kandel-Ch39_0953-0974.indd 965 14/12/20 9:44 AM966 Part V / MovementFigure 39–8 A communication brain–machine interface (BMI) can control a computer cursor using a continuous decoder based on neural activity during the execution epoch.A.Comparison of cursor control by a monkey using its arm, a standard decoder that estimates velocity (BMI with Kalman filter decoding movement velocity [V-KF]), and a feedback intention-trained decoder (BMI with recalibrated feedback intention-trained Kalman filter [ReFIT-KF]). Traces show cursor movements to and from targets alternating in the sequence indicated by the numbers shown. Traces are continuous for the duration of all reaches. (Adapted, with permission, from Gilja et al. 2012.)B.Time required to move the cursor between the central location and a peripheral location on successful trials (mean ± standard error of the mean). (Adapted, with permission, from Gilja et al. 2012.)C.Pilot clinical trial participant T6 (53-year-old femalewith amyo-trophic later sclerosis [ALS]) using a BMI to type the answer to a question. (Adapted, with permission, from Pandarinath et al. 2017.)D.Performance in a typing task for three clinical trial partici-pants. Performance can be sustained across days or even years after array implantation. (Adapted, with permission, from Pandarinath et al. 2017.)ACBArm V-KF ReFIT-KFArm51 57426 8317684 23V-KF ReFIT-KFElectrode arrayNeuralsignalsContinuousand discretedecoders Cursorvelocity +click stateMonitorQ K C G V JDELDELS I N D JW T H E A MZ B F Y PU O R LXHow did you encourage your sons to practice music?When they started their_102Time to target (s)D570 572 577Days since implantSubject T6 (with ALS)588 59120304001050Correct characters per min68 70Days since implantSubject T5 (with spinal cord injury)20304001050539 548Days since implantSubject T7 (with ALS)20304001050514728365 cmKandel-Ch39_0953-0974.indd 966 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 967Figure 39–9 A subject with paralysis drinks from a bottle using a robotic arm controlled by a motor brain–machine interface using a continuous decoder. Three sequential images from the first successful trial show the subject using the robotic arm to grasp the bottle, bring it to her mouth and drink coffee through a straw, and place the bottle back on the table. (Adapted from Hochberg et al. 2012.)It is implemented by calibrating a continuous decoder to predict the intended activity of each of several of the muscles, transiently paralyzed with a nerve block. These predictions are then used to control the intensity of stimulation of the same paralyzed muscles, which in turn controls motor outputs such as a grip angle and force. This process in effect bypasses the spinal cord and restores some semblance of voluntary control of the paralyzed arm and hand. Similar results have recently been demonstrated in patients with paraly-sis using either externally applied or fully implanted state-of-the-art FES electrodes. Intracortically recorded signals from motor cortex were decoded to restore movement via FES in a person with upper spinal cord injury (Figure 39–11). The subject was able to achieve control of different wrist and hand motions, including finger movements, and perform various activities of daily living.Subjects Can Use Sensory Feedback Delivered by Cortical Stimulation During BMI ControlDuring arm movements, we rely on multiple sources of sensory feedback to guide the arm along a desired path or to a desired goal. These sources include visual, pro-prioceptive, and somatosensory feedback. However, in most current BMI systems, the user receives only visual feedback about the movements of the computer cursor or robotic limb. In patients with normal motor out-put pathways but lacking proprioception, arm move-ments are substantially less accurate than in healthy individuals, both in terms of movement direction and extent. Furthermore, in tests of BMI cursor control in healthy nonhuman primate subjects, the arm contin-ues to provide proprioceptive feedback even though arm movements are not required to move the cursor. BMI cursor control is more accurate when the arm is passively moved together with the BMI cursor along the same path, rather than along a different path. This demonstrates the importance of “correct” propriocep-tive feedback. Based on these two lines of evidence, it is perhaps not surprising that BMI-directed movements relying solely on visual feedback are slower and less accurate than normal arm movements. This has moti-vated recent attempts to demonstrate how providing surrogate (ie, artificial) proprioceptive or somatosen-sory feedback can improve BMI performance.Several studies have attempted to write in sen-sory information by stimulating the brain using cor-tical electrical microstimulation. Laboratory animals can discriminate current pulses of different frequen-cies and amplitudes, and this ability can be utilized to provide proprioceptive or somatosensory information in BMIs by using different pulse frequencies to encode different physical locations (akin to proprioception) or different textures (akin to somatic sensation). Electrical microstimulation in the primary somatosensory cortex can be used by nonhuman primates to control a cur-sor on a moment-by-moment basis without vision. In these subjects, the use of electrical microstimulation Kandel-Ch39_0953-0974.indd 967 14/12/20 9:44 AM968 Part V / MovementFigure 39–10 A motor brain–machine interface (BMI) can control a prosthetic arm with 10 degrees of freedom.A.Examples of different hand configurations directed by the BMI. The 10 degrees of freedom are three-dimensional arm translation, three-dimensional wrist orientation, and four-dimensional hand shaping.B.A subject uses the prosthetic arm to pick up an object and move it.C.Objects of different shapes and sizes are used to test the generalization ability of the BMI. (Adapted from Wodlinger et al. 2015.)and visual feedback together led to more accurate movements than either type of sensory feedback alone.Furthermore, electrical microstimulation in the pri-mary somatosensory cortex can also be used to provide tactile information. Nonhuman primates moved a BMI-directed cursor under visual feedback to hit different visual targets, each of which elicited a different stimula-tion frequency. Subjects learned to use differences in the stimulation feedback to distinguish the rewarded target from the unrewarded targets. This demonstrates that electrical microstimulation can also be used to provide somatosensory feedback during BMI control.Finally, surrogate somatosensory information was delivered via electrical microstimulation to a person with paralysis and compromised sensory afferents. The person reported naturalistic sensations at differ-ent locations of his hand and fingers corresponding to different locations of stimulation in the primary soma-tosensory cortex.BMIs Can Be Used to Advance Basic NeuroscienceBMIs are becoming an increasingly important experi-mental tool for addressing basic scientific questions about brain function. For example, cochlear implants have provided insight into how the brain processes sounds and speech, how the development of these mechanisms is shaped by language acquisition, and how neural plasticity allows the brain to interpret a few channels of stimulation carrying impoverished auditory information. Similarly, motor and communi-cation BMIs are helping to elucidate the neural mecha-nisms underlying sensorimotor control. Such scientific findings can then be used to refine the design of BMIs.The key benefit of BMIs for basic science is that they can simplify the brain’s input and output interface with the outside world, without simplifying the com-plexities of brain processing that one wishes to study. ScoopFingers spreadThumb extensionPinchA Robotic hand con�gurations B Using the robotic hand to grasp objectsC Sample objects grasped by the robotic handKandel-Ch39_0953-0974.indd 968 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 969Figure 39–11 A motor brain–machine interface (BMI) can control the muscles of a paralyzed arm using a continuous decoder and functional electrical stimulation.Neural activity recorded in the motor cortex is decoded into command signals that control the stimulation of deltoid, pectoralis major, biceps, triceps, forearm, and hand muscles. This enables cortical con-trol of whole-arm movements and grasping. Muscle stimulation is performed through percutaneous intramuscular fine-wire electrodes. (Adapted, with permission, from Ajiboye et al. 2017. Copyright © 2017 Elsevier Ltd.)To illustratethis point, consider the output interface of the brain for controlling arm movements. Thousands of neurons from the motor cortex and other brain areas send signals down the spinal cord and to the arm, where they activate muscles that move the arm. Understand-ing how the brain controls arm movement is challeng-ing because one can typically record from only a small fraction of the output neurons that send signals down the spinal cord, the relationship between the activity of the output neurons and arm movements is unknown, and the arm has nonlinear dynamics that are difficult to measure. Furthermore, it is usually difficult to deter-mine which recorded neurons are output neurons.One way to ease this difficulty is to use a BMI. Because of the way a BMI is constructed, only those neurons that are recorded can directly affect the move-ment of the cursor or robotic limb. Neurons through-out the brain are still involved, but they can influence the cursor movements only indirectly through the recorded neurons. Thus, in contrast to arm and eye movement studies, one can record from the entire set of output neurons in a BMI, and BMI-directed move-ments can be causally attributed to specific changes in the activity of the recorded neurons. Furthermore, the mapping between the activity of the recorded neurons and cursor movement is defined by the experimenter, so it is fully known. This mapping can be defined to be simple and can be easily altered by the experimenter during an experiment. In essence, a BMI defines a simplified sensorimotor loop, whose components are more concretely defined and more easily manipulated than for arm or eye movements.These advantages of BMIs allow for studies of brain function that are currently difficult to perform using arm or eye movements. For example, one class of studies involves using BMIs to study how the brain learns. The BMI mapping defines which population activity patterns will allow the subject to successfully move the BMI-directed cursor to hit visual targets. By defining the BMI mapping appropriately, the experi-menter can challenge the subject’s brain to produce novel neural activity patterns.Motor cortexElectrodePercutaneouslead connectorElectrode arrayDecodingalgorithmExternalstimulatorKandel-Ch39_0953-0974.indd 969 14/12/20 9:44 AM970 Part V / MovementA recent study explored what types of activity patterns are easier and more difficult for the brain to generate. They found that it was easier for subjects to learn new associations between existing activity pat-terns and cursor movements than to generate novel activity patterns. This finding has implications for our ability to learn everyday skills. A second class of studies involves asking how the activity of neurons that directly control movement differ from those that do not directly control movement. In a BMI, one can choose to use only a subset of the recorded neurons (the output neurons) for controlling movements. At the same time, other neurons (the nonoutput neurons) can be passively monitored without being used for controlling movements. Comparing the activity of out-put and nonoutput neurons can provide insight into how a network of neurons internally processes infor-mation and relays only some of that information to other networks.Using this paradigm, a recent study recorded neural activity simultaneously in the primary cortex and striatum and designated a subset of the M1 neu-rons as the output neurons for controlling the BMI. They found that, during BMI learning, M1 neurons that were most relevant for behavior (the output neurons) preferentially increased their coordination with the striatum, which is known to play an impor-tant role during natural behavior (Chapter 38). Identifying output versus nonoutput neurons in a study using arm or eye movements would be challenging.BMIs Raise New Neuroethics ConsiderationsA growing number of biomedical ethics considerations centered on the brain have arisen from the dramatic expansion in our understanding of neuroscience and our capabilities with neurotechnology. These advances are driven by society’s curiosity about the function-ing of the brain, the least-well understood organ in the body, as well as the desire to address the massive unmet need of those suffering from neurological dis-ease and injury. The use of BMIs raises new ethical questions for four principal reasons.First, recording high-fidelity signals (ie, spike trains) involves risk, including the risks associated with initial implantation of the electrodes as well as possible biological (immunological or infectious) responses during the lifetime of the electrodes and the associated implanted electronics. Electrodes implanted for long periods currently have functional lifetimes on the order of many months to a few years, during which time glial scar tissue can form around the electrodes and electrode materials can fail. Efforts to increase the functional lifetime of electrodes range from nanoscale flexible electrodes made with new materials to mitigat-ing immunological responses, as is done with cardiac stents.For these reasons, patients considering receiving implanted recording technologies will need to evalu-ate the risks and benefits of a BMI, as is the case for all medical interventions. It is important for patients to have options, as each person has personal preferences involving willingness to undergo surgery, desire for functional restoration and outcome, and cosmesis—be it while deliberating cancer treatment or BMI treat-ment. BMIs based on different neural sensors (Figure 39–2) have different risks and benefits.Second, because BMIs can read out movement information from the brain at fine temporal resolu-tion, it seems plausible that they will be able to read out more personal and private types of information as well. Future neuroethics questions that may arise as the technology becomes more sophisticated include whether it is acceptable, even with patient consent, to read out memories that may otherwise be lost to Alzheimer disease; promote long-term memory con-solidation by recording fleeting short-term memories and playing them back directly into the brain; read out subconscious fears or emotional states to assist desensitization psychotherapy; or read out potential intended movements, including speech, that would not naturally be enacted.Third, intracortical write-in BMIs, similar to DBS systems currently used to reduce tremor, may one day evoke naturalistic spatial-temporal activity patterns across large populations of neurons. In the extreme it may not be possible for a person to distinguish self-produced and volitional neural activity patterns from artificial or surrogate patterns. Although there are numerous therapeutic and beneficial reasons for embracing this technology, such as reducing tremor or averting an epileptic seizure, more dubious uses can be envisioned such as commandeering a person’s motor, sensory, decision making, or emotional valence circuits.Finally, ethical questions also involve the limits within which BMIs should operate. Current BMIs focus on restoring lost function, but it is possible for BMIs to be made to enhance function beyond natu-ral levels. This is as familiar as prescribing a pair of glasses that confer better than normal vision, or overprescribing a pain medication, which can cause euphoria that is often addictive. Should BMIs be allowed, if and when it becomes technically possible, Kandel-Ch39_0953-0974.indd 970 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 971to move a robotic arm faster and more accurately than a native arm? Should continuous neural record-ings from BMIs, covering hours, days, or weeks, be saved for future analysis, and are the security and privacy issues the same or different from personal genomics data? Should BMIs withpreset content be available for purchase, for example, to skip a grade of mathematics in high school? Should an able-bodied person be able to elect to receive an implanted motor BMI? While the safe and ethical limits of such sen-sory, motor, and cognitive BMI treatments might seem readily apparent, society continues to wrestle with these same questions concerning other currently available medical treatments. These include steroids that enhance musculature, energy drinks (eg, caffeine) that enhance alertness, and elective plastic surgery that alters appearance.Although many of these ideas and questions may appear far-fetched at present, as mechanisms of brain function and dysfunction continue to be revealed, BMI systems could build on these discoveries and create even more daunting ethical quandaries. But equally important is the immediate need to help people suf-fering from profound neurological disease and injury through restorative BMIs. In order to achieve the right balance, it is imperative that physicians, scientists, and engineers proceed in close conversation and partner-ship with ethicists, government oversight agencies, and patient advocacy groups.Highlights 1. Brain–machine interfaces (BMIs) are medical devices that read out and/or alter electrophysi-ological activity at the level of populations of neurons. BMIs can help to restore lost sensory, motor, or brain processing capabilities, as well as regulate pathological neural activity. 2. BMIs can help to restore lost sensory capabilities by stimulating neurons to convey sensory infor-mation to the brain. Examples include cochlear implants to restore audition or retinal prostheses to restore vision. 3. BMIs can help to restore lost motor capabilities by measuring the activity from many individual neurons, converting this neural information into control signals, and guiding a paralyzed limb, robotic limb, or computer cursor. 4. Whereas motor BMIs aim to provide control of a robotic limb or paralyzed limb, communication BMIs aim to provide a fast and accurate interface with a computer or other electronic devices. 5. BMIs can help to regulate pathological neural activity by measuring neural activity, processing the neural activity, and subsequently stimulating neurons. Examples include deep brain stimula-tors and antiseizure systems. 6. Neural signals can be measured using different technologies, including electroencephalogra-phy, electrocorticography, and intracortical elec-trodes. Intracortical electrodes record the activity of neurons near the electrode tip and can also be used to deliver electrical stimulation. 7. To study movement encoding, one usually considers the activity of an individual neuron across many experimental trials. In contrast, for movement decoding, one needs to consider the activity of many neurons across an individual experimental trial. 8. A discrete decoder estimates one of several pos-sible movement goals from neural population activity. In contrast, a continuous decoder esti-mates the moment-by-moment details of a move-ment from neural population activity. 9. The field is making substantial progress in increasing the performance of BMIs, measured in terms of the speed and accuracy of the estimated movements. It is now possible to move a com-puter cursor in a way that approaches the speed and accuracy of arm movements.10. In addition to controlling computer cursors, BMIs can also guide a robotic limb or a paralyzed limb using functional electrical stimulation. Develop-ments from preclinical experiments with able-bodied, nonhuman primates have subsequently been tested in clinical trials with paralyzed people.11. Future advances of BMI will depend, in part, on developments in neurotechnology. These include advances in hardware (eg, neural sensors and low-power electronics), software (eg, supervisory systems), and statistical methods (eg, decoding algorithms).12. An important direction for improving BMI per-formance is to provide the user with additional forms of sensory feedback in addition to visual feedback. An area of current investigation uses stimulation of neurons to provide surrogate sen-sory feedback, representing somatosensation and proprioception, during ongoing use.13. Beyond helping paralyzed patients and ampu-tees, BMI is being increasingly used as a tool for understanding brain function. BMIs simplify the brain’s input and output interfaces and allow the experimenter to define a causal relationship between neural activity and movement.Kandel-Ch39_0953-0974.indd 971 14/12/20 9:44 AM972 Part V / Movement14. BMIs raise new neuroethics questions, which need to be considered together with the ben-efits provided by BMIs to people with injury or disease. Krishna V. Shenoy Byron M. Yu Selected ReadingAndersen RA, Hwang EJ, Mulliken GH. 2010. Cognitive neu-ral prosthetics. Annu Rev Psychol 61:169–190.Donoghue JP, Nurmikko A, Black M, Hochberg LR. 2007. Assistive technology and robotic control using motor cor-tex ensemble-based neural interface systems in humans with tetraplegia. J Physiol 579:603–611.Fetz EE. 2007. Volitional control of neural activity: implica-tions for brain-computer interfaces. J Physiol 579:571–579.Green AM, Kalaska JF. 2011. 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J Neural Eng 12:016011.Kandel-Ch39_0953-0974.indd 973 14/12/20 9:44 AMKandel-Ch39_0953-0974.indd 974 14/12/20 9:44 AMThis page intentionally left blank 1583IndexAA kinase attachment proteins (AKAPs), 303a priori knowledge, 387Aα fibersconduction velocity in, 412f, 412tin spinal cord, 429, 431fin thermal signal transmission, 424Aα wave, 412f, 413, 413fAβ fibersconduction velocity in, 412f, 412tin mechanical allodynia, 481in spinal cord, 429, 431, 431fto spinal cord dorsal horn, 474, 475fAβ wave, 412f, 413, 413fABC transporters, 1431fAbducens nerve (CN VI)in eye muscle control, 863, 863f, 982lesions of, 864b, 870origin in brain stem, 983fskull exit of, 984fAbducens nucleus, 989f, 992Abduction, eye, 861, 861f, 862f, 863tAbraira, Victoria, 431Absence seizures, typical. See Typical absence seizuresAbsent-mindedness, 1308Absolute refractory period, 220Abuse, drug. See Drug addiction; Drugs of abuseAβ (amyloid-β), 1569Aβ peptidesin Alzheimer’s disease, 1570–1573, 1571fdetection in cerebrospinal fluid, 1576immunization with antibodies to, 1577–1578, 1578fAccessory facial motor nuclei, 989f, 991Accessory trigeminal nuclei, 969, 989fAccommodationvergence and, 880visual processing pathways for, 501, 503fAcetaminophen, on COX3 enzyme, 478Acetyl coenzyme A (acetyl CoA), 360Acetylcholine (ACh)in autonomic systemreceptors, 1021tresponses, 1021tsynaptic transmission by, 1019, 1021, 1022f, 1143, 1146fbiosynthesis of, 360–361discovery of, 359enzymatic degradation of, 371GIRK channel opening by, 315, 316fprecursor of, 260trelease of, in discrete packets, 260vasoactive intestinal peptide co-release with, 370as vesicular transporter, 365, 366fAcetylcholine (ACh) receptors (receptor-channels)all-or-none currents in, 260–261, 261fgenetic factors in, 177, 178f, 1196–1197, 1197fgenetic mutations in, epilepsy and, 1467ionotropic GABAA and glycine receptor homology to, 278f, 291location of, 371muscarinic, 265, 1021tmuscle cell synthesis of, 1190, 1192fin myasthenia gravis, 267, 1434–1435, 1435fat neuromuscular junction, 255, 256fclustering of, 255, 258f, 1194–1196, 1195f, 1197fend-plate potential and. See End-plate potentialhighlights, 268–269ionic current through, in end-plate potential, 257–259, 258f–259fmolecular properties of, 324–332high-resolution structure, 267–268, 268flow-resolution structure, 257–258, 257f, 265–267, 265f–266ftransmitter binding and changes in, 263–264vs. voltage-gated action potential channels, 262–263, 264fNa+ and K+ permeability of, 260–262, 261f, 262bpatch-clamp recording of current in, 170b, 170f, 261, 261fnicotinic. See Nicotinic ACh receptorssubunits of, 278f, 1198Acetylcholinesterase (AChE), 366f, 371, 1436Acetylcholinesterase inhibitors, 1435, 1577Acquired myopathy, 1437Act, intention to. See Voluntary movement, as intention to actACTH (adrenocorticotropic hormone), in depression and stress, 1508, 1508fActinin growth cone, 1163f, 1164, 1165fmolecular forms of, 139Actin filamentsin cytoskeleton, 139–140as organelle tracks, 140in stereocilium, 604–605Actioncontrol of, 715. See also Sensorimotor controlselection, in basal ganglia. See Basal ganglia, action selection insensory processing for, 724–725, 725fAction potential, 211–234all-or-none nature of, 66f, 67–68, 67t, 211–212depolarization in, 191, 192bdiscovery of, 58fHodgkin-Huxley model of, 219–220, 219famplitude of, 58, 58fbackpropagating, 296–297, 296fcell excitability in, 65compound. See Compound action potentialconduction without decrement in, 212in dendrites, 292–293, 292f, 295–297, 296fexcitatory inputs on, 68fundamentals of,58–59, 58f, 65highlights, 233–234inhibitory inputs on, 68on ion flux balance of resting membrane potential, 198–199in monoaminergic neurons, 1001, 1001fin myelinated nerves, 207–208, 208fThe letters b, f, and t following a page number indicate box, figure, and table.Kandel-Index_1583-1646.indd 1583 19/01/21 9:18 AM1584 IndexAction potential (Cont.):neuron type and pattern of, 67–68, 229–231, 230fin nociceptive fibers, 471, 471f. See also Pain nociceptorspattern of, 67presynaptic. See also Presynaptic terminalswith hyperpolarizing afterpotential, 244on presynaptic Ca2+ concentration, 329, 330f, 332–333serotonin on, 353–354in synaptic delay, 329in transmitter release, 248–249, 249f, 269voltage-gated Ca2+ channel opening in, 248–249propagation ofall-or-none, 58f, 66f, 67–68, 67taxon diameter and myelination on, 207–208, 208faxon size and geometry on, 206–207electrotonic conduction on, 205–206, 206fvoltage-gated ion channels in. See Voltage-gated ion channels, in action potentialrefractory period after, 212, 219f, 220in sensory neuronssequence of, 396, 397ftiming of, 395–396, 395fin somatosensory information transmission, 426–427threshold for initiation of, 211, 219–220, 219fAction (intention) tremor, 909Activating factor, 1324Activation gate, 218Active fixation system, 866Active sensing, 723Active touch, 436–437Active transport, 166primary, 195–198, 197fsecondary, 197f, 198Active zones, 68in neuromuscular junction, 255, 256fin presynaptic terminals, for Ca2+ influx, 248–249, 248f, 327–332, 328fof synaptic boutons, 249–250synaptic vesicles in, 328f, 333–334Activity-dependent facilitation, 1317, 1320fActomyosin, 141AD. See Alzheimer disease (AD)Aδ fibersconduction velocity in, 412f, 412tin fast sharp pain, 472nociceptors with, 424–425, 425fin spinal cord, 429, 431fto spinal cord dorsal horn, 474, 475fAδ wave, 412f, 413, 413fADAM, 1570Adaptation, in fMRI studies, 118Adcock, Alison, 1300Addiction. See Drug addiction; Drugs of abuseAdduction, 861, 862f, 863tAdeno-associated viral vector, in gene therapy, 1428, 1429fAdenohypophysis. See Anterior pituitary glandAdenosine, 364Adenosine triphosphatase (ATPase), 144Adenosine triphosphate (ATP)autonomic functions of, 1019, 1021tin body temperature regulation, 1029bin channel gating, 173in ion pumps, 166ionotropic receptors and, 291from mitochondria, 135as transmitter, 364vesicular storage and release of, 371Adenosine triphosphate (ATP) receptor-channels, 278fADHD (attention deficit hyperactivity disorder), 947f, 949Adhesion moleculescentral nerve terminal patterning by, 1199–1203, 1201f, 1202fin retinal ganglion synapses, 1184fADNFLE (autosomal dominant nocturnal frontal lobe epilepsy), 1467, 1468–1469Adolescence, synaptic pruning and schizophrenia in, 1494, 1497, 1497fAdrenergic, 359Adrenergic neurons, location and projections of, 998, 999fAdrenocorticotropic hormone (ACTH), in depression and stress, 1508, 1508fAdrian, Edgaron all-or-none action potential in sensory neurons, 395on functional localization in cortex, 19on muscle force in motor unit, 744on sensory fibers, 67on touch receptors, 416Affective states. See EmotionsAfferent fibers, primary, 409Afferent neurons, 59Affordances, 827, 1410bAfterdepolarization, 229Afterhyperpolarization, 229, 1455Aggregate-field view, of mental function, 17Aggressive behavior, hypothalamus in regulation of, 1040–1041Aging brain, 1561–1580Alzheimer disease in. See Alzheimer diseasecognitive decline in, 1566–1567, 1567fhighlights, 1579–1580lifespan and, 1561, 1562flifespan extension research and, 1565–1164sleep changes in, 1092structure and function of, 1561–1567brain shrinkage in, 1562, 1564fcognitive capacities in, 1562, 1563fdendrites and synapses in, 1163f, 1562–1563insulin and insulin-like growth factors and receptors in, 1564on motor skills, 1562mutations extending lifespan in, 1564, 1566fneuron death in, 1563Agnosiaapperceptive, 567, 567fassociative, 567, 567fcategory-specific, 568, 573definition of, 566, 1473form, 1480f, 1488prosopagnosia, 505, 568, 1473, 1477–1478. See also Face recognitionspacial, 18Agonist, in channel opening, 172, 173fAgoraphobia, 1506Agouti-related peptide (AgRP)aversive activity of, 1038–1039in energy balance, 1036f–1037f, 1037–1038Agre, Peter, 167Agrin, 1194–1196, 1195fAguayo, Alberto, 1242–1243, 1256AKAPs (A kinase attachment proteins), 303Akinesia, 829b, 947fAlbin, Roger, 935Albright, Thomas, 575Albus, James, 105, 923, 928Alexander, Garrett, 937Alien-hand syndrome, 829bAlleles, 31, 52Allodynia, 472, 481All-trans retinol (vitamin A), 529Alpha motor neurons, 764bAlpha waves, EEG, 1450, 1451fα-bungarotoxin. See Bungarotoxinα-melanocyte-stimulating hormone, 1036f–1037f, 1037α-secretase, 1570, 1570fα-subunits, of K+ channels, 225, 226fα-synucleinin Lewy bodies, 1555in Parkinson disease, 141b, 142f, 1548, 1550, 1553α-tubulin, 139, 140fALS. See Amyotrophic lateral sclerosis (ALS)Alstermark, Bror, 778Alternatively spliced, 53Altman, Joseph, 1249Alzheimer, Alois, 1567Alzheimer disease (AD), 1567–1579Aβ peptides in, 1570–1573, 1571f, 1577–1578, 1578fKandel-Index_1583-1646.indd 1584 19/01/21 9:18 AMIndex 1585altered hippocampal function in, 1367amyloid plaques in, 141b, 142f, 1569–1570, 1569f, 1570fcognitive decline and, 1577fPET imaging of, 1576, 1576ftoxic peptides in, 1570–1573, 1571f, 1573fAPOE gene alleles in, 165f, 1575–1576basal forebrain in, 1577brain structure changes in, 1564f, 1568, 1568fcognitive decline in, 1567fdiagnosis of, 1576–1579, 1576fin Down syndrome, 1572early-onset, genes in, 48, 1572, 1573fenvironmental factors in, 1573fepidemiology of, 1568highlights, 1579–1580history of, 1567–1568memory deficits in, 1567neurofibrillary tangles incharacteristics of, 139, 141b–142b, 142f, 1569fcognitive decline and, 1577fformulation of, 1573, 1574flocations of, 1569–1570, 1570fmicrotubule-associated proteins in, 1573–1574reactive astrocytes in, 159risk factors for, 1574–1576, 1575fsigns and symptoms of, 1567–1568sleep fragmentation in, 1092tau aggregation in, 141b, 1574, 1579treatment of, 1577–1579, 1577f, 1578fAmacrine cells, 524f, 536–537, 540Ambiguous informationfrom somatosensory inputs, on posture and body motion, 897, 898fvisual, neural activity with, 1476, 1477fAmblyopia, 1213American Sign Language (ASL), 19–20Amines, biogenic, 360t, 361–364. See also specific typesAmino acid transmitters, 360t, 364GABA. See GABA (γ-aminobutyric acid)glutamate. See Glutamateglycine. See GlycineAminoglycoside antibioticson hair cells, 610on vestibular function, 647Amitriptyline, 1514Amnesiaafter temporal lobe damage, 1482, 1485episodic memory recall in, 1299hysterical (psychogenic), 1485priming in, 1294, 1295fsimulation of, in malingerer, 1485Amnestic shellfish poisoning, 1466–1467AMPA receptorsCa2+ permeability in, 279, 281fcontributions to excitatory postsynaptic current, 283–284, 285fexcitatory synaptic action regulation by, 277, 277fgene families encoding, 278–279in long-term potentiation in Schaffer collateral pathway, 1344f–1345f, 1345, 1346fpostsynaptic density in, 281–283, 282fin seizures, 1455, 1455fin spinal-cord dorsal horn, 479, 482fstructure of, 279–281, 280fAMPAfication, 1345–1346, 1346fAMPA-kainate channelsdesensitization in, 537in ON and OFF cells, 536Amphetaminesaddiction to. See Drug addictiondopamine release by, 376for narcolepsy, 1095source and molecular target of, 1072tAmplificationsignal, in chemical synapses. See Synapse, chemical, signal amplification inof sound, in cochlea, 616–618, 617f, 618fAmpulla, 600f, 631, 633fAmygdala, 1050–1055anatomy of, 14fin autism spectrum disorder, 1525f, 1539in autonomic function, 1025–1026, 1026fin drug addiction, 1055in emotional processing,978, 1056, 1059in fear responsein animals, 1052–1053, 1052fin humans, 1053–1055, 1054f, 1056, 1057fin freezing behavior, 1050, 1052flateral and central nuclei in, 1051–1052, 1052flesions of, facial expression impairment in, 1509, 1510flong-term potentiation in, 1332–1333, 1333fin mentalizing, 1527, 1528fin mood and anxiety disorders, 1055, 1509–1511, 1510fin positive emotions, 1055in schizophrenia, 1494in threat conditioning in mammals, 1331–1334, 1331f–1333f, 1335fAmygdaloid nuclei, 12bAmyloid neuropathy, 1433tAmyloid plaques, in Alzheimer disease. See Alzheimer disease (AD), amyloid plaques inAmyloid precursor protein (APP), 1570–1573, 1571fAmyotrophic lateral sclerosis (ALS)brain-machine interfaces for, 962, 965, 966fgenetic factors in, 1426–1427, 1427f, 1428induced pluripotent stem cells for, 1254, 1254fmotor neuron pathophysiology of, 1120, 1426–1428, 1551fnonneural cell reactions in, 1428symptoms of, 1426Amyotrophy, 143Anaclitic depression, 1212Analgesia, stimulation-produced, 488. See also Pain, control ofAnandamide, 310, 311f, 478Anarchic-hand syndrome, 829bAnatomical alignment, in fMRI, 116Anatomical sex, 1261Andersen, Richard, 587Androgen receptor5-α-dihydrotestosterone (DHT) receptor, 1264, 1266fdysfunction of, in spinobulbar muscular atrophy, 1555Androstadienone perception, 1280f, 1281Anencephaly, 809Anesthesia dolorosa, 474Angelman syndrome, 1533–1534, 1533fAngiotensin I (ANGI), 1033Angiotensin II (ANGII), 1033Angular gyrus, 17fAngular motion, postural response to, 895–896Anhedonia, 1503. See also Major depressive disorderAnion, 167Ankle strategy, 889, 891fAnkyrin G, 1187fAnosmia, 691Anterior cingulate cortexelectrode placement for deep brain stimulation, 1519fin emotional processing, 1049, 1049f, 1056, 1060in mood and anxiety disorders, 1510f–1511f, 1511opiates action in, 493pain control by, 485–486, 487b, 487fAnterior group, thalamic nuclei, 82f, 83Anterior intraparietal area (AIP)in decision-making, 1404f–1405fin object grasping, 825, 826f–827f, 827Anterior neural ridge, 1115, 1115fAnterior pituitary glandhormones of, 1027hypothalamic control of, 1028–1029, 1028f, 1029tAnterograde axonal transport, 143Anterolateral system, 450f–451fAntibiotics, on hair cells, 609Antibodiesto AMPA receptor in epilepsy, 278to Aβ peptides, immunization with, 1577–1578, 1578fin myasthenia gravis, 1435Anticipatory control, 723, 724fKandel-Index_1583-1646.indd 1585 19/01/21 9:18 AM1586 IndexAnticipatory postural adjustments. See also Posturefor disturbance to balance, postural orientation in, 894–895learning with practice, 892fbefore voluntary movement, 892–894, 893fAnticonvulsant drugsfor bipolar disorder, 1519–1520mechanisms of action of, 1461for seizures, 1448Antidepressant drugs. See also specific drugs and drug classesanterior cingulate cortex activity and success of, 1511, 1511fketamine as, 1515mechanisms of actions of, 1512–1515, 1516f–1517fhypotheses of, 1515monoamine oxidase in, 1513–1514, 1516f–1517fnoradrenergic systems in, 1513–1514, 1516f–1517fserotonergic systems in, 1513, 1513f, 1516f–1517fAntidiuretic hormone. See VasopressinAntigravity support, 886Antihistaminesdrowsiness and, 1007for insomnia, 1093Antiporters (exchangers), 186f, 198Antipsychotic drugsfor bipolar disorder, 1520mechanisms of action of, 1497–1499, 1498fside effects of, 1498–1499Antisense oligonucleotides (ASOs)in Huntington disease treatment, 1556–1557in spinal muscular atrophy treatment, 1428, 1429fAnxietyadaptive, 1504–1505definition of, 1504vs. fear, 1504sources of, 1505Anxiety disorders, 1504–1506diagnosis of, 1505epidemiology of, 1504fear in, 1504genetic factors in, 1505risk factors for, 1505symptoms of, 1505syndromes of, 1505–1506treatment of, 1515, 1518Aperture problem, 554–555, 556fAphasiaBroca’s. See Broca’s aphasiaclassification of, 1378–1379, 1379tconduction. See Conduction aphasiadefinition of, 16differential diagnosis of, 1379t, 1384tearly studies of, 16–18epidemiology of, 1382expressive, 13global. See Global aphasialess common, 1386–1388, 1387freceptive, 13transcortical motor. See Transcortical motor aphasiatranscortical sensory. See Transcortical sensory aphasiaWernicke’s. See Wernicke’s aphasiaAplysiagill-withdrawal reflex inclassical threat conditioning of, 1317, 1319, 1320flong-term habituation of, 1314–1315, 1316flong-term sensitization of, 1319, 1321fshort-term habituation of, 1314, 1315fshort-term sensitization of, 1316–1317, 1318f–1319finking response in, 247, 247flong-term synaptic facilitation in, 1327–1328, 1329fsynaptic strength in, 1327Apnea, sleep. See Sleep apneaApneusis, 997APOE gene alleles, in Alzheimer disease, 1575–1576, 1575FApoE protein, 1575Apoptosis (programmed cell death)of motor neurons, 1147, 1148fvs. necrosis, 1151in neurodegenerative diseases, 1556, 1557neurotrophic factors in suppression of, 1149f, 1151–1153, 1151f, 1152fAPP (amyloid precursor protein), 1570–1573, 1571fApperceptive agnosia, 567, 567fAppetite control, afferent signals in, 1034–1037, 1036f–1037f. See also Energy balance, hypothalamic regulation ofArachidonic acid, 310, 311f2-Arachidonylglycerol (2-AG), 310, 311fArchitectonic, 131Arcuate nucleusanatomy of, 1014f, 1015in energy balance and hunger drive, 1015, 1033, 1035, 1036f–1037fArea MT, in decision-making, 1398–1400, 1399f, 1400fArea postrema, 994Area under an ROC curve (AUC), 390bAristotle, on senses, 385Arm paralysis, brain-machine interface stimulation in, 965, 967, 969fAromatase, 1262, 1264f, 1265fArousalascending system for. See Ascending arousal systemconfusional, 1095monoaminergic and cholinergic neurons on, 1006–1007, 1007fArthritis, nociceptive pain in, 474Artificial intelligence (AI), 1474–1475Artificial neural networks, 404–405ARX, 1469Ascending arousal systemcomposition of, 1084–1085, 1084fdamage to, coma and, 1085early studies of, 1083, 1084monoaminergic neurons in, 1005–1006, 1006f, 1085sleep-promoting pathways of, 1085–1086, 1087f, 1088fAserinsky, Eugene, 1082ASL (American Sign Language), 19–20ASOs. See Antisense oligonucleotides (ASOs)Asperger, Hans, 1524Asperger syndrome, 1524. See also Autism spectrum disordersAspirinon COX enzymes, 478tinnitus from, 624Association areas, cortical, 88, 89fAssociation cortex, 17, 1298–1299, 1299fAssociationsloosening of, in schizophrenia, 1489bvisual, circuits for, 578–579, 579fAssociative agnosia, 567, 567fAssociative learning, organism biology on, 1307–1308Associative memory, visual, 578–579, 579f. See also Visual memoryAssociativity, in long-term potentiation, 1350Astrocytesactivation in amyotrophic lateral sclerosis, 1428in blood–brain barrier, 159from radial glial cells, 1131reactive, 159structure and function of, 134, 151, 151fin synapse formation, 159, 1205–1207, 1206fin synaptic signaling, 154, 158f, 159Asymmetric division, in neural progenitor cell proliferation, 1131, 1132fAtaxiain cerebellar disorders, 806, 909, 910fdefinition of, 909hypermetria in, 896–897spinocerebellar. See Spinocerebellar ataxias (SCAs), hereditaryATP. See Adenosine triphosphate (ATP)ATP receptor-channels, 278fATP10C deletion, 1533ATPase, 144ATP-ubiquitin-proteasome pathway, 149Atrophybrain, in Alzheimer disease, 1568, 1568fdefinition of, 1422Kandel-Index_1583-1646.indd 1586 19/01/21 9:18 AMIndex 1587dentatorubropallidoluysian, 1544, 1546, 1547t, 1549t, 1551fprogressive spinal muscular, 1428, 1429fAttentionamygdala in, 1056in object recognition, 560–562to social stimuli, in autism spectrum disorder, 1527–1528, 1528fas top-down process, cortical connections in, 559visuallateral intraparietal area in, 591, 874, 874fneural response to, 401, 402fpriority map in visual cortex in, 591b–592b, 591f,592fright parietal lobe lesions and, 589–591, 591fvoluntary attention and saccadic eye movements in, 588–589, 590fAttention deficit hyperactivity disorder (ADHD), 947f, 949Attributes, visual, cortical representation of, 559–560, 562fA-type K+ channel, 231, 232fAUC (area under an ROC curve), 390bAuditory activation, in language development, 1381Auditory cortexcentral auditory pathways in, 652, 654f, 663fmodulation of sensory processing in subcortical auditory areas, 670–671pitch and harmonics encoding in, 673–674, 674fpitch-selective neurons on, 673–674, 674fprimary and secondary areas of, 399, 400f, 668–669, 668fprocessing streams in, 670, 671fsound-localization pathway from inferior colliculus to, 669–670specialization for behaviorally relevant features of sound, in bats, 675–677, 676ftemporal and rate coding of time-varying sounds in, 671–673, 672fin vocal feedback during speaking, 677, 678fAuditory localization, 1227–1228, 1227f–1229fAuditory processing. See also Soundby the central nervous system, 651–679central auditory pathways in, 652–653, 654f, 663fcerebral cortex in. See Auditory cortexcochlear nuclei in. See Cochlear nucleihighlights, 679inferior colliculus in. See Inferior colliculussuperior olivary complex in. See Superior olivary complexin the cochlea. See Cochlea, auditory processing inmusic recognition and, 652overall perspective of, 382sound energy capture by the ear, 573–601, 602f–603fsound source localization and, 652, 653fspeech recognition and, 652Auras, seizure-related, 1449, 1458b–1459b, 1461Auricle, 599, 599fAutacoidshistamine as, 363vs. neurotransmitters, 359Autism spectrum disorders, 1523–1541behavioral criteria for, 1524brain areas implicated in, 1525, 1525fcognitive abnormalities inlack of behavioral flexibility, 1528lack of eye preference, 1527–1528, 1529fsavant syndrome, 1528–1529, 1530fsocial communication impairment, 1474, 1525–1527, 1526f–1528fepidemiology of, 1524genetic factors incopy number variations, 49, 1535, 1536fde novo mutations, 47, 48–49, 1535–1537genome-wide association studies, 1537model systems studies of, 1538–1539neuroligin mutations, 49, 1534–1535small-effect alleles, 1537systems biological approaches to, 1537–1538twin studies of, 28f, 1529–1530highlights, 1540–1541history of, 1523pathophysiology ofbasic and translation science in, 1540postmortem and brain tissue studies of, 1539–1540risk factors in, 1530–1531, 1537seizure disorders in, 1539Autobiographical memory, 1367Autogenic excitation, 766Autogenic inhibition, 769–770Automatic postural responses. See also Postureadaptation to changes in requirements for support by, 888–889, 891fsomatosensory signals in timing and direction of, 894–895, 895fspinal cord circuits in, 900–901to unexpected disturbances, 887–888, 887f–889fAutomatic stepping, 809Autonomic system, 1015–1023cell types of, 1016, 1016fcentral control of, 1025–1026, 1026fganglia, cholinergic synaptic transmission in, 313–315, 314fhighlights, 1041monoaminergic pathways in regulation of, 1002, 1002f–1003fneurotransmitters and receptors in, 1021tparasympathetic division of, 1016, 1017fpattern generator neurons in, 992, 994physiological responses linked to brain by, 1015–1023acetylcholine and norepinephrine as principal transmitters in, 1019–1021, 1021t, 1022fenteric ganglia in, 1019, 1020fparasympathetic ganglia in, 1018–1019preganglionic neurons in, 1016, 1017f, 1018fsympathetic and parasympathetic cooperation in, 1022–1023sympathetic ganglia in, 1016–1018, 1017f, 1018fvisceral motor neurons in, 1015–1016sympathetic division of, 1016, 1017fvisceral sensory information relay in, 1023, 1025f, 1026fAutoreceptors, action of, 359Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), 1467, 1468–1469Autosomes, 30–31, 1260Averaging, spike-triggered, 765Awareness, urge to act and, 1480–1481. See also ConsciousnessAwl/auchene hairs, 419, 420f–421fAxelrod, Julius, 375Axes, of central nervous system, 11b, 11fAxial (axonal) resistance, 202–203, 205, 205fAxo-axonic synapsesstructure of, 276, 276f, 294fin transmitter release, 351, 353, 354fAxodendritic synapses, 276, 276f, 295fAxon(s), 57–58, 57f, 1156–1179conductance in, Na+ and K+ channels in, 233cytoskeletal structure of, 141, 143fdiameter of, 766b, 766ton action potential propagation, 206–207, 206fearly development of, 1156–1157extracellular factors in differentiation of, 1156–1157, 1159fneuronal polarity and cytoskeleton rearrangements in, 1157, 1158f, 1159fephrins in, 1172–1176, 1174f, 1175fgrowth cone as sensory transducer and motor structure in. See Growth coneguidance of, molecular cues in, 1166–1167chemospecificity hypothesis, 1167, 1168f, 1182location and action of, 1167, 1169f, 1170f–1171fprotein-protein interactions in, 1167f, 1169f, 1170f–1171fin retinal ganglion cells, 1167, 1168fstereotropism and resonance in, 1167Kandel-Index_1583-1646.indd 1587 19/01/21 9:18 AM1588 IndexAxon(s) (Cont.):highlights, 1179injury of. See Axon injury (axotomy)myelination ofdefective, 154, 155b–157b, 155f–157fglial cells in, 152f, 153f, 154regeneration of. See Axon regenerationretinal ganglion, 1168, 1171–1176ephrin gradients of inhibitory brain signals in, 1172–1176, 1174f, 1175fgrowth cone divergence at optic chiasm in, 1171–1172, 1172f, 1173fin sensory fibers, 766b, 766tspinal neural, midline crossing of, 1176–1179chemoattractant and chemorepellent factors on, 1176–1179, 1178fnetrin direction of commissural axons in, 1176, 1177f, 1178ftrigger zone of, 231Axon hillock, 137, 137fAxon injury (axotomy)cell death from, 1248–1249chromatolytic reaction after, 1237f, 1240definition of, 1237degeneration after, 1237–1240, 1237f, 1238f, 1239fhighlights, 1256–1257in postsynaptic neurons, 1240reactive responses in nearby cells after, 1237f, 1240–1241regeneration following. See Axon regenerationtherapeutic interventions for recovery following, 1248–1256adult neurogenesis, 1248–1250, 1250f–1251fneurogenesis stimulation, 1254–1255neuron and neuron progenitor transplantation, 1250, 1252–1254, 1252f, 1253f, 1254fnonneuronal cell/progenitor transplantation, 1255, 1255frestoration of function, 1255–1256, 1256fAxon reflex, 479Axon regenerationin central vs. peripheral nerves, 1241–1242, 1241f, 1243fin retinal ganglion, 1256, 1256ftherapeutic interventions for promotion ofenvironmental factors in, 1243–1244injury-induced scarring and, 1246, 1246fintrinsic growth program for, 1246–1247, 1247f, 1248fmyelin components on neurite outgrowth in, 1244–1338, 1244f, 1245fnew connections by intact axons in, 1247–1248, 1249fperipheral nerve transplant for, 1242–1243, 1242fAxon terminals, 136f, 142Axonal neuropathies, 1430, 1432f, 1433tAxonal transportanterograde, 144, 146ffast, of membranous organelles, 143–146, 146f, 147ffundamentals of, 142–143, 143fmembrane trafficking in, 142, 144fin neuroanatomical tracing, 145b, 145fslow, of protein and cytoskeletal elements, 146–147Axoneme, 606Axoplasmic flow, 143Axosomatic synapses, 276, 276f, 295fAxotomy. See Axon injury (axotomy)BBabinski sign, 1426Backpropagation, of action potentials, 296–297, 296f, 1457Bagnall, Richard, 1466Balance, 884. See also Posturedisturbance to, postural orientation in anticipation of, 894–895in postural control systemsintegration of sensory information in, 899f, 900, 901finternal models of, 898, 899fspinocerebellum in, 901–902in upright stance, 884, 885b, 885fvestibular information for, in head movements, 895–897, 896fwater, 1031–1033, 1032fBalint syndrome, 874–875Band-pass behavior, 534b, 535fBarber-pole illusion, 555, 556fBarbiturates, 1072t. See also Drug addictionBarclay, Craig, 1298Bard, Philip, 19, 1048, 1049fBarlow, Horace, 399Barnes maze, 1355fBaroceptor reflex,laboratory at Harvard.Tom then joined the faculty of Harvard’s Department of Neu-robiology as an Assistant Professor in 1981, where he explored the mechanisms of sensory synaptic transmission and the development of the somatosensory input to the spinal cord. In 1985 Tom was recruited to the position of Associate Professor and investigator of the Howard Hughes Medical Institute in the Center for Neurobiology and Behav-ior (now the Department of Neuroscience) and Department of Bio-chemistry and Molecular Biophysics at Columbia University’s College of Physicians and Surgeons. Over the next 33 years, Tom, together with a remarkable group of students and collaborators, applied a mul-tidisciplinary cellular, biochemical, genetic, and electrophysiological approach to identify and define spinal cord microcircuits that control sensory and motor behavior. His studies revealed the molecular and cellular mechanisms by which spinal neurons acquire their identity and by which spinal circuits are assembled and operate. He defined key concepts and principles of neural development and motor control, and his discoveries generated unprecedented insight into the neural Kandel_FM.indd 8 20/01/21 9:04 AMprinciples that coordinate movement, paving the way for therapies for motor neuron disease.Eric Kandel and Jimmy Schwartz, the initial editors of Principles of Neural Science, recruited Tom as co-editor as they began to plan the third edition of the book. Tom’s role was to expand the treatment of developmental and molecular neural science. This proved to be a pres-cient choice as Tom’s breadth of knowledge, clarity of thought, and precise, elegant style of writing helped shape and define the text for the next three editions. As co-authors of chapters in Principles during Tom’s tenure, we can attest to the rigor of language and prose that he encouraged his authors to adopt. In the last years of his life, Tom bravely faced a devasting neuro-degenerative disease that prevented him from actively participating in the editing of the current edition. Nonetheless Tom’s vision remains in the overall design of Principles and its philosophical approach to pro-viding a molecular understanding of the neural bases of behavior and neurological disease. Tom’s towering influence on this and future edi-tions of Principles, and on the field of neuroscience in general, will no doubt endure for decades to come. Kandel_FM.indd 9 20/01/21 9:04 AMContents in BriefContents xiiiPreface xliAcknowledgments xliiiContributors xlvPart IOverall Perspective 1 The Brain and Behavior 7 2 Genes and Behavior 26 3 Nerve Cells, Neural Circuitry, and Behavior 56 4 The Neuroanatomical Bases by Which Neural Circuits Mediate Behavior 73 5 The Computational Bases of Neural Circuits That Mediate Behavior 97 6 Imaging and Behavior 111Part IICell and Molecular Biology of Cells of the Nervous System 7 The Cells of the Nervous System 133 8 Ion Channels 165 9 Membrane Potential and the Passive Electrical Properties of the Neuron 19010 Propagated Signaling: The Action Potential 211Part IIISynaptic Transmission11 Overview of Synaptic Transmission 24112 Directly Gated Transmission: The Nerve-Muscle Synapse 25413 Synaptic Integration in the Central Nervous System 27314 Modulation of Synaptic Transmission and Neuronal Excitability: Second Messengers 30115 Transmitter Release 32416 Neurotransmitters 358Part IVPerception17 Sensory Coding 38518 Receptors of the Somatosensory System 40819 Touch 43520 Pain 47021 The Constructive Nature of Visual Processing 49622 Low-Level Visual Processing: The Retina 52123 Intermediate-Level Visual Processing and Visual Primitives 54524 High-Level Visual Processing: From Vision to Cognition 56425 Visual Processing for Attention and Action 58226 Auditory Processing by the Cochlea 59827 The Vestibular System 62928 Auditory Processing by the Central Nervous System 65129 Smell and Taste: The Chemical Senses 682Kandel_FM.indd 11 20/01/21 9:04 AMxii Contents in Brief49 Experience and the Refinement of Synaptic Connections 121050 Repairing the Damaged Brain 123651 Sexual Differentiation of the Nervous System 1260Part VIIILearning, Memory, Language and Cognition52 Learning and Memory 129153 Cellular Mechanisms of Implicit Memory Storage and the Biological Basis of Individuality 131254 The Hippocampus and the Neural Basis of Explicit Memory Storage 133955 Language 137056 Decision-Making and Consciousness 1392Part IXDiseases of the Nervous System57 Diseases of the Peripheral Nerve and Motor Unit 142158 Seizures and Epilepsy 144759 Disorders of Conscious and Unconscious Mental Processes 147360 Disorders of Thought and Volition in Schizophrenia 148861 Disorders of Mood and Anxiety 150162 Disorders Affecting Social Cognition: Autism Spectrum Disorder 152363 Genetic Mechanisms in Neurodegenerative Diseases of the Nervous System 154464 The Aging Brain 1561Index 1583Part VMovement30 Principles of Sensorimotor Control 71331 The Motor Unit and Muscle Action 73732 Sensory-Motor Integration in the Spinal Cord 76133 Locomotion 78334 Voluntary Movement: Motor Cortices 81535 The Control of Gaze 86036 Posture 88337 The Cerebellum 90838 The Basal Ganglia 93239 Brain–Machine Interfaces 953Part VIThe Biology of Emotion, Motivation, and Homeostasis40 The Brain Stem 98141 The Hypothalamus: Autonomic, Hormonal, and Behavioral Control of Survival 101042 Emotion 104543 Motivation, Reward, and Addictive States 106544 Sleep and Wakefulness 1080Part VIIDevelopment and the Emergence of Behavior45 Patterning the Nervous System 110746 Differentiation and Survival of Nerve Cells 113047 The Growth and Guidance of Axons 115648 Formation and Elimination of Synapses 1181Kandel_FM.indd 12 20/01/21 9:04 AMAs in previous editions, the goal of this sixth edition of Principles of Neural Science is to provide readers with insight into how genes, molecules, neurons, and the circuits they form give rise to behavior. With the expo-nential growth in neuroscience research over the 40 years since the first edition of this book, an increasing chal-lenge is to provide a comprehensive overview of the field while remaining true to the original goal of the first edition, which is to elevate imparting basic principles over detailed encyclopedic knowledge. Some of the greatest successes in brain science over the past 75 years have been the elucidation of the cell biological and electrophysiological functions of nerve cells, from the initial studies of Hodgkin, Huxley, and Katz on the action potential and synaptic transmis-sion to our modern understanding of the genetic and molecular biophysical bases of these fundamental pro-cesses. The first three parts of this book delineate these remarkable achievements. The first six chapters in Part I provide an overview of the broad themes of neural science, including the basic anatomical organization of the nervous system and the genetic bases of nervous system function and behavior. We have added a new chapter (Chapter 5) to introduce the principles by which neurons participate in neural circuits that perform specific computations of behavioral relevance. We conclude by considering how application of modern imaging techniques to the human brain provides a bridge between neuroscience and psychology. The next two parts of the book focus on the basic properties of nerve cells, including the generation and conduction of the action potential (Part II) and the electrophysiological and molecular mechanisms of synaptic transmission (Part III). We then consider how the activity of neurons in the peripheral and central nervous systems gives rise to sensation and movement. In Part IV, we discuss the various aspects of sensory perception,994, 1023, 1027fBarrels, somatosensory cortexcharacteristics of, 456, 456b–457b, 456f–457fdevelopment of, 1125–1126, 1127fBarrington’s nucleus (pontine micturition center), 1023, 1024fBartlett, Frederic, 1298b, 1308Basal body, 1137, 1139fBasal forebrain, in Alzheimer disease, 1569, 1577Basal gangliaaction selection in, 941–944arguments against, 943–944choosing from competing options and, 941intrinsic mechanisms for, 943for motivational, affective, cognitive, and sensorimotor processing, 941–942, 942fneural architecture for, 940f, 942–943anatomy of, 12b, 13f, 933–935, 933f, 934fbehavioral selection in, 946–947, 947fconnections with external structures, reentrant loops in, 936f, 937–939dysfunction of, 710, 947–948, 947fin addiction, 949–950. See also Drug addictionin attention deficit hyperactivity disorder, 949in Huntington disease, 948. See also Huntington diseasein obsessive-compulsive disorder, 949. See also Obsessive-compulsive disorder (OCD)in Parkinson disease, 948. See also Parkinson diseasein schizophrenia, 948–949. See also Schizophreniain Tourette syndrome, 949evolutionary conservation of, 940–941functions of, 12bon gaze control, 873–874, 873fhighlights, 950–951internal circuitry of, 935–937, 936fin language, 1388in learning of sensorimotor skills, 1304in locomotion, 807–809neuroactive peptides of, 367tphysiological signals infrom cerebral cortex, thalamus, and ventral midbrain, 939disinhibition as final expression of, 940, 940fto ventral midbrain, 939–940in posture control, 902, 904freinforcement learning in, 944–946, 945fsuperior colliculus inhibition by, 873–874, 873fBasal laminain neuromuscular junction, 255, 256fon presynaptic specialization, 1192, 1193fBasic helix-loop-helix (bHLH) transcription factorsin central neuron neurotransmitter phenotype, 1145, 1145fin neural crest cell migration, 1141, 1143fin neuron and glial cell generation, 1131–1135, 1134f, 1135fin ventral spinal cord patterning, 1119Basilar membrane, 602f–603f, 603–604Bassett, Daniella, 1304Bats, specialized cortical areas for sound features in, 675–677, 676fBautista, Diana, 425Bayes’ rule, 405Bayesian inference, 721, 721bBayliss, William, 167Bcl-2 proteins, in apoptosis, 1151–1152, 1151fBDNF. See Brain-derived neurotrophic factor (BDNF)Beams, of synaptic vesicles, 349, 350fKandel-Index_1583-1646.indd 1588 19/01/21 9:18 AMIndex 1589Bear, Mark, 1351Beating neurons, 68Beck, Aaron, 1473, 1474bBecker muscular dystrophy, 1437, 1438t, 1440f–1441fBed nucleus of stria terminalis (BNST)in homosexual and transsexual brains, 1281, 1281fin sexually dimorphic behaviors, 1272Behavior. See also Cognitive function/processes; specific typesbrain and. See Brain, behavior andfMRI of. See Functional magnetic resonance imaging (fMRI)genes in. See Gene(s), in behaviornerve cells and. See Neuron(s)neural circuits in mediation of, 4, 62–64. See also Neural circuit(s), computational bases of behavior mediation by; Neural circuit(s), neuroanatomical bases of behavior mediation byneural signals in. See Neuron(s), signaling inselection, in basal ganglia, 946–947, 947fselection disorders. See Basal ganglia, dysfunction ofsexually dimorphic. See Sexually dimorphic behaviorsunconscious. See Unconscious mental processesBehavior therapy, 1473, 1474bBehavioral observation, subjective reports with, 1483–1485, 1484fBehavioral rules, 835, 836fBékésy, Georg von, 603Bell, Charles, 390Bell palsy, 983–984Bell phenomenon, 993Bensmaia, Sliman, 444Benzer, Seymour, 34, 40, 1330Benzodiazepines, 1072t, 1092. See also Drug addictionBerger, Hans, 1448, 1461Bergmann glia, 154Berkeley, George, 387, 497Bernard, Claude, 8, 1011Berridge, Kent, 1038Beta axons, 767Beta fusimotor system, 767β2-adrenergic receptor, 306fβ-amyloid, in Alzheimer disease. See Alzheimer disease, amyloid plaques inβ-endorphins, 490, 490t, 491fβ-secretasein Alzheimer disease, 141b, 1570, 1571fdrugs targeting, 1577β-site APP cleaning enzyme 1 (BACE1), 1572β-tubulin, 139, 140fbHLH transcription factors. See Basic helix-loop-helix (bHLH) transcription factorsBias, 1308Biased random walks, in decision-making, 1401, 1402fBilingual speakers, language processing in, 1378Binding, of actions and effects, 1480, 1480fBinocular circuits, in visual cortex. See under Visual cortexBinocular disparity, in depth perception, 550, 552f, 553fBinomial distribution, 335b–336bBiogenic amine transmitters, 360t, 361–364. See also specific transmittersBiological learning networks, 103fBipolar cells, 523, 523fdiffuse, 536, 537fmidget, 536, 537fparallel pathway in interneuron retinal network in, 524f, 531, 536, 537fin rods, 524f, 540Bipolar disorderdepressive episodes in, 1504diagnosis of, 1503manic episodes in, 1503–1504, 1503tonset of, 1504treatment of, 1519–1520Bipolar neurons, 59, 60folfactory. See Olfactory sensory neuronsBirdsauditory localization in owls, 690, 1227–1228, 1227f–1229fimprinting in learning in, 1211language learning in, 1371sexually dimorphic neural circuit on song production in, 1267, 1271fBirthday, neuron, 1137Bitter taste receptor, 698f–700f, 700–701BK K+ channels, 229Bladder control, 1023, 1024fBlind sight, 1475Blind spot, 524, 525fBlindness, change, 562, 1476, 1477, 1479fBliss, Timothy, 1342Bliss, Tom, 284Bloch, Felix, 125Blocking, of memory, 1308Blood glucose, on appetite, 1035Blood osmolarity, 1031Blood oxygen level–dependent (BOLD) activityin fMRI, 115, 117f, 118–119. See also Functional magnetic resonance imaging (fMRI)in resting state in brain areas, 399Blood pressurebaroceptor reflex in regulation of, 1023, 1027fhypothalamus in regulation of, 1013tBlood–brain barrier, 159Blue cones, 393, 394fBMAL1 protein, 1088–1090, 1089fBMIs. See Brain-machine interfaces (BMIs)BMPs. See Bone morphogenetic proteins (BMPs)BNST. See Bed nucleus of stria terminalis (BNST)Body, estimation of current status. See State estimationBody movements, cerebellum on. See Cerebellum, movement control byBody temperature, regulation of, 1013t, 1029–1031, 1029bBois-Reymon, Emil du, 8BOLD activity. See Blood oxygen level–dependent (BOLD) activityBone morphogenetic proteins (BMPs)in axon growth and guidance, 1178fcharacteristics of, 1111in dorsal neural tube patterning, 1119in neural crest induction and migration, 1141in neural induction, 1110–1112, 1111fBony labyrinth, 630Border cells, 1361–1362, 1364fBorder ownership, 554, 554fBottom-up processesin high-level visual processing, 578in motion perception, 555in visual perception, 560–562Botulism, 1436–1437Bounded evidence accumulation, 1401Bourgeron, Thomas, 1535Brachium conjunctivum, 911, 912fBrachium pontis, 911, 912fBradykininnociceptor sensitization by, 478on TRP channel, 473fBraille dots, touch receptor responses to, 442, 444, 445fBrainanatomical organization of, 10–16, 12b–15b. See also specific structuresatrophy of, in Alzheimer disease, 1568, 1568fbehavior and, 7–23complex processing systems for, 20cytoarchitectonic method and, 18, 18felementary processing units in, 21–23highlights, 23history of study of, 8–10localization of processes for. See Cognitive function/processes, localization ofmind in, 7neural circuits in, 7–8. See also Neural circuit(s), computational bases of behavior mediation by; Neural circuit(s), neuroanatomical bases of behavior mediation byviews of, 8–10cellular connectionism, 10chemical and electrical signaling, 8–9dualistic, 9functional localization, 9–10, 9fKandel-Index_1583-1646.indd 1589 19/01/21 9:18 AM1590 IndexBrain, behavior and, views of (Cont.):holistic, 10, 18neuron doctrine, 8damage to/lesions of. See also specific typesfrom prolonged seizures, 1465–1466repair of. See Axon injury (axotomy), therapeutic interventions fortreatment of, recentimprovements in, 1236functional principles ofconnectional specificity, 59dynamic polarization, 59signal pathways, 58functional regions of, 16, 19–20mind and, 1419–1420neuroanatomical terms of navigation, 11boverall perspective of, 3–4signaling in, 165–166Brain reward circuitryin addiction and drug abuse, 1070–1071, 1070f, 1072fin goal selection, 1066–1068, 1067fBrain stem, 981–1008. See also specific partsanatomy of, 12b, 13f, 982cranial nerve nuclei in. See Cranial nerve nucleicranial nerves in, 982–986, 983f. See also Cranial nervesdevelopmental plan of, 986, 986fin emotion, 1048f, 1098functions of, 977highlights, 1007–1008lesionson eye movements, 870–871on smooth-pursuit eye movements, 878–879in locomotion, 801–804, 803f, 804fmonoaminergic neurons in, 998–1007in arousal maintenance, 1006–1007, 1007fautonomic regulation and breathing modulation by, 1002, 1002f–1003fcell groups ofadrenergic. See Adrenergic neuronscholinergic. See Cholinergic neuronsdopaminergic. See Dopaminergic neuronshistaminergic. See Histaminergic neuronsnoradrenergic. See Noradrenergic neuronsserotonergic. See Serotonergic neurons/systemshared cellular properties of, 1001–1002, 1002fmonoaminergic pathways inascending, 998, 1004–1006, 1005f, 1006f. See also Ascending arousal systemmotor activity facilitation by, 1004pain modulation by, 1002, 1004motor circuits for saccades in, 868–870brain stem lesions on, 870mesencephalic reticular formation in vertical saccades in, 863f, 870pontine reticular formation in horizontal saccades in, 868–870, 869fin newborn behavior, 981posture and, integration of sensory signals for, 901–902reticular formation of. See Reticular formationBrain stimulation reward, 1066–1068, 1067fBrain-derived neurotrophic factor (BDNF)on ocular dominance columns, 1223overexpression, in Rett syndrome, 1532in pain, 479, 481freceptors for, 1148, 1150fBrain-machine interfaces (BMIs), 953–972in basic neuroscience research, 968–970biomedical ethics considerations in, 970–971highlights, 971–972motor and communicationconcepts of, 954–955, 955fprosthetic arms for reaching and grasping in, 965, 967f, 968fstimulation of paralyzed arms in, 965, 967, 969ffor using electronic devices, 964–965, 964fmovement decoding in, 958–960, 959f, 960fcontinuous decoding in, 961–962, 962f–963fdecoding algorithms for, 959f, 960–961discrete decoding in, 961, 961fneurotechnology forlow-power electronics for signal acquisition, 957–958measurement of large number of neurons, 957neural sensors, 956–957, 957fsupervisory systems, 958for restoration of lost capabilitiesantiseizure devices, 956cochlear implants, 624, 927f, 954deep brain stimulation, 956. See also Deep brain stimulation (DBS)in motor and communication functions, 954–955, 955freplacement parts, 956retinal prostheses, 954sensory feedback by cortical stimulation for control of, 967–968Brauer, Jens, 1381Breathingchemoreceptors in, 995–996, 996fmedulla in, 995, 995fmovements of, 994–995pattern generator neurons in, 994–998serotonergic neurons in, 1002, 1002f–1003fvoluntary control of, 997–998Brightness, context in perception of, 555–558, 557fBrightness illusion, 540, 541fBritish Sign Language, 19–20Broca, Pierre Paulon languagebrain studies of, 16, 1291neural processing, 1378on visceral brain, 10, 1049–1050Broca’s aphasiacharacteristics of, 16differential diagnosis of, 1379tlesion sites and damage in, 1382–1384, 1385f, 1386spontaneous speech production and repetition in, 1382–1383, 1384tBroca’s area, 16, 17f, 1291damage to, aphasia and. See Broca’s aphasiadamage to, on signing, 20language processing and comprehension in, 17, 19Brodie, Benjamin, 375Brodmann, Korbinian, 18, 18f, 86–87, 87f, 502Brodmann’s area, 819, 820f, 825Brown, Sanger, 568Brown adipose tissue, 1029bBruchpilot, 349Brücke, Ernest, 167Brunger, A.T., 347Bucy, Paul, 1049BuffersK+, astrocytes in, 154spatial, 154Bulb. See PonsBulk endocytosis, 151Bulk retrieval, 343, 343fBungarotoxin, 255, 257fBurst neurons, in gaze control, 868–870, 869fBursting neuronsin central pattern generators, 792, 796bdefinition of, 68firing patterns of, 230f, 232fBushy cells, 655–656, 658f–659fCC. See Capacitance (C)C fibersconduction velocity in, 412f, 412tin itch, 425nociceptors with, 425pain transmission by, 472polymodal nociceptor signals in, 472to spinal cord dorsal horn, 474, 475fvisceral, in spinal cord, 431, 431fin warm sensation reception, 424C4 gene, 50C9orf72 mutations, 1426, 1427tCA1 pyramidal neurons, of hippocampusin explicit memory, 1340, 1341flong-term potentiation in, 1347–1349, 1347f, 1349fKandel-Index_1583-1646.indd 1590 19/01/21 9:18 AMIndex 1591Ca2+in growth cone, 1164permeability, in AMPA receptor-channel, 279, 281fresidual, 351synaptotagmin binding of, 347synaptotagmin of, in exocytosis in synaptic vesicles, 348f–349fCa2+ channelsclasses of, 328f, 329, 331t, 332high-voltage-activated, 227, 329, 331t, 332locations of, 329low-threshold, 796blow-voltage-activated, 331t, 332in Parkinson disease, 1550structure of, 329voltage-dependent, inactivation of, 174, 174fvoltage-gatedin disease, 332G protein-coupled receptors on opening of, 315, 316fgenetic factors in diversity of, 177, 178f, 225, 227–228, 232fhigh-voltage activated (HVA), 227in Lambert-Eaton syndrome, 332, 1436–1437low-voltage activated (LVA), 227mutations in, epilepsy and, 1468, 1468fin neuromuscular junction, 255, 256fin seizures, 1455Ca2+ concentrationon ion channel activity, 229on synaptic plasticity, 351in transmitter release, 329, 330f, 351Ca2+ influxin long-term potentiation, 1342, 1344f–1345f, 1347on synaptic plasticity, 351in transmitter release, 327–332active zones in, presynaptic terminal, 327–332, 328fCa2+ channel classes in, 328f, 329, 331t, 332dual functions of Ca2+ in, 327presynaptic Ca2+ concentration in, 329, 330fvia voltage-gated Ca2+ channels, 327, 327fCa2+ pumps, 197–198, 197fCA2 pyramidal neurons, in social memory, 1360CA3 pyramidal neuronsin explicit memory, 1340, 1341f, 1343fin pattern completion, 1360in pattern separation, 1359CAAT box enhancer binding protein, in long-term sensitization (C/EBP), 1321f, 1323, 1324fCacosmia, 691Cade, John, 1519Cadherinsin axon growth and guidance, 1170f–1171fin hair cell transduction machinery, 611, 612fin neural crest cells, 1141Caenorhabditis elegansolfactory mechanisms in, 694–695, 695f, 696fstudies of nervous system of, 1151, 1151fCAG trinucleotide repeat diseasesdentatorubropallidoluysian atrophy, 1544, 1546, 1547t, 1549t, 1551fhereditary spinocerebellar ataxias. See Spinocerebellar ataxias (SCAs), hereditaryHuntington disease. See Huntington diseasemouse models of, 1552–1553neuronal degeneration and, 1551fspinobulbar muscular atrophy, 1546, 1547t, 1551f, 1552CAH (congenital adrenal hyperplasia), 1253, 1265t, 1279–1280CAIS (complete androgen insensitivity syndrome), 1264, 1265t, 1279–1280Cajal-Retzius cells (neurons), 1138Calcitonin gene-related peptide (CGRP)in dorsal root ganglion neurons, 410, 411fin neurogenic inflammation, 479, 480fin pain, 475release and action of, 371in spinal-cord dorsal horn pain nociceptors, 475Calcium channels. See Ca2+ channelsCalcium ion. See Ca2+Calcium sensor, 329Calcium spike, 327Calcium-activated K+ channels, 229Calcium/calmodulin-dependent protein kinase (CaM kinase), 307f, 308, 351Calcium-calmodulin-dependent protein kinase II (CaMKII), 286f–287f, 1344f–1345f, 1345, 1351Calcium-calmodulin-dependent protein kinase II (CaMKII-Asp286), 1351, 1355fCalmodulin (CaM), 174, 174fCalor, 479Caloric restriction, for lifespan extension, 1566Calyx of Held, 329, 330f, 661, 662fcAMP (cyclic AMP)in consolidation, 1319in growth cone, 1164, 1166fin olfactory sensory neurons, 1186fpathway, 303–305in regeneration of central axons, 1246signaling, in long-term sensitization, 1319–1323, 1321f, 1322fcAMP recognition element (CRE)in catecholamine production, 362bin long-term sensitization, 1319, 1321f, 1322fcAMP response element-binding protein (CREB)on catecholamine production, 362bin long-term sensitization, 1319–1323, 1321f, 1322f, 1323in memory consolidation switch, 1323, 1324ftranscription activation by, 317cAMP response-element binding protein (CREB)-binding protein (CBP)in long-term sensitization, 1319, 1321f, 1322ftranscription activation by, 317cAMP-CREB pathway, upregulation by drugs of abuse, 1074, 1075f, 1076fcAMP-dependent phosphorylation, in synaptic capture, 1327, 1328fcAMP-dependent protein kinase (PKA). See Protein kinase A (PKA)cAMP-PKA-CREB pathway, in fear conditioning in flies, 1330–1331Cannabinoid(s), 1072t. See also Drug addictionCannabinoid receptors, 310Cannon, Walter B.on fear and rage, 1048, 1049f, 1050fon “fight or flight” response, 1021–1022on homeostasis, 1011Cannon-Bard central theory, 1048, 1049fCanonical splice site mutation, 33fCapacitance (C)definition of, 200membrane, 203–204, 204fCapacitive current (Ic), in voltage clamp, 213Capacitordefinition of, 138leaky, 200Capgras syndrome, 1478–1479Capsaicin, on thermal receptors, 424Capture, synaptic, 1326f, 1327, 1328fCarandini, M., 404Carbamazepine, mechanism of action of, 1455–1456Carbon dioxide (CO2) chemoreceptors, on breathing, 995, 996fCardiac muscle, 1421Cardiotrophin-1, 1146Carlsson, Arvid, 361, 1498Caspasein apoptosis, 1152–1153, 1152fin neurodegenerative diseases, 1556, 1557fCataplexy, 1094–1095Cataracts, 1212Catecholamine transmittersdopamine. See Dopamineepinephrine. See Epinephrineneuronal activity on production of, 362bnorepinephrine. See Norepinephrinestructure and characteristics of, 361–363Catecholaminergic, 359Catechol-O-methyltransferase (COMT), 375, 1382Kandel-Index_1583-1646.indd 1591 19/01/21 9:18 AM1592 IndexCategorical perceptionin behavior simplification, 572–573, 574fin language learning, 1373Category-specific agnosia, 568, 573Cation, 167Caudal, 11b, 11fCaudal ganglionic eminences, neuron migration to cerebral cortex from, 1140, 1140fCaudal spinal cord, 78fCav channels, 227Cavernous sinus, 984f, 986CB1 receptors, 310CB2 receptors, 310CBP. See cAMP response-element binding protein (CREB)-binding protein (CBP)CCK. See Cholecystokinin (CCK)cDNA (complementary DNA), 52Cell assemblies, memory storage in, 1357–1358, 1358f–1359fCell body, 57, 57fCell death, programmed. See ApoptosisCell death (ced) genes, 1151, 1151fCell (plasma) membrane. See also specific typesconductance in, from voltage-clamp currents, 217–218, 218b, 218fdepolarization of, 216, 217fdepolarization of, on Na+ and K+ current magnitude and polarity, 217fmultiple resting K+ channels in, 201permeability to specific ions, 199proteins of, synthesis and modification of, 147–149, 148fstructure and permeability of, 166–169, 168f–169fCell surface adhesion, in axon growth and guidance, 1169fCell theoryin brain, 58origins of, 58Cellular connectionism, 10, 17Cellular memory, 351Cellular motors, in growth cone, 1164, 1165fCenter of gaze, retinal, 526Center of masscenter of pressure and, 884, 885b, 885fdefinition of, 884postural orientation on location of, 884Center of pressure, 884, 885b, 885fCenter-surround receptive field, 531, 532fCentral chemoreceptors, 995–996, 996fCentral core, of growth cone, 1163–1165, 1163fCentral nervous systemanatomical organization of, 12b–14b, 13fcells of, 133–162choroid plexus, 160–162, 160fependyma, 160–162, 161fglial cells. See Glial cellshighlights, 162neurons. See Neuron(s)diseases of, 1419–1420. See also specific diseasesneuroanatomical terms of navigation, 11b, 11fCentral neuron regeneration. See Axon regenerationCentral nucleus, of amygdala, 1052, 1052fCentral pattern generators (CPGs)characteristics of, 791–792, 791fflexor and extensor coordination, 793, 794f–795fin humans, 809left-right coordination, 793, 794f–795fmolecular codes of spinal neurons in, 796bneuronal ion channels in, 796bquadrupedal, 793, 794f–795fswimming, 792, 794f–795fCentral sensitization, 479, 481, 483fCentral sulcus, 16, 17fCentral touch system, 450–460cortical circuitry studies in, 456b–457b, 456f–457fcortical magnification in, 456somatosensory cortex incolumnar organization of, 452, 453fdivisions of, 452, 452fneuronal circuits organization, 452, 453fpyramidal neurons in, 452–454, 458freceptive fields in, 457–460, 458f, 459fsomatotopic organization of cortical columns in, 454–456, 454f–455fspinal, brain, and thalamic circuits in, 450, 450f–451f“Centrencephalic” hypothesis, of generalized onset seizures, 1139Centromere, 52Cephalic flexure, 1112, 1113fCerebellar ataxia, 909, 910fCerebellar disorders. See also specific typeslesions, on smooth-pursuit eye movements, 878–879, 912, 916, 916fmovement and posture abnormalities in, 710, 909, 910fsensory and cognitive effects of, 909–911Cerebellar glomeruli, 918, 919fCerebellar hemispheres, 911, 912fCerebellopontine angle, 984f, 986Cerebellum, 908–929anatomy of, 12b, 13f, 14f, 15f, 911, 912fin autism spectrum disorder, 1528f, 1539cortical connections of, 911, 913fdisorders of/damage to. See Cerebellar disordersexcitatory neurons in, 1145in eye movements, 867f, 878–879, 878f, 912, 916fgeneral computational functions of, 922–923feedforward sensorimotor control in, 922integration of sensory inputs and corollary discharge in, 923internal model of motor apparatus in, 922–923timing control in, 923highlights, 929inhibitory neurons in, 1145cerebellar Purkinje cell termination of, 1187, 1187fin locomotion, 806–807long-term depression in, 1353microcircuit organization of, 918–922afferent fiber systems in, information coding by, 918–920, 919f–920fcanonical computation in, 920–921, 921fparallel feedforward excitatory and inhibitory pathways, 921recurrent loops, 921functionally specialized layers in, 918, 919fmotor skill learning in. See Motor skill learning, in cerebellummovement control by. See also Movement, control ofcoordination with other motor system components, 91, 91ffunctional longitudinal zones in, 911–917, 914f. See also Cerebrocerebellum; Spinocerebellum; Vestibulocerebelluminput and output pathways for, 915f, 916interposed and dentate nuclei in, 917, 917fsensory input and corollary discharge integration in, 923vermis in, 916in neurodevelopmental disorders, 1539neuronal representations as basis for learning in, 104–105, 104fin orientation and balance, 901–902in posture, 901–902in sensorimotor skill learning, 1304Cerebral cortexanatomy of, 12b, 13f, 14f, 15fanterior cingulate. See Anterior cingulate cortexauditory processing in. See Auditory cortexin autism spectrum disorder, 1525f, 1539basal ganglia connections to, 937–939, 938fcerebellar connections to, 911, 913ffunction of, 12b, 16hemispheres of, 14f, 15f, 16insular. See Insular cortex (insula)lobes of, 12b, 13dneuronal migration in layering of, 1135–1138, 1136f–1137f, 1139forganization of, 85–88, 85f–87fin postural control, 905Kandel-Index_1583-1646.indd 1592 19/01/21 9:18 AMIndex 1593receptive fields in, 458f, 459–460, 459fin sensory information processing, 84–88ascending and descending pathways for, 75f, 88, 88f, 90fassociation areas for, 88, 89fcortical area dedicated to, 84–85, 84ffeedback pathways for, 403–404functional areas for, 399, 400fneocortex layers for, 85–87, 85f, 86f, 87fserial and parallel networks for, 402–403, 403fin smooth-pursuit eye movements, 867f, 878–879, 878fspecialization in humans and other primates, 1141–1143, 1144fvascular lesions of, 1567vestibular information in, 645–647, 646fvisual processing in. SeeVisual cortexin voluntary movement, 89, 90f, 91f. See also Primary motor cortex; Voluntary movementCerebral palsy, 780Cerebrocerebellum. See also Cerebellumanatomy of, 912f, 917input and output targets of, 914f, 917Cerebrospinal fluid (CSF), production of, 160–162, 161fCerebrovascular accident (stroke). See StrokeCerebrovascular disease, dementia in, 1567Cervical flexure, 1112, 1113fCervical spinal cord, 13f, 78–79, 78fCF (constant-frequency) component, 675–677, 676fcGMP. See Cyclic GMP (cGMP)cGMP-dependent protein kinase (PKG), 312CGRP. See Calcitonin gene-related peptide (CGRP)Chain migration, 1140, 1140fChange blindnessdefinition of, 562demonstration of, 1476, 1477, 1479ftest for, 588, 590fChangeux, Jean-Pierre, 264Channel density, 205Channel gating. See Gating, channelChannel opening, length of, 260Charcot-Marie-Tooth diseasedisordered myelination in, 156b, 156fgenetic and molecular defects in, 1430–1432, 1431f, 1433tinfantile, 1433tpathophysiology of, 248X-linked, 1431f, 1433tCharles Bonnet syndrome, 1476, 1478fChattering cells, 229, 230fChemical cage, 329, 330fChemical driving force, 193, 260Chemical mutagenesis, 35bChemical synapses/transmission. See Synapse, chemicalChemoattraction, in axon growth and guidance, 1169f, 1176–1179, 1177f, 1178fChemogenetic methodology, in manipulation of neuronal activity, 99bChemoreceptorscentral, on breathing, 995–996, 996fcharacteristics of, 391f, 392t, 393dorsal root ganglia neuron axon diameter in, 410–411graded sensitivity of, 393Chemorepulsion, in axon growth and guidance, 1169f, 1176–1179, 1178fChemospecificity hypothesis, 1167, 1168f, 1182Chesler, Alexander, 427Chewing, pattern generator neurons on, 994Cheyne-Stokes respiration, 996, 997fChildrenmajor depressive disorder in, 1503social deprivation and development of, 1211–1212, 1213fChimeric channels, 176–177Chloride channels. See Cl- channelsChloride ion (Cl-), active transport of, 135f, 197f, 198Chlorpromazine, 1498, 1498fCholecystokinin (CCK)in appetite control, 1034, 1036f–1037fin myenteric plexus, 1020fon vagal nerve, 985Cholesterol, in steroid hormone biosynthesis, 1262, 1264fCholine acetyltransferase, 1436Choline transporter (CHT), 366fCholinergic, 359Cholinergic neuronsin arousal maintenance, 1006–1007, 1007flocation and projections of, 360–361, 1000f, 1001synaptic transmission in, 313–315, 314fChomsky, Noam, 1373Chondroitin sulfate proteoglycans (CSPG), 1245f, 1246Chondroitinase, 1246Chordin, 1111f, 1112Choreain Huntington disease, 1010t, 1545, 1547tin spinocerebellar ataxia, 1546Choroid plexus, 160–162, 161fChromatin, 136fChromatolytic reaction, 1237f, 1240Chromosomal sex, 1261–1262, 1262fChromosomes, 30–31, 31fChromosomes, sex, 1260Chronic traumatic encephalopathy (CTE), 1567CHT (choline transporter), 366fChymotrypsin, 368Cilia, nasal, sensory receptors in, 683–684, 684fCiliary neurotrophic factors (CNTFs)on axon growth, 1246, 1248fin neurotransmitter phenotype switch, 1146, 1146fin sexual differentiation, 1267Cingulate cortex, 12b, 13fCingulate gyrus. See Anterior cingulate cortexCingulate motor area, 831Circadian rhythmmolecular mechanisms of, 41–42, 43fin sleep. See Sleep, circadian rhythms intranscriptional oscillator in, 34, 41–42, 41f–43fCircuit (electrical), short, 201Circuit plasticity, 1077Circumvallate papillae, 697, 697fCirelli, Chiari, 1092Cl-, active transport of, 135f, 197f, 198Cl- channelsinhibitory actions at synapses and opening of, 289f, 290mutations in, epilepsy and, 1468fresting, multiple, in cell membrane, 201selective permeability in, 185–187, 185fstructure of, 185, 185fClassical conditioningamygdala in. See Amygdala, in fear responsedefinition of, 1317fear, 1050–1051, 1052f, 1506, 1509fundamentals of, 1306history of, 1306vs. operant conditioning, 1307stimuli pairing in, 1306, 1307fthreat. See Threat conditioningClassical genetic analysis, 34Clathrin coats, 150Clathrin-coated vesiclesendocytic traffic in, 149–150membranes of, 345–346Clathrin-independent endocytosis, ultrafast, 341Clathrin-mediated recycling, transmitter, 341, 343fCLC proteins/channels, 179, 185, 185f, 187ClC-1 channels, 185, 185fClimbing fibers, in cerebellumactivity of, on synaptic efficacy of parallel fibers, 924–925, 924finformation processing by, 918–919, 920fclock gene/CLOCK protein, 40–41, 42f–43f, 1088–1090, 1089fClonic movements, 1449Clonic phase, 1449Cloning, 52Clozapine, 1498–1499, 1498fCNF (cuneiform nucleus), 800, 802fCNTFs. See Ciliary neurotrophic factors (CNTFs)CNV. See Copy number variation (CNV)Kandel-Index_1583-1646.indd 1593 19/01/21 9:18 AM1594 IndexCO2 chemoreceptors, on breathing, 995, 996fCoat proteins (coats), 150Cocaine. See also Drug addictionneural correlates of craving for, 1071, 1073fsource and molecular target of, 1072tCochleaacoustic input distortion by amplification of, 618anatomy of, 599–600, 599f, 600fauditory processing in, 598–626cochlear nerve in. See Cochlear nerveevolutionary history of, 620bhair bundles in. See Hair bundleshair cells in. See Hair cells, in auditory processinghighlights, 626mechanical stimuli delivery to receptor cells in, 603–606basilar membrane in, 602f–603f, 603–604organ of Corti in, 604–606, 605f–607fsound energy capture in, 600–602sound on air pressure in, 601, 602f–603fWeber-Fechner law in, 601sound energy amplification in, 616–618, 617f, 618fCochlear nerve, 599f, 600f, 621–624axon responsiveness as tuning curve in, 613f, 622firing pattern of, 623, 623finformation distribution via parallel pathways by, 655innervation of, 621f, 622–623stimulus frequency and intensity coding by, 622–624, 623ftonotopic organization by, 655, 656fCochlear nuclei, 652–657bushy, stellate, and octopus cells in, 655–656, 658f–659fcochlear nerve and. See Cochlear nervecochlear nerve fiber innervation of, 655dorsalfeatures of, 655, 656ffusiform cells in, 657unpredictable vs. predictable sound processing in, 657use of spectral cues for sound localization by, 656–657, 658–659ffunctional columns of, 989f, 990fusiform cells in, 657, 658f–659fneural pathways via, 652–653, 654fventralfeatures of, 655, 656ftemporal and spectral sound information extraction in, 655–656, 658f–659fCochlear prosthesis/implant, 624, 625f, 954Co-contraction, 775Codon, 33fCognitive behavior therapy, 1474bCognitive function/processes. See also Behaviorage-related decline in, 1562, 1563f, 1566–1567, 1567fbrain systems for, 20complex, neural architecture for, 70–71conscious, neural correlates of, 1474–1476. See also Consciousnessdefinition of, 1473, 1474disorders of. See Conscious mental process disorders; Neurodevelopmental disorders; Unconscious mental process disordersearly experience and, 1211–1212, 1216femotions and, 1056history of study of, 1473impairment ofaberrancies in, 1473from birth, 1473–1474mild, 1566, 1567flocalization ofaggregate-field view, 17aphasia studies in, 16–18association areas and pathways in, 20cytoarchitectonic approach to, 18distributed processing in, 17evidence for, 19–20for language processing, 19–20. See also Language processingtheory of mass action in, 18–19as product of interactions between elementary processing units in the brain, 21–23on visual perception, 560–562Cognitive maps, 1288Cognitive psychology, fMRI studies and, 121Cognitive therapy, 1474, 1474bCohen, Neal, 1301Cohen, Stanley, 1147Coincidence detector, 1319Cole, Kenneth, 212, 212f. See also Voltage-clamp studiesColeman, Douglas, 1035Color blindnesscongenital forms of, 538f, 539–539, 539fgenes in, 539–540, 539ftests for, 538–539, 538fColor constancy, 1412Color perceptioncontext in, 555–556, 557fgraded sensitivity of photoreceptors in, 393–395, 394fColor vision, in cone-selective circuits, 538Coma, ascendingarousal system damage in, 1085Commissural axons, netrin directing of, 1176, 1177f, 1178fCommissural neurons, 1176Commitment, neural, 1377Competence, of cell, 1108Complement factor C4, in schizophrenia, 1497, 1497fComplementary DNA (cDNA), 52Complete androgen insensitivity syndrome (CAIS), 1264, 1265t, 1279–1280Complex cells, in visual cortex, 548, 549fComplex mutation, 33bComplex partial seizure, 1449. See also Seizure(s), focal onsetComplex regional pain syndrome, 474Compound action potentialdefinition of, 206in myasthenia gravis, 1434, 1434fby nociceptive fiber class, 471fin peripheral somatosensory nerve fibers, 412–414, 413f, 1425, 1425fComputational module, cortical, 512, 512fComputational network modeling, of locomotor circuits, 809COMT (catechol-O-methyltransferase), 375, 1382Conan Doyle, Arthur, 1409Concentration gradients, 193Conceptual priming, 1303Conditioned place preference, 1071bConditioned stimulus (CS), 1050, 1052f, 1306, 1307fConditioningclassical. See Classical conditioningoperant, 1306–1307pseudo-, 1305threat. See Threat conditioningConductanceion channel, 171, 171f, 200membrane, from voltage-clamp currents, 218b, 218fConduction, saltatory, 152, 153f, 208Conduction aphasiacharacteristics of, 18differential diagnosis of, 1379tposterior language area damage in, 1386spontaneous speech production and repetition in, 1384, 1384t, 1386Conduction block, 1430Conduction velocitycompound action potential measurement of, 412, 413fin conduction defect diagnosis, 207in disease diagnosis, 414measurement of, 1425, 1425fin myelinated vs. unmyelinated axons, 1430in peripheral nerve sensory fibers, 410–414, 412t, 413fConductive hearing loss, 601Cone(s)functions of, 525–526graded sensitivity of, 393, 394f, 526fopsin in, 529response to light, 391f, 393structure of, 524, 525fCone circuit, rod circuit merging with, 524f, 540Kandel-Index_1583-1646.indd 1594 19/01/21 9:18 AMIndex 1595Confabulation, 1482Conformational changes, in channel opening and closing, 172–174, 172f–173fConfusional arousals, 1095Congenital adrenal hyperplasia (CAH), 1253, 1265t, 1279–1280Congenital central hypoventilation syndrome, 996Congenital myasthenia, 1436Congenital sensory neuropathy, 1433tConnectional specificity, 59Connexin, 244, 245fConnexin 32, 248Connexon, 244, 245fConscious mental process, neural correlates of, 1474–1476Conscious mental process disordersbehavioral observation in, subjective reports with, 1483–1485, 1484fhighlights, 1485–1486history of study of, 1474–1475neural correlates of consciousness and, 1475–1477perception in, brain damage on, 1476–1479, 1476f–1479fambiguous figures in, 1476, 1476fCapgras syndrome in, 1478–1479change blindness in, 1476, 1477, 1479fhallucinations in, 1476–1477, 1478fprosopagnosia in, 1477–1478unilateral neglect in, 1475f, 1477recall of memory in, 1482–1483, 1482fConscious recall, of memory, 1482–1483, 1482fConsciousness. See also specific aspectscomponents of, 1474decision-making as lens for understanding, 1412–1415independent hemispheric circuits in, 21–22levels of arousal and, 1412memory and, 1297neural correlates of, 21–22, 1475–1477theory of mind and, 1413–1414Conservation, of genes, 32–34, 34f, 52Consolidationdefinition of, 1319in episodic memory processing, 1297medial temporal lobe and association cortices in, 1298non-coding RNA molecules in, 1323, 1324fConstant-frequency (CF) component, 675–677, 676fConstitutive secretion, 150Contact inhibition, in axon growth and guidance, 1169fcontactin associated protein-like 2, 1539Contextmodulation of, in visual processing, 513f, 551fon visual perception, 546–547, 555–558of color and brightness, 555–558, 557fof receptive-field properties, 558Contextual control, of voluntary behavior, 829–831, 830fContinuation, 497, 498fContinuous decoding, of neural activity, 960, 961–962, 962f–963fContinuous positive airway pressure (CPAP) device, 1093Continuous speech, transitional probabilities for, 1376–1377Contourillusory, and perceptual fill-in, 545–546, 546fintegration of, 545horizontal connections in, 551f, 559in visual processing, 547–548, 551fsaliency of, 497, 498fhorizontal connections in, 551f, 559visual processing of, 507–508Contractile force. See Muscle fibersContractile proteins, in sarcomere, 745–747, 748f–749fContractionisometric, 749lengthening, 749, 751f, 757f, 758shortening, 749, 757f, 758tetanic, 739–740, 740ftwitch, 739–740, 740f, 741fContraction time, 739, 740fContraction velocity, 749, 751f, 754–755Contrast sensitivityspatial, 534b, 535ftemporal, 534b, 535fContrast sensitivity curve, 534b, 535fControl policy, 817f, 818Convergenceof eyes, 867f, 880of sensory inputs on interneurons, 772–773, 772fof sensory modalities, 488, 489fin transcutaneous electrical nerve stimulation, 488, 489fConvergent neural circuits, 63, 63f, 102f, 103Cooperativity, in long-term potentiation, 1349–1350, 1349fCoordinationof behavior, neuropeptides in, 44–45eye-hand, 925, 926fin locomotion, 786–789, 788f, 789f. See also Locomotionmotor. See Motor coordinationmuscle, 755–758, 755f, 756fof stress response, glucocorticoids in, 1275COPI coats, 150COPII coats, 150Copy number variation (CNV)in autism spectrum disorder, 47, 49, 1535, 1536fdefinition of, 33b, 52Corbetta, Maurizio, 399Cornea, 521, 522fCorneal reflex, 993Corollary dischargeintegration with sensory input in cerebellum, 923in visual perception, 583–585, 586fCoronal plane, of central nervous system, 11bCorpus callosumanatomy of, 12b, 13f, 14fseverance of, effects of, 21–22in visual processing, 502Cortex, cerebral. See Cerebral cortexCortical barrels. See Barrels, somatosensory cortexCortical computational module, 512, 512fCortical magnification, 456Cortical neuronsadaptation of, 229, 230f, 231, 232fin auditory processing. See Auditory cortexexcitability properties of, 229, 230f, 452–454, 453forigins and migration of, 1138–1140, 1140freceptive fields of, 458f, 459–460, 459fin sleep, 1082, 1083fvibratory response, 448fCortical plasticity. See Plasticity, corticalCortical protomap, 1123Cortico-hippocampal synaptic circuit, 1340, 1341f. See also HippocampusCorticomotoneuronal cells, 821, 841, 843f, 844Corticospinal tractscortical origins of, 819–821, 822fvoluntary movement and, 89, 90f, 91fCorticotropin-releasing hormone (CRH)in depression and stress, 1508, 1508fhypothalamus in release of, 1027f, 1028, 1029tCortisol, in depression and stress, 1508Costamere, 747, 748f–749fCotranslational modification, 148Cotranslational transfer, 147Cotransporters, 197f, 198. See also specific typesCourtship rituals, environmental cues in, 1272COX enzymesaspirin and NSAIDs on, 478in pain, 478CPAP (continuous positive airway pressure) device, 1093CPE (cytoplasmic polyadenylation element), in synaptic terminal synthesis, 1329fCPEB. See Cytoplasmic polyadenylation element binding protein (CPEB)CPGs. See Central pattern generators (CPGs)Craik, Fergus, 1297Kandel-Index_1583-1646.indd 1595 19/01/21 9:18 AM1596 IndexCraik, Kenneth, 718bCramer, William, 359Cranial nerve nuclei, 986–992adult, columnar organization of, 987–992, 989fgeneral somatic motor column, 987, 990general somatic sensory column, 991–992general visceral motor column, 990–991special somatic sensory column, 990special visceral motor column, 991visceral sensory column in, 990brain stem developmental plan of, 986–987, 986fin brain stem vs. spinal cord, 992embryonic, segmental organization of, 987, 988fCranial nerves, 982–986, 983f. See also specific nervesassessment of, 982locations and functions of, 982–985numbering and origins of, 982, 983freflexes of, mono- and polysynaptic brain stem relays in, 992–994, 993fskull exits of, 982, 984f, 985–986in somatosensorysystem, 429CRE. See cAMP recognition element (CRE)Creatine kinase, 1423t, 1425CREB. See cAMP response element-binding protein (CREB)Cre/loxP system, for gene knockout, 35b–36b, 37fCreutzfeldt-Jakob disease, 1328CRH. See Corticotropin-releasing hormone (CRH)Crick, Francis, 1080, 1475CRISPR, for gene targeting, 36b, 38b, 52Critical oscillator, 618, 619bCritical periodsclosing ofreason for, 1224synaptic stabilization in, 1223–1224, 1224fin different brain regionis, 1228–1229, 1230fearly postnatal, 1221in language learning, 1377reopening in adulthood, 1229–1233in mammals, 1231–1232in owls, 1230–1231, 1232fin somatosensory cortex, 1230–1231, 1231fvisual circuit reorganization during. See Visual cortex, binocular circuit reorganization during critical periodCrocodile tears, 993Cross bridges, formation of, 747–749, 751fCross-bridge cycle, 749, 750fCrossed-extension reflex, 771Cross-talk, 1430CS (conditioned stimulus), 1050, 1052f, 1306, 1307fCSF (cerebrospinal fluid), production of, 160–162, 161fCSPG (chondroitin sulfate proteoglycans), 1245f, 1246CTE (chronic traumatic encephalopathy), 1567CTG repeats, in hereditary spinocerebellar ataxias, 1548, 1549tCues, in addiction, 1068, 1071b, 1073fCullen, Kathy, 923Cuneate fascicle, 77f, 81, 450f–451fCuneate nucleus, 75f, 80f, 81Cuneiform nucleus (CNF), 800, 802fCupula, of semicircular canal, 632, 633fCurareas ACh antagonist, 257fon motor neuron death, 1148fCurrent (I) capacitive, in voltage clamp, 213direction of, 191Current sink, 1452b, 1452fCurrent-voltage relations, in ion channels, 171, 171fCurtis, Howard, 212, 212fCushing disease, depression and insomnia in, 1508Cutaneous mechanoreceptors. See also specific typeson adjustment to obstacles in stepping, 798–799in hand, 437–438, 437f, 438trapidly adapting fibers in. See Rapidly adapting type 1 (RA1) fibers; Rapidly adapting type 2 (RA2) fibersslowly adapting fibers in. See Slowly adapting type 1 (SA1) fibers; Slowly adapting type 2 (SA2) fibersfor touch and proprioception, 414–416, 415t, 416f, 417fCutaneous reflexes, 763f, 770–772Cutaneous sensation, impaired, 1428Cuticular plate, 605Cyclic AMP (cAMP). See cAMP (cyclic AMP)Cyclic GMP (cGMP)actions of, 312in growth cone, 1164Cyclic GMP-dependent phosphorylation, 312Cyclooxygenase enzymes. See COX enzymesCytoarchitectonic method, 18, 18fCytochrome gene, 1088–1090, 1089fCytoplasm, 134Cytoplasmic polyadenylation element (CPE), in synaptic terminal synthesis, 1329fCytoplasmic polyadenylation element binding protein (CPEB)in local RNA translation, 145–146in long-term memory formation in fruit flies, 1331in long-term synaptic facilitation, 1327–1329, 1329fin threat learning in mammals, 1333–1334Cytoplasmic resistance, 204–206, 205fCytoskeletonrearrangements of, in neuronal polarity in axons and dendrites, 1157, 1158f, 1159fstructure of, 139–141Cytosol, 134–135Dd’ (discriminability/discrimination index), 389b–390bDab1, 1138DAG. See Diacylglycerol (DAG)Dahlstrom, Annica, 998Dale, Henry, 242, 250, 359Darwin, Charleson emotional expression, 978, 1045, 1047bon facial expression, 992, 1509on pattern generators, 994DAT (dopamine transporter), 366f, 376DaVinci stereopsis, 554Daytime sleepiness, 1092, 1095db/db mice, 1035DBS. See Deep brain stimulation (DBS)DCC (deleted in colorectal cancer) receptors, in axon growth and guidance, 1170f–1171f, 1178f, 1179de Kooning, William, 1313Deafnessconductive hearing loss, 601genetic factors in, 611–613, 612fsensorineural hearing loss, 601, 624, 625fsign language processing in, 19–20, 20fDeath effector proteins, 1153Decerebrate preparation, for spinal circuitry studies, 762, 785b, 786fDecision boundaries, in neural activity decoding, 961, 961fDecision rules, 1393–1395, 1401Decision theory, 389bDecision-making, 1392–1415cortical neurons in provision of noisy evidence for, 1397–1400, 1399f, 1400fevidence accumulation in speed vs. accuracy of, 1401, 1402fas framework for understanding thought processes, states of knowing, and states of awareness, 1409–1412, 1410b, 1411fhighlights, 1414–1415parietal and prefrontal association neurons as variable in, 1401, 1403–1404, 1404f–1405fperceptual. See Perceptual discriminations/decisionsKandel-Index_1583-1646.indd 1596 19/01/21 9:18 AMIndex 1597in understanding consciousness, 1412–1415value-based, 1408–1409Declarative memory. See Memory, explicitDecoding, of movement. See Brain-machine interfaces (BMIs), movement decoding inDecomposition of movement, 909Decussation, pyramidal, 89Deep brain stimulation (DBS)for depression, 1518–1519, 1519fprinciples of, 956Deep cerebellar nucleiconvergence of excitatory and inhibitory pathways in, 921, 921flearning in, 928, 928fin voluntary movements, 917Deep encoding, 1297Deep neural networks, 122Defensive behavior, hypothalamus in regulation of, 1013t, 1021–1022, 1504Degenerative nervous system disease. See Neurodegenerative diseasesDehydration, 1033Deiters’ cells, 604, 605f, 607fDeiters’ nucleus, 636Deiters’ tract, 641fDejerine, Jules, 10Dejerine-Roussy syndrome (thalamic pain), 485Dejerine-Sottas infantile neuropathy, 1431f, 1433f. See also Charcot-Marie-Tooth diseasedel Castillo, José, 260, 327, 333Delay, in feedback control, 719, 720fDelay eyeblink conditioning, 108Delay line, 657, 660f–661fDelayed match-to-sample task, 576b, 576f, 1293fDelayed-rectifier K+ channel, 313Delayed-response task, 576bDelta (δ) receptors, opioid, 489, 490, 490tDelta waves, EEG, 1450ΔFosB, 1074–1075, 1076fDelta-notch signaling, 1134fin neuron and glial cell generation, 1131–1135, 1134f, 1135fDelusionsin Capgras syndrome, 1478–1479definition of, 1474in depression, 1503paranoid, 1490in schizophrenia, 1490Dementia. See also Alzheimer diseasein cerebrovascular disease, 1567in dentatorubropallidoluysian atrophy, 1547tin Huntington disease, 1545in Parkinson disease, 1548, 1550tin spinocerebellar ataxias, 1546Dementia praecox, 1489, 1567. See also SchizophreniaDemyelinating diseasescentral, 154, 155b–157b, 155f–157fperipheral, 1430, 1431f, 1433t. See also Charcot-Marie-Tooth diseaseDemyelination, 208Dendritesamplification of synaptic input by, 295–297, 296f, 298fanatomy of, 57, 57fdopamine release from, 367early development of, 1156–1161branching in, 1157, 1160f, 1162fextracellular factors in, 1157, 1159fintrinsic and extrinsic factors in, 1157, 1160–1161, 1160f, 1161f, 1162fneuronal polarity and cytoskeleton rearrangements in, 1157f, 1158f, 1159fgrowth cone as sensory transducer and motor structure in. See Growth coneprotein and organelle transport along. See Axonal transportstructure of, 136f, 137, 137f, 138ftrigger zones in, 292–293, 292fvoltage-gated ion channels in, 231, 233Dendritic spines, 1157, 1160fdefinition of, 1221density lossage-related, 1563, 1565fin schizophrenia, 1494, 1496fexcitatory inputs on, 297, 298fmotility and number of, on visual cortex, 1221, 1222fplasticity of, 1221, 1222fproteins, ribosomes, and mRNA location in, 146, 147fstructure of, 137, 137ftypes of, 138fDenervation supersensitivity, 1196, 1197fDentate gyrus, of hippocampuslong-term potentiation at, 1342neurogenesis in, 1249, 1250f, 1359–1360, 1512pattern separation in, 1359–1360Dentate nucleusin agonist/antagonist activation in rapid movements, 917, 917fanatomy of, 14f, 911, 912fDentatorubropallidoluysian atrophy, 1544, 1546, 1547t, 1549t, 1551fDeoxyribonucleic acid (DNA). See DNADependence, 1072. See also Drug addictionDephosphorylation, 149Depolarizationaxon, 133membraneon action potential duration, 219–220, 219fdefinition of, 65, 191on Na+ and K+ current magnitude and polarity, 216, 217frecording of, 192b, 192fprolonged, on K+ and Na+ channels, 217–219, 219fDepressionanaclitic, 1212anteriorcingulate cortex in, 1060in bipolar disorder, 1504. See also Bipolar disorderof eye, 861, 861f, 863thomosynaptic, 1314major. See Major depressive disordersynaptic, 350, 352f–353fDeprivationsocial, 1211–1212, 1213fvisual, 1213–1215, 1214f–1215fDepth perception. See Visual processing, intermediate-level, depth perception inDermatomes, 429, 430fDermatomyositis, 1437Descartes, René, 9, 387, 1340Descending axons and pathwayslateral corticospinal, 89, 90fmonoaminergic pathways, in pain control, 488–489, 489fspinal cord axons, 77f, 78Descending vestibular nucleus, 636, 637f. See also Vestibular nucleiDesensitization, 173Designer genes, 39b, 39fDesipramine, 1514, 1516f–1517fDesmin, 747, 748f–749fDetwiler, Samuel, 1147Deuteranomaly, 539Deuteranopia, 539DHT (5-α-dihydrotestosterone), 1263, 1264fDHT (5-α-dihydrotestosterone) receptor, 1264, 1266fDiabetic neuropathy, compound action potential in, 414Diacylglycerol (DAG)from phospholipase C hydrolysis of phospholipids in, 305–308, 307fin synaptic plasticity, 351Diagnosis, 1489. See also specific disordersDiameterof axons. See Axon(s), diameter ofof neurons. See Neuron(s), diameter ofDiaschisis, 21Diazepam, on channel gating, 174DiCarlo, James, 404–405Dichromacy, 539Diencephalon, 12b, 13f, 15fDifferentiation, of neurons. See Neuron(s), differentiation ofDiffuse bipolar cell, 536, 537fDiffusion, of transmitters from synaptic cleft, 371Diffusion tensor imaging (DTI), in language development studies, 1371, 1380–1381, 1382Kandel-Index_1583-1646.indd 1597 19/01/21 9:18 AM1598 IndexDiGeorge (velocardiofacial) syndrome, 48, 14925-α-Dihydrotestosterone (DHT), 1263, 1264f5-α-Dihydrotestosterone (DHT) receptor, 1264, 1266fDiploid, 30Diplopia, extraocular muscle lesions in, 864bDirect channel gating, 250–251, 251f, 302–303, 302f. See also Second messengersDirect G-protein gating, steps of, 305Direct perception, 1410bDirection-sensitive neurons, 460, 461fDirectly gated synaptic transmission. See end-plate); Neuromuscular junction (NMJDirect-matching hypothesis, 838Discrete decoding, of neural activity, 960, 961, 961fDiscriminability/discrimination index (d’), 389b–390bDishabituation, 1305–1306, 1316Disinhibition, in basal ganglia, 940, 940fDissociated state, 1485Dissociation constant, 171Distortion, in memory, 1308Distortion-product otoacoustic emissions, 618Distributed code, 518Distributed processing, 17Distributed settling point model, of homeostasis, 1012f, 1013Disulfide linkages, in protein modification, 147–148Divergence, of eyes, 867f, 880Divergent neural circuits, 63, 63f, 102f, 103Dlx1, 1140, 1145Dlx2, 1140, 1145DMD gene mutations, 1437, 1440f–1441fDNAcomplementary, 52mitochondrial, 31structure of, 27, 29ftranscription and translation of, 27, 30fDodge, Raymond, 866Dok-7, 1195f, 1196Doll’s eye movements, 993Dominant hemisphere, 16Dominant mutations, 32Domoic acid, in amnestic shellfish poisoning, 1466–1467Dopaminecatechol-O-methyltransferase on, 375glutamate co-release with, 371intracellular signaling pathways activated by, 1076fas learning signal, 1068–1069, 1069fmodulatory action on pyloric circuit neurons, 320, 321fin parkinsonism, deficiency of, 70in place field mapping, 1367precursor of, 360trelease from dendrites, 367release through nonexocytotic mechanism, 376replacement therapy, for Parkinson disease, 1556in schizophrenia, 1499synthesis of, 361, 1513Dopamine transporter (DAT), 366f, 376Dopaminergic neuronsin basal ganglia, 935in brain stimulation reward, 977, 1067f, 1068error in reward prediction by, 122, 1068, 1069ffMRI studies of, 122location and projections of, 998, 1000fDopaminergic systemantipsychotic drugs on, 1497–1499, 1498fin motivational state and learning, 977Doppler-shifted constant-frequency (DSCF) area, in bats, 675, 676fDorsal column–medial lemniscal system, 74, 75f, 450f–451fDorsal columns, spinal cord, 76, 77fDorsal horn (spinal cord)anatomy of, 76, 77f, 79enhanced excitability of, in hyperalgesia, 481, 482f, 486fmicroglia activation in, 481, 484fneuropeptides and receptors in, 476, 477f, 478fpain signal transmission to lamina of, 474–476, 475f, 476ftouch and pain fiber projections to, 429–430, 431fDorsal motor vagal nucleus, 989f, 991Dorsal pathways, cerebral cortex. See Visual pathwayDorsal premotor cortex (PMd)anatomy of, 819, 820fin applying rules that govern behavior, 832f, 833, 835, 836fin planning sensory-guided arm movement, 831–833, 832f–834fDorsal respiratory group, 995Dorsal root, 77fDorsal root gangliacell body of, 409, 410fcentral axon terminals of, 81neurons ofaxon diameter of, 410–412cell body of, 409, 410fprimary sensory, 79, 79f, 81, 409–410, 410fproperties and structure of, 136f, 410, 411fin transmission of somatosensory information, 79–81, 80f–81f, 426–427, 428f–429fDorsal root ganglion cell, 136fDorsal stream, 12bDorsal visual pathways. See Visual pathways, dorsalDorsal-ventral axis, of central nervous system, 11b, 11fDorsoventral patterning, of neural tube. See Neural tube developmentDostoyevsky, Fyodor, 1419, 1449Dostrovsky, John, 1360doublecortin mutant, 1136f–1137f, 1138, 1469Double-step task, 584, 584fDown syndrome, Alzheimer disease in, 1572Dreams, 1080. See also Sleepacting out of, 1095in REM and non-REM sleep, 1082, 1086, 1088fDrift-diffusion process, in decision-making, 1401, 1402fDrive reduction theory, 1038–1039, 1039fDriving forcechemical, 193electrical, 193electrochemical, 195, 201in ion flux, 195Drosophila. See Fruit fly (Drosophila)Drug addiction, 1069–1079. See also Drugs of abuseanimal models of, 1071bbasal ganglia dysfunction in, 947f, 949–950brain reward circuitry in, 1055, 1069–1070, 1070fcellular and circuit adaptations in, 1075–1077circuit plasticity, 1077synaptic plasticity, 1075, 1077whole-cell plasticity, 1077definition of, 1069–1070genetic factors in, 1072highlights, 1078–1079molecular adaptations in brain reward regions in, 1074induction of ΔFosB, 1074–1075, 1076fupregulation of cAMP-CREB pathway, 1074, 1075f, 1076fvs. natural addictions, 1077–1078Drugs of abuse. See also specific drugsbehavioral adaptions from repeated exposure to, 1071–1074classes of, 1072tneurotransmitter receptors, transporters, and ion channel targets of, 1070–1071, 1073fDSCF (Doppler-shifted constant-frequency) area, in bats, 675, 676fDTI (diffusion tensor imaging), in language development studies, 1371, 1380–1381Dualistic view, of brain, 9Dual-stream model, of language processing, 1379–1380, 1380fDuchateau, Jacques, 741Duchenne muscular dystrophy, 1436–1439, 1438t, 1440f–1441fDuctus reuniens, 630f, 631Kandel-Index_1583-1646.indd 1598 19/01/21 9:18 AMIndex 1599dumb gene, 1330Dynamic polarizationlaw of, 1156–1157principle of, 59, 64fDyneins, 144–145Dynorphin gene, 490Dynorphinsin endogenous pain control, 490, 490t, 491fglutamate co-release with, 371Dysarthriain progressive bulbar palsy, 1428in spinocerebellar ataxias, 1546, 1547tDysdiadochokinesia, 909, 910fDysesthesias, 485Dysferlin mutation, 1438t, 1439, 1442fDyskinesia, levodopa-induced, 1556Dyslexia, 1474Dysmetria, 909, 910fDysphagia, 1433Dyspnea, 998Dystrophin, 1437, 1440f–1441fDystrophin-glycoprotein complex, 747EE (electromotive force), 200, 200fEar. See also Auditory processingexternal, 599, 599finner, 599–600, 599f. See also Cochleamiddle, 599, 599fsound energy capture by, 573–601, 602f–603fEar disorders. See Deafness; Hearing lossEbert, Thomas, 1336Eccentricity, of receptive fields, 506–507, 509fEccles, Johnon EPSP in spinal motor cells, 277, 777on IPSP in spinal motor neurons, 288on synaptic transmission, 242, 274Echo planar imaging (EPI), in fMRI, 114–115Echolocation, in bats, 675, 676fECoG (electrocorticography), 956, 957fEconomo, Constantin von, 1083ECT (electroconvulsive therapy), for depression, 1518Ectodermbone morphogenetic proteins on, 1111f, 1112induction factors on, 1108in neural tube development, 1108, 1109fEctodomain, 1572Edge response, 531, 532fEdin, Benoni, 444Edinger-Westphal nucleuscolumns of, 989f, 991in pupillary reflex and accommodation, 503f, 992–993, 993fEdrophonium, in myasthenia gravis, 1433, 1433fEdwards, Robert, 365EEG. See Electroencephalogram (EEG)Efference copy, 436Efferent neurons, 59Efficacy, synaptic, 337Efficient coding, 399Egg-laying hormone (ELH), 368, 373fEhrlich, Paul, 8, 250Eichenbaum, Howard, 1301Eichler, Evan, 1382Eicosanoids, 310Eimas, Peter, 1373Eisenman, George, 169EK (K+ equilibrium potential), 193, 194fElbert, Thomas, 1336Elderly. See Aging brainElectric ray, 257fElectrical circuit, equivalent. See Equivalent circuitElectrical driving force, 193Electrical signals, transient, 190. See also specific typesElectrical synapses. See Synapse, electricalElectrical transmission. See Synapse, electricalElectrochemical driving force, 195, 201Electroconvulsive therapy (ECT), for depression, 1518Electrocorticography (ECoG), 956, 957fElectroencephalogram (EEG)cellular mechanisms of rhythms during sleep, 1083fdesynchronization of, 1450frequencies of, 1450fundamentals of, 1450individual nerve cell contributions to, 1452b–1453b, 1452f, 1453fin language development studies, 1370, 1381normal, awake, 1450, 1451ffor seizure focus localization, 1450, 1454, 1454f, 1463in sleep, 1081–1082, 1081f, 1083fsurface, 1450, 1453b, 1453fin typical absence seizure, 1461, 1462fElectroencephalogram (EEG) cap, 956, 957fElectrogenic pump, 195Electrolytes, hypothalamus in regulation of, 1013tElectromotive force (E), 200, 200fElectromyography (EMG)motor units and muscle contractions in, 738–739in myopathic vs. neurogenic disease, 1423–1424, 1423t, 1424fElectrotonic conduction/transmissionin action potential propagation, 205–206, 206fin electrical synapses, 244length constant and, 205membrane and cytoplasmic resistance on, 204–205, 204fElectrotonic potentials, 191Elementary processing units, in brain, 21–23Elevation, eye, 861, 863tELH (egg-laying hormone), 368, 373fElliott, Thomas Renton, 358Ellis, Albert, 1473, 1474bEllis, Haydn, 1478–1479ELN gene, 1532Embryocranial nerve nuclei organization in, 987, 988fgonadal differentiation in, 1261–1262, 1262fEmbryogenesis, sex hormones in, 1260–1261Embryonic stem cells, 1252–1253, 1252fEMG. See Electromyography (EMG)Emotions, 1045–1064amygdala in. See Amygdalaon cognitive processes, 1056cortical areas in processing of, 1058–1059, 1058bdefinition of, 1045evolutionary conservation of, 1045facial expression of, 994fMRI in studies of, 1059–1060, 1061fhighlights, 1062–1063history of study of, 1049fhomeostasis and, 1062measurement of, 1046b–1047b, 1046tneural circuitry of, early studies of, 1047–1050, 1048f, 1049f, 1050foverall perspective of, 977–979positive, 1055stimuli triggering, 1046updating through extinction and regulation, 1055–1056Emx2, in forebrain patterning, 1123, 1126fEn1, 1114Encephalitis, anti-NMDA receptor, 287Encephalitis lethargica, 1083Encodingof complex visual stimuli in inferior temporal cortex, 568, 568fin episodic memory processing, 1297in olfactory sensory neurons. See Olfactory sensory neuronsof pitch and harmonics, in auditory cortex, 673–674, 674fspike train, 395, 395fof visual events, medial temporal lobe in, 1298, 1299fEnd-inhibition, 549, 550fEndocannabinoids, 310, 311f, 360tEndocytic traffic, 150–151Endocytosisbulk, 151receptor-mediated, 151in transmitter recycling, 337–338, 339fultrafast clarithin-independent, 341Kandel-Index_1583-1646.indd 1599 19/01/21 9:18 AM1600 IndexEndodermembryogenesis of, 1108, 1109fsignals from, in neural plate patterning, 1112–1113, 1114fEndolymph, 604, 606f, 630f, 631Endoplasmic reticulumprotein synthesis and modification in, 147–149, 148frough, 135–137, 136fsmooth, 135, 136f, 137, 137fEndosomes, 135, 136f, 1151End-plate. See Neuromuscular junction (NMJ, end-plate)End-plate currentcalculation of, from equivalent circuit, 269–271, 269f–270fend-plate potential and, 259–260, 259ffactors in, 262, 263fEnd-plate potential, 255, 332–333end-plate current and, 259–260, 259fgeneration of, 258–260isolation of, 257, 257f–258flocal change in membrane permeability and, 255, 257miniature, 332–333“miniature,” 260in myasthenia, 1434f, 1436normal, 1434, 1434freversal potential of, 261, 261f, 262bEnergy balance, hypothalamic regulation of, 1013t, 1033afferent signals in appetite control, 1034–1037, 1036f–1037fdysregulation in obesity, 1034fat storage in, 1033–1034intake and energy expenditure matching, 1034psychologic concepts and, 1038–1039, 1039fEnhancers, 29, 30fEnkephalins, 477f, 490, 490t, 491fEnteric ganglia, 1019, 1020fEntorhinal cortexanatomy of, 14fin hippocampal spatial map, 1361–1365, 1362f–1364flong-term potentiation in, 1342Environmental changes, in sensorimotor control, 715Enzymatic degradation, of transmitters in synaptic cleft, 371Enzymes. See also specific enzymes and systemsin myopathies, 1425turnover rates of, 166Ependyma, 160–162, 161fEphrinin axon growth and guidance, 1170f–1171f, 1172–1176, 1174f, 1175fin hindbrain segmentation, 1115, 1116fin neural crest cell migration, 1141in neuromuscular junction development, 1190, 1191fEphrin kinases, in axons, 1173–1174, 1175fEphrin receptors, 1122, 1125fEphrin-ephrin interactions, in axons, 1173–1174, 1175fEPI (echo planar imaging), in fMRI, 114–115Epigenetic regulation, 1323Epilepsy, 1447–1472autism spectrum disorder and, 1539autoantibodies to AMPA receptor in, 278classification of, 1448–1450, 1449tcriteria for, 1449–1450definition of, 1447development of, 1467–1470genetic factors in, 1467–1468, 1468fion channel mutations in, 1467–1469, 1468fkindling in, 1469maladaptive responses to injury in, 1469–1470, 1470fEEG of. See Electroencephalogram (EEG)epidemiology of, 1448generalized penicillin, 1461genetic factors in, 1467–1469, 1468fhighlights, 1470–1471history of, 1447–1448nocturnal, 1460psychosocial factors in, 1448seizure focus localization in. See Seizure focus, localization ofseizures in, 1449–1450. See also Seizure(s)silent interval in, 1469sudden unexpected death in, 1466syndromes, 1449, 1449tEpileptiform activity, 1454Epinephrinefeedback regulation of, 362–363synthesis of, 361–362Episodic memory. See Memory, episodicEPSC (excitatory postsynaptic current), in Schaffer collateral pathway, 1345, 1346fEpsin, 604EPSP. See Excitatory postsynaptic potential (EPSP)Equilibrium, postural. See Balance; Posture, postural equilibrium inEquilibrium potentialion, 193–194K+, 193, 194fNa+, 198–199Equivalent circuitdefinition of, 199of end-plate current, 269–271, 269f–271fneuron functioning as, 199–201battery in series and, 200, 200fcapacitance and leaky capacitors in, 200definition of, 199electrochemical driving force in, 201electromotive force in, 200–201, 200fhighlights, 208–209K+ channel electrical properties in, 200, 200fpassive and active current flow in, 201, 201fpassive current flow and short circuit in, 201, 201fresting membrane potential calculation via, 202b–203b, 202f, 203fErb, Wilhelm, 1430Erectile function, control of, 1266f–1267f, 1270fError-based learning, 730–732, 731f, 732f17-β-Estradiol, 1262, 1264fEstratetraenol (EST), perception of, 1280f, 1281Estrogen, 1263–1264Estrogen receptors, 1262, 1264, 1265f, 1266fEthical considerations, in brain-machine interfaces, 970–971Ethosuximide, 1461Ethyl alcohol, 1072t. See also Drug addictionEuchromatin, 52Eukaryote, 52Eustachian tube, 599, 599fEuthymia, 1504Evarts, Ed, 831, 845, 851Evidence, in decision-makingaccumulation to a threshold, 1401,1402fnoisy, 1397–1400, 1399f, 1400fsignal detection theory framework for, 1393, 1394fvalue-based, 1408–1409Evoked otoacoustic emission, 616f, 617Ewins, Arthur, 359Exchangers (antiporters), 186f, 187Excitabilityof neurons, 131, 133in active zones, 65axon size on, 206–207plasticity of, 233region on, 231, 233type on, 229–231, 230fvoltage-gated channel regulation of, 231, 232fof spinal cord dorsal horn, in hyperalgesia, 481, 482f, 486fExcitatory postsynaptic current (EPSC), in Schaffer collateral pathway, 1345, 1346fExcitatory postsynaptic potential (EPSP), 255AMPA and NMDA receptor-channels in, 283–284, 285fto central neurons, 274, 339fin EEG, 1452b–1453b, 1452fat neuromuscular junction. See End-plate potentialin short-term habituation, 1314, 1315fExcitatory signals, in stretch reflexes, 63Kandel-Index_1583-1646.indd 1600 19/01/21 9:18 AMIndex 1601Excitatory synaptic transmission, ionotropic glutamate receptor-channels in. See Glutamate receptors (receptor-channels), ionotropicExcitotoxicity, in seizure-related brain damage, 1466–1467Executive control processes, 1292Exocytosis, 68, 135, 144ffrom large dense-core vesicles, 370in synaptic vesicles, 248, 249f, 345–347, 370Ca2+ binding to synaptotagmin in, 347, 348f–349ffusion machinery in active zone protein scaffold in, 344f, 347–347, 350fSNARE proteins in, 344f, 345–347, 346fsynapsins in, 339, 344ftransmembrane proteins in, 343, 344f, 345in transmitter release, 337–338, 339ffusion pore in, temporary, 338, 341, 342fkinetics of, capacitance measurements of, 338, 340f–341fExons, 27, 30f, 52, 53Expectation, in visual processing, 546–547Experiencechanges in cortical circuitry from, in visual processing, 546–547on maternal behavior in rodents, 1274–1275, 1274fsynaptic connection refinement and. See Synaptic connections, experience in refinement ofExperience sampling, 1047bExplicit learning, 1055, 1288Explicit memory. See Memory, explicitExposure therapy, 1518Expressive aphasia, 17External auditory meatus, 599, 599fExternal globus pallidus, 935, 936, 936fExteroception, 408Extinction, 1306Extinction learning, 1518Extorsion, 861, 861f, 863tExtracellular matrix adhesion, in axon growth and guidance, 1169fExtrafusal muscle fibers, 764bExtraocular eye muscles, 862–865agonist-antagonist pairs of, 861f, 862, 862fcoordinated movements of two eyes by, 862coordinated movements of two eyes in, 863tcranial nerve control of, 862–863, 863f, 864b, 865feye rotation in orbit by, 860–861lesions of, 864boculomotor neurons for eye position and velocity in, 867, 868fExtrinsic reinforcement, 945f, 946Eye(s)position and velocity of, oculomotor neurons in, 867, 868fposition in orbit, visual neuron responses to, 587–588, 588frotation in orbit of, 860–861Eye fieldfrontal, 875, 878f, 879frontal lesions of, 875supplementary, 875Eye movements, 860–861active sensing in, 723cerebellum on, 925, 927fcoordination of, 862, 863tpathways for, 501, 503fsaccadic. See Saccadessmooth-pursuit, cerebellum in. See Smooth-pursuit eye movementsin vision, 582, 583f. See also SaccadesEye muscles, extraocular, 862–865agonist-antagonist pairs of, 861f, 862, 862fcoordinated movements of two eyes by, 862coordinated movements of two eyes in, 863tcranial nerve control of, 862–863, 863f, 864b, 865feye rotation in orbit by, 860–861lesions of, 864boculomotor neurons for eye position and velocity in, 867, 868fEye rotation, in orbit, 860–861Eye-blink responsecerebellum in, 108, 109fclassical conditioning of, 925, 1306Eye-hand coordination, 925, 926fFFace recognitionfMRI in studies of, 120–121fusiform gyrus in. See Fusiform gyrus, in face perceptiontemporal lobe in, 569–570, 570fFacial expression, pattern generators in, 994Facial motor nucleus, 988f, 989f, 991Facial nerve (CN VII)autonomic component of, 983injury to, in Bell palsy, 983–984internal genu of, 969as mixed nerve, 983origin in brain stem, 983fprojections of, 1019Facilitation, presynaptic, 353, 354fF-actin, 745–746, 748f–749fFADD, 1153Failures, 333Falck, Bengt, 372bFalse alarm, in decision-making, 1394f, 1395False memory, 1482–1483False positive rate, 390bFalse recognition, 1308False transmitters, 365, 367. See also Fluorescent false neurotransmitters (FFNs)Familial advanced sleep-phase syndrome, 1090Familial epileptic syndromes, 1467Familial startle disease, 288Fasciculation, in axon growth and guidance, 1169fFasciculations, in neurogenic diseases, 1426Fascin, 604Fast axonal transport, 143–146, 146fFast channel syndrome, 1436Fastigial nucleus, 911, 912fFasting, eating behavior and, 1038–1039, 1039fFast-spiking neurons, 231Fast-twitch motor units, 740–741, 740fFast-twitch muscle fibers, 1189fFat storage, 1033–1034Fatigability, muscle, 742Fatt, Paul, 257–258, 258f–259f, 260, 332Fearamygdala in. See Amygdala, in fear responsevs. anxiety, 1504. See also Anxiety disordersconditioning of, 1050–1051, 1306. See also Threat conditioningdefinition of, 1504fMRI studies of, 1060, 1061fmeasurement of, 1046b–1047b, 1046tstimulation of neuronal assembly associated with, 1357, 1358f–1359fFeature detectors, in bats, 675, 676fFechner, Gustav, 387, 1393, 1483Feedback control. See also Sensorimotor controlgain and delay in, 719, 720ffor movement correction, 719, 720foptimal, 728–729, 729ffor rapid movements, 717f, 719Feedback inhibition, 401fFeedback projections, 559Feedforward control, 716–717, 717fFeedforward inhibitionin motor neurons, 63–64, 63fin sensory systems, 399–400, 401fFeedforward neural circuitscharacteristics of, 63f, 64, 102–103, 102fin visual processing and object recognition, 103–104, 103fFeelings, 1045. See also EmotionsFEF (frontal eye field), 875, 878f, 879Feinberg, Irwin, 1494Ferrier, David, 841Fever, 1031FFNs (fluorescent false neurotransmitters), 374b, 374fFfytche, Dominic, 1476Fibrillations, 1424f, 1426Kandel-Index_1583-1646.indd 1601 19/01/21 9:18 AM1602 IndexFibroblast growth factors (FGFs)in neural induction, 1112in neural patterning, 1113–1114, 1114fField potentials, 1450“Fight or flight” response, 1013t, 1021–1022, 1504filamin A, 1469Filopodia, 1163f, 1164Fimbrin, 604Fingerprint structure, in touch sensitivity, 440b–441b, 440fFingertip, tactile acuity on, 440–441, 443fFirst pain, 471f, 472, 490Fissures, 16Fixation neurons, 879fFixation system, 866Fixation zone, 873Flanagan, Randy, 464Flavor, 696, 702Flexion reflex, 763f, 771–772Flexion-withdrawal reflex, 763f, 770–772Flexor and extensor coordination circuit, 793, 794f–795fFlickering, 345as visual field stimulus, 534b, 535fFlies. See Fruit fly (Drosophila)Flip angle, in fMRI, 114Flocculonodular lobe. See VestibulocerebellumFlocculus target neurons, 643Flourens, Pierre, 10, 21Fluid balance, 1031–1033, 1032fFluorescent false neurotransmitters (FFNs), 374b, 374fFluoxetineindications for, 1515mechanisms of action of, 1515, 1516f–1517fprenatal exposure to, 1377Flutter-vibration frequency, 1395–1396, 1396fFMR1 gene mutation, 146, 1531FMRFamide, on S-type K+ channel, 317fMRI. See Functional magnetic resonance imaging (fMRI)FMRP (fragile X mental retardation protein), 47, 1531Focal onset seizures. See Seizure(s), focal onsetFoliate papillae, 697, 697fFollistatin, 1111f, 1112Footplate (stapes)anatomy of, 599, 600in hearing, 601, 602f–603ffor gene, 42, 44, 44fForce, muscle. See Muscle forceForced grasping, 829Forebrainanatomy of, 12b, 13fembryogenesis of, 1112, 1113fpatterning ofafferent inputs in, 1124–1126, 1127finductive signals and transcription factors in, 1123–1124, 1126fisthmic organizer signals in, 1113–1115, 1114f, 1115fprosomeres in, 1123Forgetting, 1308Forgotten memory, imprint of, 1482, 1482fForm, detection of, 444Form agnosia, 1480f, 1488Formant frequencies, 1371–1372, 1372fForm-cue invariance,in object identification, 571, 572fForward interference, in fMRI studies, 123Forward model, sensorimotor, 718b, 718fFosB, 1074Foster, Michael, 773Fourneret, Pierre, 1481Fovea, 522f, 523Foveola, 522f, 523Fragile X mental retardation protein (FMRP), 47, 1531Fragile X syndrome, 47, 1531Frameshift mutations, 33fFraternal twins, 27Freedman, David, 573Freeze-fracture electron microscopy, of transmitter storage and release, 337–338, 339fFreezing behavior, amygdala in, 1050, 1052fFreiwald, Winrich, 569Frequency code, 624Frequency-modulated (FM) component, in bats, 675–677, 676fFreud, Sigmundon agnosia, 566, 1473on consciousness, 1412on dreams, 1080on fear, 1316Frey, Uwe, 1327, 1348Friederici, Angela, 1379Friedman, Jeffrey, 1035Fritsch, Gustav, 16, 841Frontal cortex/lobeanatomy of, 12b, 13f, 16in autism spectrum disorder, 1525fin emotional processing, 1058–1059, 1058bfunction of, 12b, 16fin language, 1380, 1380f, 1388lesions ofBroca’s aphasia with, 1379t, 1384, 1385fon saccades, 875in voluntary movement, 818–819, 820fFrontal eye field (FEF), 875, 878f, 879Fronto-orbital cortex, sexual dimorphisms in, 1279, 1279fFrontotemporal dementias, tau protein in, 141bFruit fly (Drosophila)cAMP-PKA-CREB pathway in threat conditioning in, 1330–1331long-term memory in, 1331mating behavior of, genetic and neural control of, 1266, 1268b, 1269fmemory formation in, 1330–1331olfactory pathways in, 692–694, 693fprotein kinase activation and activity level in, 42, 44, 44frandom mutagenesis in, 35btransgenic, generation of, 35b, 39b, 39fFu, Ying-hui, 42Functional connectivity analysis, in fMRI, 117f, 119–120Functional electrical stimulation, in brain-machine interfaces, 954, 965, 967, 969fFunctional localization, 9–10, 9fFunctional magnetic resonance imaging (fMRI)advantages of, 111of attention to visual stimulus, 402fdata analysis in, 115–120approaches to, 115, 117ffor decoding information represented in, 118–119for localization of cognitive functions, 118for measurement of correlated activity across brain networks, 119–120preprocessing for, 115–116tools for, 116bfuture progress in, 123–125insights from studies using, 120–122challenges to theories from cognitive psychology and systems neuroscience, 121–122design of neurophysiological studies in animals, 120–121testing predictions from animal studies and computational models, 122interpretation and real-world applications of, 122–123, 124f, 125bin language development studies, 1370–1371, 1380–1381of language processing, 19of language processing deficits, 1387, 1387fin memory studies, 1298, 1300, 1301f, 1302fof mentalizing system, 1527, 1528fin mood and anxiety disorders, 1509–1511, 1510fneurovascular activity measurement in, 112–115biology of neurovascular coupling in, 115physics of magnetic resonance in, 112, 114–115principles of, 112, 113fin schizophrenia, 1494, 1495fin studies on emotion, 1059–1060, 1061fFunctional neuroimagingKandel-Index_1583-1646.indd 1602 19/01/21 9:18 AMIndex 1603in language development studies, 1370–1371, 1380–1381in mood and anxiety disorders, 1509–1511, 1511fin studies on emotion, 1060Fungiform papillae, 697, 697fFurshpan, Edwin, 243FUS gene mutations, 1427, 1427tFusiform cells, in dorsal cochlear nucleus, 657, 658f–659fFusiform gyrus, in face perceptionfMRI studies of, 120–121imaginary, 1484, 1484fmeasurement of, 1476, 1477fduring visual hallucinations, 1477, 1479fFusimotor system, 766–767, 770fFusion, vesiclein exocytosis, 338, 341, 342fsteps in, 347–349, 348f–349f, 350fFuxe, Kjell, 998GG proteineffector targets for, 305interactions with β2-adrenergic receptor, 305, 306fion channel modulation by, direct, 315, 316f, 317fstructure of, 305, 306fsubunit types in, 305G protein transducin, rhodopsin on phosphodiesterase via, 526f–527f, 529–530G protein-coupled receptors, 302, 302fcAMP pathway initiation by, 303–305common sequence in, 305glutamate, 277, 277fmechanism of, 251, 251fmembrane-spanning domains in, 305, 306fodorant, 684, 685fin sensitization, 1317, 1318f–1319fon voltage-gated Ca2+ channel opening, 315, 316fG protein-gated inward-rectifier K+ (GIRK) channel, 315, 316f, 317fG protein-gating, direct, 305GABA (γ-aminobutyric acid)action of, 287in critical period for language learning, 1377uptake into synaptic vesicles, 364, 366fGABA receptors (receptor-channels)at central synapses, 1198–1199, 1201fopening of, 288GABA transporter (GAT1), 366fGABAA receptors (receptor-channels), 287function of, 288ionotropic, 278f, 287–288mutations in, epilepsy and, 1468fnicotinic, subunits of, 278fpostsynaptic cell inhibition by Cl- current through, 288–290, 289f, 290fin seizures, 1455, 1455fGABAB receptors (receptor-channels), 287GABAergic neuronsin cerebellum, 1143, 1145, 1145fin circadian rhythm, 1088, 1091in dorsal nucleus of lateral lemniscus, 664excitability properties of, 229, 230finhibitory actions produced by, 293–295, 294f, 295fin modulation of primary axon terminals, 777, 777fin neuropathic pain, 481, 483fin ocular dominance plasticity, 1220, 1221fin seizure focus, 1456, 1456fin sleep promotion, 1085–1086in striatum, 935Gabapentin, 474GAD (generalized anxiety disorder), 1505, 1506. See also Anxiety disordersGag reflex, 993–994Gage, Phineas, 1058bGain, in feedback control, 719, 720fGain field, 587, 588fGait ataxia, 909Galanin, in spinal-cord dorsal horn pain nociceptors, 475Galen, 8Gall, Franz Joseph, 9–10, 9fGalton, Francis, 27Galvani, Luigi, 8Gamma motor neuronscoactivation with alpha neurons, in voluntary movement, 767, 769f, 773–775, 775fin sensitivity of muscle spindles, 765f, 766–767, 770f, 771fin spinal stretch reflex, 764b, 765fγ-aminobutyric acid (GABA). See GABA (γ-aminobutyric acid)γ-secretasein Alzheimer’s disease, 1570–1572, 1571fdrugs targeting, 1567–1568Gangliaautonomic. See Autonomic systembasal. See Basal gangliadorsal root. See Dorsal root gangliaretinal. See Retinal ganglion cellsGanglionic eminences, neuron migration from, to cerebral cortex, 1138–1140, 1140fGap junctiondefinition of, 239, 244in glial cells, 248Gap-junction channels, 239, 242, 243fgene superfamily in, 177, 178fin glial cells, 248in glial function and disease, 248interconnected cell firing in, rapid and synchronous, 247–248, 247fstructure of, 244, 245f, 246f, 247Garcia-Sierra, Adrian, 1378Gardner, John, 381Gaskell, Walter, 1015Gastrins, 368tGastrointestinal tractbrain stem control of reflexes in, 993enteric ganglia in, 1019, 1020fvagal neurons in, 985visceral afferents in, 990–991Gata2, 1143f, 1145Gateactivation, 218inactivation, 218–219Gate control theory, of pain, 488, 488fGating. See specific typesGating, channel. See also specific channelsdirect (ionotropic), 250–251, 251f, 302–303, 302f. See also Second messengersdirect G-protein, steps of, 305exogenous factors on, 174, 175indirect (metabotropic), 251, 251f, 302–303, 302f. See also G protein-coupled receptors; Receptor tyrosine kinasesmolecular mechanisms of, 171–172physical models of, 172–174, 172f–173fof transduction channels, in hair cells, 609, 610fGating charge, 221, 223fGating current, 221, 223fGating springs, in hair bundles, 609, 610fGaze control, 860–881brain stem motor circuits for saccades in, 868–870brain stem lesions on, 870–871mesencephalic reticular formation in vertical saccades in, 863f, 870pontine reticular formation in horizontal saccades in, 868–870, 869fcerebral cortex, cerebellum, and pons in smooth pursuit in, 867f, 878–879, 878f, 916, 916fextraocular eye muscles in, 860–863agonist-antagonist pairs of, 861f, 862, 862fcoordinated movements of two eyes in, 862, 863tcranial nerve control of, 862–863, 863f, 864b, 865feye rotation in orbit by, 860–861oculomotor neuronsincluding how information from the primary organs of sensation is transmitted to the central nervous system and how it Prefaceis processed there by successive brain regions to gener-ate a sensory percept. In Part V, we consider the neural mechanisms underlying movement, beginning with an overview of the field that is followed by a treatment ranging from the properties of skeletal muscle fibers to an analysis of how motor commands issued by the spinal cord are derived from activity in motor cor-tex and cerebellum. We include a new treatment that addresses how the basal ganglia regulate the selection of motor actions and instantiate reinforcement learn-ing (Chapter 38).In the latter parts of the book, we turn to higher-level cognitive processes, beginning in Part VI with a discussion of the neural mechanisms by which sub-cortical areas mediate homeostatic control mecha-nisms, emotions, and motivation, and the influence of these processes on cortical cognitive operations, such as feelings, decision-making, and attention. We then consider the development of the nervous system in Part VII, from early embryonic differentiation and the initial establishment of synaptic connections, to their experience-dependent refinement, to the replacement of neurons lost to injury or disease. Because learning and memory can be seen as a continuation of synap-tic development, we next consider memory, together with language, and include a new chapter on decision-making and consciousness (Chapter 56) in Part VIII. Finally, in Part IX, we consider the neural mechanisms underlying diseases of the nervous system.Since the last edition of this book, the field of neuroscience has continued to rapidly evolve, which is reflected in changes in this edition. The continued development of new electrophysiological and light microscopic–based imaging technologies has enabled the simultaneous recording of the activity of large pop-ulations of neurons in awake behaving animals. These large data sets have given rise to new computational and theoretical approaches to gain insight into how the activity of populations of neurons produce spe-cific behaviors. Light microscopic imaging techniques Kandel_FM.indd 41 20/01/21 9:04 AMxlii Prefaceusing genetically encoded calcium sensors allow us to record the activity of hundreds or thousands of defined classes of neurons with subcellular resolution as an animal engages in defined behaviors. At the same time, the development of genetically encoded light-activated ion channels and ion pumps (termed optogenetics) or genetically engineered receptors activated by synthetic ligands (termed chemogenetics or pharmacogenetics) can be used to selectively activate or silence geneti-cally defined populations of neurons to examine their causal role in such behaviors. In addition to includ-ing such material in chapters throughout the book, we introduce some of these developments in the new Chapter 5, which considers both the new experimen-tal technologies as well as computational principles by which neural circuits give rise to behavior.Over the past 20 years, there has also been an expan-sion of new technologies that enable noninvasive and invasive recordings from the human brain. These studies have narrowed the gap between neuroscience and psy-chology, as exemplified in the expanded discussion of different forms of human memory in Chapter 52. Non-invasive brain imaging methods have allowed scientists to identify brain areas in humans that are activated dur-ing cognitive acts. As discussed in a new chapter on the brain–machine interface (Chapter 39), the implantation of electrodes in the brains of patients permits both elec-trophysiological recordings and local neural stimulation, offering the promise of restoring some function to indi-viduals with damage to the central or peripheral nerv-ous system. An understanding of basic and higher-order neural mechanisms is critical not only for our under-standing of the normal function of the brain, but also for the insights they afford into a range of inherited and acquired neurological and psychiatric disorders. With modern genetic sequencing, it is now clear that inherited or spontaneous mutations in neuronally expressed genes contribute to brain disease. At the same time, it is also clear that environmental factors interact with basic genetic mechanisms to influence disease progression. We now end the book with a new section, Part IX, which presents the neuroscientific principles underlying disorders of the nervous system. In previous editions, many of these chapters were dis-persed throughout the book. However, we now group these chapters in their own part based on the increas-ing appreciation that the underlying causes of what appear to be separate diseases, including neurode-generative diseases, such as Parkinson and Alzheimer disease, and neurodevelopmental disorders, such as schizophrenia and autism, share certain common prin-ciples. Finally, these chapters emphasize the historical tradition of how studies of brain disease provide deep insights into normal brain function, including memory and consciousness. In writing this latest edition, it is our hope and goal that readers will emerge with an appreciation of the achievements of modern neuroscience and the challenges facing future generations of neuroscien-tists. By emphasizing how neuroscientists in the past have devised experimental approaches to resolve fundamental questions and controversies in the field, we hope that this textbook will also encourage read-ers to think critically and not shy away from ques-tioning received wisdom, for every hard-won truth likely will lead to new and perhaps more profound questions in brain science. Thus, it is our hope that this sixth edition of Principles of Neural Science will provide the foundation and motivation for the next generation of neuroscientists to formulate and inves-tigate these questions.Kandel_FM.indd 42 20/01/21 9:04 AMContributorsLaurence F. Abbott, PhDWilliam Bloor Professor of Theoretical NeuroscienceCo-Director, Center for Theoretical NeuroscienceZuckerman Mind Brain Behavior InstituteDepartment of Neuroscience, and Department of Physiology and Cellular BiophysicsColumbia University College of Physicians and SurgeonsRalph Adolphs, PhDBren Professor of Psychology, Neuroscience, and BiologyDivision of Humanities and Social SciencesCalifornia Institute of TechnologyThomas D. Albright, PhD Professor and Conrad T. Prebys ChairThe Salk Institute for Biological StudiesDavid G. Amaral, PhDDistinguished ProfessorDepartment of Psychiatry and Behavioral SciencesThe MIND InstituteUniversity of California, DavisDora Angelaki, PhDCenter for Neural ScienceNew York UniversityCornelia I. Bargmann, PhDThe Rockefeller UniversityBen A. Barres, MD, PhD* Professor and Chair, Department of NeurobiologyStanford University School of MedicineAllan I. Basbaum, PhD, FRSProfessor and ChairDepartment of AnatomyUniversity California San FranciscoAmy J. Bastian, PhDProfessor of Neuroscience, Neurology, and Physical Medicine and RehabilitationDepartment of NeuroscienceJohns Hopkins UniversityDirector of the Motion Analysis LaboratoryKennedy Krieger InstituteBruce P. Bean, PhDDepartment of NeurobiologyHarvard Medical SchoolRobert H. Brown, Jr, DPhil, MDProfessor of NeurologyDirector, Program in NeurotherapeuticsUniversity of Massachusetts Medical SchoolRandy M. Bruno, PhDAssociate ProfessorKavli Institute for Brain ScienceMortimer B. Zuckerman Mind Brain Behavior InstituteDepartment of NeuroscienceColumbia University Linda B. Buck, PhDProfessor of Basic SciencesFred Hutchinson Cancer Research CenterAffiliate Professor of Physiology and BiophysicsUniversity of Washington*DeceasedKandel_FM.indd 45 20/01/21 9:04 AMxlvi ContributorsStephen C. Cannon, MD, PhDfor eye position and velocity in, 867, 868fgaze shifts in, coordinated head and eye movements in, 877–878, 877fgaze system in, 860highlights, 880–881Kandel-Index_1583-1646.indd 1603 19/01/21 9:18 AM1604 IndexGaze control (Cont.):neuronal control systems in, 866–868active fixation system in, 866overview of, 866saccadic system in, 866–867, 867f, 879fsmooth-pursuit system in, 866–867, 879fvergence system in, 879–880sound-localization pathway from inferior colliculus in, 669–670superior colliculus control of saccades in, 871–875basal ganglia inhibition of, 873–874, 873fcerebral cortex control of, 871f, 873–877, 874f, 876f, 879fcortical pathways in, 871, 871fexperience on, 877frontal eye field in, 875movement-related neurons in, 875, 876frostral superior colliculus in visual fixation in, 873–874supplementary eye field in, 875visual neurons in, 875, 876fvisuomotor integration into oculomotor signals to brain stem in, 871–873, 873fvisuomovement neurons in, 875Gaze system, 860GBA1 mutations, 1549Gbx2, 1114, 1114fGDNF (glial cell line-derived neurotrophic factor), 1148, 1149fGEFS+ syndrome (generalized epilepsy with febrile seizures plus), 1468f, 1469Gender, 1261Gender identity, 1261. See also Sexually dimorphic behaviorsGender role, 1261Gene(s), 7behavior and. See Gene(s), in behavioron chromosomes, 30–31, 31fconservation of, 32–34, 34f, 52expression ofin brain, 29–30regulation of, 35b–36bfamilial risk of psychiatric disorders in, 28fgenotype vs. phenotype and, 31–32glossary of, 53–54heritability and, 27, 28fmutations in, 32, 33borthologous, 32, 34f, 52splicing of, 30fstructure and expression of, 29–30, 30ftransgenic expression. See Transgenic expressionin twins, identical vs. fraternal, 27, 28fGene(s), in behavior, 26–52animal models of, 34–45circadian rhythm in, transcriptional oscillator in, 34, 40–42, 41f–43fclassical genetic analysis of, 34mutation generation in, 35b–36bneuropeptide receptors on social behaviors, 44–45, 45f, 46fprotein kinase regulation of activity in flies and honeybees, 42, 44, 44freverse genetics in, 34heritability of, 27, 28fhighlights, 51–52humanenvironmental influences and, 46neurodevelopmental disorders and. See Neurodevelopmental disorderspsychiatric disorders and, 48. See also Alzheimer disease (AD); Parkinson disease; SchizophreniaGene knockoutCre/loxP system for, 35b–36b, 37fdevelopmental abnormalities from, 1351Gene replacement therapy, for spinal muscular atrophy, 1428, 1429fGeneral linear model (GLM), in fMRI, 118General somatic motor column, 989f, 991–992General somatic sensory column, 987, 989f, 990General visceral motor column, 989f, 990–991Generalized anxiety disorder (GAD), 1505, 1506. See also Anxiety disordersGeneralized epilepsy with febrile seizures plus (GEFS+ syndrome), 1468f, 1469Generalized onset seizures. See Seizure(s), generalized onsetGeneralized penicillin epilepsy, 1461Genetic analysis, classical, 34Genetic diversity, mutations in, 32, 33bGenetic imprinting, 1533–1534, 1533fGeniculate nucleus, lateral. See Lateral geniculate nucleus (LGN)Geniculate nucleus, medial, 82f, 83Geniculostriate pathway, in visual processing, 499–502, 503fGenitalia, sexual differentiation of, 1262, 1263fGenome, 52Genome-wide association studies (GWAS)in autism spectrum disorder, 1537in mood and anxiety disorders, 1507in schizophrenia, 50–51, 1491–1492Genotype, 31–32, 52Gentamicin, on vestibular function, 647Geometry, object, internal models of, 547–550, 548f–550fGephyrin, in central receptors in, 1199, 1201fGeschwind, Norman, 1378Gestalt, 497, 498fGFP (green fluorescent protein), 372fGhitani, Nima, 427Ghrelin, 1035, 1036f–1037fGHRH, GRH (growth hormone-releasing hormone), 1028, 1029tGibbs, F.A., 1461Gibson, James, 827, 1409, 1410bGilbert, Charles, 515Ginty, David, 410, 411f, 431GIRK (G protein-gated inward-rectifier K+) channel, 315, 316f, 317fgl (leakage conductance), 213, 218bGli proteins, 1118–1119Glial cell line-derived neurotrophic factor (GDNF), 1148, 1149fGlial cells, 151–160astrocytes. See Astrocytesfunctions of, 61–62GABA uptake into, 366fgap junctions in, 248highlights, 162as insulating sheaths for axons, 151–154, 152f, 153fK+ permeability of open channels in, 191f, 193–194, 194fmicroglia. See Microgliaoligodendrocytes. See Oligodendrocyte(s)quantity of, 61radial. See Radial glial cellsSchwann cells. See Schwann cellsstructural and molecular characteristics of, 134–141in synapse formation and elimination, 1205–1207, 1206ftransporter proteins in, 133types of, 133–134, 134f. See also specific typesGlial scar, 1240, 1241fGlobal aphasiabrain damage in, 1386differential diagnosis of, 1379tspontaneous speech production and repetition in, 1384t, 1386Globus pallidusanatomy of, 14f, 933fconnections of, 934f, 936, 936fexternal, 935Glomeruluscerebellar, 918, 919folfactory bulb, 687–688, 688f, 689fGlossopharyngeal nerve (CN IX)information conveyed by, 429, 985injury of, 985as mixed nerve, 985origin in brain stem, 983fprojections of, 1019Glove-and-stocking pattern, 1428GluA2 gene, 279, 280f, 281fGlucagon-like peptide-1 (GLP-1), 1034, 1036f–1037fGlucocorticoid(s), in stress response coordination, 1275Glucocorticoid receptor gene, tactile stimulation of, 1275Kandel-Index_1583-1646.indd 1604 19/01/21 9:18 AMIndex 1605Glucopenia, 1035Glucose, blood, 1035Glutamatedopamine co-release with, 371dynorphin co-release with, 371metabolic, 365as neurotransmitter, 278, 365receptors for. See Glutamate receptors (receptor-channels)in spinal-cord dorsal horn pain nociceptors, 475, 478fvesicular uptake of, 365, 366fGlutamate AMPA-kainate channels, in ON and OFF cells, 536Glutamate excitotoxicity, 284–285Glutamate receptors (receptor-channels)astrocytes on, 154, 158fat central synapses, 1198–1199, 1201fionotropic, 277–283, 277ffamilies/categories of, 277–279, 278f. See also AMPA receptors; Kainate receptors; NMDA-type glutamate receptors (receptor-channels)glutamate excitotoxicity in, 284protein network at postsynaptic density in, 284, 285fstructure and function of, 277–281, 277f–278f, 280fmetabotropic, 277, 277f, 1531overactivation of, in prolonged seizures, 1466in spinal-cord dorsal horn, 479, 482fGlutamate transporters, 365, 366f, 375–376Glutamate-gated channel subunits, P-regions in, 178, 179fGlutamatergic neuronsin cerebellum, 1145as chemoreceptors for CO2, 996Glycineon ionotropic receptors, 287synthesis of, 364Glycine receptors (receptor-channels)at central synapses, 1198–1199, 1201ffunction of, 288inhibitory actions of, 288–290, 289fionotropic, 278f, 287–288nicotinic, subunits of, 278fpostsynaptic cell inhibition by Cl- current through, 288–290, 289f, 290fGlycine transporter (GLYT2), 366fGlycogen synthase kinase type 3 (GSK3), lithium on, 1520Glycosylation, 149GnRH (gonadotropin-releasing hormone), 1028, 1029tGoal-directed behaviorbasal ganglia in, 946–947episodic memory in, 1300, 1301f, 1302fmotivational states on. See Motivational statesGold particles, electro-opaque, 373f, 374bGoldman equation, 199Goldstein, Kurt, 21Golgi, Camillo, 8Golgi cellin cerebellar cortex recurrent loops, 921, 921fin cerebellum, 918, 919fGolgi complexdendrites from, 137, 137fsecretory protein modification in, 149–150structure of, 135, 136f, 137fGolgi staining method, 58–59Golgi tendon organs, 421discharge rate of population of, 771b, 771fIb inhibitory interneurons from, 770, 772fstructure and function of, 769–770, 771b, 771fGonadal hormones, 1262Gonadal sex, 1261Gonadotropin-releasing hormone (GnRH), 1028, 1029tGonadsembryonic differentiation of, 1261–1262, 1262fhormone synthesis in, 1262–1263, 1263f–1265f, 1265tGo/no-go motor decision, 835Goodale, Melvin, 1488Gottesman, Irving, 1491Gouaux, Eric,279Goupil, Louise, 1483Gracile fascicle, 77f, 81, 450f–451fGracile nucleus, 77f, 79Graham Brown, Thomas, 783, 790, 790fGrammarbrain processing of, 20universal, 19Grand mal seizures. See Seizure(s), generalized onsetGrandmother cell, 518Grandour, Jackson, 1382Granit, Ragnar, 773Granule cells/granular layer, of cerebellumanatomy of, 918, 919f, 920connections to Purkinje cells, 105inputs to and connectivity of, 104–105synaptic plasticity of, 108–109, 109fGrasping and reachingabnormal movements for, 779dorsal premotor cortex in planning for, 831–833, 831f–835ferror-based learning in, 730, 731fexpansion of visual receptive field after, 827, 828fforced, 829with paralyzed arm, brain-machine interfaces for, 965, 967, 969fparietal cortex areas in, 825–828, 826f–827f, 828fprimary motor cortical neurons in, 847–849, 848fpropriospinal neurons in, 778with prosthetic arm, brain-machine interfaces for, 965, 967f, 968fsensory and motor signals for, 719unconscious guidance system in, 1479–1480, 1480fventral premotor cortex in planning for, 835, 837fGrating stimuli, 534b, 534fGravito-inertial force, orienting to, 895, 896fGravity, in falling, 896Gray, E.G., 276Gray matterloss of, in schizophrenia, 1494, 1495f–1496fin spinal cord, 76, 77f, 429–430, 431fGray type I and II synapses, 276, 276fGreen cones, 393, 394fGreen fluorescent protein (GFP), 372fGreengard, Paul, 345Grendel, 381Grid cells, 1361, 1362fGrid fields, 1361, 1363fGrillner, Sten, 1004Grip control, touch receptors in, 446–450, 449fGroping movements, 829bGross, Charles, 568Ground reaction force, 884, 885b, 885fGrowth conediscovery of, 8, 1162–1163optic chiasm divergence of, 1171–1172, 1172f, 1173fas sensory transducer and motor structure, 1161–1165, 1163f, 1165factin and myosin in, 1163f, 1164, 1165fcalcium in, 1164cellular motors in, 1164–1165, 1165fcentral core of, 1163–1165, 1163ffilopodia of, 1163f, 1164lamellipodia of, 1163f, 1164microtubules in, 1164–1165, 1165ftubulin in, 1163fGrowth hormone release-inhibiting hormone. See SomatostatinGrowth hormone-releasing hormone (GHRH, GRH), 1028, 1029tGSK3 (glycogen synthase kinase type 3), lithium on, 1520Guanosine triphosphatases (GTPases), in growth cone, 1164Guard hairs, 419, 420f–421fGuillain-Barré syndrome, 154, 208, 1429Guillemin, Roger, 1028Gurfinkel, Victor, 898Gustatory cortex, 702, 703fGustatory sensory neurons, 697, 697f, 702, 703fGustatory system, 696–703anatomy of, 696–697, 697f, 702fbehavior and, in insects, 702–703in flavor perception, 702sensory neurons in, 687f, 702, 703fsensory receptors and cells in, 698–702, 698f–700fKandel-Index_1583-1646.indd 1605 19/01/21 9:18 AM1606 IndexGWAS. See Genome-wide association studies (GWAS)Gyri, 16. See also specific typesGyromagnetic ratio, 112HHabit learning, 1304Habituationhistory and definition of, 1314long-term, 1316, 1316f, 1324, 1325fnonassociative learning in, 1305physiological basis of, 1314short-term, 1314, 1315fsynaptic transmission in, activity-dependent presynaptic depression of, 1314–1315, 1315f, 1316fHagbarth, Karl-Erik, 773–774Haggard, Patrick, 1480Hairnerve fibers of, 419, 420f–421ftypes, 419, 420f–421fHair bundlesactive motility and electromotility of, 617–618anatomy of, 604–606, 606f, 607fdeflection of, in mechanoelectrical transduction, 606–608, 608fevolutionary history of, 620bin linear acceleration sensing, 634–635, 635fin otoacoustic emissions, 618in tuning hair cells to specific frequencies, 613–614Hair cells, 598anatomy of, 604, 605f–607fin auditory processing, 606–621dynamic feedback mechanisms of, 613–618adaptation to sustained stimulation in, 614–616, 615fcochlea amplification of acoustic input sin, 618cochlea sound energy amplification in, 616–618, 616f, 617fHopf bifurcation in, 618, 619b, 619f, 620btuning in, 613–614, 613fion channels in, 608–609mechanical sensitivity of, 606–608, 608fpresynaptic active zone of, 620–621, 621freceptor potential of, 608–609, 608fribbon synapses in, specialized, 618–621, 621ftransduction channels in, 609–610transformation of mechanical energy into neural signals by, 606–613direct mechanoelectrical transduction in, 610–611hair bundle deflection in, 606–609, 608fmechanical force in transduction channel opening in, 609–610, 610f, 611fmolecular composition of machinery in, 611–613, 612fvariations in responsiveness in, 613drugs on, 609evolutionary history of, 620bin vestibular systemlinear acceleration sensing by, 634–635, 635ftransduction of mechanical stimuli into neural signals by, 631–632, 631fHalf-centers, 880Halligan, Peter, 1475Hallucinationsdefinition of, 1474hypnagogic, 1094hypnopompic, 1094olfactory, 691perception in, 1476–1477, 1478fin schizophrenia, 1476–1477, 1490Hamburger, Viktor, 1147, 1148fHandgrasping of. See Grasping and reachinglocation of, sensory inputs for, 720–721mechanoreceptors of, 437–438, 437f, 438t. See also Cutaneous mechanoreceptorsmotor cortex representation of, in stringed instrument players, 1335f, 1336movement of, stereotypical features of, 725–726, 726fproprioception in, 733b, 733freceptive fields of, 457–459, 458fslowly adapting fibers in. See Slowly adapting type 1 (SA1) fibers; Slowly adapting type 2 (SA2) fiberstactile acuity in, 439–441, 443fHandwriting, motor equivalence in, 726, 727fHaploinsufficiency, 32Haplotype, 52Harlow, Harry and Margaret, 1212Harmonicsin bats, 675, 676fspecialized cortical neurons for encoding, 673Harris, Geoffrey, 1028Harris, Kenneth, 404Harrison, Ross, 8Hartline, H. Keffer, 506Hauptmann, Alfred, 1448HCN channels, 796bHCN (hyperpolarization-activated cyclic nucleotide-gated) channels, 228, 232fHeadmovements ofcompensation by translation vestibulo-ocular reflex, 642–643vestibular information for balance in, 895–897, 896frotation ofcompensation by rotational vestibulo-ocular reflex, 640–642, 641f, 642fsemicircular canal sensing of, 632–634, 633f, 634fHead, Henry, 18, 898Head direction cells, 1361, 1364fHead shadowing, 661Head-impulse test, 638Head-movement system, 866Hearing. See also Auditory processingbinaural, in sound localization, 652evolutionary history of, 620binteraural time delay in, 653f, 688music recognition in, 652screening, in newborns, 618sound energy capture by ear in, 600–601, 602f–603fsound shadows in, 652spectral filtering in, 652, 653fspeech recognition in, 652Hearing loss. See also Deafnessconductive, 601sensorineural, 601, 624, 626ftinnitus in, 624Heat receptors, 423Hebb, Donaldon cell assemblies, 284, 1356on memory storage, 1340, 1353on synaptic connections, 1218Hebbian synaptic plasticity, 108, 108fHebb’s rule, 1340, 1353Hegel, Georg Wilhelm Friedrich, 387Helmholtz, Hermann vonon basilar membrane, 604on cortical plasticity, 559on electrical activity in axon, 8on eye movement control, 866on localization of visual objects, 721on motor commands from saccades, 582–583on sensation, 387on unconscious inference, 1474Hematopoietic system, regeneration in, 1249Hemichannels, 244, 245fHemifield, 501, 502fHemiretina, 501, 502fHemispherescerebellar, 911, 912f. See also Cerebellumcerebral, 14f, 15f, 16. See also Cerebral cortexHemizygous, 32Hemodynamic response function, in fMRI, 115Hemorrhage, brain. See StrokeHenneman, Elwood, 743, 765Hensch, Takao, 1377Hensen’s cells, 607fHering-Breuer reflex, 779, 995Heritability, of neurological, psychiatric, and behavioral traits, 27, 28f. See also Gene(s); specific traits and disordersKandel-Index_1583-1646.indd 1606 19/01/21 9:18 AMIndex 1607Heroin, 1072t. See also Drug addictionHerpes simplex virus (HSV), axonal transport of, 145b, 145fHerpes zoster infection, 984Heterochromatin, 52Heteronymous muscle, 765Heterosynaptic process, 1316Heterozygous, 31Heuser, John, 337–338, 339fHickok,Gregory, 1379High vocal centers (HVCs), 1267, 1271fHigh-voltage-activated (HVA) Ca2+ channels, 227, 329, 331t, 332Hill, A.V., 250Hillarp, Nils-Åke, 372bHille, Bertil, 167, 222Hindbrainanatomy of, 12b, 13fembryogenesis of, 1112, 1113fpatterning of, isthmic organizer signals in, 1113–1115, 1114f, 1115fsegmentation of, 1115, 1116fHip extension, in walking, 795, 798fHip strategy, 889, 891fHippocampusanatomy of, 14fastrocytes in, 158fin autism, 1539autobiographical memory disorders and dysfunction of, 1367cytoarchitecture of, 93, 93f, 138fdamage to, 121, 1050in emotion expression, 1050in episodic memoryfor building relational associations, 1300–1302, 1302ffor goal-directed behavior, 1300, 1302fexplicit memory and synaptic plasticity in, 1340–1353cortical connections for, 94–95, 94f, 95fgeneral mechanisms of, 1340–1342, 1341flong-term potentiation inat distinct pathways, 1342–1345, 1343f, 1344f–1345fearly and late phases of, 1347–1349, 1347fmolecular and cellular mechanisms of, 1345–1347, 1346fproperties of, 1349–1350, 1349fspatial memory and. See Memory, spatialspike-timing-dependent plasticity for altering synaptic strength, 1349explicit memory processing in subregions of, 1358–1360pattern completion in CA3 region, 1360pattern separation in dentate gyrus, 1359–1360social memory encoding in CA3 region, 1360functions of, 12bintegrated circuits in, 94in memory retrieval, 1300in mood disorders, 1512neurons ofgenerated in adults, 1249, 1250f, 1359–1360, 1512growth and polarity of, 1157, 1158fin post-traumatic stress disorder, 1512, 1518ribosomal RNA in, 147fin schizophrenia, 1494spatial cognitive maps in, 99–102, 1360–1367entorhinal cortex neurons in, 1361–1362, 1362f, 1363f, 1364f, 1365place cells in, 89f, 99–101, 1365–1367, 1365f, 1366fshort-wave ripples in, 101–102, 101fin stimulus-response learning, 1304, 1305fvisual memory and, 578Histamineitch from, 425nociceptor sensitization by, 478synthesis and action of, 363–364Histaminergic neuronslocation and projections of, 999f, 1001in sleep-wake cycle, 1085Histochemical analysis, of chemical messengers, 372b–374b, 372f, 373fHistone acetylation, in long-term sensitization, 1322f, 1323Hitzig, Eduard, 16, 841Hodgkin, Alan, 199, 212–217. See also Voltage-clamp studiesHodgkin-Huxley model, 219–220, 219fHoffmann reflexnoninvasive tests in humans, 772b, 773, 779technique for measurement of, 768b, 768fHolistic view, of brain, 10Holmes, Gordon, 909Homeobox, 1119Homeodomain proteins, 1114in motor neuron differentiation, 1120, 1121fin ventral spinal cord patterning, 1118f, 1119Homeostasisemotional response and, 1060, 1062hypothalamus in. See Hypothalamus, in homeostatic regulationprinciples of, 1011–1013, 1012fHomogenetic induction, in dorsoventral patterning, 1116Homonymous muscle, 765Homosexual brains, sexually dimorphic structures in, 1280f, 1281, 1281fHomosynaptic depression, 1314Homozygous, 765Homunculus, 84–85, 84f, 454, 454f–455fHoneybee activity, protein kinase regulation of, 44, 44fHopf bifurcation, 618, 619b, 619f, 620bHorizontal cells, photoreceptor, 524f, 536–537Horizontal motion, postural response to, 895–897Horizontal plane, of central nervous system, 11bHormones. See also specific hormonesaction of, 359vs. neurotransmitters, 359physiologic responses to, hypothalamus in. See Hypothalamus, neuroendocrine system ofprocessing of precursors of, 368, 369fregulation by, 1261sex, 1260–1261steroid, biosynthesis of, 1262, 1264fHorner syndrome, 864bHorsley, Victor, 1448Hortega, Rio, 159Hospitalism, 1212Hox genesconservation of, in Drosophila, 1120, 1121fon motor neuron differentiation and diversification, 1120–1121, 1121f, 1123fHox proteinson motor neuron differentiation and diversification, 1121–1123, 1124fon motor neuron subtype in brain and spinal cord, 1120, 1121fHoxb1in hindbrain segmentation, 1115, 1116fon motor neuron subtype in hindbrain and spinal cord, 1120, 1121f, 1123fHPA (hypothalamic-pituitary-adrenal) axis, 1508–1509, 1508fHPETEs (hydroperoxyeicosatetraenoic acids), 311fH-reflex. See Hoffmann reflex5-HT. See Serotonin (5-hydroxytryptamine, 5-HT)HTT gene, 1546Hubel, Davidon auditory cortex, 667–668on receptive fields of retinal ganglion cells, 507–508on sensory deprivation, 1213–1214, 1214f–1216fon stereoscopic vision, 1217–1218Hughes, F. Barbara, 375Hume, David, 387, 497Humphrey, David, 850Hunger drive, 1038–1039, 1039f. See also Energy balance, hypothalamic regulation ofHuntingtin, 1545–1546Kandel-Index_1583-1646.indd 1607 19/01/21 9:18 AM1608 IndexHuntington diseasebasal ganglia dysfunction in, 948epidemiology of, 1545gene expression alteration from protein misfolding in, 1555–1556genetics of, 1545–1556mouse models of, 1552, 1554fpathophysiology of, 285, 948, 1545signs and symptoms of, 1545striatum degeneration in, 1545treatment of, 1556–1557Huxley, A.F., 212–217, 747. See also Voltage-clamp studiesHuxley, H.E., 747HVA (high-voltage-activated) Ca2+ channels, 227, 329, 331t, 332HVCs (high vocal centers), 1267, 1271fHydranencephaly, 981Hydration, waters of, 167Hydroperoxyeicosatetraenoic acids (HPETEs), 311f5-Hydroxytryptamine. See Serotonin (5-hydroxytryptamine, 5-HT)Hyperacusis, 993Hyperalgesia, 476–484axon reflex in, 479C fiber repetitive firing in, 479, 482fcentral sensitization in, 479definition and symptoms of, 472dorsal horn neuron excitability in, 481, 482fneurogenic inflammation in, 479, 480fneuropeptides and small molecules in, 476, 478–479neurotrophins in, 479, 481fnociceptor sensitization in, 476, 478–479, 479fsecond-messenger pathways in, 481tissue inflammation in, 479, 480fHypercapnia, 995–996Hypercolumns, in primary visual cortex, 508, 510f–511fHyperekplexia, 288Hyperkalemic periodic paralysis, 1442–1444, 1443fHypermetria, 896Hyperpolarization, 65, 191, 192b, 192fHyperpolarization-activated cyclic nucleotide-gated (HCN) channels, 228, 232fHyperreflexia, from spinal cord transection, 780Hypertropia, trochlear nerve lesion in, 864b, 865fHypnagogic hallucinations, 1094Hypnogram, 1081fHypnopompic hallucinations, 1094Hypocretins, in narcolepsy, 1094–1095, 1094fHypoglossal nerve (CN XII), 983f, 985, 995Hypoglossal nucleus, 989f, 992Hypokalemic periodic paralysis, 1442, 1444fHypomanias, 1504Hyposmia, 691Hypothalamic-pituitary-adrenal (HPA) axis, 1508–1509, 1508fHypothalamus, 14f, 1010–1042anterior, sexual dimorphism and, 1278, 1278fin depression, 1508, 1508fin emotional expression, 978, 1049highlights, 1041–1042in homeostatic regulation, 12b, 978, 1013, 1013t, 1015body temperature, 1029–1031, 1029benergy balance. See Energy balance, hypothalamic regulation ofthirst drive, 1033water balance, 1031–1033, 1032fneural circuit of, on mating behavior, 1272neuroactive peptides of, 367tneuroendocrine system of, 978, 1026–1029, 1027faxon terminals in posterior pituitary on, 1027, 1028fneurons on endocrine cells in anterior pituitary on, 1028–1029, 1028f, 1029tparaventricular nucleus on, 1027, 1027fsexually dimorphic regions ofcontrol of sexual, aggressive, and parenting behaviors in, 1039–1041, 1040folfactory activation in, 1280f, 1281in sleep-wake cycle. See Ascending arousal systemstructure of, 1013, 1014fHypotonia, in cerebellar disorders, 909Hypoxia, 995Hysteria, on subjective reports, 1485Hysterical amnesia, 1485Hyvärinen, Juhani, 463II. See Current (I)I (intensity), of stimulus, 387Ia fibers, 763f, 764–765, 767fIa inhibitory interneurons. See Inhibitory interneuronsIb interneurons. See Inhibitory interneuronsIB4, 410, 411fIc (capacitive current), in voltage clamp, 213Ictal phase, 1454Ideas of reference, 1490Identical twins, 27Identity, gender, 1261Il (leakage current), 213, 216f, 218bIL-6 class cytokines, 1146,1146fIlluminant intensity, variation in, 540Im (membrane current), 213Imagination, episodic memory and, 1300, 1301fImaging, and behavior. See Functional magnetic resonance imaging (fMRI)Imipramine, 1514, 1516f–1517fImmunoglobulins, in axon growth and guidance, 1170f–1171fImmunohistochemical localization, of chemical messengers, 372b–374b, 372f, 373fImplicit memory. See Memory, implicitImprintinggenetic (parental), 1533–1534, 1533fin learning in birds, 1211In vitro preparations, for studies of central organization of networks, 787b, 787fInactivationof Ca2+ channel, voltage-dependent, 174, 174fof K+ channel, 217, 219fof Na+ channel, 217–219, 219fin prolonged depolarization, 217–218, 219fof voltage-gated channels, 174, 174fin skeletal muscle, 1441, 1443fInactivation gate, 218–219Incentive motivation theory, 1038, 1039fIncentive stimuli, rewarding, 1066Incusanatomy of, 599, 599fin hearing, 601, 602f–603fIndirect channel gating, 250–251, 251f, 302–303, 302f. See also G protein-coupled receptors; Receptor tyrosine kinasesIndirect immunofluorescence, 372f, 373bIndirect pathway, in explicit memory storage, 1340Individuality, learning-induced brain structure changes in, 1335f, 1336Indoles, 363Induced pluripotent stem (iPS) cellsfor ALS treatment of, 1254fmethods for creating, 1142–1143, 1253–1254, 1253forganoid generated from, 1144fInduction, neuralbone morphogenetic proteins in, 1110–1112, 1111fdefinition of, 1108in neural development, 1110in rostrocaudal neural tube patterning, 1112Infant-directed speech, 1377–1378Infants, sleep in, 1092Inferior cerebellar peduncle, 911, 912fInferior colliculusafferent auditory pathway convergence in, 663f, 664–665anatomy of, 664response inhibition by lateral lemniscus, 663–664Kandel-Index_1583-1646.indd 1608 19/01/21 9:18 AMIndex 1609sound localization from, in superior colliculus spatial sound map, 665, 666ftransmission of auditory information to cerebral cortex from, 665–671auditory cortex mapping of sound and, 668–669, 668fauditory information processing in multiple cortical areas in, 669cerebral cortex auditory circuit processing streams in, 670, 671fgaze control in, 669–670stimulus selectivity along the ascending pathway in, 665, 667–668, 667fInferior salivatory nucleus, 989f, 991Inferior temporal cortex, object recognition in. See Object recognition, inferior temporal cortex inInferior vestibular nerve, 630f, 632Inflammationneurogenic, 479, 480ftissue, 478, 479Information processing, 1473Information transfer rate (ITR), 964–965Inhalants, 1072t. See also Drug addictionInheritance, sex-linked, 31Inhibitionautogenic, 769–770at chemical synapses, mechanisms of, 288–289, 289ffeedback, 63f, 64feedforward, 63f, 64–65postsynaptic, 353, 354fin postsynaptic neuron, distance traveled in effect of, 294, 295fpresynaptic, 317, 353, 354fsculpting role of, 290, 290fInhibitory interneuronsconvergence of sensory inputs on, 772–773feedforward and feedback in, 63f, 64–65input from Golgi tendon organs, 770, 771bin locomotion, 770, 772fon muscles surrounding a joint, 775, 776fin relay nucleus, 400, 401fin spinal cord, 89synaptic terminals of, 276, 276fInhibitory postsynaptic potential (IPSP)to central neurons, 274, 275fmechanism of, in Cl- channels, 288, 289fInhibitory signals, 63–64Inhibitory surround, 1456–1457, 1456f, 1457fInitial segment, 57fInitial segment, of axon, 58Inking response, in Aplysia, 247, 247fInnate fear. See FearInner ear, 599–600, 600f. See also Cochlea; Vestibular apparatusInner plexiform layer, 1182–1183, 1184fInnervation number, 739, 739tInput signal, 66, 66fInsertional plaque, 614Inside-out neuronal migration, 1136f–1137f, 1138Insomnia, 1092–1093Insular cortex (insula)anatomy of, 12bin emotional processing, 1056, 1058b, 1060pain control by, 485–486, 487b, 487fInsulinin aging process, 1564on appetite, 1035, 1036f–1037fas neuroactive peptide, 368tInsulin-like growth factors, in aging process, 1564Intact preparations, for locomotion studies, 785bIntegrationcontour. See Contour, integration ofin neural circuits, 105–107, 106fof sensory informationin balance, 899f, 900, 901fin posture, 894–897, 901–902. See also Posturein vestibular nuclei. See Vestibular nucleisynaptic. See Synaptic integrationvisuomotor, in superior colliculus, 871–873, 873fIntegrinsin neural crest cells, 1141in neuron migration along glial cells, 1137Intellectual disability, 1523. See also Neurodevelopmental disordersIntensity (I), of stimulus, 387Intention (action) tremor, 909Intentional binding, 1480, 1480fInteraction torques, 909, 910fInteraural intensity differences, lateral superior olive in, 659, 661–662, 662fInteraural time differences (ITDs)in auditory localization in owls, 1227–1228, 1227f–1229fmedial superior olive map of, 657, 659, 660f–661fin sound localization, 652, 653fInterconnected neuronal pathways, 68Interictal period, 1454Interlimb coordination, 788, 795Intermediate-level visual processing. See Visual processing, intermediate-levelInternal genu, of facial nerve, 991Internal globus pallidus, 935, 935f, 936, 936fInternal medullary lamina, of thalamus, 82f, 83Internal models, sensorimotor, 718b, 718fInternational League Against Epilepsy, seizure classification, 1448–1449, 1449tInterneurons, 61functional components of, 64, 64finhibitory. See Inhibitory interneuronsin olfactory bulb, 687, 687fprojection, 61, 64, 64frelay, 61in retina. See Retina, interneuron network in output ofInternuclear ophthalmoplegia, 870Interoception, 408Interspike intervals, 396, 397fIntorsion, 861, 861f, 863tIntracortical electrodes, penetrating, 956–957, 957fIntrafusal muscle fibersgamma motor neurons on, 766–767, 769fin muscle spindles, 421, 422f, 764b, 765fIntralaminar nuclei, of thalamus, 82f, 83Intralimb coordination, 788Intraperiod line, 1431fIntrinsic reinforcement, 944–946, 945fIntrons, 27, 30f, 52, 53Inverse model, sensorimotor, 718b, 718fInward current, ionic, 258Ion(s). See specific ionsIon channels, 65, 165–188. See also specific channelsblockers of, 172in central pattern generator function, 796bcharacteristics of, 171–174conformational changes in opening/closing, 172–174, 172f–173fpassive ion flux, 171–172, 171fsingle, currents through, 169–171, 170b, 170fvoltage-gated. See Voltage-gated ion channels; specific channelsconductance of, 171–172, 171fdefinition of, 167desensitization of, 173dysfunction of, diseases caused by, 165functional characteristics of, 169–171functional states of, 172–173gated, 190genes for, 175–176genetic mutations in, epilepsy and, 1467–1469, 1468fhighlights, 187–188vs. ion pumps, 186f, 187ion size on movement through, 167in mechanoreceptors, 415–416, 416f, 417fproperties of, 166receptor gating ofdirect (ionotropic), 250–251, 251f, 302–303, 302f. See also Second messengersindirect (metabotropic), 250–251, 251f, 302–303, 302f. See also G protein-coupled receptors; Receptor tyrosine kinasesresting, 190roles of, 165–166saturation effect in, 171selectivity filters in, 167–168, 168f–169fKandel-Index_1583-1646.indd 1609 19/01/21 9:18 AM1610 IndexIon channels (Cont.):selectivity of, 166, 167–168, 168f–169fin signaling, rapid, 166structure ofprotein in, 165–167, 168f–169fstudies of, 174–177amino acid sequences, 176, 176fchimeric channels, 176–177gene families, 177–179, 178f, 179fhydrophobicity plot, 176, 176fsecondary structure, 176, 176fsite-directed mutagenesis in, 177subunits in, 175, 175fIon fluxconductance and driving forces in, 195vs. diffusion, 171–172, 171fIon pump, 165, 166ATP in, 166vs. ion channel, 186fIon transporter, 165–166, 186f. See also specific typesIonotropic receptors. See also Glutamate receptors (receptor-channels)on balance of charge, 301–302functional effectsof, 312, 312tfunctions of, 250–251, 251fvs. metabotropic receptors, 251, 312–313, 312t, 313f, 314fneurotransmitter activation of, 239, 301–302, 302fIP3from phospholipase C hydrolysis of phospholipids in, 305–308, 307fin synaptic plasticity, 351iPS cells. See Induced pluripotent stem (iPS) cellsIsa, Tadashi, 778Ishihara test, 538f, 539Isometric contraction, 749, 758Isoprenylation, 148Isthmic organizer, 1113–1114, 1114f, 1115fItchC fibers in, 425from histamine, 425properties of, 425–426spinothalamic system in, 450f–451fITDs. See Interaural time differences (ITDs)Ito, Masao, 923, 928Ivry, Richard, 923JJackson, John Hughlings, 10, 841, 1448Jacksonian march, 1448Jahnsen, Henrik, 1461JAK2, 1133JAK/STAT signaling, in axon regeneration, 1247, 1248fJames, Williamon attention, 588on fear, 1047–1048, 1049fon learning of visual associations, 575on memory, 1292on perception, 383on selection, 941Jasper, Herbert, 1448, 1461Jeannerod, Marc, 1481Jeffress, Lloyd, 657jimp mouse, 156bJohansson, Rolandon grip control, 446on tactile sensitivity, 438, 441–442Joint receptors, 421Joints, coordination of muscles at, 775–776, 776fJorgensen, Erik M., 341Jugular foramen, 984f, 986Julius, David, 423Junctional folds, 255, 256fKK+ buffering, astrocytes in, 154K+ channelsin central pattern generator function, 796belectrical properties of, 200–201, 200f, 201finactivation of, 217, 219fM-type (muscarine-sensitive), 313, 314f, 315non–voltage gated (KcsA), 180–182, 181f, 184fpermeability and selectivity of, 180–182, 181fP-regions in, 178, 179fresting potential, 195, 196fserotonin-sensitive (S-type), 317, 318f, 353–354structure of, 167, 168f–169fvs. CIC-1 channels, 185, 186gene families in, 178–179, 178fx-ray crystallographic analysis of, 180–182, 181fvoltage-gated, 227–231in action potential. See Voltage-gated ion channels, in action potentialA-type, 231, 232fautoantibodies to, in peripheral neuropathies, 1432calcium-activated, 229, 1468fchannel gating mechanisms in, 182–185, 183f, 184fin epilepsy, 1455, 1455fgenetic factors in diversity of, 178, 179f, 225, 226f, 227–228genetic mutations in, epilepsy and, 1467, 1468fion conduction in, 261Na+ channel interdependence with, 212–213, 214b–215bpore-forming α-subunits in, 225, 226fK+ currentmembrane depolarization on magnitude and polarity of, 216–217, 217foutward, 220voltage-gated, on conductance, 217–219, 218b, 218f–219fK+ equilibrium potential (EK), 193, 194fK+ permeability, of glial cell open channels, 191f, 193–194, 194fKainate receptorsexcitatory synaptic action regulation by, 277, 277fgene families encoding, 278structure of, 279Kalman, Franz, 1490Kalman filter, 962, 965, 966fKanner, Leo, 1524Kant, Immanuelon perception, 497on senses and knowledge, 387, 391Kanwisher, Nancy, 569, 1382Kappa (κ) receptors, opioid, 489, 490, 490tKarlin, Arthur, 264, 265fKatz, Bernardon action potential, 212on Ca2+ influx in transmitter release, 327on end-plate potential, 257–258, 258f–259f, 260on membrane potential, 199on presynaptic terminal depolarization in transmitter release, 324–326, 325f–326fon quantal synaptic transmission, 332–333K+-Cl- cotransporter, 197f, 198–199K-complexes, EEG, 1081f, 1082KcsA (non–voltage gated) K+ channels, 180–182, 181f, 184fKeele, Steven, 923Kennedy disease (spinobulbar muscular atrophy), 1546, 1547t, 1551f, 1552Kenyon cells, 1330Ketamine, 1515Kety, Seymour, 1490–1491Kindling, 1469Kinesin, 144Kinocilium, 606, 606fKiss-and-run pathway, 341, 343fKiss-and-stay pathway, 341, 343fKisspeptin, 1028Klatzky, Roberta, 436Kleitman, Nathaniel, 1082Klüver, Henrich, 1049Klüver-Bucy syndrome, 1049Knee-jerk reflex, 62, 62f, 66, 66fKnowledge, semantic, 1303Koch, Christof (Christopher), 1475Koffka, Kurt, 497Köhler, Wolfgang, 95Kohn, Alfred, 359Kommerell, Guntram, 877Koniocellular layers, lateral geniculate nucleus, 501, 512Konorski, Jerzy, 71Kouider, Sid, 1483Kandel-Index_1583-1646.indd 1610 19/01/21 9:18 AMIndex 1611Kraepelin, Emil, 1489, 1567Krebs, Edward, 303krox20, 1115, 1116fKuffler, Stephen, 258–259, 506, 558Kuhl, Patricia, 1373–1374, 1381Kunkel, Louis, 1439Kuypers, Hans, 998Kv1 gene family, 227–228LL cones, 525, 526f, 529, 538L opsin, 528fLabeled line, 517, 1170f–1171fLabyrinthbony, 630membranous, 630, 630f, 631Lacunes, 1567Lambert-Eaton syndrome, 332, 1436–1437Lamellipodia, 1163f, 1164Laminadorsal horn, 474–475, 475f, 476fspinal cord, 429–430, 431fLamina-specific synapsesin olfactory system, 1184–1185, 1185fin retinal, 1184fin retinal ganglion cells, 1182–1184Lamininin axon growth and guidance, 1170f–1171fin neurite outgrowth, 1243–1244in presynaptic specialization, 1192, 1194fLaminin-211, in presynaptic specialization, 1192Lampreys, swimming in, 784f–795f, 786–788, 788f, 792Landott, Edwin, 866Langley, J.N.on autonomic system, 1015on axonal outgrowth, 1166on neurotransmitters, 358on receptors, 8, 250on synaptic connection specificity, 1182, 1183fLanguage learninghighlights, 1388–1389in infants and children, 1371, 1372–1378, 1374f–1375fcontinuous speech in, transitional probabilities for, 1376–1377critical period in, 1377early neural architecture development, 1380–1381native-language discrimination and, 1374“parentese” speaking style in, 1377–1378prosodic cues for words and sentences in, 1376second language exposure and, 1378Skinner vs. Chomsky on, 1373specialization by 1 year in, 1373, 1374f–1375fspeech motor patterns in, 1373speech perception and production in, 1373–1374, 1374f–1375fstages of, 1372–1373visual system in, 1376neural commitment in, 1377in non-human species, 1371of second language, 1378Language processingin Broca’s area. See Broca’s areadisorders of, brain functional localization in, 1382–1388brain damage studies of, 19–20in Broca’s aphasia. See Broca’s aphasiain conduction aphasia. See Conduction aphasiaearly studies of, 16–18in global aphasia, 1386in less common aphasias, 1386–1388, 1387fin transcortical aphasias, 1386in Wernicke’s aphasia. See Wernicke’s aphasiafunctional brain imaging of, 19, 1370–1371highlights, 1388–1389neural basis ofdual-stream model for, 1379–1380, 1380fleft hemisphere dominance in, 1381–1382neural architecture development in infancy, 1380–1381prosody in, right and left hemispheres engagement in, 1382, 1383fWernicke model of, 17Wernicke-Geschwind model of, 1378–1379, 1379tright hemisphere in, 18of sign language, 19–20, 20fstructural levels of, 1371–1372in Wernicke’s area. See Wernicke’s areaLarge dense-core vesicles, 144f, 150, 359, 365, 370Larmor equation, 112Lashley, Karl, 18–19, 1340Lateral, 11b, 11fLateral columns, spinal cord, 77, 77fLateral ganglionic eminences, neuron migration to cerebral cortex from, 1140, 1140fLateral geniculate nucleus (LGN)anatomy of, 82f, 1214, 1214fprojections to visual cortex ofcolumns of, 508–509, 511fintrinsic circuitry of, 512–516, 514foptic radiations, 74receptive fields of, 508fsynapse formed by, 83receptive fields in, 506, 508fretinal input segregation in, in utero, 1224–1225, 1225f, 1226fin visual processing, 501Lateral hypothalamic area, 1013Lateral intraparietal area (LIP)in decision-making, 1401, 1403, 1404f–1405f, 1406flesions of, 874on saccades, 875in visual attention and saccadesparietal neuron activation for, 874, 874fpriority map for, 591, 592b–593b, 592f, 593fin visual processing, 504f–505f, 505in voluntary movement, 825, 826f–827fLateral lemniscus, 663–664. See also Inferior colliculus; Superior olivary complexLateral nuclear group, nociceptive information relay to cerebral cortex by, 484–485Lateral nucleus, of amygdala, 1051, 1052fLateral protocerebrum, 693f, 694Lateral sclerosis, 1426Lateral ventricles, in schizophrenia, 1492, 1493fLateral vestibular nucleus. Seealso Vestibular nucleiin locomotion, 802–803, 803fin vestibulo-ocular reflex, 636, 641fLateral vestibulospinal tract, in automatic postural response, 902Lauterbur, Paul, 125Law of dynamic polarization, 1156–1157Leakage channels, 203b, 213Leakage conductance (gl), 213, 218bLeakage current (Il), 213, 216f, 218bLearning. See also Memory; specific typesassociative, 1304–1306brain structure changes in, in individuality, 1335f, 1336constraint of, by sensorimotor representations, 734critical periods in, 1211dopamine as signal in, 1068–1069, 1069ferror-based, 730–732, 731f, 732fexplicit, 730, 1055fMRI studies of, 122implicit. See Learning, implicitmemory and. See Memorymotor skill. See Motor skill learningnonassociative, 1305–1306overall perspective of, 1287–1289perceptual, 559, 561fof sensorimotor skills, 1304skill, 1304spatial. See Memory, spatialstatistical, 1303–1304trial-and-error, 1307Learning, implicitamygdala and hippocampus in, 1054–1055motor tasks, 729–730in visual memory, selectivity of neuronal responses in, 573, 574fKandel-Index_1583-1646.indd 1611 19/01/21 9:18 AM1612 IndexLederman, Susan, 436Left hemispherein language processing, 1381–1382in prosody, 1382, 1383fLeft temporal cortex, in language, 1387–1388, 1387fLeft-right coordination, in locomotion, 793, 794f–795fLegsmuscle contractions of, in stepping, 788–789, 789fmuscles of, 752–754, 753tLeibel, Rudolph, 1035Lemniscus, medial, 80f–81f, 81–82, 450f–451fLength constant, 205, 205fLengthening contraction, 749, 751f, 757f, 758Lenneberg, Eric, 1377Lens, 521, 522fLeptin, 1035, 1036f–1037fLeukemia inhibitory factor (LIF), 1146, 1146fLevi-Montalcini, Rita, 1147Lewy bodies, in Parkinson disease, 141b, 142f, 1553, 1554fL-glutamate, 1143Liberles, Stephen, 426Libet, Benjamin, 1480Lichtheim, 1378Licking movements, pattern generator neurons on, 994Liddell, E.G.T, 762Lie detection, fMRI in, 125bLife spanaverage human, 1561, 1562fgenetic control of, 1564, 1566fresearch on extending, 1566Ligand-gated channels, 132, 166. See also Glutamate receptors (receptor-channels); specific typesenergy for, 173–174gene superfamily in, 177, 178fphysical models of, 172–173, 173frefractory states in, 173Light activation, of pigment molecules, 526f, 528–529, 528f, 529fLight adaptation, in retina. See Retina, light adaptation inLikely gene disrupting (LGD) mutations, 33f, 49LIM homeodomain proteins, 1125fLimb ataxia, 909Limb movements, cerebellum in learning of, 925, 926fLimb proprioception, mechanoreceptors for, 415tLimb-girdle muscular dystrophy, 1437, 1439Limbic system, 1050, 1051fLine label, 517, 517fLinear motionotolithic organ sensing of, 634–635postural response to, 895–897vestibulo-ocular reflex compensation for, 642–643LIP. See Lateral intraparietal area (LIP)Lipid bilayer, 165, 167, 168f–169f, 200Lipoxygenases, on arachidonic acid, 310Lis1 mutations, 1136f–1137f, 1138Lisman, John, 1348Lissencephaly, neuronal migration in, 1136f–1137f, 1138Lithium, for bipolar disorder, 1519Llinás, Rodolfo, 327, 327f, 1461Lloyd, David, 411, 412tLocal field potentials, in brain-machine interfaces, 954Local interneurons, 64, 64fLocal sleep, 1091Localizationauditory, in owls, 1227–1228, 1227f–1229fin brain, language processing and, 16–20immunohistochemical, of chemical messengers, 372b–374b, 372f, 373fof seizure focus, for epilepsy surgery, 1463–1465of sound. See Sound, localization ofultrastructure, of chemical messengers, 373b–374b, 373fLocke, John, 387, 497Lockhart, Robert, 1297Locomotion, 783–812basal ganglia in, 807–809cerebellum on regulation and descending signals in, 806–807computational network modeling of circuits in, 809highlights, 811–812human, 809–811, 810blocomotor system in, 783, 784fmuscle activation pattern in, 786–789, 788f, 789fposterior parietal cortex in planning of, 806, 807f, 808fsomatosensory inputs in modulation of, 795–799mechanoreceptors in adjustment to obstacles, 798–799proprioception on regulation of timing and amplitude, 795, 798, 798f, 799fspinal organization of motor pattern of, 790–795central pattern generators in, 791–792experience on, 792flexor and extensor contraction in, 790–791, 790frhythm- and pattern-generated circuits in, 792–795flexor and extensor coordination, 793, 794f–795finterlimb coordination, 795left-right coordination, 793, 794f–795fquadrupedal central pattern generator, 793, 794f–795fswimming central pattern generator, 792, 794f–795fspinal cord transection studies of, 790–792, 790f, 791fstudies of, 783–785, 785b–787b, 786f–787fsupraspinal structures in adaptive control of, 799–804brain stem nuclei for posture regulation, 802–804midbrain nuclei for initiation and maintenance, 800, 801f, 802fmidbrain nuclei projection to brain stem neurons, 800–802, 801fvisually guided, motor cortex in, 804–806, 805fLocus (gene), 30Locus ceruleusin ascending arousal system, 1084, 1084fin attentiveness and task performance, 1005, 1005ffiring patterns of, in sleep-wake cycle, 1001, 1001fLoewi, Otto, 180, 315, 316f, 359Lømo, Terje, 284, 1342Long arm, chromosome, 53Long noncoding RNAs, 29Longevity. See Life spanLongitudinal fasciculusmedial, lesions on eye movements, 869f, 870superior, in language development, 1382Long-term depression (LTD)after eye closure, on visual development, 1220of auditory input to amygdala, 1334behavioral role of, 1356f, 1357in cerebellum, 1353in drug addiction, 1075of synaptic transmission, in memory, 1353, 1356f, 1357Long-term memory. See Memory, explicit; Memory, implicitLong-term potentiation (LTP)AMPA receptors in, 1334in amygdala, 1332–1333, 1333fdefinition of, 1350in drug addiction, 1075in fear conditioning, 1332–1333, 1333fgene expression in, 1333–1334in hippocampus. See Hippocampusinduction vs. expression of, 1345NMDA receptors in, 284, 286f–287f, 1332–1333in spatial memory. See Memory, spatialin synaptic plasticity, 351Lou Gehrig disease. See Amyotrophic lateral sclerosis (ALS)Lower motor neuron(s), 1426Lower motor neuron disorders, 1426. See also Motor neuron diseasesLow-pass behavior, 534b, 534fLow-pass spatial filtering, 534b, 534fLow-threshold mechanoreceptors (LTMRs), 420f–421fLow-voltage activated (LVA) Ca2+ channels, 227Kandel-Index_1583-1646.indd 1612 19/01/21 9:18 AMIndex 1613L-pigment genes, on X chromosome, 539–540, 539fLRRK2 mutations, 1549LTD. See Long-term depression (LTD)LTP. See Long-term potentiation (LTP)L-type Ca2+ channel, 329, 331t, 332Lumbar spinal cord, 13f, 78–79, 78fLumpkin, Ellen, 419Lundberg, Anders, 778Luria, Alexander, 1309Lysosomes, 135, 136fMM cones, 525, 526f, 529, 538M opsin, 528fMachado-Joseph disease, 1546, 1548, 1549tMachine learning networks, 103fMacKinnon, Rod, 180, 182MacLean, Paul, 1049–1050MacMahan, Jack, 349Macula, hair cells, 634MAG. See Myelin-associated glycoprotein (MAG)Magnetic resonance imaging (MRI). See also Functional magnetic resonance imaging (fMRI)normal human brain, 15ffor seizure focus localization, 1463Magnetoencephalography, in language studies, 1370, 1381Magnocellular layers, lateral geniculate nucleus, 501, 511f, 512, 514fMahowald, M.W., 1095Main olfactory epithelium (MOE), 1272, 1273fMajor depressive disorderin childhood, 1503environmental risk factors for, 1507–1508epidemiology of, 1502genetic risk factors for, 1506–1507hippocampal volume decrease in, 1512hypothalamic-pituitary-adrenal axis activation in, 1508–1509, 1508fneural circuit malfunction in, 1509–1511, 1511fvs. sadness or grief, 1502suicide with, 1503symptoms and classification of, 1502–1503, 1502ttreatment ofantidepressant drugs in. See Antidepressant drugscognitive therapy in, 1474belectroconvulsive therapy in, 1518ketamine in, 1515neuromodulation in, 1518–1519, 1519fpsychotherapy in, 1515, 1518Majorhistocompatibility complex (MHC), schizophrenia risk and, 50, 1497Malingering, 1485Malinow, Roberto, 1346Malleusanatomy of, 599, 599fin hearing, 601, 602f–603fMamiya, Ping, 1382Mangold, Hilde, 1108–1110Mania/manic episode, 1503–1504, 1503t. See also Bipolar disorderMapauditory, critical period for refinement of, 1227–1229, 1227f–1229fbody surface, in dorsal root ganglia, 362cognitive, 1288cortical, protomap, 1123of interaural time differences in medial superior olive, 657, 660–661fmotor periphery, in primary motor cortex, 841, 842fneural. See Neural mapsof sound location information in superior colliculus, 665, 666fspatial, in hippocampus. See Hippocampus, spatial cognitive maps intonotopic, 604MAP2 proteinin dendrites, 1157, 1158fin hippocampal neuronal polarity, 1157, 1158fMAPKs. See Mitogen-activated protein kinases (MAPKs, MAP kinases)Mapping, for seizure focus localization in epilepsy, 1463Marginal layer, of spinal cord dorsal horn, 474, 475fMarijuana, 1072t. See also Drug addictionMárquez, Gabriel Garcia, 1291Marr, Davidcerebellum in motor learning, 105, 923, 928on hippocampal circuit for memory, 1340, 1359–1360Marshall, John, 1475Marshall, Wade, 19Martin, Kelsey, 1324–1325, 1327Mash1, in cerebral cortex, 1134–1135, 1141, 1143f, 1145, 1145fMass action, theory of, 18Match/nonmatch perceptual decision, 835Maternal behavior in rodents, early experience on, 1274–1275, 1274fMath-1, 1145, 1145fMating behaviorin fruit fly, genetic and neural control of, 1266, 1268b, 1269fhypothalamic neural circuit on, 1272Mauk, Michael, 925Mauthner cell, 247Maxillary palps, 692, 693fMaximal force, of muscle, 740, 742Maximum entropy codes, 404MBP (myelin basic protein), in demyelinating neuropathies, 1431fMC4R (melanocortin-4 receptor), 1036f–1037f, 1037–1038McCarroll, Steven, 50McCarthy, Gregory, 569McCormick, David, 1461M-cells, retinal ganglion, 523f, 531MDS (MECP2 duplication syndrome), 1532Meaney, Michael, 1274Measles-mumps-rubella (MMR) vaccine, autism spectrum disorder risk and, 1530–1531Mechanical allodynia, 481Mechanoreceptorsactivation of, 414–415, 416f, 471, 471fcharacteristics of, 391f, 392, 392tcutaneous. See Cutaneous mechanoreceptorsdorsal root ganglia neuron axon diameter in, 410–412ion channels in, 415–416, 416f, 417fmechanisms of action of, 424–425, 425fmuscle, 415trapidly adapting, 396, 397frapidly adapting low-threshold, 419, 420f–421fskeletal, 415tslowly adapting, 396, 397f. See also Slowly adapting type 1 (SA1) fibers; Slowly adapting type 2 (SA2) fibersto spinal cord dorsal horn, 474, 475ffor touch and proprioception, 414–416, 415t, 416f, 417fMECP2 duplication syndrome (MDS), 1532MECP2 mutations, 1467, 1532Medial, 11b, 11fMedial ganglionic eminences, neuron migration to cerebral cortex from, 1140fMedial geniculate nucleus, 82f, 83Medial group, thalamic nuclei, 82f, 83Medial intraparietal region (MIP)in control of hand and arm movements, 825, 826f–827fin decision-making, 1404f–1405fMedial lemniscus, 80f–81f, 81–82, 450, 450f–451fMedial longitudinal fasciculus lesions, on eye movements, 869f, 870Medial nuclear group, nociceptive information relay to cerebral cortex by, 485Medial premotor cortex, contextual control of voluntary actions in, 829–831, 830fMedial superior temporal area lesions, 878Medial temporal lobein autism, 1525fin encoding of visual events, 1298–1299, 1299fin episodic memory, 1294–1297, 1295f–1296fin implicit memory, 1303–1304in memory storage, 1294, 1295fin visual memory, 577–578Kandel-Index_1583-1646.indd 1613 19/01/21 9:18 AM1614 IndexMedial vestibular nucleus, 636, 641f. See also Vestibular nucleiMedial vestibulospinal tract, in automatic postural response, 902Medial-lateral axis, of central nervous system, 11b, 11fMedian preoptic nucleus (MnPO), 1014f, 1015in body temperature control, 1030in fluid balance, 1032, 1032fin sleep promotion, 1085–1086in thirst drive, 1033Medulla (oblongata)anatomy of, 12b, 13f, 14f, 15fbreathing generation in, 995, 995fbreathing regulation in, 996, 996fcranial nerve nuclei in, 967fMedullary pyramids, 89Meissner corpusclesfiber group, name, and modality for, 415tin human hand, 438, 439f, 442finnervation and action of, 391f, 438, 441fRA1 fibers in. See Rapidly adapting type 1 (RA1) fibersin touch, 437–438, 437f, 438tMEK (mitogen-activated/ERK), 1150fMelanocortin-4 receptor (MC4R), 1036f–1037f, 1037–1038Melanopsin, 992, 993f, 1090Melzack, Ronald, 488Memantine, 1577Membrane, cell. See Cell (plasma) membraneMembrane capacitance, 203–204, 204fMembrane current (Im), 213Membrane potential (Vm), 190–201highlights, 208–209membrane capacitance and, 203–204, 204fneuron as electrical equivalent circuit and, 199–201. See also Equivalent circuitresting. See Resting membrane potential (Vr)in voltage clamp, 213, 214bMembrane resistance, 204–206, 205fMembrane time constant, 204Membrane trafficking, in neuron, 142, 144fMembranous labyrinth, 630, 630f, 631Membranous organelles, 135Memory, 1291–1309. See also Learningage-related decline in, 1562, 1563fin Alzheimer disease. See Alzheimer diseaseautobiographical, 1367cellular, 351conscious recall of, 1482–1483, 1482fas creative process, 1482–1483declarative. See Memory, explicitdefinition of, 1292episodic. See Memory, episodicerrors and imperfections in, 1308–1309false, 1482–1483fMRI studies of, 121–122forgotten, imprint of, 1482, 1482fhighlights, 1309hippocampus in. See Hippocampusimmediate (working). See Memory, short-termnondeclarative. See Memory, implicitoverall perspective of, 1287–1289procedural. See Memory, implicitsleep and formation of, 1096social, 1360visual. See Visual memoryMemory, episodic, 1294–1302accuracy of, 1298bbrain regions involved in, 124fcontribution to imagination and goal-directed behavior, 1300, 1301fdefinition of, 1296early work on, 1294medial temporal lobe and association cortices interaction in, 1298–1300medial temporal lobe in storage of, 1294–1297, 1295fprocessing of, 1297–1298retrieval of, 1300, 1301f, 1482Memory, explicitautobiographical, 1367brain systems in transference of, 403, 1312–1313, 1313fconscious recall of, 1482definition of, 1296, 1297episodic. See Memory, episodicfMRI studies of, 121–122semantic, 1296storage of, 1339–1367cell assemblies in, 1357–1358, 1358f–1359fhighlights, 1367–1368hippocampus in. See Hippocampuslong-term depression of synaptic transmission in, 1353–1357, 1356fMemory, implicit, 1303–1308associative vs. nonassociative, 1304–1306brain systems in transference of, 403, 1312–1313, 1313fdefinition and properties of, 1296, 1297ffMRI studies of, 121–122neural circuits in, 1303–1304in perceptual learning, 1304in sensorimotor skill learning, 1304in statistical learning, 1303–1304stimulus-reward learning and, 1304, 1305fstorage of, synaptic transmission in, 1313–1319habituation and presynaptic depression of, 1314–1315, 1315f, 1316flong-term habituation of, 1314, 1316fpresynaptic facilitation of, in sensitization, 1316–1317, 1318f–1319fshort-term habituation of, 1314–1315, 1315fthreat conditioning and, 1317, 1319, 1320fsynaptic changes mediated by cAMP-PKA-CREB pathway in long-term storage of, 1319–1330cAMP signaling in long-term sensitization for, 1319, 1321f–1322f, 1323facilitation of, in threat conditioning, 1317, 1319, 1320fnoncoding RNAs in regulation of transcription in, 1323–1324, 1324f, 1325fpresynaptic facilitation of, 1316–1317, 1318f–1319fprion-like protein regulator in maintenance of, 1327–1329, 1329fsynapse specificity of, 1324–1327, 1326f, 1328fvisual priming in, 1303, 1303fMemory, long-termexplicit. See Memory, explicitimplicit. See Memory, implicitMemory, procedural, 1482Memory, semantic, 1296Memory, short-termdefinition of, 1292executive controlprocesses in, 1292prefrontal cortex in, 1292, 1293fselective transfer to long-term memory from, 1293–1294, 1295ftransient representation of information for immediate goals in, 1292, 1293ffor verbal information, 1292for visuospatial information, 1292Memory, spatiallong-term potentiation and, 1350–1353deficits in, reversibility of, 1351, 1355fMorris water maze for tests of, 1350, 1352f–1353f, 1354fNMDA receptors in, 1350–1351, 1352f–1353f, 1353, 1354fplace cells as substrate for, 1365–1367, 1366fvestibular signals in orientation and navigation, 646–647Memory storage. See also specific types of memoryin different parts of brain, 1292of episodic memory, 1297hippocampus in, 1294, 1295fmedial temporal lobe in, 1293–1294, 1295fMendelian (simple) mutation, 33bMendell, Lorne, 765Mental processes. See Cognitive function/processesKandel-Index_1583-1646.indd 1614 19/01/21 9:18 AMIndex 1615Mental retardation, 1523Mentalizingbrain areas used in, 1527, 1528fstudies of, 1525–1527, 1526f–1527fMerkel cells (Merkel disk receptor)fiber group, fiber name, and modality in, 415tin finger skin, 440b–441bin human hand, 437f, 438, 438t, 442f, 504finnervation and functions of, 417–419, 418f, 441fSA1 fibers in. See Slowly adapting type 1 (SA1) fibersMerleau-Ponty, Maurice, 1409Merritt, Houston, 1448Merzenich, M.M., 1229–1230Mesaxon, 151, 152fMesencephalic locomotor region (MLR), 800, 801f, 802fMesencephalic reticular formation, in vertical saccades, 863f, 870Mesencephalic trigeminal nucleus, 989f, 990Mesencephalon, 1112, 1113fMesial temporal sclerosis, in temporal lobe seizures, 1463Mesodermembryogenesis of, 1108, 1109fsignals from, in neural plate patterning, 1112–1113, 1114fMessenger RNA (mRNA)definition of, 53in dendritic spines, 146, 147fin genome translation, 27in synaptic facilitation, 1327Metabolic mapping, in seizure focus localization, 1463Metabotropic receptors. See also specific typesfamilies of, 302, 302fG protein-coupled. See G protein-coupled receptorsvs. ionotropic receptors, 251, 312–313, 312t, 313f, 314fmechanism of, 239, 250–251, 251fneurotransmitter activation of, 302–303, 302fphysiologic actions of, 312, 312treceptor tyrosine kinase. See Receptor tyrosine kinasesMetacognition, 1483–1484Metarhodopsin II, 528–529Methadone, 1072tmGluR5 (type 5 metabotropic glutamate receptor), 1531MHC (major histocompatibility complex), schizophrenia risk and, 50, 1497MHC (myosin heavy chain) isoforms, 741–742, 741fMice. See Mouse modelsMicrocephaly, in neurodevelopmental disorders, 1540Microfilaments, 139, 140fMicrogliaactivation by peripheral nerve injury, 481, 484factivation in amyotrophic lateral sclerosis, 1428functions of, 159–160, 160f, 1240in schizophrenia, 1497, 1497fstructure of, 160fin synapse elimination, 1206, 1207fMicroneurography, 773MicroRNA (miRNA)in gene transcription, 29in memory consolidation switch, 1323–1324, 1324fMicrosleeps, 1091Microstimulation, 1400, 1400fMicrotubule(s)in cytoskeleton, 139, 140f, 143fin fast axonal transport, 144in kinocilium, 606in neuron migration along glial cells, 1137, 1139fas organelle tracks, 141in slow axonal transport, 146–147structure of, 136f, 139, 141Microtubule-associated protein kinase (MAPK), 1148, 1150fMicrotubule-associated proteins (MAPs)in cytoskeleton, 139in neurofibrillary tangles, 1573–1574, 1574fMicrovilli, taste cell, 697, 697fMicturition reflex, 1023, 1024fMidbrain. See also specific structuresanatomy of, 12b, 13f, 15fin ascending arousal system, 1084, 1084fembryogenesis of, 1112, 1113finput from basal ganglia, 939–940in locomotion, 800–802, 801f, 802fpatterning of, isthmic organizer signals in, 1113–1115, 1114f, 1115fsignals to basal ganglia, 939Midbrain-hindbrain boundary, 1114, 1114fMiddle cerebellar peduncle, 925Middle ear cavity, 599, 599fMiddle temporal area, in visual processing, 504f–505f, 505Middle temporal area lesions, 878Midget bipolar cell, 536, 537fMidline crossing, of spinal neuron axons, 1176–1179chemoattractant and chemorepellent factors on, 1176–1179, 1178fnetrin direction of commissural axons in, 1176, 1177f, 1178fMidline nuclei, of thalamus, 82f, 83Midline vermis, 925MigraineP/Q-type Ca2+ channel mutation in, 332treatment of, 1004Migration, chain, 1140, 1140fMigration, neuronalglial cells as scaffold for excitatory cortical neurons, 1137–1138, 1138f, 1139finside-out, 1139fintegrins in, 1137of interneurons, 1138–1139, 1140fin lissencephaly, 1138, 1139fof neural crest cells in peripheral nervous system, 1141, 1142f, 1143fRamón y Cajal, Santiago on, 1137tangential, 1138–1140, 1140fMild cognitive impairment (MCI), 1566, 1567fMiledi, Ricardoon Ca2+ influx in transmitter release, 327on presynaptic terminal depolarization in transmitter release, 324–326, 325f–326fMill, James, 404Mill, John Stuart, 382, 404Miller, Christopher, 162bMiller, Earl, 573, 575Mills, Deborah, 1381–1382Milner, Brenda, 1293, 1340Milner, David, 1488Milner, Peter, 1066Mindbrain and, 1419–1420definition of, 7science of, 4Mind blindness, 1525–1527Miniature end-plate potential, 332–333Miniature synaptic potentials, spontaneous, 334fMIP. See Medial intraparietal region (MIP)Mirror neurons, 838, 839fMisattribution, 1308Mishkin, Mortimer, 402Miss, in decision-making, 1395Missense mutations, 33bMitochondria, 31DNA in, 31function of, 135origins of, 135structure of, 136fMitochondrial dysfunction, on neurodegenerative disease, 1556Mitogen-activated protein kinases (MAPKs, MAP kinases)activation of, 308–309, 309fin long-term sensitization, 1321f, 1323Mitogen-activated/ERK (MEK), 1150fMitosis, in embryonic brain cells, 1131Mitral cell, 683f, 688, 690, 690fMiyashita, Yasushi, 578MK801, on NMDA receptor, 277f, 283MLR (mesencephalic locomotor region), 800, 801f, 802fMMR (measles-mumps-rubella) vaccine, autism spectrum disorder risk and, 1530–1531MnPO. See Median preoptic nucleus (MnPO)Mobility, of ions, 167Kandel-Index_1583-1646.indd 1615 19/01/21 9:18 AM1616 IndexModafinil, for narcolepsy, 1095Model-based reinforcement, 734Modular processing, in brain, 21–22Modulatory synaptic actions, 313fMOE (main olfactory epithelium), 1272, 1273fMolaison, Henry, 94, 1293–1294Molecular layer, of cerebellum, 918, 919fMolecular organizers, in presynaptic specialization, 1192, 1193fMoment arm, 50, 754fMonoamine oxidase (MAO), 1513–1514Monoamine oxidase (MAO) inhibitors, 375, 1514, 1516f–1517fMonoaminergic neurons. See Brain stem, monoaminergic neurons inMonoaminergic pathwaysascending, 998, 1004–1006, 1005f, 1006f. See also Ascending arousal systemdescending, 488–489, 489f, 998motor activity facilitation by, 1004pain modulation by, 1002, 1004Monoamines. See also specific monoamineson motor neurons, 745, 746fstructure and functions of, 360t, 361–364Monocular crescent, 502fMonogenic epilepsies, 1467, 1468fMonosynaptic pathways, in stretch reflex, 716, 762–765, 763f, 773fMonoubiquitination, 149Montage, EEG electrode, 1451fMood and anxiety disorders, 1501–1521. See also Anxiety disorders; Bipolar disorder; Major depressive disorderenvironmental factors in, 1507–1508fMRI in, 1509–1511, 1510fgenetic risk factors in, 1506–1507highlights, 1520–1521hippocampal volume decrease in, 1512neural circuit malfunction in, 1509–1512, 1510f–1511fMood stabilizing drugs, 1519–1520Morgan, Thomas Hunt, 31Morphemes, 1372Morphine. See also Drug addictionpain control mechanisms of, 489f, 490–493, 492fsource and molecular target of, 1072tMorris, Richard, 1327, 1348Morris water maze, 1350, 1352f–1353f, 1354fMoser, Edvard, 99Moser, May-Britt, 99Mossy fiber pathway, 1340, 1341f, 1342, 1343fMossy fibers, in cerebelluminformation processing by, 105, 918–920, 920fsynaptic reorganization of, 1469, 1470fMotion. See also Locomotion; Voluntarymovementangular, postural response to, 895–896of basilar membrane, 602f–603fbody, ambiguous information from somatosensory inputs for, 897, 898fhorizontal, postural response to, 895–897linear. See Linear motionneurons sensitive to, successive central synapses for, 460, 461fPacinian corpuscle detection of, 445f, 446perception of, bottom-up processes in, 555rapidly adapting fibers for detection of. See Rapidly adapting type 1 (RA1) fibers; Rapidly adapting type 2 (RA2) fibersMotion correction, in fMRI, 116Motion sickness, sensory information mismatch in, 898Motion-sensitive neurons, 460, 461fMotivational stateson goal-directed behavior, 1111–1114brain reward circuitry in, 1066–1068, 1067fdopamine as learning signal in, 1068–1069, 1069finternal and external stimuli in, 1065–1066regulatory and nonregulatory needs in, 1066highlights, 1078pathological. See Drug addictionMotor apparatus, cerebellar internal model of, 922Motor commands. See Sensorimotor control; Voluntary movementMotor coordination. See also specific typescerebellum in, 925–927, 926f–927ffor locomotion. See Locomotionin muscle movement, 755–758, 755f–757fMotor cortex, primary. See Primary motor cortexMotor equivalence, 726, 727fMotor homunculus, 84–85, 84fMotor imagery, 837Motor learning. See Motor skill learningMotor molecules, for fast axonal transport, 144Motor nerve terminal, differentiation of, 1190–1192, 1193f, 1194fMotor neuron(s), 1120alpha, 764bconduction velocity of, 1425, 1425fdeath and survival of, 1147, 1148fdefinition of, 59development of subtypes of, 1119–1123ephrin signaling in, 1122, 1125fHox genes and proteins in, 1120–1121, 1122f–1124frostrocaudal position on, 1120–1121, 1121f, 1125ftranscriptional circuits with, 1121–1123, 1124f–1125fWnt4/5 signals in, 1122electrically coupled, simultaneous firing of, 247–248, 249ffunction of, 1120functional components of, 64, 64fgamma. See Gamma motor neuronsin innervation number, 739, 739tinput-output properties of, 745, 746flower, 1426monoamines on, 745, 746f, 1004in motor units, 737–738, 738fin NMJ postsynaptic muscle membrane differentiation, 1192f, 1194–1196, 1195fsize of, on recruitment, 743–744, 744fin spinal cord, 76, 77fstructure of, 136fupper, 1426visceral, in autonomic system, 1015–1016Motor neuron diseases, 1426–1428amyotrophic lateral sclerosis. See Amyotrophic lateral sclerosis (ALS)lower, 1426poliomyelitis, 1428progressive spinal muscular atrophy, 1428upper, 1426Motor periphery map, 841, 842fMotor plans. See Sensorimotor controlMotor pools, 1120, 1124fMotor predominant neuropathy, 1433tMotor primitives, 734Motor signals, in reflex action, 68, 69f. See also Sensorimotor control, motor signal control inMotor skill learningin cerebellum, 923–929climbing fiber activity on synaptic efficacy of parallel fibers in, 924–925, 924fdeep cerebral nuclei in, 928–929, 928fof eye-blink response, 108, 109f, 925in eye-hand coordination, 925, 926fnew walking patterns, 928saccadic eye movements/adaption, 925, 927, 927fvestibular plasticity in, 108–109vestibulo-ocular reflex, 643, 644f, 925, 927fnetwork functional connectivity changes during, 1304in primary motor cortex, 852, 854–856, 854f, 856fsensorimotor control of. See Sensorimotor control, of motor learningMotor skills, age-related decline in, 1341Motor systems. See Locomotion; specific systemsMotor unit, 737–745actions of, 1421–1422components of, 737–739, 738fdefinition of, 737, 1421force of, action potential rate on, 739–742, 740fhighlights, 758Kandel-Index_1583-1646.indd 1616 19/01/21 9:18 AMIndex 1617innervation number of, 739, 739tin muscle contraction, 738–739on muscle force, 742–745, 743f, 744fproperties ofphysical activity on, 741f, 742variation in, 739–742, 741fMotor unit diseasesdifferential diagnosis of, 1423–1426, 1423ttypes of, 1422, 1422f. See also Motor neuron diseases; Myopathies; Neuromuscular junction disorders; Peripheral neuropathiesMotor-error signals, 855, 856fMountcastle, Vernonon cortical organization, 452on perceptual decisions, 1395–1396on sensorimotor circuits in parietal cortex, 463on sensory thresholds and neural responses, 395on visual neurons response to position of eye in orbit, 587Mouse modelsjimp, 94b, 156bof neurodegenerative diseases, 1552–1553, 1553f, 1554fob/ob, 1035reeler, 1136f–1137ftargeted mutagenesis in, 35b–36b, 36ftotterer, 1463, 1467f, 1468transgene introduction in, 39b, 39ftrembler, 155b, 155fWlds, 1238, 1238f, 1239fMovement. See also specific types and systemscontrol of. See also Sensorimotor control; Voluntary movementin cerebellum. See Cerebellum, movement control byin cerebral cortex. See Primary motor cortexcoordination of motor system components in, 89, 91f, 714–715, 714fin locomotion, posterior parietal cortex in, 806, 807f, 808fdecoding of. See Brain-machine interfaces (BMIs), movement decoding indirectional selectivity of, 554, 555fguidance of, dorsal visual pathways in, 505local cues for, in object and trajectory shape, 554–555muscle. See Muscle, movement ofoverall perspective of, 709–711speed–accuracy trade-off in, 727–728, 728fMovement field, 872Movement-related neurons, 875, 876fMoving objects, retinal output and, 531, 533f, 534b–535bretinal ganglion cell representation of, 531, 533fspatiotemporal sensitivity of human perception in, 531, 534b–535b, 535fMoving stimuli, in visual processing, 549Movshon, J. Anthony, 390b, 1397M-pigment genes, on X chromosome, 539–540, 539fMPZ (Myelin protein zero), 156bMrg protein family, 472MRI. See Magnetic resonance imaging (MRI)mRNA. See Messenger RNA (mRNA)mTOR inhibitors, 1469mTOR pathway, in axon regeneration, 1246–1247, 1248fM-type K+ channel, 313, 314f, 315, 1468fMu (μ) receptors, opioid, 489, 490, 490tMueller, Paul, 162bMüller, Johannes, 8, 390Müllerian duct differentiation, 1262, 1263fMüllerian inhibiting substance (MIS), 1262, 1263fMüller’s muscle, innervation of, 863Multimodal association cortex, 88, 89fMultiple sclerosiscompound action potential in, 414demyelination in, 208postural responses in, 892, 892fMultiple Sleep Latency Test, 1086–1087, 1095Multipolar neurons, 59, 60fMultivariate pattern analysis, in fMRI, 117f, 118–119Munc13, 344f, 349, 351Munc18, 344f, 346, 346fMuscarine-sensitive K+ channel, 313, 314fMuscarinic ACh receptors, 255, 1021tMuscle. See also specific muscles and actionsanatomy offiber number and length in, 750–754, 753fon function, 750–754, 752fin human leg muscles, 752–754, 753tsarcomeres in, 750–752types of arrangements in, 750–752, 752fcontraction of, 762flexion reflex in, 763fmuscle spindles in, 764b, 765fsensory fibers in, 762, 766b, 766tstretch reflex in, 762, 763ffiber types in, 1188, 1189fforce of. See Muscle forcemechanoreceptors in, 415tmovement of, 754–758contraction velocity variation in, 751f, 754–755, 754fmuscle coordination in, 755–758, 755f, 756fpattern of activation in, 758, 793fproprioceptors for activity of, 421–422, 422fsensory fibers from, classification of, 766tstiffness of, 749synergistic activation of, for posture, 890fsynergy of, 756torque of, 754, 754ftypes of, 1421Muscle biopsy, 1423t, 1425Muscle fiberson contractile force, 747–749, 751fcontractile properties of, 741–742, 741f, 742fextrafusal, 764binnervation number of, 739, 739tintrafusal, 421, 422f, 764b, 765fmyosin adenosine triphosphatase assay of, 741myosin heavy chain isotopes in, 741–742, 741fnumber and length of, 752, 753f, 753tproperties of, variation in, 739–742, 740f, 741fMuscle field, 844Muscle force, 745–754highlights, 758–759motor unit control of, 742–745, 743f, 744fmuscle structure on, 745–754contractile force in, 747–749, 751fnoncontractile elements in, structural support from, 747, 748f–749fsarcomere contractile proteins in,745–747, 748f–750ftorque and muscle geometry in, 750–754, 752f–754fMuscle signals, in reflex action, 69fMuscle spindles, 62afferent activity in reinforcement of central commands for movement, 773–775, 775fgamma motor neurons on sensitivity of, 766–767, 769f, 770fintrafusal fibers in, 421, 422f, 764b, 765fin proprioception, 421–422, 422fstructure and function of, 764b–765b, 765fMuscular dystrophies, 1422–1423, 1437–1441Becker, 1437, 1438t, 1440f–1441fDMD mutation in, 1437, 1439, 1440f–1441fDuchenne, 1436–1439, 1440f–1441fdysferlin in, 1439, 1442fgenetic defects in, 1437tinheritance of, 1437limb-girdle, 1437, 1439myotonic, 1439, 1443fMushroom bodies, 693f, 694, 1330MuSK (muscle-specific trk-related receptor with a kringle domain)in ACh receptor action at synaptic sites, 1194, 1195f, 1196antibody to, in myasthenia gravis, 1433, 1435Kandel-Index_1583-1646.indd 1617 19/01/21 9:18 AM1618 IndexMutagenesischemical, 35brandom, in flies, 35bsite-directed, 177targeted, in mice, 35b–36b, 37fMutations. See also specific types and disordersdefinition of, 53dominant, 32generation of, in animal models, 35b–36b, 36fgenetic diversity and, 32, 33brecessive, 32Mutism, 829bMyalgia, 1422Myasthenia gravis, 1433–1436ACh receptors in, 267, 1433–1435, 1435fantibodies in, 1435autoimmune, 1433congenital, 1433, 1435–1436ptosis in, 1433, 1433fsynaptic transmission failure in, 1433–1435, 1434fthymus tumors in, 1434treatment of, 1435Mydriasis, oculomotor nerve lesion in, 864bMyelin, 57f, 58age-related changes in, 1563axon insulation by, 152f, 153f, 154in closing of critical period for monocular deprivation, 1223, 1224fdefects inin demyelinating neuropathies, 1431f. See also Charcot-Marie-Tooth diseaseon nerve signal conduction, 154, 155b–157b, 155f–157fon neurite outgrowth, 1244–1245, 1244f, 1245fproteolipid protein in, 156bSchwann cells on, after axotomy, 1240structure of, 154Myelin basic protein (MBP), in demyelinating neuropathies, 1431fMyelin protein zero (MPZ or P0), 156bMyelin-associated glycoprotein (MAG)on axon regeneration, 1245, 1245fin nerve signal conduction, 155b–156bMyelinationon action potential propagation velocity, 208, 208fin central nervous system, 152f, 153fin peripheral nervous system, 152f, 153frestoration of, oligodendrocyte transplantation for, 1255, 1255fMyocardial infarction, referred pain in, 474, 476fMyofibril, 745, 748f–749fMyoglobinuria, 1422Myopathies (primary muscle diseases), 1422characteristics of, 1437dermatomyositis, 1437differential diagnosis of, 1422–1426, 1423t, 1424f, 1425finheritedmuscular dystrophies. See Muscular dystrophiesmyotonia congenita, 1444–1445, 1444fperiodic paralysis. See Periodic paralysisvoltage-gated ion channel genetic defects in, 1441–1442, 1443fvs. neurogenic diseases, 1423–1426, 1423t, 1424f, 1425fMyosinin actin filaments, 141in growth cone, 1163f, 1164, 1165fin hair bundles, 614in thick filaments, 745, 748f–749fMyosin adenosine triphosphatase, 741Myosin heavy chain (MHC) isoforms, 741–742, 741fMyotome, 429Myotonia, 1422, 1443f, 1444fMyotonia congenita, 1444–1445, 1444fMyotonic dystrophy, 1439, 1443fNNa+ channelsresting, multiple, in cell membrane, 201resting potential, 195, 196fstructure of, 167, 168f–169fvoltage-gatedin action potential. See Voltage-gated ion channels, in action potentialgenetic factors in diversity of, 177, 178f, 225–227genetic mutations in, epilepsy and, 1467, 1468finactivation ofin periodic paralysis, 1441–1444, 1443fduring prolonged depolarization, 217–219, 219finterdependence of K+ channel with, 212–213, 214b–215bion conduction in, 261Na+ selection criteria of, 222, 224opening/closing of, charge redistribution in, 220–222, 223fpersistent Na+ current in, 231, 232frecovery from inactivation of, 220, 221fin seizures, 1455–1456Na+ currentinward, 219persistent, 231, 232fvoltage-gated, on conductance, 217–219, 218b, 218f–219fNa+ equilibrium potential, 198–199Na+-Ca2+ exchanger, 197f, 198N-acylation, 148Nadel, Lynn, 1361Nader, Karim, 1330Na+-K+ pump (Na+-K+ ATPase), 65, 195–198, 197fNa+-K+-Cl- cotransporter, 197f, 198Narcolepsy, 1085, 1093–1095, 1094fNav1 gene family, 226, 228, 472NCAM, in axon growth and guidance, 1170f–1171fNear response, 880Nebulin, 747, 748f–749fNecker cube, 1476, 1476fNecrosis, 1151Negative feedback, in voltage clamp, 214b–215b, 214fNegative reinforcement, 1308Neglectspatial, 1475, 1475f, 1477unilateral, 505, 1475, 1475f, 1477visual. See Visual neglectNeher, Erwin, 162b, 171, 260, 329NeocortexBrodmann’s areas of, 87, 87fcolumnar organization of, 88layers of, 85–86, 85f–87fin sensorimotor skill learning, 1304Neospinothalamic tract, 485Neostigmine, on myasthenia gravis, 1434Nernst equation, 194Nernst potential, 194Nerve block, from demyelination, 1430Nerve cells. See Neuron(s)Nerve growth factor (NGF)in neurotrophic factor hypothesis, 1147, 1148f, 1149fin pain, 478, 479, 481freceptors for, 1150–1151, 1150fNerve-muscle synapse. See Neuromuscular junction (NMJ, end-plate)Nerve-stimulation tests, axon size on, 207Netrinsin axon growth and guidance, 1170f–1171fcommissural axon direction by, 1176, 1177f, 1178fconservation of expression and action of, 1176, 1178fin growth cone attraction or repellent, 1166fin presynaptic differentiation, 1203fNeural activitydecoding, 99estimating intended movements from, 960–962, 960f, 961f, 962f–963fintegrated, recurrent circuitry for, 105–107, 106fmeasurement of, 97–98, 97b, 98b, 957sensory information encoded by, 98in sharpening of synaptic specificity, 1187–1188, 1188f, 1189fNeural circuit(s). See also Neuron(s), signaling inconvergent, 63, 63f, 102f, 103development of, 1103–1104divergent, 63, 63f, 102f, 103Kandel-Index_1583-1646.indd 1618 19/01/21 9:18 AMIndex 1619experience and modification of, 71feedback, 63f, 64feedforward, 63–64, 63f, 102–103, 102fknee-jerk reflex and, 62, 62fknowledge of, importance of, 4, 7–8mediation of behavior by, 4, 62–64. See also Neural circuit(s), computational bases of behavior mediation by; Neural circuit(s), neuroanatomical bases of behavior mediation byfor memory-based goal-directed behavior, 1300, 1302fmotifs, 102–107, 103frecurrent, 102f, 103, 105–107, 106fin stretch reflexes, 62–64Neural circuit(s), computational bases of behavior mediation by, 97–110in complex behavior, 70–71highlights, 110methods of study, 97–98, 98b, 99bneural circuit motifs, 102–107, 102fneural firing patterns, 98–102, 100f–101fsynaptic plasticity, 107–109, 108f. See also Synaptic plasticityNeural circuit(s), neuroanatomical bases of behavior mediation byin complex behaviorshippocampal system connections in memory, 93–95, 93f, 94f, 95f. See also Hippocampuslocal circuits for neural computations, 74, 75f, 76fcortical-spinal cord connections for voluntary movement, 89, 90f, 91f. See also Primary motor cortexmodulatory systems on motivation, emotion, and memory, 89, 92peripheral nervous system in, 92–93, 92fsensory information circuits in, 73–81. See also Somatosensory cortex/systemanterolateral system in, 80f–81fcentral axon terminals and body surface map in, 81culmination in cerebral cortex. See Cerebral cortex, in sensory information processingdorsal column–medial lemniscal system, 75f, 80–81fdorsal root ganglia, 79–81, 79f, 80f. See also Dorsal root gangliahighlights, 95spinal cord, 76–79, 77f, 78f. See also Spinal cordsubmodality processing in, 81–82thalamus as link between sensory receptors and cerebral cortex in, 82–84, 82f. See also Thalamic nucleiNeural coding. See also Sensory coding; Sensory neuronsstudy of, 388–390in visual processing, 517–518, 517fNeural commitment, 1377Neural correlates of consciousness, 1475–1476Neural crest cellsdefinition of, 1141migration fromProfessor and Chair of PhysiologyInterim Chair of Molecular and Medical PharmacologyDavid Geffen School of MedicineUniversity of California, Los AngelesDavid E. Clapham, MD, PhD Aldo R. Castañeda Professor of Cardiovascular Research, EmeritusProfessor of Neurobiology, EmeritusHarvard Medical SchoolVice President and Chief Scientific OfficerHoward Hughes Medical InstituteRui M. Costa, DVM, PhDProfessor of Neuroscience and NeurologyDirector/CEO Zuckerman Mind Brain Behavior InstituteColumbia UniversityAniruddha Das, PhDAssociate ProfessorDepartment of NeuroscienceMortimer B. Zuckerman Mind Brain Behavior Institute Columbia UniversityJ. David Dickman, PhDVivian L. Smith Endowed Chair of NeuroscienceDepartment of NeuroscienceBaylor College of MedicineTrevor Drew, PhDProfessorGroupe de Recherche sur le Système Nerveux Central (GRSNC)Department of NeurosciencesUniversité de MontréalGammon M. Earhart, PT, PhD, FAPTAProfessor of Physical Therapy, Neuroscience, and NeurologyWashington University in St. LouisJoel K. Elmquist, DVM, PhDProfessor, Departments of Internal Medicine and PharmacologyDirector, Center for Hypothalamic ResearchCarl H. Westcott Distinguished Chair in Medical ResearchMaclin Family Professor in Medical Science The University of Texas Southwestern Medical CenterRoger M. Enoka, PhDProfessorDepartment of Integrative PhysiologyUniversity of ColoradoGerald D. Fischbach, MDDistinguished Scientist and Fellow, Simons FoundationExecutive Vice President for Health and Biomedical Sciences, EmeritusColumbia UniversityWinrich Freiwald, PhDLaboratory of Neural SystemsThe Rockefeller UniversityChristopher D. Frith, PhD, FMedSci, FRS, FBAEmeritus Professor of Neuropsychology, Wellcome Centre for Human NeuroimagingUniversity College LondonHonorary Research FellowInstitute of PhilosophySchool of Advanced StudyUniversity of LondonDaniel Gardner, PhDProfessor of Physiology and BiophysicsDepartments of Physiology and Biophysics, Neurology, and NeuroscienceWeill Cornell Medical CollegeEsther P. Gardner, PhDProfessor of Neuroscience and PhysiologyDepartment of Neuroscience and PhysiologyMember, NYU Neuroscience InstituteNew York University Grossman School of MedicineCharles D. Gilbert, MD, PhDArthur and Janet Ross ProfessorHead, Laboratory of NeurobiologyThe Rockefeller UniversityKandel_FM.indd 46 20/01/21 9:04 AMContributors xlvii*DeceasedT. Conrad Gilliam, PhDMarjorie I. and Bernard A. Mitchel Distinguished Service Professor of Human GeneticsDean for Basic ScienceBiological Sciences Division and Pritzker School of MedicineThe University of ChicagoMichael E. Goldberg, MDDavid Mahoney Professor of Brain and BehaviorDepartments of Neuroscience, Neurology, Psychiatry, and OphthalmologyColumbia University Vagelos College of Physicians and SurgeonsZuckerman Mind Brain Behavior Institute Joshua A. Gordon, MD, PhDDirector, National Institute of Mental HealthDavid M. Holtzman, MDDepartment of Neurology, Hope Center for Neurological DisordersKnight Alzheimer’s Disease Research CenterWashington University School of MedicineFay B. Horak, PhD, PT Professor of NeurologyOregon Health and Science UniversityJohn P. Horn, PhDProfessor of NeurobiologyAssociate Dean for Graduate StudiesDepartment of NeurobiologyUniversity of Pittsburgh School of MedicineSteven E. Hyman, MDStanley Center for Psychiatric ResearchBroad Institute of MIT and Harvard UniversityDepartment of Stem Cell and Regenerative BiologyHarvard UniversityJonathan A. Javitch, MD, PhDLieber Professor of Experimental Therapeutics in PsychiatryProfessor of PharmacologyColumbia University Vagelos College of Physicians and SurgeonsChief, Division of Molecular TherapeuticsNew York State Psychiatric InstituteThomas M. Jessell, PhD*Professor (Retired) Department of Neuroscience and Biochemistry and BiophysicsColumbia UniversityJohn Kalaska, PhDProfesseur TitulaireDépartement de NeurosciencesFaculté de Médecinel’Université de MontréalEric R. Kandel, MDUniversity ProfessorKavli Professor and Director, Kavli Institute for Brain ScienceCo-Director, Mortimer B. Zuckerman Mind Brain Behavior InstituteSenior Investigator, Howard Hughes Medical InstituteDepartment of NeuroscienceColumbia UniversityOle Kiehn, MD, PhDProfessor, Department of NeuroscienceUniversity of Copenhagen Professor, Department of NeuroscienceKarolinska InstitutetStockholm, SwedenJohn D. Koester, PhDProfessor Emeritus of Clinical NeuroscienceVagelos College of Physicians and SurgeonsColumbia UniversityPatricia K. Kuhl, PhDThe Bezos Family Foundation Endowed Chair in Early Childhood LearningCo-Director, Institute for Learning and Brain SciencesProfessor, Speech and Hearing SciencesUniversity of WashingtonJoseph E. LeDoux, PhDHenry And Lucy Moses Professor of ScienceProfessor of Neural Science and PsychologyProfessor of Psychiatry and Child and Adolescent PsychiatryNYU Langone Medical SchoolDirector of the Emotional Brain InstituteNew York University and Nathan Kline InstituteKandel_FM.indd 47 20/01/21 9:04 AMxlviii ContributorsStephen G. Lisberger, PhDDepartment of NeurobiologyDuke University School of MedicineAttila Losonczy, MD, PhDProfessor, Department of Neuroscience Mortimer B. Zuckerman Mind Brain Behavior InstituteKavli-Simons FellowKavli Institute for Brain ScienceColumbia University Bradford B. Lowell, MD, PhDProfessor, Division of Endocrinology, Diabetes, and MetabolismDepartment of MedicineBeth Israel Deaconess Medical CenterProgram in NeuroscienceHarvard Medical SchoolGeoffrey A. Manley, PhDProfessor (Retired), Cochlear and Auditory Brainstem PhysiologyDepartment of NeuroscienceSchool of Medicine and Health SciencesCluster of Excellence “Hearing4all”Research Centre Neurosensory ScienceCarl von Ossietzky UniversityOldenburg, GermanyEve Marder, PhD Victor and Gwendolyn Beinfield University ProfessorVolen Center and Biology DepartmentBrandeis UniversityPascal Martin, PhDCNRS Research DirectorLaboratoire Physico-Chimie CurieInstitut Curie, PSL Research UniversitySorbonne UniversitéParis, FranceMarkus Meister, PhDProfessor of BiologyDivision of Biology and Biological EngineeringCalifornia Institute of TechnologyEdvard I. Moser, PhDKavli Institute for Systems NeuroscienceNorwegian University of Science and TechnologyTrondheim, NorwayMay-Britt Moser, PhDKavli Institute for Systems NeuroscienceNorwegian University of Science and Technology Trondheim, NorwayEric J. Nestler, MD, PhDNash Family Professor of NeuroscienceDirector, Friedman Brain InstituteDean for Academic and Scientific AffairsIcahn School of Medicine at Mount SinaiJens Bo Nielsen, MD, PhDProfessor, Department of NeuroscienceUniversity of CopenhagenThe Elsass FoundationDenmarkDonata Oertel, PhD*Professor of NeurophysiologyDepartment of NeuroscienceUniversity of WisconsinFranck Polleux, PhDProfessor, Columbia UniversityDepartment of NeuroscienceMortimer B. Zuckerman Mind Brain Behavior InstituteKavli Institute for Brain SciencePeter Redgrave, PhDUniversity Professor, EmeritusDepartment of PsychologyUniversity of SheffieldUnited KingdomLewis P. Rowland, MD* Professor of Neurology and Chair EmeritusDepartment of NeurologyColumbia University *DeceasedKandel_FM.indd 48 20/01/21 9:04 AMContributors xlixC. Daniel Salzman, MD, PhD Professor, Departments of Neuroscience and PsychiatryInvestigator, Mortimer B. Zuckerman Mind Brain Behavior InstituteInvestigator, Kavli Institute for Brain ScienceColumbia UniversityJoshua R. Sanes, PhDJeff C. Tarr Professor of Molecular and Cellular BiologyPaul J. Finnegan Family Director, Center for Brain ScienceHarvard UniversityClifford B. Saper, MD, PhDJames Jackson Putnam Professor of Neurology and NeuroscienceHarvard Medical SchoolChairman, Department of NeurologyBeth Israelneural tube, 1117f, 1119migration in peripheral nervous system, 1141, 1142f, 1143fNeural decoding, in brain-machine interfaces, 954Neural firing patternsin hippocampal spatial maps, 98–102information decoded from, 98in sensory information encoding, 98Neural groove, 1108Neural induction. See Induction, neuralNeural mapsexperience on, 1335f, 1336somatotopic, of neuron cortical columns, 454–456, 454f–455fNeural networksartificial, 404–405integration in, 105–107, 106fin mood and anxiety disorders, 1509, 1510fNeural platecells in, 1130–1131development ofcompetence in, 1108earliest stages of, 1108induction factors and surface receptors in, 1108, 1110–1112organizer region signals in, 1108–1110, 1110fneural tube formation from, 1108, 1109fNeural progenitor cellsexpansion in humans and other primates, 1141–1143, 1144fradial glial cells as. See Radial glial cellssymmetric and asymmetric division in proliferation of, 1131, 1132fNeural prostheses. See Brain-machine interfaces (BMIs)Neural science, overall perspective of, 3–4. See also specific topicsNeural tube developmentof brain stem, 986–987, 986fdorsoventral patterning in, 1115–1119bone morphogenetic proteins in, 1119conservation of mechanisms along rostrocaudal neural tube in, 1114f, 1118homogenetic induction in, 1116–1117mesoderm and ectodermal signals in, 1116sonic hedgehog protein in, 1117–1119, 1118fspinal cord neurons in, 1116, 1117fformation from neural plate, 1108, 1109fregionalization in, 1112, 1113frostrocaudal patterning in, 1112–1115inductive factors in, 1112mesoderm and endoderm signals in, 1112–1113, 1114forganizing center signals in, 1113–1115, 1114f, 1115frepressive interactions in hindbrain segmentation, 1115, 1116fNeurexin-neuroligin interactions, 1199–1203, 1202f, 1203fNeurexins, in presynaptic differentiation, 1199–1203, 1202f, 1203fNeurite outgrowth, myelin in inhibition of, 1244–1245, 1244f, 1245fNeuroactive peptides. See Neuropeptide(s)Neuroanatomical tracing, axonal transport in, 145b, 145fNeurodegenerative diseases. See also specific diseasesanimal models ofinvertebrate, 1553mouse, 1552–1553, 1553fepidemiology of, 1544hereditary, 1544–1545highlights, 1558neuronal loss after damage to ubiquitously expressed genes in, 1550–1552, 1551fpathogenesis of, 1553–1556apoptosis and caspase in, 1556mitochondrial dysfunction in, 1556overview of, 1556, 1557fprotein misfolding and degradation in, 1553–1555, 1555fprotein misfolding and gene expression alterations in, 1555–1556sporadic, 1544treatment of, 1556–1567Neurodevelopmental disorders15q11-13 deletion in, 1533–1534, 1533f22q11 deletion in, 48, 50, 1492Angelman syndrome, 1533–1534, 1533fautism spectrum disorders. See Autism spectrum disordersfragile X syndrome, 47, 1531genetic factors in, 46–48Prader-Willi syndrome, 1533–1534, 1533fRett syndrome. See Rett syndromesocial cognition mechanisms insight from, 1534Williams syndrome, 47, 1532Neuroendocrine cell, 64, 64fNeuroendocrine system. See Hypothalamus, neuroendocrine system ofNeurofascin, 1187, 1187fNeurofibrillary tangles, in Alzheimer disease. See Alzheimer disease (AD), neurofibrillary tangles inNeurofilament heavy polypeptide (NFH), 411fKandel-Index_1583-1646.indd 1619 19/01/21 9:18 AM1620 IndexNeurofilamentsin slow axonal transport, 147structure of, 136f, 139, 140fNeurogenesisin adult mammalian brain, 1249–1250, 1250f, 1251fin mood disorders, 1512recent research on, 1237stimulation of, in regions of injury, 1253throughout adulthood, 1359–1360Neurogenic inflammation, 479, 480fNeurogeninsin cerebral cortex, 1134–1135, 1143f, 1146fin neural crest cell migration, 1141, 1143fNeurohypophysis. See Posterior pituitary glandNeurokinin-1 (NK1) receptor, activation of, 477f, 482fNeuroliginsmutations of, in autism spectrum disorder, 49, 1534–1535in presynaptic differentiation, 1199–1203, 1202f, 1203fNeuromodulatorsmultiple, convergence on same neuron and ion channels, 320, 321fproperties of, 319Neuromuscular junction (NMJ, end-plate)acetylcholine receptors at. See Acetylcholine (ACh) receptorsaxon growth cones at, 1190, 1191fcalculating current of, from equivalent circuit, 269–271, 269f–270fcell types of, 1189chemical driving force in, 261–262current. See End-plate currentdevelopment of, 1189–1190, 1191f, 1192fmaturation of, steps of, 1197–1198, 1199fmotor nerve terminal differentiation in, 1190–1192, 1193f, 1194fpostsynaptic muscle membrane differentiation in, 1192f, 1194–1196, 1195fpostsynaptic potential at. See End-plate potentialpresynaptic and postsynaptic structures of, 255, 256fsynaptic differentiation at, 1189–1198acetylcholine receptor gene transcription in, 1196–1197, 1197fcell types in, 1189maturation in, steps of, 1197–1198, 1199fsynaptic signaling at, 255, 256f, 258fNeuromuscular junction disorders, 1432–1437botulism, 1436–1437categories of, 1433differential diagnosis of, 1422–1426, 1423t, 1424f, 1425fLambert-Eaton syndrome, 332, 1436–1437myasthenia gravis. See Myasthenia gravisNeuron(s), 56–61, 133–151. See also specific typesafferent, 59asymmetry of, 133axonal transport in. See Axonal transportaxons of, 57–58, 57fbasic features of, 56–57, 131–132beating, 68bipolar, 59, 60fbursting, 68cell body (soma) of, 57, 57fchattering, 229, 230fconnections of, 56, 102–103, 102fcortical, origins and migration of, 1137–1140, 1140fcytoplasm of, 136fcytoskeleton of, 139–141death of, 1237, 1562–1563definition of, 131dendrites of. See Dendritesdevelopment of, 1103–1105diameter ofin dorsal root ganglia, 410–411on length constant, 205in peripheral nerve, 410–412, 412f, 412tvariation in, 205differentiation of, 1103–1104, 1130–1131cerebral cortex layering in, 1135–1138, 1136f–1137fdelta-notch signaling and basic helix-loop-helix transcription factors in, 1131–1135, 1134f, 1135fhighlights, 1153–1154neural progenitor cell proliferation in, 1131, 1132fneurotransmitter phenotype plasticity in, 1143, 1145–1147, 1145f, 1146fradial glial cells in, 1131, 1133f. See also Radial glial cellsdirection-sensitive, 1398, 1399f, 1400, 1400fefferent, 59as electrical equivalent circuit. See Equivalent circuitendocytic traffic in, 150–151excitability. See Excitability, of neuronsfast-spiking, 230f, 231generation of. See Neural progenitor cellshighlights, 162integration of, 291–292interneurons. See Interneuronsmembrane trafficking in, 142, 144fmolecular level differences in, 68–69motor, 59multipolar, 59, 60fmyelin of, 57f, 58neurotransmitter release by, 131–132nodes of Ranvier in, 57f, 58organelles of, 136foverall perspective of, 131–132overproduction of, 1147passive electrical properties of, 201–208axial (axonal) resistance, 202–203, 205, 205faxon size and excitability, 206–207membrane and cytoplasmic resistance, 204–206, 205f, 206fmembrane capacitance, 203–204, 204fmyelination and axon diameter, 206f, 207–208, 208fpolarity of, 1157, 1158f, 1159fpolarization of, 131postsynapticastrocytes and, 158f, 159characteristics of, 57f, 58inhibitory current effect in, 294, 295fpresynapticastrocytes and, 158f, 159characteristics of, 57f, 58propriospinal, 778, 778fprotein synthesis and modification in, 147–150, 148fpseudo-unipolar, 59, 60fquantity of, in brain, 56secretory properties of, 131–132sensory, 59, 61fsignaling in, 64–69, 132. See also specific typesaction potential in, 57–58, 58f, 65–67, 66f, 67tin complex behavior, 70–71depolarization and hyperpolarization in, 65dynamic polarization in, 64ffunctional components of, 64, 64fion channels in, 65Na+-K+ pump in, 65neuron type on, 68output component in, 68rapid, ion channels in, 166receptor potential in, 65–66, 66f, 67tresting membrane potential in, 64sensory to motor transformation in, 68, 69fsignal types in, 64synaptic potentialin, 66–67, 67ttrigger zone in, 66f, 67structural and molecular characteristics of, 133–139, 135fsurvival of, 1147–1153Bcl-2 proteins in, 1151–1152, 1151fcaspases in, 1152–1153, 1152fcell death (ced) genes in, 1151, 1151fhighlights, 1153–1154nerve growth factor and neurotrophic factor hypothesis in, 1147, 1148f, 1149f, 1150fneurotrophic factors and, 1149f, 1151–1153, 1151f, 1152fneurotrophins in, 1147–1151, 1150f, 1151fsustained, 531, 532fKandel-Index_1583-1646.indd 1620 19/01/21 9:18 AMIndex 1621synapses of, 57f, 58synaptic cleft of, 57f, 58synaptic connections to, number of, 241synaptic input to, ion gated channels on response to, 229, 231, 232ftransplantation of, 1252–1253, 1252ftypes of, 133unipolar, 59, 60fNeuron doctrine, 8, 58Neuron progenitor transplantation, 1252–1254, 1252f–1254fNeuropathic pain, 474, 481, 483fNeuropathies, peripheral. See Peripheral neuropathiesNeuropeptide(s) (neuroactive peptides), 359, 367–371. See also specific typesbehavior coordination by, 44–45categories and actions of, 367–368, 367tin dorsal horn pain nociceptors, 477ffamilies of, 368, 368tpackaging of, 359processing of, 368–370, 369fon sensory perception and emotions, 368vs. small molecule neurotransmitters, 370–371in spinal-cord dorsal horn pain nociceptors, 475–476, 478fsynthesis of, 367–368Neuropeptide receptors, in social behavior regulation, 45f, 46fNeuropeptide Y, 1020f, 1021tNeuropsychology, 16Neurostimulator, for seizure detection and prevention, 1459b, 1459fNeurotechnology, for brain-machine interfaces. See Brain-machine interfaces (BMIs), neurotechnology forNeurotransmitters, 358–377. See also specific typesaction of, 359astrocytes on concentrations of, 154, 158fvs. autacoids, 359autonomic, 1021tat chemical synapses, 249–250, 249fcriteria for, 359definition of, 248, 359highlights, 376–377history of, 358–359vs. hormones, 359identification and neuronal processing of, 371, 372b–374b, 372f–374fionotropic receptor activation by, 301–302, 302flong-term effects of, 317, 319fmetabotropic receptor activation by, 302–303, 302fneuroactive peptides. See Neuropeptide(s)neuronal, phenotype plasticity of, 1143, 1145–1147neuronal target signals in, 1146–1147, 1146ftranscription factors in, 1143, 1145, 1145forganelles with, 68postsynaptic receptor on action of, 249–250receptor interaction of, duration of, 359release of, action potentials in, 66f, 68short -term effects of, 319fsmall-molecule. See Small-molecule neurotransmittersspontaneous firing of neurons and, 231synaptic cleft removal of, on transmission, 256f, 371targets of, 359transporter molecules for, 275transporters, 345vesicular uptake of, 364–365, 366fvolume transmission of, 935Neurotrophic factor(s). See also specific typesin apoptosis suppression, 1151–1153, 1151f, 1152fdiscovery of, 1147, 1149finitial theories on, 1147, 1148fnerve growth factor as, 1147, 1149fneurotrophins as, 1147–1151, 1149f. See also Neurotrophin(s)Neurotrophic factor hypothesis, nerve growth factor in, 1147, 1148fNeurotrophin(s)in neuron survival, 1147–1151, 1149f, 1150fin pain, 479brain derived neurotrophic factor, 479, 481fnerve growth factor, 476, 479, 481freceptors for, 1148, 1150–1151, 1150ftypes and functions of, 1150–1151, 1150fNeurotrophin-3 (NT-3), 1148, 1149f, 1150fNeurulation, 1108, 1109fNeville, Helen, 1382Newbornsbrain stem activity in, 981sleep in, 1092Newsome, William, 390b, 1396, 1398Newton’s law of acceleration, in muscle movement, 755fNewton’s law of action and reaction, in muscle movement, 757NFH (neurofilament heavy polypeptide), 411fNGF. See Nerve growth factor (NGF)Nialamide, 790Nicotine, 1007, 1072t. See also Drug addictionNicotinic ACh receptors, 255antibodies to, in myasthenia gravis, 1433, 1435functions of, 1021tgenetic mutations in, epilepsy and, 1467structure ofhigh-resolution models of, 266f, 267–268, 268flow-resolution models of, 264–267, 265f, 266fstudies of, 258fNight blindness, stationary, 530Night terrors, 1096Night vision, rods in, 526, 526fNitric oxide (NO)autonomic functions of, 1021tin long-term potentiation, 1344f–1345f, 1347precursor of, 360tas transcellular messenger, 310NK1 (neurokinin-1) receptor, activation of, 477f, 482fNLGN3X/4X mutations, 49, 1535N-linked glycosylation, 149NMDA (N-methyl-D-aspartate)-type glutamate receptors (receptor-channels)biophysical and pharmacological properties of, 283–284, 283fin central pattern generator function, 796bcontributions to excitatory postsynaptic current, 283–284, 285fin dorsal horn neuron excitability in pain, 479, 482fin dorsal nucleus neurons of lateral lemniscus, 664excitatory synaptic action regulation by, 277, 277fgene families encoding, 278–279, 278fin long-term depression of synaptic transmission, 1353, 1356f, 1357in long-term potentiation at hippocampal pathways, 1342–1345, 1344f–1345f, 1360long-term synaptic plasticity and, 284, 286f–287fin neuropsychiatric disease, 284–287NR1 subunit of, in spatial memory, 1350–1351, 1353fpostsynaptic density in, 281–283, 282fin seizures, 1455, 1455fstructure of, 134–135, 279voltage in opening of, 283NMNAT1/2, 1238, 1239fNO. See Nitric oxide (NO)Nociception. See PainNociception-specific neurons, 474Nociceptive pain, 474Nociceptors, 415taction potential propagation by class of, 471fAδ fiber, 424–425, 425fC fiber, 425classes of, 471–472, 471fdefinition of, 424dorsal root ganglia neuron axon diameter in, 410–412mechanical. See Mechanoreceptorspain. See Pain nociceptorspolymodal. See Polymodal nociceptorsthermal, 471, 471f, 474, 475fNocturnal epilepsy, 1460Kandel-Index_1583-1646.indd 1621 19/01/21 9:18 AM1622 IndexNodes of Ranvieraction potential propagation at, 207, 208f, 413structure of, 57f, 58, 151–152, 153fNoebels, Jeffrey, 1463Noggin, 1111f, 1112Nogoon critical period for monocular deprivation, 1223, 1224finhibition of axon regeneration by, 1245, 1245fNoise, in sensory feedback, 714–715, 714fNoisy evidence, in decision-making, 1397–1400, 1399f, 1400fNon–24-hour sleep–wake rhythm disorder, 1090Nonassociative learning, 1304–1306Noncoding RNAs, in memory consolidation switch, 1323–1324Nondeclarative memory. See Memory, implicitNonneuronal cell transplantation, 1255, 1255fNon-NMDA receptors. See AMPA receptors; Kainate receptorsNonregulatory needs, motivational states for, 1066Non-REM sleepascending arousal system pathways in, 1085–1086, 1087f, 1088fEEG of, 1081, 1081fparasomnias in, 1095–1096physiologic changes during, 1082Nonsense mutations, 33bNonsilent synapses, 1346–1347Nonspecific nuclei, of thalamus, 83Nonsteroidal anti-inflammatory drugs (NSAIDs)on COX enzymes, 478on fever, 1031Nonsynchronized neurons, in auditory cortex, 672, 672fNoradrenergic neuronsin ascending arousal system, 1084, 1084fon attentiveness and task performance, 1005, 1005flocation and projections of, 998, 999fmotor neuron responses and, 1004in pain perception, 1004in pons and medulla, 1513, 1514fNorepinephrinein autonomic system, 1019, 1021t, 1022f, 1146, 1146fon motor neurons, 745, 746fneuronal activity on production of, 362bas neurotransmitter, 361receptors, 1021tsynthesis of, 361, 1513, 1514fNorepinephrine transporter (NET), 366fNormalization, 400Notch signaling, in neuronal and glial production, 1131–1135, 1134f, 1135fNotch-Intra, 1134fNotochord, 1109f, 1116, 1117Noxious information, pain nociceptors for, 471–474. See also Pain nociceptorsNpy2r, 410, 411fNR1 subunit of NMDA receptor, in spatial memory, 1350–1351, 1353fNSAIDs. See Nonsteroidal anti-inflammatory drugs (NSAIDs)NSF, 346f, 347NSS (sodium symporters) , 275, 375–376NT-3 (neurotrophin-3), 1148, 1149f, 1150fN-type Ca2+ channel, 329, 331t, 332Nuclear envelope, 136f, 137Nuclear import receptors (importins),137Nucleic acid hybridization, mRNA detection via, 373bNucleoporins, 137Nucleus accumbens neurons, 1077Nucleus ambiguus, 989f, 991, 994Nucleus of solitary tract (NTS)functional columns of, 989f, 990in gastrointestinal reflexes, 994in relay of visceral sensory information, 990, 1023, 1025f, 1026fNucleus raphe magnus, in pain control, 488, 489fNuma, Shosaku, 265Numb, in neurogenesis, 1134–1135Nystagmus, 640optokinetic, 643right-beating, 640vestibular, 642, 642fOObesity, 1034. See also Energy balance, hypothalamic regulation ofObject recognitionattention in, 560–562categorical, in behavior simplification, 572–573, 574fcognitive processes in, 560–562feedforward representations in, 103–104, 103ffigure vs. background in, 497, 498fin high-level visual processing, 565, 566finferior temporal cortex in, 565–570associative recall of visual memories in, 578–579, 579fclinical evidence for, 566–568, 567fcortical pathway for, 565–566, 566fcortical projections of, 566f, 570face recognition in, 569–570, 570ffunctional columnar organization of neurons in, 568–569, 568f, 569fneurons encoding complex visual stimuli in, 568, 568fposterior and anterior divisions of, 565, 566fperceptual constancy in, 571, 572fvisual memory on, 573Object shape, local movement cues in, 554–555Object-vector cell, 1362ob/ob mice, 1035Observer model, of state estimation, 722, 722fObsessive-compulsive disorder (OCD). See also Anxiety disordersbasal ganglia dysfunction in, 947f, 949risk factors for, 1507treatment of, 1515, 1518Obstructive sleep apnea, 1092, 1093, 1093fOccipital cortex/lobeanatomy of, 12b, 13f, 14ffunctions of, 16in visual priming for words, 1303, 1303fOctopus cells, 655–656, 658f–659fOcular counter-rolling reflex, 643Ocular dominance columnsbrain-derived neurotrophic factor on, 1223electric activity and formation of, 1215–1218, 1218fexperimental induction of, in frog, 1218, 1219finputs from eyes to, 1214, 1214fmodification of critical period for, 1231plasticity of, critical period for, 1220, 1221fsensory deprivation and architecture of, 1214–1215, 1216f, 1217fstructure of, 508–509, 510f–511fsynchronous vs. asynchronous optic nerve stimulation on, 1218Oculomotor nerve (CN III)in extraocular eye muscle control, 863, 863f, 982lesions of, 864borigin in brain stem, 983fprojections of, 1019skull exit of, 984fOculomotor neuronsfor eye position and velocity, 867, 868fneural activity in, 105–106, 106fin saccades, 587, 589fsympathetic, 864bOculomotor nucleus, 969, 989fOculomotor proprioception, 586–587, 587f, 588fOculomotor systemfunction and structure of, 860vestibular nuclei connection to, 636, 637fOdorants. See also Olfactiondefinition of, 683detection by humans, 682receptors forcombinations encoding, 685–686, 686fin mammals, 684–685, 685fOFF cells, 530–531, 536Off-center receptive fields, 506, 508fOhmic channel, 171fKandel-Index_1583-1646.indd 1622 19/01/21 9:18 AMIndex 1623Ohm’s lawin action potential, 211axoplasmic resistance and, 207in contribution of single neuron to EEG, 1452b–1453bin equivalent circuit, 200in single ion channels, 171Ojemann, George, 19O’Keefe, John, 99–100, 1360, 1361Olausson, Håkan, 419Olds, James, 1066Olfaction, 682–695acuity in, 691anatomy of, 683–684, 683f, 684f. See also Olfactory bulbbehavior and, 691–695evolution of strategies for, 695–696odor coding and, invertebrate, 691–694, 693fpheromone detection in, 691, 692fstereotyped, nematode, 694–695, 695f, 696fdisorders of, 690evolution of strategies for, 695in flavor perception, 702highlights, 703–704information pathways to brain in. See Olfactory bulb; Olfactory cortexodorant detection by, breadth of, 682overall perspective of, 382sensory neurons in. See Olfactory sensory neuronssexually dimorphic patterns of, 1280f, 1281Olfactory bulbglomeruli in, 687–688, 687f, 689finterneurons in, 687f, 688neurogenesis in, 1249, 1251fodorant coding in. See Olfactory sensory neuronssensory inputs to, 687–688, 687f, 689ftransmission to olfactory cortex by, 688–690, 690fOlfactory cortexafferent pathways to, 688–690, 690fareas of, 688definition of, 688output to higher cortical and limbic areas from, 690–691Olfactory sensory neuronsodorant receptors in, 684–685, 685f, 1184–1185in olfactory bulb, 687–688, 687fin olfactory epithelium, 686–687, 687freceptors encoding odorants inaxon targeting of, 688, 1185–1186, 1185fcombinations of, 685–686, 686fexpression of guidance and recognition molecules in, 1186fstructure of, 391f, 683–684, 683f, 684fOligodendrocyte(s)functions of, 134, 151generation of, 1132–1134, 1132f, 1136floss of, after brain injury, 1255structure of, 134, 134ftransplantation of, for myelin restoration, 1255, 1255fOligodendrocyte myelin glycoprotein (OMgp), 1245, 1245fOliver, George, 358Olivocochlear neurons, 662–663, 663fOlson, Carl, 571Omnipause neurons, 869–870, 869fON cells, 530–531, 536On-center, off-surround response, 506, 508fOn-center receptive fields, 506, 508fOnuf’s nucleus, 1278Open channels. See also specific channelsin glial cell, K+ permeability of, 191f, 193–194, 194fin resting nerve cells, ion conductance in, 194–195, 196fOpen-loop control, 716–717, 717fOperant conditioning, 1306–1307Opioid receptors, 489–490, 490tOpioids/opiatesclasses of, 489–490, 491fas drug of abuse, 1074. See also Drug addictionendogenous, 489–490, 491fmechanism of action of, 490–493, 492fpeptides of, 368tside effects of, 491source and molecular target of, 1072ttolerance and addiction to, 493. See also Drug addictionOpsin, 528, 528f, 529Optic chiasmaxonal crossing in, 1176growth cone divergence at, 1171–1172, 1172f, 1173fOptic disc, 522f, 523–524Optic nerve (CN II)origin in brain stem, 983fsignaling pathways regulating axon regeneration in, 1246–1247, 1248fskull exit of, 1030fOptic radiation, 501, 503fOptical neuroimaging, 98bOptimal feedback control, 817f, 818Optimal linear estimator, 962Optogenetic methodologyin manipulation of neuronal activity, 99bin research on emotions in animals, 1049in research on reinforcement, 945Optokinetic eye movementsin image stabilization, 866with vestibulo-ocular reflexes, 643Orbit, eye rotation in, 860–861Orbitofrontal cortex lesions, 690Orexins, in narcolepsy, 1094–1095, 1094fOrgan of Corti. See also Hair bundles; Hair cellsanatomy of, 600fcellular architecture of, 605fin hearing, 604–606Organellesaxonal transport of, 143, 145bmembranous, 135Organizer region, on neural plate development, 1108–1110, 1110fOrganizing center signals, in forebrain, midbrain, and hindbrain patterning, 1113–1115, 1114f, 1115fOrientationcerebellum in, 901–902to environment, visual inputs for, 896f, 897local, computation of, 545postural. See Posture, postural orientation insensory signals in internal models for optimization of, 898, 899fsexual, 1261touch, neurons sensitive to, 460, 461fOrientation columns, in primary visual cortex, 508, 510f–511fOrientation selectivity, 547–548, 548fOrientation tuning, 399Orientation-sensitive neurons, 460, 461fOrofacial movements, pattern generators in, 994Orphanin FQ receptor, 489, 490tOrthologous genes, 32, 34f, 52Osmolarity, blood, 1031Osmoreceptors, 392, 1031–1033, 1032fOssiclesanatomy of, 599, 599fin hearing, 601, 602f–603fOtitis media, 601Otoacoustic emissions, 616f, 617–618Otoconia, 635, 635fOtolith organsanatomy of, 630f, 632linear acceleration on, 634–635, 635fOtolithic membrane, 634, 635fOtosclerosis, 601Otx2, 1114, 1114fOval window, 600fOVLT. See Vascular organ of the lamina terminalis (OVLT)Owls, auditory localization in, 690, 1227–1228, 1227f–1229fOxycodone, 1072t. See also Drug addictionOxytocinfunctions of, 1027, 1275hypothalamic neurons on release of, 1027, 1028fon maternal bonding and social behaviors, 1275on social behavior, 45synthesisof, 1027PP elements, 35b, 39bP0 (myelin protein zero), 156bP2X receptorgenes coding for, 291structure of, 291in threat conditioning in flies, 1330Kandel-Index_1583-1646.indd 1623 19/01/21 9:18 AM1624 IndexPacemaking, by neurons, 231Pacinian corpusclefiber group, name, and modality for, 415tin human hand, 438–439, 439f, 442fin motion and vibration detection, 439, 446, 447fRA2 fibers in. See Rapidly adapting type 2 (RA2) fibersin touch, 416, 437f, 438tPain, 470–494control of, endogenous opioids in, 489–490classes and families of, 490t, 491fhistory of, 489mechanisms of, 490–493, 492ftolerance and addiction in, 493. See also Drug addictiondefinition of, 470first, 471f, 472, 490gate control theory of, 488, 488fhighlights, 493–494hyperalgesia in. See Hyperalgesiaillusory, in cerebral cortex, 487b, 487fneuropathic, 474, 481, 483fnociceptive, 474perception of, 408cortical mechanisms in, 485–489cingulate and insular areas, 485–486, 487b, 487fconvergence of sensory modalities, 488, 488fdescending monoaminergic pathways, 488–489, 489fstimulation-produced analgesia, 488monoaminergic modulation of, 1002, 1004nociceptors in. See Pain nociceptorsspinothalamic system in, 450f–451f, 470–471, 484, 485fthalamic nuclei in, 484–485, 486fTRP receptor-channels in, 472, 473fpersistent, 470, 474prostaglandins in, 478referred, 474, 476fsecond, 471f, 472, 490spontaneous, 481tissue inflammation in, 476Pain nociceptors, 69, 415t, 424–425, 425factivation of, 471–474, 471f, 473fmechanical. See Mechanoreceptorspolymodal. See Polymodal nociceptorssensitization of. See Hyperalgesiasignal transmission byto dorsal horn neurons, 474–476, 475f, 476f, 477fin hyperalgesia. See Hyperalgesiaopioids on, 490–491, 492fsilent, 472, 474, 475fthermal, 471, 471f, 474, 475fPainful stimuli, 470Pair-bonding in mammals, differences in, 45, 46fPaired-association task, 576b, 576fPalay, Sanford, 8Paleospinothalamic tract, 485Palsy, 1428Panic attacks/disorder, 997, 1505–1506. See also Anxiety disordersPapez, James, 1048–1049, 1049fPapez circuit, 1049, 1049fPapillae, taste bud, 697, 697fPapillary ridges, of finger, 440b–441b, 440fPar proteins, in neuronal polarity, 1157, 1158fParabrachial complex, 1006Parallel fibers and pathwayson Purkinje cells, 920, 920fsynaptic efficacy of, 924–925, 924fParallel processing, in visual columnar systems, 512, 513fParalysis. See also specific injuries and disordersperiodic. See Periodic paralysissleep, 1094, 1095Paramedian pontine reticular formation lesions, on eye movements, 870Paranoid delusions, 1490Paraphasias, 18, 1384Parasomnias, 1095–1096Parasympathetic division, autonomic system, 1016, 1017fParasympathetic ganglia, 1017f, 1018–1019Paraventricular nucleus, hypothalamus, 1027, 1027f. See also HypothalamusParavertebral ganglia, 1017–1018, 1017f, 1018fParental behavior, hypothalamus in control of, 1013t, 1041Parentese, 1377–1378Paresthesias, 1428, 1430. See also Peripheral neuropathiesParietal cortex/lobeactive touch on sensorimotor circuits of, 463–464anatomy of, 12b, 13f, 14f, 16function of, 12b, 16flesions/injuriesdeficits in use of sensory information to guide action in, 824btactile deficits from, 464, 465fvisual neglect in, 589–591, 591fin locomotion, 806, 807f, 808fposterior, 452fpriority map of, 591b–592b, 591f, 592ftemporoparietal, in postural control, 905visual information to motor system from, 592–595, 594f, 595fvoluntary movement control in, 823–828areas active when motor actions of others are observed, 837–840, 839fareas for body position and motion for, 824–825areas for spatial/visual information for, 825–827, 826f–827f. See also Lateral intraparietal area (LIP)areas supporting, 819, 820faspects shared with premotor cortex, 840, 840finternally generated feedback in, 827–828sensory information linked to motor action in, 824, 824bvisual receptive field expansion in, 827, 828fParietal reach region (PRR), 825, 826f–827f, 832fParkinson disease, 1548–1549, 1550tclinical features of, 948, 1548, 1550tearly-onset, 48epidemiology of, 1548gait problems in, 808genetics of, 1548–1549, 1550tmouse models of, 1552–1553, 1554fpathophysiology ofbasal ganglia dysfunction in, 947f, 948dopamine deficiency in, 70, 361, 948Lewy bodies in, 141b, 142f, 1553, 1554fneuronal degeneration in, 1004, 1007, 1550, 1551fprotein misfolding and degradation in, 1553–1554postural responses in, 892spinocerebellum and adaptation of posture in, 902, 903f, 904ftreatment ofdopamine replacement therapy for, 1556embryonic stem cell grafts for, 1252, 1252ftype 17, tau gene in, 1573types of, 1548–1549, 1550tParkinsonism, autosomal recessive juvenile, 1549Parkinson-like side effects, of antipsychotics, 1498Paroxetine, 1515, 1516f–1517fParoxysmal activity, 1450Paroxysmal depolarizing shift, 1153Partial seizures. See Seizure(s), focal onsetPartner choice in mice, pheromones on, 1272, 1273fParvocellular layers, lateral geniculate nucleus, 501, 511f, 512, 514fParvocellular neuroendocrine zone, of hypothalamus, 1027f, 1028PAS domain, 40Passive electrical properties, of neuron. See Neuron(s), passive electrical properties ofPassive touch, 436–437Patapoutian, Ardem, 416, 421Patch-clamp studiesof ACh receptor channel current, 260, 261fof ion channel molecules, 220, 222fof NMDA receptors, 283, 283fof single ion channels, 170b, 170fwhole-cell, 215, 215fKandel-Index_1583-1646.indd 1624 19/01/21 9:18 AMIndex 1625patched, 1118Pattern completion, 1360Pattern generators. See also Central pattern generators (CPGs)in breathing, 994–998, 995f–997fin stereotypic and autonomic behaviors, 992, 994Pattern separation, 1359–1360Patterning, in nervous system, 1107–1129diversity of neurons in, 1115in forebrain. See Forebrain, patterning ofhighlights, 1128local signals for functional neuron subclasses in. See Motor neuron(s), development of subtypes ofneural cell fate promotion in, 1108–1110competence in, 1108induction factors in, 1108organizer region signals in neural plate development, 1108–1109, 1110fpeptide growth factors and their inhibitors in, 1110–1112, 1111fsurface receptors in, 1108in neural tube. See Neural tube developmentPavlov, Ivanon classical conditioning, 1306on fear, 1316holistic view of brain, 18Pavlovian conditioning, 1050–1051, 1306. See also Classical conditioningPax6, in forebrain patterning, 1123, 1126fP-cells, retinal ganglion, 523f, 531, 538PCP (phencyclidine), on NMDA receptor, 277f, 283PDZ domains, 281, 1199, 1201fPedunculopontine nucleus (PPN), 800, 802f, 808–809Pegs, of synaptic vesicle, 349, 350fPelizaeus-Merzbacher disease, 156bPendular reflexes, 909Penetrance, genetic, 32Penfield, Wilderon conscious experiences from cortical stimulation, 1477on cortical areas for language processing, 19on motor functions in cerebral cortex, 841on seizures, 1448, 1461, 1463on somatosensory cortex, 84Penicillin epilepsy, generalized, 1461Pennation angle, muscles, 752–754, 753tPeptidases, 368Peptide growth factors, in neural induction, 1110–1112, 1111fPeptide Y (PYY), 1034, 1036f–1037fPER, 40–41, 43fper gene, 40, 41f, 43fPerani, Daniela, 1380Perception. See also specific typescategorical, 1373in behavior simplification, 572–573, 574fin language learning, 1373overall perspective of, 381–383relationship to other brain functions, 383sensory coding in. See Sensory codingsensory processing for, 724–725, 725fvisual. See Visual perceptionPerceptive field, 397Perceptual constancy, in object identification, 571, 572fPerceptual discrimination threshold, 518Perceptual discriminations/decisionsdecision rules for, 1393–1395, 1394finvolving deliberation, 1395–1397, 1396f, 1397fprobabilistic reasoning in, 1404–1408, 1407fPerceptual fill-in, illusory contours and, 545–546, 546fPerceptuallearning, 559, 561fPerceptual priming, 1303Perceptual task, 562Perforant pathway, 1340, 1341f, 1342, 1343fPeriaqueductal gray (matter)analgesia from stimulation of, 488in ascending arousal system, 1084, 1084fin autonomic function, 1025, 1026fin freezing behavior, 1052in learned fear response, 1053, 1060, 1061fopioids on, 489f, 490Perilymph, 604, 605f, 630f, 631Perineuronal net, on critical period for monocular deprivation, 1223, 1231Period gene, 1088–1090, 1089fPeriodic limb movement disorder, 1095Periodic paralysis, 1441–1444, 1443fgene mutations in, 1444fhyperkalemic, 1442–1444, 1443fhypokalemic, 1442, 1444fPeripheral feedback theory, 1048, 1049fPeripheral myelin protein 22 (PMP22), 156b, 156f, 157fPeripheral nerve(s)atrophy of, 1422diseases of. See Peripheral neuropathiesinjury ofcentral sensitization and, 481, 483fmicroglia activation after, 481, 484fregeneration after, 1241–1242, 1241f, 1243fsensory fiber classification inby compound action potentials, 412–413, 412fby diameter and conduction velocity, 410–412, 412f, 412tPeripheral nerve and motor unit diseases, 1421–1445differential diagnosis of, 1422–1426, 1423t, 1424f, 1425fhighlights, 1445motor neuron diseases. See Motor neuron diseasesmyopathies. See Myopathiesneuromuscular junction disorders. See Neuromuscular junction disordersperipheral neuropathies. See Peripheral neuropathiesPeripheral nervous systemautonomic division of, 92f, 93in behavior, 92–93neural crest cell migration in, 1139f, 1141, 1142f, 1143fsomatic division of, 92–93, 92fPeripheral neuropathies, 1428–1430. See also specific disordersacute, 1429–1430axonal, 1430, 1432f, 1433tchronic, 1430demyelinating, 1430, 1433t. See also Charcot-Marie-Tooth diseasedifferential diagnosis of, 1423–1426, 1423f, 1424f, 1425fsensorimotor control in, 733b, 733fsymptoms of, 1428–1430Permeability. See also specific ions and receptorsof blood–brain barrier, 159of cell membrane. See Cell (plasma) membrane, structure and permeability ofPeroxisomes, 135Persistence, 1308–1309PET. See Positron emission tomography (PET)Petit mal seizure. See Typical absence seizuresPettito, Laura-Anne, 1382Phalangeal cells, 604Phantom limb, 1481Phantom limb painneural activation in, 485, 486fneuropathic pain in, 474Pharmacology, history of, 8–9Phase-dependent reflex reversal, 799Phase-locking, 657, 660f–661f, 671Phasic mode, of locus ceruleus neurons, 1005, 1005fPhencyclidine (PCP), on NMDA receptor, 277f, 283Phencyclidine-like drugs, 1072t. See also Drug addictionPhenelzine, 1514, 1516f–1517fPhenotypedefinition of, 53genotype and, 31–32Phenylketonuria (PKU), 46Phenytoin, 1455–1456Pheromonesdefinition and functions of, 691olfactory structures detecting, 691, 692fon partner choice in mice, 1272, 1273fperception of, 1280f, 1281Phobias, 1504, 1506, 1515, 1518Phonemes, 1371Phonemic paraphasia, 18, 1384Kandel-Index_1583-1646.indd 1625 19/01/21 9:18 AM1626 IndexPhonetic prototypes, 1374Phonetic units, 1371Phonotactic rules, 1372Phosphatidylinositol 3 kinase (PI3 kinase) pathway, 1148, 1150fPhosphatidylinositol 4,5-bisphosphate (PIP2), 305, 307f, 315Phosphoinositide 3 kinase (PI3 kinase), 1329fPhosphoinositol system, steps of, 305Phospholipase A2, 305, 310, 311fPhospholipase C, 305, 307f, 309fPhospholipase D, 305Phospholipidsin cell membranes, 166–168, 168f–169fphospholipase A2 hydrolysis of, on arachidonic acid, 310, 311fphospholipase C hydrolysis of, IP3 and diacylglycerol from, 305–308, 307fPhosphorylationcAMP-dependent, in K+ channel closing, 317, 318fcGMP-dependent, 312in posttranslational modification, 149of rhodopsin, 526f–527f, 529–530Phosphorylation consensus sequences, 303Phosphorylation-gated channel, physical models of, 172, 173fPhotoreceptor(s)characteristics of, 391f, 392t, 393density of, visual resolution and, 397–398, 399fgraded sensitivity of, 393–395, 394fhorizontal cells in, 524f, 536–537in retina, 521–522, 522fribbon synapse in, 536Photoreceptor layers, retinal, 522–526ocular optics on retinal image quality in, 522–524, 522f, 525frods and cones in, 524–526, 525f, 526fPhototransduction, in retina. See Retina, phototransduction inPhox2, 1143fPhrenic nerve, 995fPhrenology, 10, 16, 21PI3 kinase (phosphoinositide 3 kinase), 1329fPI3 kinase (phosphatidylinositol 3 kinase) pathway, 1148, 1150fPIB (Pittsburgh compound B), 1576, 1576fPiezo protein family, 416, 417f, 421, 472Pigment, visualgenes for, 539–540, 539flight activation of, 526f, 528–529, 528f, 529fPIH (prolactin release-inhibiting hormone), 1029tPillar cells, 604, 605f, 607fPiloerection, 1029PIP2 (phosphatidylinositol 4,5-bisphosphate), 305, 307f, 315Pitch perception, 673–674, 674fPittsburgh compound B (PIB), 1576, 1576fPituitary gland. See Anterior pituitary gland; Posterior pituitary glandPIWI-interacting RNAs (piRNAs), 1323, 1324fPKA. See Protein kinase A (PKA)PKC. See Protein kinase C (PKC)PKG (cGMP-dependent protein kinase), 312PKM (protein kinase M), 307fPKM ζ (PKM zeta), 1344f–1345f, 1348PKU (phenylketonuria), 46Place cellshippocampal, 99–100, 100f, 1360–1361, 1362fas substrate for spatial memory, 1365–1367, 1365fPlace code, 624Place fieldsdisruption of, 1366, 1366fhippocampal, 99–101, 100f, 1360–1361, 1362f, 1363fPlacebo, responses to, 493Plane of fixation, 550, 552fPlanes, of central nervous system, 11b, 11fPlasma membrane. See Cell (plasma) membranePlasmalemma, 134–135Plasmapheresisdefinition of, 1430for myasthenia gravis, 1435Plasticitycircuit, 1077corticalin adults, 559, 560flearning on, 1335f, 1336in perceptual learning, 559, 560fof nervous systemdendritic spines in, 1221, 1222fearly experience and, 1210–1212, 1213fhypothesis, 71short-term, 350, 352f–353f. See also Synaptic plasticityof neuronal excitability, 233. See also Excitability, of neuronsof neurotransmitter phenotype, 1143, 1145–1147, 1145f, 1146fof ocular dominance columns, 1220, 1221fsynaptic. See Synaptic plasticitywhole-cell, 1077Plastin, 604Plateau potentials, 796bPlato, on decision-making, 1393Plato’s Cave, 381Pleasure, neural basis of, 1055, 1062PLP (proteolipid protein), 156bPM. See Premotor cortex (PM)PMd. See Dorsal premotor cortex (PMd)PMP22 gene mutations, 156b, 1431f, 1434PMv. See Ventral premotor cortex (PMv)Pneumotaxic center, 997POA. See Preoptic hypothalamus (POA)Poeppel, David, 1379Point mutations, 33fPolarization, neuron, 131Poliomyelitis, 1428Polygenic risk scores, in mood and anxiety disorders, 1507Polyglutamine diseases. See CAG trinucleotide repeat diseasesPolymodal nociceptorsactivation of, 471, 471fmechanisms of action of, 425to spinal cord dorsal horn, 474, 475fPolymorphismdefinition of, 32, 53single nucleotide, 53Polyproteins, 368, 369fPolysomes, structure and function of, 136fPolysomnogram, 1080–1081, 1081fPolysynaptic pathwaysin flexion reflex, 763fin stretch reflex, 767–769POMC. See Proopiomelanocortin (POMC)Ponsanatomy of, 12b, 13f, 14f, 15f, 1428in smooth-pursuit eye movements, 867f, 878–879, 878fPontifical cell, 518Pontine flexure, 1112, 1113fPontine micturition center (Barrington’s nucleus), 1023, 1024fPontine respiratory group, 997Pontine reticular formation, in horizontal saccades, 868–870, 869fPontomedullary reticular formation, in locomotion, 802–803, 803f, 804fPop-out phenomenon, 559–560, 562fPopulation codes, 395–396, 517, 517fPopulation vectors, 849, 850f, 962Position constancy, in object identification, 571, 572fPositive emotions, neural basis of, 1055, 1062Positron emission tomography (PET)of amyloid plaques, 1576, 1576fin cue-induced cocaine craving, 1071, 1073fin language studies, 1370for seizure focus localization, 1463–1464in studies on emotion, 1060Postcentral gyrus, 12, 17fPosterior group, thalamic nuclei, 82f, 83Posterior hypothalamus, 1013Posteriorpituitary glandhormones of, 367t, 368thypothalamic control of, 1027, 1027f, 1028fPostganglionic neurons, 1016, 1016fPost-herpetic neuralgia, 474Post-ictal period, 1449Postsynaptic cell domain, synaptic inputs directed to, 1186–1187, 1187fPostsynaptic density, in NMDA and AMPA receptors, 281–283, 282fPostsynaptic inhibition, 353Postsynaptic muscle membrane differentiation, 1192f, 1194–1196, 1195fKandel-Index_1583-1646.indd 1626 19/01/21 9:18 AMIndex 1627Postsynaptic neuron. See Neuron(s), postsynapticPost-tetanic potentiation, 351, 352f–353fPosttranslational modification, of protein, 148–149Post-traumatic stress disorder (PTSD)causes of, 1506. See also Anxiety disordershippocampal volume in, 1512symptoms of, 1506Postural equilibrium. See Balance; Posture, postural equilibrium inPostural tone, 886Posture, 883–906control of, nervous system in, 900–901attentional ability and demands in, 905brain stem and cerebellum integration of sensory signals in, 900–902cerebral cortex centers in, 905emotional state in, 905spinal cord circuits in antigravity support, but not balance in, 900–901spinocerebellum and basal ganglia in adaptation of posture in, 902, 903f, 904fhighlights, 906integration of sensory information in, 894–898, 899fambiguous information from single sensory modality in, 897, 898finternal models for balance in, 898, 899fsomatosensory signals in automatic postural response timing and direction in, 894–895, 895fspecific sensory modalities on balance and orientation according to task in, 899f, 900, 901fvestibular information for balance on unstable surfaces and in head movements in, 895–897, 896fvisual inputs infor advanced knowledge of destabilizing situations, 897for orienting to environment, 896f, 897during locomotion, 802–804, 803fpostural equilibrium in, control of center of mass in, 886–888anticipatory postural adjustments in, for changes in voluntary movements, 892–894, 892f, 893fautomatic postural responses inadaptation to changes in requirements for support by, 888–889, 891fsomatosensory signals in timing and direction of, 894–895, 895fspinal cord circuits in, 900–901to unexpected disturbances, 886–888, 887f–889fcenter of pressure in, 884, 885b, 885fdefinitions and fundamentals of, 884postural orientation in, 884in anticipation of disturbance to balance, 894–895on center of mass location, 884integration of sensory information in, 894–898, 899fvs. postural equilibrium, 884for sensation interpretation, 894for task execution, 892synergistic activation of muscles in, 890b, 890fPotassium channels. See K+ channelsPotentiation, 351, 352f–353f. See also Long-term potentiation (LTP)Potter, David, 243PPN (pedunculopontine nucleus), 800, 802f, 808–809P/Q-type Ca2+ channel, 329, 331t, 332Prader-Willi syndrome, 1533–1534, 1533fPre-Bötzinger complex, 995, 995fPrecedence effect, 694Precentral gyrus, 16, 17fPrecession, 112Prediction-error signal, 1068Predictive control mechanisms, 723–724, 724fPredictive relationships, 1308Preferred movement direction, 845Prefrontal cortexcategory-specific representations in, 573, 574fin encoding of episodic memory, 1297, 1299fin extinction learning, 1518medialin autonomic function, 1025, 1026fin fear response, 1060, 1061fin mentalizing, 1527, 1528neurons of, in decision-making, 1401, 1403–1404in schizophrenia, 1494, 1495f, 1496f, 1499in short-term memory, 1292, 1293fventromedial, in emotional processing, 1058–1059, 1058bin working memory, 1292, 1293fPreganglionic neuronsfunctions of, 1016, 1016flocations of, 1016, 1017f, 1018fP-regions, ion channels with, 178, 179fPremotor cortex (PM)anatomy of, 819, 820flesions of, voluntary behavior impairment in, 829bmedial, contextual control of voluntary actions in, 829–831, 830fvoluntary movement control in, 710, 828–829application of rules governing behavior for, 832f, 833, 835, 836fareas active when motor actions of others are observed, 837–840, 839faspects shared with parietal cortex, 840, 840fcontextual control of voluntary actions for, 829–831, 830fperceptual decisions that guide motor actions for, 835–836, 838fplanning motor actions of hand for, 835, 837fplanning sensory-guided hand movement for, 831–833, 832f–834fPremotor neurons, 1426Preoptic hypothalamus (POA), 1013. See also Hypothalamuscontrol of sexual behavior, aggression, and parental behavior in, 1039–1041, 1040f, 1272olfactory activation in, 1280f, 1281Preplate, 1135, 1137f–1138fPreprocessing, of fMRI data, 115–116Pre-prodynorphin, 369fPresenilin-1, 1568, 1572, 1573fPresenilin-2, 1572, 1573fPressure, slowly adapting fibers for, 444, 446. See also Slowly adapting type 1 (SA1) fibers; Slowly adapting type 2 (SA2) fibersPressure-gated channel, physical models of, 172, 173fPresupplementary motor area, 819, 820fPresynaptic active zone, hair cell, 620–621, 621fPresynaptic facilitation, 353, 354fPresynaptic inhibitionaction potential in, 353, 354fmodulation by, 777, 777fPresynaptic neurons. See Neuron(s), presynapticPresynaptic terminals, 57f, 58in neuromuscular junction, 256f, 258neurotransmitters at, 248–249, 248fin transmitter release, 324–325, 325f, 332–333axo-axonic synapse and, 351, 352–353, 354fcalculating probability of, 335b–336bdepolarization and, 324–327, 325fquantal transmission in, 335–337, 335b–336bvoltage-gated Ca2+ channels in, 233Prevertebral ganglia, 1017–1018, 1017f, 1018fPrimary active transport, 195–198, 197fPrimary afferent fibers, 409Primary generalized seizures. See Seizure(s), generalized onsetPrimary motor cortexcoordination with other motor system components, 89, 91f, 710corticospinal tract transmission to, 89, 90f, 819–821, 822ffunctional anatomy of, 84f, 819, 820fhand representation in, in stringed instrument players, 1335f, 1336lesions in, motor execution impairments and, 844bKandel-Index_1583-1646.indd 1627 19/01/21 9:18 AM1628 IndexPrimary motor cortex (Cont.):motor execution in, 841–856activity as reflection of higher-order features of movement, 851–852activity as reflection of spatial and temporal features of motor output, 844–851neuron activity correlation with changes in muscle forces, 845, 846fneuron activity correlation with level and direction of isometric force, 846–847, 847fneuron activity correlation with patterns of muscle activity, 849, 849fneuron and muscles tune to direction of reaching, 848–849, 848fpopulation codes and vectors for measurement of, 849–851, 850fadaptability of, 852, 854–856, 854f, 856fcorticomotoneuronal cells for, 841, 843f, 844motor periphery map for, 841, 842fsensory feedback transmission to, 852, 853fvisual information from, in locomotion, 804–806, 805f. See also LocomotionPrimary muscle diseases. See Myopathies (primary muscle diseases)Primary somatic sensory cortex, 88, 89f. See also Somatosensory cortex/systemPrimary visual cortex. See Visual cortexPrimingmemory, in amnesia, 1294, 1296fin synaptic vesicles, 341, 343fvisual, for words, 1303, 1303fPrince, David, 1456Principal sensory trigeminal nucleus, 989f, 990Prions, 1328Probabilistic classification task, 121–122Probe trial test, of memory, 1352f–1353f, 1354fProcedural memory, 1482. See also Memory, implicitProdynorphin, 490tProenkephalin (PENK), 369f, 490tProgenitor cells, neural, proliferation of, 1131, 1132fProgesterone, 1262, 1264, 1264fProgesterone receptor, 1264, 1266fProgrammed cell death. See ApoptosisProgressive bulbar palsy, 1428Progressive spinal muscular atrophy, 1428, 1429fProgressive supranuclear palsy, 141bProjection interneurons, 61, 64, 64fProkaryote, 53Prolactin release-inhibiting hormone (PIH), 1029tPromoters, 29, 30fProneural region, 1132Proopiomelanocortin (POMC)in energy balance regulation, 1036f–1037f, 1037–1038as opioid peptide,490tprecursor of, 369fvariation in peptides produced by, 370Proprioception, 408mechanoreceptors for, 415t, 416f, 421–422, 422fmuscle spindle as receptor for, 421–422, 422foculomotor, 586–587, 587f, 588freflexes in, 779SA2 fibers in, 446sensations for, loss of, 1428in sensorimotor control, 733b, 733fin timing and amplitude of stepping, 795, 798fPropriospinal neurons, 778, 778fProsodic cues, 1376Prosody, right and left hemispheres in, 1382Prosomeres, 1115, 1123Prosopagnosiacharacteristics of, 1473, 1477–1478fMRI studies of, 121inferior temporal cortex damage in, 505, 568Prostaglandin(s)in fever, 1031in pain, 478Prosthetic armsbrain-machine interfaces in, 965, 967f, 968fconcept of, 954–955, 955fProtanomaly, 539Protanopia, 539Proteasomes, 135Protein. See also specific proteinsabnormal accumulation of, in neurological disorders, 141b, 142faxon transport of, 142, 144fin dendritic spines, 146, 1466fsynthesis of. See Protein synthesisProtein kinasecAMP-dependent. See Protein kinase A (PKA)GMP-dependent, 312variation in, on fly and honeybee activity, 42, 44, 44fProtein kinase A (PKA), 303, 304f, 362b, 1317in growth cone, 1166fin long-term potentiation, 1348in long-term sensitization, 1319, 1321f, 1323in sensitization, 1317, 1318f–1319fstructure of, 1323–1324in synaptic capture, 1327, 1328fin synaptic terminal synthesis, 1329fProtein kinase C (PKC)isoforms, 307fin long-term potentiation of synaptic transmission, 286f–287fin sensitization, 1317, 1318f–1319fProtein kinase M (PKM), 307fProtein misfoldinggene expression alterations from, 1555–1556in Parkinson disease, 1553–1554Protein phosphatases, in growth cone, 1164Protein synthesisat axon terminals, CPEB as self-perpetuating switch of, 1327–1328, 1329flocalprion-like protein regulator of, in long-term memory, 1327–1328, 1329fin synaptic capture, 1327, 1328fin neurons, 147–150in endoplasmic reticulum, 147–149, 148fmodification in Golgi complex, 149–150Protein transport, in neuron. See Axonal transportProteolipid protein (PLP), 156bProteolipids, 156bProteome, 53Proteomics, 134Protocadherin 14, 611, 612fProtocerebrum, lateral, 693f, 694Protofilaments, 139, 140fProtomap, cortical, 1123Provisional affordance, 1413PRR (parietal reach region), 825, 826f–827f, 832fPruning, of synaptic connections. See Synaptic pruningPrusiner, Stanley, 1328Pruszynski, Andrew, 441–442PSD. See Postsynaptic density (PSD)Pseudo-conditioning. See SensitizationPseudo-unipolar cells, 409Pseudo-unipolar neurons, 59, 60fPsychiatric illness. See also specific typesbrain function in, 7multigenic traits in, 48Psychogenic amnesia, 1485Psychometric function, 388, 388f, 1398Psychomotor Vigilance Test, 1087, 1091Psychophysics, 387–388, 388fPsychophysiology, 1046b–1047bPsychostimulants, 1072t, 1074. See also Drug addictionPsychotherapy, for mood and anxiety disorders, 1515, 1518Psychotic episodes/symptomsin major depressive disorder, 1503in mania, 1504in schizophrenia, 1490Ptáček, Louis, 42PTEN, in axon regeneration, 1247, 1248fPtf1a, 1145, 1145fPtosisin myasthenia gravis, 1433, 1433foculomotor nerve lesion in, 864bPTSD. See Post-traumatic stress disorder (PTSD)PTX3 receptor, in pain, 472P-type ATPases, 97, 197fKandel-Index_1583-1646.indd 1628 19/01/21 9:18 AMIndex 1629Pulse sequence, in fMRI, 114Pulvinar, 82f, 83, 503f, 504f–505f, 505Pump, ion. See Ion pumpPupil(s), 521, 522fPupillary light reflexes, 992–993, 993fPupillary reflexes, visual processing pathways for, 501, 503fPurcell, Edward, 125Purine(s), 364Purinergic receptors, 291, 364Purkinje cellsin autism spectrum disorder, 1539in cerebellum, 105, 918, 919fdepression of synaptic input to, 924–925, 924fexcitability properties of, 229excitatory and inhibitory inputs on, 105, 920in eyeblink conditioning, 108, 109fmorphology of, 1160, 1161fin saccadic adaptation, 925, 927fsimple and complex spikes from, 108–109, 918, 920fsynaptic plasticity in, 108–109, 109fPursuitsmooth. See Smooth-pursuit eye movementsvestibular responses to, 642Pushing vector, of neuron, 962, 962f–963fPutnam, Tracey, 1448Pyramidal decussation, 89Pyramidal neuronscortical. See Cortical neuronsexcitability properties of, 229, 230fexcitatory postsynaptic potential and, 1452b, 1452fmorphology of, 1160, 1161fin schizophrenia, 1494, 1496fPyramidal tracts, 821Pyridostigmine, for myasthenia gravis, 1435PYY (peptide Y), 1034, 1036f–1037fQ15q11-13 deletion, 1533–1534, 1533f22q11 deletion, 48, 50, 1492Q-SNAREs, 344f, 345Quadriceps muscle stretch reflex, 274, 275fQuadrupedal locomotion, 788–789, 793, 794f–795f. See also LocomotionQuanta, 332Quantal content, 335b–336bQuantal output, 335b–336bQuantal synaptic potential, 332Quantal units, of transmitter release, 332–333, 334fQuick phase, 640Quinine, tinnitus from, 624RRab3, 344f, 349Rab27, 344f, 349Rabi, Isidor, 125Radial glial cellsastrocytes from, 1131delta-notch signaling and basic helix-loop-helix in generation of, 1131–1135, 1134f, 1135fas neural progenitors and structural scaffolds, 1131, 1133fneuronal migration along, 1137–1138, 1138f, 1139fRadial migration, glial cells as scaffold for, 1137, 1138f, 1139fRaichle, Marcus, 399RA-LTMRs (rapidly adapting low-threshold mechanoreceptors), 419, 420f–421fRamirez, Naja Ferjan, 1378Ramirez-Esparza, Nairan, 1378Ramón y Cajal, Santiagoon axon vs. dendrite differentiation, 1156–1157on axonal chemotactic factors, 8cellular brain studies of, 10, 1103on central nerve pathway axon regeneration, 1243on chemotactic factors, 1176on glial function, 151, 151fGolgi’s staining method use by, 58–59on growth cone, 8, 1162, 1163fon neuron death and regeneration, 1237on neuron migration, 1137plasticity hypothesis, 71Random mutagenesis, 35bRandom-dot motion discrimination task, 1396–1397, 1397fRandom-dot stereograms, 552Range of motion, muscle torque in, 754, 754fRapid eye movement (REM) sleep. See REM sleepRapidly adapting low-threshold mechanoreceptors (RA-LTMRs), 419, 420f–421fRapidly adapting type 1 (RA1) fibersin grip control, 446–450, 449fin motion detection, 445f, 446receptive fields of, 438–439, 442fin touch receptors, 437–438, 437f, 438tin vibration detection, 446, 448fRapidly adapting type 2 (RA2) fibersin grip control, 446–450, 449freceptive fields of, 438–439, 442fin touch receptors, 437–438, 437f, 438tin vibration detection, 439, 446, 447f, 448fRapsyn, 1195f, 1196, 1198Ras protein, 308–309Rate codingin sensory neurons, 395of time-varying sounds, 672–673, 672fRauschecker, Josef, 1379Reaching. See Grasping and reachingReaction-time tasks, 821, 823fReactive astrocytosis, 159Readiness potential, 830–831Rebound sleep, 1086Recall of memoryconscious, 1482–1483, 1482fin conscious mental process disorders, 1482–1483, 1482fvisual, associative, 578–579, 579fReceiver operating characteristic (ROC) analyses, 390b, 390fReceptive aphasia, 17Receptive fields, 531center-surround, 531, 532fof cortical neurons, 457–459, 458f, 459fdefinition of, 558end-inhibited, 549, 550forigin of, 506of parietal neurons, 825–827, 826f–827f, 828fof relay neurons, 399–400of sensory neurons, 397–398, 398f, 399fin visual processingeccentricity in, 506–507, 509fon-center, off-surround in, 506, 508fon-center and off-center in, 506, 508fremapping of, with saccadic eye movements, 583–584, 585fat successive relays, 506–508, 507f–509fin zone of tactile sensitivity, 438–439, 442fReceptor(s). See also specific typesat central synapses, 1198–1199, 1201fconcentration of, at nerve terminals, 1198–1199ion channel gating by, 250–251, 251fpostsynaptic, neurotransmitter binding to, 249–250sensory. See Sensory receptorssomatosensory system. See Somatosensory cortex/system, receptorssurface, in ectodermal cell differentiation, 1108transmembrane, genes encoding, 33Receptor potential, 65, 66f, 67t, 391, 410Receptor tyrosine kinases, 302, 302ffunctions of, 308ligands for, 308metabotropic receptor effects of, 308–309, 309fReceptor-channelsacetylcholine. See Acetylcholine (ACh) receptors (receptor-channels)GABAA. See GABAA receptors (receptor-channels)glutamate. See Glutamate receptors (receptor-channels)glycine. See Glycine receptors (receptor-channels)G-protein coupled. See G protein-coupled receptorsionotropic vs. metabotropic, 251, 312–313, 312t, 313f, 314fReceptor-mediated endocytosis, 151Recessive mutations, 32Kandel-Index_1583-1646.indd 1629 19/01/21 9:18 AM1630 IndexRechtschaffen, Allan, 1096Reciprocal inhibition, 63f, 64Reciprocal inhibitory synapse, 537Reciprocal innervation, 762, 766, 775Recognition molecules, in selective synapse formation, 1182–1184, 1183f–1186fRecombination, 53Reconsolidation, of memory, 1330Rectifier channel, 171, 171fRectifying synapses, 244Recurrent loops, in cerebellum, 912, 913fRecurrent networks, 399Recurrent neural circuits, 102f, 103, 105–107, 106fRed cones, 393, 394fRed-green defect, 539, 539f5-α-Reductase II deficiency, 1253, 1265t, 1279–1280reeler mutant, 1136f–1137fReelin signaling pathway mutations, 1136f, 1138Reese, Thomas, 337–338, 339fReferred pain, 474, 476fReflectance, 540Reflexesaxon, 479baroceptor, 994, 1023, 1027fvs. complex mental function, 70corneal, 993cranial nerve, 992–994crossed-extension, 771cutaneous, 763f, 770–772flexion, 763f, 771–772flexion-withdrawal, 763f, 770–772gag, 993–994gastrointestinal, 993gill-withdrawal, in Aplysia. See AplysiaHering-Breuer, 779hierarchy of, 716Hoffmann. See Hoffmann reflexknee-jerk, 62, 62f, 66, 66fneural architecture for, 70phase-dependent reversal of, 799proprioceptive, 779pupillary light, 992–993, 993fsensory, motor, and muscle signals in, 68, 69f, 716spinal pathways for, 779stapedial, 993state-dependent reversal of, 776strength of, alterations in, 780stretch. See Stretch reflextendon, 780vestibulo-ocular. See Vestibulo-ocular reflexesRefractory periodabsolute, 220after action potential, 212, 219fafter recovery of Na+ channel from inactivation, 220, 221frelative, 220Refractory state, of ion channels, 173, 174fRegenerationaxon. See Axon regenerationin hematopoietic system, 1249Regulated secretion, 150Regulatory needs, motivational states for, 1066Reinforcement, 1306Reinforcement learningin basal ganglia, 944–946, 945fvs. error-based learning, 734types of, 734Reinforcing stimulus, 1306Reissner’s membrane, 600, 600f, 605fRelapse, in drug addiction, 1073. See also Drug addictionRelational associations, hippocampus in, 1300–1302, 1302fRelative refractory period, 220Relay interneurons, 61Relay neurons, in sensory systems, 399–400, 401fRelay nuclei, of thalamus, 83Reliability, synaptic, 337REM sleepascending arousal system pathways in, 1085–1086, 1087f, 1088fdreams in, 1082, 1086, 1088fEEG of, 76, 1081fphysiologic changes in, 1081, 1081f, 1082rebound, 1086switch, 1088fREM sleep behavior disorder, 1095Remodeling, thalamic input to visual circuit for, 1221–1223, 1223fREM-OFF neurons, 1088fREM-ON neurons, 1088fRenin, 1033Renshaw cells, 775–776, 776fRensink, Ron, 1476Repair, of damaged brain. See Brain, damage to/lesions ofRepetition, in learning, 1304Repetition suppression, in fMRI studies, 118Repetitive behaviors, in autism spectrum disorder, 1525f, 1530Replay, in place cells, 101f, 102, 1366Representational model, 817Representational similarity analysis, in fMRI, 119Reproductive behavior, hypothalamus on, 1013tRER (rough endoplasmic reticulum), 135–137, 136fReserpine, 1516f–1517fResidual Ca2+, 351Resistanceaxial, 205axonal, 204fof currents through single ion channel, 171cytoplasmic, 204–205, 204fintracellular axial, 202–203membrane, 204–205, 204fResonance, 1167Resonant frequency, 112Restiform body, 912Resting ion channel, 132, 166, 190Resting membrane potential (Vr)action potential on ion flux balance in, 198–199charge separation across membrane and, 191, 191fdefinition of, 64, 191equivalent circuit model for calculation of, 202b–203b, 202f, 203fGoldman equation on ion contribution to, 199nongated and gated ion channels in, 191–198active transport in electrochemical gradients of Na+, K+, and Ca2+ in, 195–198, 196f, 197fCl- active transport in, 198ion concentration gradients in, 193ion conductance in open channels in resting nerve cells in, 194–195, 196fion distribution across membrane in, 193, 193tK+ permeability of glial cell open channels in, 191f, 193–194, 194frecording of, 192b, 192fRestless leg syndrome, 1095REST/NRSF, 1135Restriction endonuclease, 53Resveratrol, 1566Reticular formation, 992–998mono- and polysynaptic brain stem relays of, in cranial nerve reflexes, 992–994, 993fpattern generators ofin breathing, 994–998, 995f–997fin stereotypic and autonomic behaviors, 992, 994Reticular nucleus, of thalamus, 82, 82fRetina, 521–544bipolar cells in, 536, 537fcircuitry of, 522, 524fdisease from phototransduction defects in, 530functional anatomy of, 521–522, 522f–524fganglion cells in. See Retinal ganglion cellshighlights, 543interneuron network in output of, 536–540color blindness and, 538–539, 538f, 539fcolor vision in cone-selective circuits in, 538parallel pathway origin in bipolar cells in, 524f, 531, 536, 537frod and cone circuit merging in inner retina in, 524f, 540spatial filtering via lateral inhibition in, 524f, 536–537Kandel-Index_1583-1646.indd 1630 19/01/21 9:18 AMIndex 1631temporal filtering in synapses and feedback circuits in, 524f, 526f–527f, 532f, 535f, 537layers and synapses of, 522–524, 523flight adaptation in, 540–543gain controls in, 526f–527f, 535f, 541, 541f, 542freflectance in, 540, 541fin retinal processing and visual perception, 540–541, 542fon spatial processing, 524f, 532f, 534b–535b, 535f, 543photoreceptor layers in, 391f, 522–526ocular optics on retinal image quality in, 522–524, 522f, 525frods and cones in, 524–526, 525f, 526fphototransduction in, 521–522, 522f, 526–530excited rhodopsin on phosphodiesterase via G protein transducin in, 526f–527f, 529–530general mechanism of, 526, 526f–527flight activation of pigment molecules in, 526f, 528–529, 528f, 529fmechanisms to shut off cascade in, 526f–527f, 530transmission of neural images in. See Retinal ganglion cellsRetinal, 528, 528fRetinal center of gaze, 522f, 526Retinal disparity, 880Retinal ganglion cells, 522, 523faxons of, 1101f–1102f, 1182, 1183fgrowth and guidance of, 1168–1176, 1170f–1171f, 1172fephrin gradients of inhibitory brain signals in, 1172–1176, 1174f, 1175fgrowth cone divergence at optic chiasm in, 1171–1172, 1172f, 1173fregeneration of, 1256, 1256fin circadian rhythm, 1090electrical activity and synaptic connection specificity in, 1187, 1188fM-cells, 523f, 531P-cells, 523f, 531in pupillary light reflex, 992, 993fsegregation in lateral geniculate nucleus, 1224–1225, 1225f, 1226fsynapses of, layer-specific, 1182–1184, 1184ftemporal changes in stimuli on output of, 531, 532ftransgenic labeling of, 1101f–1102ftransmission of neural images to brain in, 530–536ganglion cell parallel pathways to brain in, 531, 536image edge response in, 531, 532fON and OFF cells in, 530–531, 536parallel pathways to brain in, 523fretinal output and moving objects in, 531, 533f, 534b–535btemporal changes in stimuli on output in, 531, 532fRetinal prosthesis, 954Retinitis pigmentosa, 530Retinoic acid, in neural patterning, 1114, 1116fRetinotectal map, 1226–1227Retinotopic areas, 504f–505fRetinotopic organization, 501, 509fRetinotopy, 501Retraction bulbs, 1242Retrievalbulk, 343, 343fin episodic memory processing, 1294b, 1297–1298Retrograde axonal transport, 144, 144fRett syndromegenetics of,47–48, 1467, 1532seizures in, 1467symptoms of, 1531–1532Reuptake, of transmitters from synaptic cleft, 375Reverse genetics, 34Reverse inference, in fMRI studies, 123Reverse (reversal) potentials, 218b, 261, 262bReverse transcriptase, 52Rewardamygdala in processing of, 1055definition of, 1066neural circuitry for, 1066–1068, 1067fpathological. See Drug addictionshort and long timescales for, 1066Reward prediction error, 122Rho kinase (ROCK), 1245, 1245fRhodopsin, 528, 528fexcited, on phosphodiesterase via G protein transducin, 526f–527f, 529–530phosphorylation of, 526f–527f, 529–530Rhombomeresformation of, 1115, 1116fHox gene expression and, 1120, 1121fsegmental organization of, 987, 988fRhythmic movements, 715Ribbon synapse, 536, 618–621, 621fRibosomal RNA (rRNA), 29, 146, 147fRibosomes, 135, 136f, 146, 147fRibs, of synaptic vesicles, 349, 350fRichter, Joel, 1327rig-1 protein, in axon growth and guidance, 1178–1179, 1178fRight hemisphere, in prosody, 1382, 1383fRight-beating nystagmus, 640RIM, 349, 351RIM-binding proteins, 349Rinne test, 601RNA, 27. See also specific typesRNA interference (RNAi)definition of, 53on gene function, 36bmechanism in, 149RNAscope, 372f, 373bRNS System, for seizure detection and prevention, 1459b, 1459fRobo, in axon growth and guidance, 1178–1179, 1178fRobust nucleus of the archistriatum (RA), 1267, 1271fROC (receiver operating characteristic) analyses, 390b, 390fRod(s)functions of, 525–526graded sensitivity of, 393, 394f, 526fresponse to light, 391f, 393structure of, 524, 525fvisual pigments in, 528fRod circuit, in inner retina, 524f, 540Romo, Ranulfo, 461, 1403Rosenthal, David, 1490–1491Rostral, 11b, 11fRostral spinal cord, 78fRostral superior colliculus, in visual fixation, 873Rostral-caudal axis, of central nervous system, 11b, 11f, 14fRostrocaudal patterning, of neural tube. See Neural tube development, rostrocaudal patterning inRotating visual field, orienting to, 895–896, 896fRotational vestibulo-ocular reflex. See Vestibulo-ocular reflexesRothman, James, 345Rough endoplasmic reticulum (RER), 135–137, 136fRound window, 599f, 600, 600frRNA (ribosomal RNA), 29, 146, 147fR-SNAREs, 345R-type Ca2+ channel, 329, 331t, 332Rubin figure, 1476, 1476fRubinstein-Taybi syndrome, 1323Rubor, 479Rudin, Donald, 162bRuffini endingsfiber group, name, and modality for, 415tin human hand, 437f, 438–439, 438t, 442finnervation and action of, 421SA2 fibers in. See Slowly adapting type 2 (SA2) fibersRule cue, 835Runx1, 1143fRunx3, 1143frutabaga gene, 1330Ryanodine receptors, 1441SS cones, 525–526, 526f, 538S opsin, 528fS0 (sensory threshold), 387–388, 1401, 1402fSA1 fibers. See Slowly adapting type 1 (SA1) fibersSA2 fibers. See Slowly adapting type 2 (SA2) fibersKandel-Index_1583-1646.indd 1631 19/01/21 9:18 AM1632 IndexSaccadesbrain stabilization of images duringchallenges of, 582, 583f, 584fcorollary discharge in, 583–587, 586fdouble-step task in, 584, 584fmotor commands copied to visual system in, 582–583, 585freceptive field remapping in, 583, 585fbrain stem motor circuits for, 868–870brain stem lesions on, 870mesencephalic reticular formation in vertical saccades in, 863f, 870pontine reticular formation in horizontal saccades in, 868–870, 869fcerebellar learning on, 925, 927fcontrol of, 105–106, 106f, 877cortical pathways for, 871, 871fin fish, 247–248function of, 531in pointing fovea to objects of interest, 866–867, 867f, 879fproprioceptive eye measurement in, 587–588, 587f, 589fin reading, 866superior colliculus control of, 871–875basal ganglia inhibition in, 873–874, 873fcerebral cortex in, 871f, 873–877, 874f, 876f, 879fcortical pathways in, 871, 871fexperience in, 877frontal eye field in, 875movement-related neurons in, 875, 876frostral superior colliculus in visual fixation in, 873supplementary eye field in, 875visual neurons in, 875, 876fvisuomotor integration into oculomotor signals to brain stem in, 871–873, 872f, 873fvisuomovement neurons in, 875Saccadic eye movements. See SaccadesSaccadic pulse, 867, 868fSaccadic step, 867, 868f, 870Saccadic system, 866–867, 867f, 879fSaccule, 600f, 630, 630fSacktor, Todd, 1348Sacral spinal cord, 13f, 78–79, 78fSAD kinases, in hippocampal neuronal polarity, 1158fSadnesscortical regions in, 1058, 1060vs. major depressive disorder, 1502. See also Major depressive disorderSaffran, Jenny, 1376Sagittal plane, of central nervous system, 11bSakmann, Bert, 162b, 171, 260, 329Salivary glands, 1021Salivary neurons, 993Sally-Anne test, 1526, 1526fSaltatory conduction, 152, 153f, 208Saltatory movement, axonal, 143Salty taste receptor, 698f, 701Sarcomereanatomy of, 745, 748f–749fcontractile proteins in, 745–747, 748f–749flength and velocity of, on contractile force, 749, 751fon muscle function, 752SARM1, 1238, 1239fSAT (system A transporter), 366fSaturation effect, 171Savant syndrome, in autism spectrum disorder, 1528–1529, 1530fSBMA. See Spinobulbar muscular atrophy (Kennedy disease)Scaffoldactive zone protein, fusion machinery in, 344f, 349, 350fradial glial cells as, 1131, 1133ffor radial migration, glial cells as, 1137, 1138f, 1139fScala media, 600, 600f, 602f–603fScala tympani, 599, 600f, 602f–603fScala vestibuli, 599, 600f, 602f–603fScarring, on axonal regeneration, 1245f, 1246SCAs. See Spinocerebellar ataxias (SCAs), hereditaryScene segmentation, 555, 560Schäffer, Edward Albert, 358, 566Schaffer collateral pathwaylong-term potentiation ininduction of, 1344f–1345fneural mechanisms of, 1342, 1343fNMDA receptor-dependent, 284, 286f–287fpostsynaptic contribution to, 1345, 1346foverview of, 1340, 1341fin spatial memory, 1351tetanic stimulation of, 1342, 1343fSchally, Andrew, 1028Schenck, C.H., 1095Schizophrenia, 1488–1499brain structure and function abnormalities in, 1492–1497basal ganglia dysfunction, 947f, 949brain development abnormalities in adolescence, 1494, 1497, 1497fconnectivity disruptions, 1494, 1496fgray matter loss, 1492, 1493f, 1494lateral ventricle enlargement, 1492, 1493fprefrontal cortex deficits, 1494, 1495fsynapse elimination, 1497, 1497fcognitive deficits in, 1567course of illness, 1490diagnosis of, 1489–1490dopamine in, 1498environmental risk factors, 49, 1490epidemiology of, 1488, 1490episodic nature of, 1490fMRI in, 1494, 1495fgenetics inheritability and, 28f, 49as risk factor, 1490–1492, 1491fstudies of, 50–51hallucinations in, 1476–1477highlights, 1499hippocampal function alterations in, 1367NMDA receptor malfunction in, 286–287speech in, 1489bsymptoms of, 948, 1489–1490treatment of, 1497–1499, 1498fSchizotypal disorder, 1491Schleiden, Jacob, 58Schultz, Wolfram, 1068Schwann, Theodor, 58Schwann cellsfunctions of, 134, 151gap-junction channels in, 248genetic abnormalities of, 1431fon myelin, after axotomy, 1240structure of, 134, 134fSchwannoma, vestibular, 986SCN9A, in pain, 472Scoville, William, 1293Sculpting role, of inhibition, 290, 290fSDN-POA (sexually dimorphic nucleus of the preoptic area), 1272Second messengers, 303–322. See also specific typesCa2+ as, 327, 327fcytosolic proteins in, 135G protein-coupled receptor-initiatedin cAMP pathway, 303–305molecular logic of, 305–308G proteins activating pathways of, 304f, 305IP3 and diacylglycerol from phospholipase C hydrolysis of phospholipids in, 305–308, 307fmembrane-spanning domains in, 305, 306fphospholipid hydrolysis by phospholipase A2 on arachidonic acid in, 310, 311fprotein kinase C isoforms in, 307fin growth cone, 1164highlights, 321–322ionotropic vs. metabotropic receptor actions in, 312–315cAMP-dependent protein phosphorylation closing of K+ channels in, 317, 318ffunctional effects in, 312, 312tG protein ion channel modulation in, direct, 315, 316fion channel openingin, increase or decrease of, 312t, 313–315, 313f, 314fpresynaptic and postsynaptic modulation, 312–313, 313fKandel-Index_1583-1646.indd 1632 19/01/21 9:18 AMIndex 1633long-lasting consequences of synaptic transmission with, 317, 319fin postsynaptic ion channels, 251, 251freceptor tyrosine kinases in metabotropic receptor effects of, 308–309, 309ftranscellular, in presynaptic function, 310–312endocannabinoids, 310, 311fnitric oxide, 310Second pain, 471f, 472, 490Secondary active transport, 197f, 198Second-messenger pathways, in hyperalgesia, 481Secretins, 368tSecretory proteinsmodification in Golgi complex, 149–150synthesis in endoplasmic reticulum, 147–149, 148fSecretory vesicles, 135, 136fSections, 11b, 11fSedative-hypnotics, 1072t. See also Drug addictionSegmentation, in visual processing, 497, 498f, 499fSeizure(s), 1447–1472animal models of, 1454in autism spectrum disorder, 1539as brain function disruptions, 1448–1449classification of, 1448–1449, 1449tdefinition of, 1447detection and prevention, 956, 1458b–1459b, 1458f, 1459fEEG in. See Electroencephalogram (EEG)epilepsy development and, 1467. See also Epilepsy, development offocal onset, 1448, 1449auras in, 1449early study of, 1448rapid generalization of, 1460seizure focus in, 1454–1461abnormal bursting activity of neurons and, 1454–1455, 1455fdefinition of, 1449inhibitory surround breakdown in, 146f, 1456–1457phases of development of, 1454spatial and temporal organization of, 1456, 1456fspread from, normal cortical circuitry in, 1460–1461, 1460fsynchronization of, 1154f, 1454–1456, 1454f, 1457ftermination of, 1457f, 1460focus of. See Seizure focusgeneralized onset, 1449hemispheric disruption in, 1460, 1460fthalamocortical circuits in propagation of, 1461–1463, 1462ftonic-clonic, 1449typical absence seizure, 1449, 1461, 1462fhighlights, 1470–1471history of, 1447–1448negative signs of, 1448positive signs of, 1448prolonged, as medical emergency, 1465–1466simple partial, 1449termination of, 1457f, 1460typical absence, 1449, 1461, 1462fSeizure focus, 1454–1461definition of, 1449in focal seizures, 1454–1461inhibitory surround in, 1456–1457, 1456flocalization of, for surgery, 1463–1465on cure rate, 1464–1465EEG mapping in, 1463metabolic mapping in, 1463MRI in, 1463PET scans in, 1464–1465SPECT and ictal SPECT in, 1464in temporal lobe epilepsy, 1463, 1464b–14532b, 1464f, 1465fparoxysmal depolarizing shift and afterhyperpolarization in, 1455phases of development of, 1454spatial and temporal organization of, 146f, 1456–1457, 1456fspread from, normal cortical circuitry in, 1457f, 1460–1461synchronization of, 1454f, 1456–1457, 1456f, 1457fSelection disorders. See Basal ganglia, dysfunction ofSelective serotonin reuptake inhibitors (SSRIs), 1511f, 1515, 1516f–1517fSelectivityin basal ganglia, 940, 940fdirectional, of movement, 554, 555fof ion channels, 166, 167–168, 168f–169f. See also specific ions and channelsorientation, 547–548Selectivity filter, 167–168, 168f–169fSelegiline, 1516f–1517fSelf-renewal, 1131, 1132fSelf-sustained firing, 745Semantic memory, 1296. See also Memory, explicitSemaphorins, 1157, 1159f, 1170f–1171fSemicircular canalsbilateral symmetry of, 632, 633ffunction of, 632–634, 634fhead rotation sensing by, 632–634, 633f, 634fstructure of, 600fSemi-intact preparations, for locomotion studies, 785b–786bSemon, Richard, 1340Sensation. See also specific typescutaneous, 1428pain. See Painphantom limb, 1481postural orientation in interpretation of, 894proprioceptive, 1428purposes of, 385Senses. See specific senses and sensationsSensitive periods, 1211. See also Critical periodsSensitizationcentral, 479, 481, 483fdefinition of, 1305, 1316dishabituation and, 1305–1306, 1316to drug, 1072length of, 1316long-termcAMP signaling in, 1319, 1321f, 1322f, 1323presynaptic facilitation of synaptic transmission in, 1316–1317, 1318f–1319f, 1324, 1325fmodulatory neurons in, 1317, 1318f–1319fnociceptor, by bradykinin and histamine, 478Sensorcalcium, 329voltage, 173Sensorimotor control, 713–735. See also Voluntary movementchallenges of, 714–715, 714fhierarchy of processes in, 715–716highlights, 735monoaminergic pathways in, 1004of motor learning, 729–734error-based, adaptation of internal models in, 730–732, 731f, 732fproprioception and tactile sense in, 733b, 733fsensorimotor representations in constraint of, 734skill learning, multiple processes for, 732–734motor plans for translation of tasks into purposeful movement in, 725–729optimal feedback control for error correction, 728–729, 729foptimization of costs with, 726–728, 727f, 728fstereotypical patterns in, 725–726, 726fmotor signal control in, 716–725different sensory processing for action and perception, 724–725, 725ffeedback, for movement correction, 717f, 719, 720ffeedforward, for rapid movements, 716–717, 717finternal sensorimotor models of, 717, 718bsensorimotor delays in, prediction to compensate for, 723–724, 724fsensory and motor signals for estimation of body’s current state in, 719–723Bayesian inference in, 721, 721bobserver model of, 722, 722ftheoretical frameworks for, 816–818, 817ftypes of, 715unconscious mental processes in, 709–710, 715, 1479–1481, 1480f–1481fKandel-Index_1583-1646.indd 1633 19/01/21 9:18 AM1634 IndexSensorimotor skills, learning of. See Motor skill learningSensorineural hearing loss, 601, 626, 626fSensory areas. See specific areasSensory coding, 385–406central nervous system circuits infeedback pathways, 403–404, 403ffunctional specialized cortical areas, 399, 400fparallel pathways in cerebral cortex, 402–403, 403frelay neurons, 400–401, 401ftop-down learning mechanisms, 404–405variability in central neuron response, 400, 402fhighlights, 405–406history of study of, 385neurons in. See Sensory neuronspsychophysics in, 387–388, 388freceptors in. See Sensory receptorsSensory disorders. See specific disordersSensory homunculus, 84–85, 84fSensory informationcerebral cortex pathways for, 402–403, 403fdefinition of, 385neural activity encoding of, 98types of, 385–386, 386fSensory inputs. See specific typesSensory neurons. See also specific typesdefinition of, 59of dorsal root ganglia, 79, 79f, 409–410, 410ffiring rates ofstimulus intensity and, 395–396, 395fstimulus time course and, 396, 397ffunctional components of, 64, 64ffunctional groups of, 61fgroups of, 59interspike intervals of, 396, 397fperceptive field of, 397receptive field of, 397–398, 398f, 399fin spinal cord, 76, 77ftuning of, 402variability in response of, 401, 402fSensory pathways. See also specific typescomponents of, 386–387synapses in, 399, 401fSensory physiology, 387Sensory prediction error, 723Sensory receptors, 132. See also specific typesadaptation of, 396classification of, 392–393, 392thigh-threshold, 396low-threshold, 396rapidly adapting, 396, 397fslowly adapting, 396, 396fspecialization of, 390–393, 391fsubclasses and submodalities of, 393–395, 394fsurface of, in early stages of response, 400–402types of, 386, 386fSensory signals/feedbackin reflex action, 68, 69ftransmission to primary motor cortex, 852, 853ftransmission to somatosensory cortex, 399–400, 401f, 403–404Sensory stimulation. See specific typesSensory systems. See also specific typesdefinition of, 399relay neurons in, 399–400, 401fspatial resolution of, 397–398, 399ftypes of, 392tSensory threshold (S0), 387–388, 1401, 1402fSentences, prosodic cues for, 1376SER (smooth endoplasmic reticulum), 135, 137, 137fSerial processing, in visual columnar systems, 512Serine proteases, 368Serotine reuptake blockers, 1007Serotonergic neurons/systemin ascending arousal system, 1186, 1186fin autonomic regulation and breathing modulation, 996, 1002, 1002f–1003fDeaconess Medical CenterEditor-in-Chief, Annals of NeurologyNathaniel B. Sawtell, PhDAssociate ProfessorZuckerman Mind Brain Behavior InstituteDepartment of Neuroscience Columbia UniversityThomas E. Scammell, MDProfessor of NeurologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolDaniel L. Schacter, PhDWilliam R. Kenan, Jr. ProfessorDepartment of Psychology, Harvard UniversityKristin Scott, PhDProfessorUniversity of California, BerkeleyDepartment of Molecular and Cell BiologyStephen H. Scott, PhDProfessor and GSK Chair in NeuroscienceCentre for Neuroscience StudiesDepartment of Biomedical and Molecular SciencesDepartment of MedicineQueen’s UniversityKingston, CanadaMichael N. Shadlen, MD, PhDHoward Hughes Medical InstituteKavli Institute of Brain ScienceDepartment of NeuroscienceZuckerman Mind Brain Behavior InstituteColumbia University Irving Medical CenterColumbia UniversityNirao M. Shah, MBBS, PhDDepartment of Psychiatry and Behavioral SciencesDepartment of NeurobiologyStanford UniversityKrishna V. Shenoy, PhDInvestigator, Howard Hughes Medical InstituteHong Seh and Vivian W. M. Lim ProfessorDepartments of Electrical Engineering, Bioengineer-ing, and NeurobiologyWu Tsai Neurosciences Institute and Bio-X InstituteStanford UniversityDaphna Shohamy, PhDProfessor, Department of PsychologyZuckerman Mind Brain Behavior InstituteKavli Institute for Brain ScienceColumbia UniversitySteven A. Siegelbaum, PhDChair, Department of NeuroscienceGerald D. Fischbach, MD, Professor of NeuroscienceProfessor of PharmacologyColumbia UniversityMatthew W. State, MD, PhDOberndorf Family Distinguished Professor and ChairDepartment of Psychiatry and Behavioral SciencesWeill Institute for Neurosciences University of California, San FranciscoBeth Stevens, PhDBoston Children’s HospitalBroad Institute of Harvard and MITHoward Hughes Medical Institute Thomas C. Südhof, MDAvram Goldstein Professor in the School of MedicineDepartments of Molecular and Cellular Physiology and of NeurosurgeryHoward Hughes Medical InstituteStanford UniversityKandel_FM.indd 49 20/01/21 9:04 AMl ContributorsDavid Sulzer, PhDProfessor, Departments of Psychiatry, Neurology, and PharmacologySchool of the ArtsColumbia UniversityDivision of Molecular TherapeuticsNew York State Psychiatric InstituteLarry W. Swanson, PhDDepartment of Biological SciencesUniversity of Southern California Carol A. Tamminga, MDProfessor and ChairmanDepartment of PsychiatryUT Southwestern Medical SchoolMarc Tessier-Lavigne, PhDPresident, Stanford UniversityBing Presidential ProfessorDepartment of BiologyStanford UniversityRichard W. Tsien, DPhilDruckenmiller Professor of NeuroscienceChair, Department of Physiology and NeuroscienceDirector, NYU Neuroscience InstituteNew York University Medical CenterGeorge D. Smith ProfessorEmeritusStanford University School of MedicineNicholas B. Turk-Browne, PhDProfessor, Department of PsychologyYale UniversityAnthony D. Wagner, PhDProfessor, Department of Psychology Wu Tsai Neurosciences InstituteStanford UniversityMark F. Walker, MDAssociate Professor of NeurologyCase Western Reserve UniversityStaff Neurologist, VA Northeast Ohio Healthcare SystemXiaoqin Wang, PhDProfessorLaboratory of Auditory NeurophysiologyDepartment of Biomedical EngineeringJohns Hopkins University Gary L. Westbrook, MDSenior Scientist, Vollum InstituteDixon Professor of NeurologyOregon Health and Science UniversityDaniel M. Wolpert, PhD, FMedSci, FRSDepartment of Neuroscience Mortimer B. Zuckerman Mind Brain Behavior Institute Columbia University Robert H. Wurtz, PhDDistinguished Investigator EmeritusLaboratory of Sensorimotor ResearchNational Eye Institute National Institutes of HealthByron M. Yu, PhDDepartment of Electrical and Computer EngineeringDepartment of Biomedical Engineering Neuroscience InstituteCarnegie Mellon UniversityRafael Yuste, MD, PhDColumbia UniversityProfessor of Biological SciencesDirector, Neurotechnology CenterCo-Director, Kavli Institute of Brain Sciences Ikerbasque Research ProfessorDonostia International Physics Center (DIPC)Huda Y. Zoghbi, MDInvestigator, Howard Hughes Medical InstituteProfessor, Baylor College of MedicineDirector, Jan and Dan Duncan Neurological Research InstituteTexas Children’s HospitalCharles Zuker, PhD Departments of Neuroscience, and Biochemistry and Molecular BiophysicsColumbia UniversityHoward Hughes Medical InstituteKandel_FM.indd 50 20/01/21 9:04 AMPart VKandel-Ch30_0707-0736.indd 707 18/01/21 6:00 PMPreceding PageFresco of dancing Peucetian women from the Tomb of the Dancers in the Corso Cotugno necropolis of Ruvo di Puglia, 4th–5th century BC.The tomb has a semicham-ber design. Its six painted panels depict30dancing women, moving from left to right with arms interlocked as though they were dancing in a circle around the interior of the tomb. The skeletal remains of the deceased in the tomb clearly belonged to a distin-guished male warrior. The tomb is named after the dancing women that appear on the frescoes in the tomb. The panels with the frescoes are now exhibited in theNaples National Archaeological Museum, inv. 9353. (Source: https://en.wikipedia.org/wiki/Tomb_of_the_Dancers.)Kandel-Ch30_0707-0736.indd 708 18/01/21 6:00 PMhttps://en.wikipedia.org/wiki/Tomb_of_the_Dancershttps://en.wikipedia.org/wiki/Tomb_of_the_DancersV MovementThe capacity for movement,as many dictionaries remind us, is a defining feature of animal life. As Sherrington, who pio-neered the study of the motor system pointed out, “to move things is all that mankind can do, for such the sole executant is mus-cle, whether in whispering a syllable or in felling a forest.”*The immense repertoire of motions that humans are capable of stems from the activity of some 640 skeletal muscles—all under the control of the central nervous system. After processing sensory information about the body and its surroundings, the motor centers of the brain and spinal cord issue neural commands that effect coor-dinated, purposeful movements. The task of the motor systems is the reverse of the task of the sensory systems. Sensory processing generates an internal represen-tation in the brain of the outside world or of the state of the body. Motor processing begins with an internal representation: the desired purpose of movement. Critically, however, this internal represen-tation needs to be continuously updated by internally generated information (efference copy) and external sensory information to maintain accuracy as the movement unfolds. Just as psychophysical analysis of sensory processing tells us about the capabilities and limitations of the sensory systems, psy-chophysical analyses of motor performance reveal the control rules used by the motor system. Because many of the motor acts of daily life are unconscious, we are often unaware of their complexity. Simply standing upright, for example, requires continual adjustments of numerous postural muscles in response to the vestibular signals evoked by miniscule swaying. Walking, running, and other forms of locomotion involve the combined action of central pattern generators, gated sensory information, and descending commands, which together generate the complex patterns of alternating excitation and inhibition to the appropriate sets of muscles. Many actions, such as serving a tennis *Sherrington CS. 1979. 1924 Linacre lecture. In: JC Eccles, WC Gibson (eds). Sherrington: His Life and Thought, p. 59. New York: Springer-Verlag.Kandel-Ch30_0707-0736.indd 709 18/01/21 6:00 PMball or executing an arpeggio on a piano, occur far too quickly to be shaped by sensory feedback. Instead, centers, such as the cerebel-lum, make use of predictive models that simulate the consequences of the outgoing commands and allow very short latencyin brain stem, 363, 1513, 1513fas chemoreceptors, 996, 996ffunctions of, 363location and projections of, 999f, 1001in migraine, 1004in pain perception, 1004in sudden infant death syndrome, 1002, 1002f–1003fSerotonin (5-hydroxytryptamine, 5-HT)chemical structure of, 363histone acetylation regulation by, 1322f, 1323ionotropic receptors and, 291K+ channel closing by, 317, 318fin long-term facilitation of synaptic transmission, 1325, 1326fin memory consolidation switch, 1323, 1324fon motor neurons, 745, 746fin pain processing, 1004in sensitization, 1317, 1318f–1319fsynthesis of, 363, 1513Serotonin syndrome, 1004Serotonin transporter (SERT), 366fSerpentine receptors, 305. See also G protein-coupled receptorsSertraline, 1515, 1516f–1517fServomechanism, 773Set pointcalcium, in growth cone, 1164in homeostasis, 1012–1013, 1012fSettling point model, in homeostasis, 1012f, 1013fSexanatomical, 1261chromosomal, 1261–1262, 1262fdefinition of, 1261gonadal, 1261Sex chromosomes, 1260–1261Sex determination, 1261, 1262fSex hormones, 1260–1261Sex-linked inheritance, 31Sex-reversed male, 1261Sexual behavior, hypothalamus in regulation of, 1013t, 1040–1041, 1040f, 1070Sexual differentiation, 1260–1272behavioral differences in, 1260–1261in fruit fly mating behavior, 1266, 1268b, 1269fgenetic origins of, 1260–1261highlights, 1281–1272physical differences in, 1261–1264disorders of steroid hormone biosynthesis affecting, 1262–1263, 1265f–1266f, 1324tembryo gonadal differentiation and, 1261–1262, 1262fgonadal synthesis of hormones promoting, 1262–1263, 1263f–1265fsexually dimorphic behaviors in. See Sexually dimorphic behaviorsSexual orientation, 1261Sexually dimorphic behaviors, 1261, 1264–1277core mechanisms in brain and spinal cord underlying, 1275–1277, 1276f, 1277fenvironmental cues in, 1272–1277in courtship rituals, 1272early experience on later maternal behavior in rodents in, 1274–1275, 1274fpheromones on partner choice in mice in, 1272–1274, 1273fgenetic factors in, 1264, 1266in humans, 1277–1281bed nucleus of stria terminalis size and, 1281, 1281fgender identity and sexual orientation and, 1279–1281hormonal action or experience and, 1279hypothalamus and, 1278, 1278folfactory activation and sexual orientation, 1280f, 1281sexual differentiation of the nervous system and, 1264–1272in erectile function, 1266–1267, 1270fhypothalamic neural circuits on sexual, aggressive, and parenting behavior, 1039–1041, 1040f, 1272song production in birds and, 1267Shadlen, Michael, 390bSham rage, 1048, 1050fShapecortical representation of, in visual search, 559–560, 562fobject geometry in analysis of, internal models of, 547–550, 548f–550fvisuomotor processing of, 840, 840fKandel-Index_1583-1646.indd 1634 19/01/21 9:18 AMIndex 1635Shellfish poisoning, amnestic, 1466–1467Shereshevski, 1309Sherrington, Charleson brain compensation for eye movement in vision, 587cellular brain studies of, 10on habituation, 1314on integration in nervous system, 67, 761–762on motor units, 737, 1421on movement, 709on proprioceptive signals, 779, 795on receptive field, 506sensory studies of, 408on spinal circuitry, 762on spinal cord in locomotion, 783on synapses, 241–242Shh. See Sonic hedgehog (Shh)shiverer (shi) mutant mice, 155b, 155fShock, spinal, 780–781Short arm, chromosome, 53Short circuit, 201Short-circuiting (shunting) effect, 290Shortening contraction, 749, 754, 757fShort-range stiffness, 749Short-term memory. See Memory, short-termShort-wave ripples, in hippocampus, 101–102, 101fShprintzen, Robert, 48Si, Kausik, 1327SIDS (sudden infant death syndrome), 1002, 1002f–1003fSign language processing, 19–20, 20fSignal detection theoryframework of, 1394, 1394ffor quantification of sensory detection and discrimination, 389b–390b, 389f, 390f, 1483Signal pathways, 58Signaling, in neurons. See Neuron(s), signaling inSignaling endosomes, 1151Sigrist, Stephan, 349Silent interval, epilepsy, 1469Silent mutation, 33fSilent nociceptors, 472, 474, 475fSilent synapses, 1077, 1345, 1346fSimple cells, in visual cortex, 548, 549fSimple (Mendelian) mutation, 33bSimple partial seizures, 1449. See also Seizure(s), focal onsetSimple phobias, 1504, 1506, 1515. See also Anxiety disordersSingle nucleotide polymorphism (SNP), 53Single-photon emission computed tomography (SPECT), 1464Sirtuins, 1566Site-directed mutagenesis, in ion channel structure, 177Size constancy, in object identification, 571, 572fSize–weight illusion, 724–725, 725fSK channels, 229Skelemins, 747, 748f–749fSkeletal mechanoreceptors, 415tSkeletal muscle, 1421ion channel dysfunction in, 1441, 1443f. See also Myopathies (primary muscle diseases)legs, properties of, 752–754, 753tSkeletal muscle cellsmotor neuron activity on biochemical and functional properties of, 1188, 1189ftypes of, 1188Skeletal muscle diseases. See MyopathiesSkill learning, 1304Skinmechanoreceptors in. See Cutaneous mechanoreceptorstemperature changes in, thermal receptors for, 422–424, 423fSkinner, B.F., 1306, 1373Sleep, 1080–1098age-related changes in, 1092, 1562ascending arousal system in. See Ascending arousal systemcircadian rhythms inclock for, in suprachiasmatic nucleus, 1087–1088, 1089f, 1090hypothalamic relays on, 1090–1091, 1091fdisruptions in. See Sleep disordersEEG of, 1081–1082, 1081f, 1083ffunctions of, 1096–1097highlights, 1097–1098homeostatic pressure for, 1086–1087hypnogram of, 1081floss, effects of, 1091–1092in newborns, 1092polysomnogram of, 1080–1081, 1081fpressure for, 1086–1087REM and non-REM periods in, 1081–1082, 1081f, 1083funstable respiratory patterns during, 996, 997fSleep apneaobstructive, 1092respiratory motor patterns in, 996, 997fsleep pattern disruption by, 1093, 1093fSleep disorders, 1092–1096familial advanced sleep-phase syndrome, 1090insomnia, 1092–1093narcolepsy, 1085, 1093–1095, 1094fnon–24-hour sleep–wake rhythm disorder, 1090parasomnias, 1095–1096periodic limb movement disorder, 1095REM sleep behavior disorder, 1095restless leg syndrome, 1095sleep apnea. See Sleep apneaSleep drive, 1087–1088, 1089fSleep paralysis, 1094Sleep spindles, 1081f, 1082, 1083f, 1461, 1462fSleep talking, 1095–1096Sleepiness, 1091–1092Sleep-wake cycleascending arousal system in control of, 1082, 1083–1084, 1084fcircadian rhythm and, 1088–1090, 1089ffiring patterns of monoaminergic neurons in, 1001, 1001fhypothalamus in regulation of, 1013t, 1091fSleepwalking, 1095–1096Slice-time correction, in fMRI, 116Sliding filament hypothesis, 747Slits, in axon growth and guidance, 1170f–1171f, 1178–1179, 1178fSlow axonal transport, 143, 146–147Slow channel syndrome, 1436Slow wave, EEG, 1081f, 1082, 1083fSlowly adapting type 1 (SA1) fibersin grip control, 446–450, 449fin object pressure and form detection, 444receptive fields of, 438–439, 442fsensory transduction in, 417–419, 418fin touch receptors, 437–438, 437f, 438t, 441fin vibration and detection, 446, 448fSlowly adapting type 2 (SA2) fibersin grip control, 446–450, 449fin proprioception, 447receptive fields of, 438–439, 442fin stereognosis, 442f, 444in touch receptors, 437–438, 437f, 438tSlow-twitch motor units, 740, 740fSlow-twitch muscle fibers, 1189fSlug, 1141SM proteins, 344f, 346Small noncoding RNAs, 29Small synaptic vesicles, 150, 359Small-molecule neurotransmitters, 360–370. See also specific neurotransmittersacetylcholine. See Acetylcholine (ACh)active uptake of, into vesicles, 364–367, 366famino acid transmitters, 364. See also GABA (γ-aminobutyric acid); Glutamate; GlycineATP and adenosine, 364. See also Adenosine triphosphate (ATP)biogenic amines, 360t, 361–364catecholamine transmitters, 361–363, 362bhistamine. See Histamineserotonin. See Serotonintrace, 363vs. neuroactive peptides, 370–371overviewcorrections. Motor learning provides one of the most fruitful subjects for studies of neural plasticity. Motor systems are organized in a functional hierarchy, with each level concerned with a different decision. The highest and most abstract level, likely requiring the prefrontal cortex, deals with the purpose of a movement or series of motor actions. The next level, which is concerned with the formation of a motor plan, involves interactions between the posterior parietal and premotor areas of the cerebral cortex. The premotor cortex specifies the spatiotemporal characteristics of a movement based on sensory information from the posterior parietal cortex about the environment and about the position of the body in space. The lowest level of the hierarchy coor-dinates the spatiotemporal details of the muscle contractions needed to execute the planned movement. This coordination is executed by the primary motor cortex, brain stem, and spinal cord. This serial view has heuristic value, but evidence suggests that many of these processes can occur in parallel. Some functions of the motor systems and their disturbance by disease have now been described at the level of the biochemistry of specific transmitter systems. In fact, the discovery that neurons in the basal ganglia of parkinsonian patients are deficient in dopamine was the first important clue that neurological disorders in the central nervous system can result from altered chemical transmission. Neu-rophysiological studies have provided information as to how such transmitters play a critical role in action selection and the reinforce-ment of successful movements.Understanding the functional properties of the motor system is not only fundamental in its own right, but it is of further importance in helping us to understand disorders of this system and explore the possibilities for treatment and recovery. As would be expected for such a complex apparatus, the motor system is subject to various malfunctions. Disruptions at different levels in the motor hierarchy produce distinctive symptoms, including the movement-slowing characteristic of disorders of the basal ganglia, such as Parkinson disease, the incoordination seen with cerebellar disease, and the spasticity and weakness typical of spinal cord damage. For this rea-son, the neurological examination of a patient inevitably includes tests of reflexes, gait, and dexterity, all of which provide information about the status of the nervous system. In addition to pharmacologi-cal therapies, the treatment of motor system disorders has been aug-mented by two new approaches. First, focal stimulation of the basal ganglia has been shown to restore motility to certain patients with Parkinson disease; such deep-brain stimulation is also being tested in the context of other neurological and psychiatric conditions. And Kandel-Ch30_0707-0736.indd 710 18/01/21 6:00 PMsecond, the motor systems have become a target for the application of neural prosthetics; neural signals are decoded and used to drive devices that aid patients with paralysis caused by spinal cord injury and stroke.Part Editors: Daniel M. Wolpert and Thomas M. JessellPart VChapter 30 Principles of Sensorimotor ControlChapter 31 The Motor Unit and Muscle ActionChapter 32 Sensory-Motor Integration in the Spinal CordChapter 33 LocomotionChapter 34 Voluntary Movement: Motor CorticesChapter 35 The Control of GazeChapter 36 PostureChapter 37 The CerebellumChapter 38 The Basal GangliaChapter 39 Brain–Machine InterfacesKandel-Ch30_0707-0736.indd 711 18/01/21 6:00 PM39Brain–Machine InterfacesUnderstanding the normal function of the nervous system is central to understand-ing dysfunction caused by disease or injury and designing therapies. Such treatments include pharmacological agents, surgical interventions, and, increasingly, electronic medical devices. These medi-cal devices fill an important gap between largely molecularly targeted and systemic medications and largely anatomically targeted and focal surgical lesions.In this chapter, we focus on medical devices that measure or alter electrophysiological activity at the level of populations of neurons. These devices are referred to as brain–machine interfaces (BMIs), brain–computer interfaces, or neural prostheses. We use the term BMI to refer to all such devices because there is no standard distinction among them. BMIs can be organized into four broad categories: those that restore lost sensory capabilities, those that restore lost motor capabilities, those that regulate pathological neural activity, and those that restore lost brain pro-cessing capabilities.BMIs can help people perform “activities of daily living,” such as feeding oneself, physically dressing and grooming oneself, maintaining continence, and walking. A type of BMI that we will discuss extensively in this chapter converts electrical activity from neurons in the brain into signals that control prosthetic devices to help people with paralysis. By understanding how neuroscience and neuroengineering work together to create current BMIs, we can more clearly envision how many neurological diseases and injuries can be treated with medical devices.BMIs Measure and Modulate Neural Activity to Help Restore Lost CapabilitiesCochlear Implants and Retinal Prostheses Can Restore Lost Sensory CapabilitiesMotor and Communication BMIs Can Restore Lost Motor CapabilitiesPathological Neural Activity Can Be Regulated by Deep Brain Stimulation and Antiseizure BMIsReplacement Part BMIs Can Restore Lost Brain Processing CapabilitiesMeasuring and Modulating Neural Activity Rely on Advanced NeurotechnologyBMIs Leverage the Activity of Many Neurons to Decode MovementsDecoding Algorithms Estimate Intended Movements From Neural ActivityDiscrete Decoders Estimate Movement GoalsContinuous Decoders Estimate Moment-by-Moment Details of MovementsIncreases in Performance and Capabilities of Motor and Communication BMIs Enable Clinical TranslationSubjects Can Type Messages Using Communication BMIsSubjects Can Reach and Grasp Objects Using BMI-Directed Prosthetic ArmsSubjects Can Reach and Grasp Objects Using BMI-Directed Stimulation of Paralyzed ArmsSubjects Can Use Sensory Feedback Delivered by Cortical Stimulation During BMI ControlBMIs Can Be Used to Advance Basic NeuroscienceBMIs Raise New Neuroethics ConsiderationsHighlightsKandel-Ch39_0953-0974.indd 953 14/12/20 9:44 AM954 Part V / MovementBMIs Measure and Modulate Neural Activity to Help Restore Lost CapabilitiesCochlear Implants and Retinal Prostheses Can Restore Lost Sensory CapabilitiesOne of the earliest and most widely used BMIs is the cochlear implant. People with profound deafness can benefit from restoration of even some audition. Since the 1970s, several hundred thousand people who have a peripheral cause of deafness that leaves the cochlear nerve and central auditory pathways intact have received cochlear implants. These systems have restored considerable hearing and spoken language, even to children with congenital deafness who have learned to perceive speech using cochlear implants.Cochlear implants operate by capturing sounds with a microphone that resides outside the skin and sending these signals to a receiver surgically implanted under the skin near the ear. After conversion (encod-ing) to appropriate spatial-temporal signal patterns, these signals electrically stimulate spiral ganglion cells in the cochlear modiolus (Chapter 26). In turn, sig-nals from the activated cochlear cells are transmitted through the auditory nerve to the brain stem and higher auditory areas where, ideally, the neural signals are interpreted as the sounds captured by the microphone.Another example of a BMI is a retinal prosthesis. Blindness can be caused by diseases such as retinitis pigmentosa,an inherited retinal degenerative disease. At present, there is no cure and no approved medical therapy to slow or reverse the disease. Retinal prosthe-ses currently enable patients to recognize large letters and locate the position of objects. They operate by cap-turing images with a camera and sending these signals to a receiver positioned within the eye. After conver-sion to appropriate spatial-temporal patterns, these electrical signals stimulate retinal ganglion cells in the retina through dozens of electrodes. In turn, these cells send their signals through the optic nerve to the thala-mus and higher visual areas where, ideally, the afferent signals are interpreted as the image captured by the camera.Motor and Communication BMIs Can Restore Lost Motor CapabilitiesBMIs are also being developed to assist paralyzed peo-ple and amputees by restoring lost motor and com-munication function. This is the central topic of this chapter. First, electrical neural activity in one or more brain areas is measured using penetrating multi-electrode arrays placed, for example, in the arm and hand region of the primary motor cortex, dorsal and ventral premotor cortex, and/or intraparietal cortex (particularly the parietal reach region and medial intraparietal area) (Figure 39–1).Second, an arm movement is attempted but cannot be made in the case of people with paralysis. Action potentials and local field potentials are measured dur-ing these attempts. With 100 electrodes placed in the primary motor cortex and another 100 in the dorsal premotor cortex, for example, action potentials from approximately 200 neurons and local field potentials from 200 electrodes are measured. Local field poten-tials are lower-frequency signals recorded on the same electrodes as the action potentials and believed to arise from local synaptic currents of many neurons near the electrode tips. Together, these neural signals con-tain considerable information about how the person wishes to move her arm.Third, the relationship between neural activity and attempted movements is characterized. This relation-ship makes it possible to predict the desired movement from new neural activity, a statistical procedure we refer to as neural decoding. Fourth, the BMI is then oper-ated in its normal mode where neural activity is meas-ured in real time and desired movements are decoded from the neural activity by a computer. The decoded movements can be used to guide prosthetic devices, such as a cursor on a computer screen or a robotic arm. It is also possible to electrically stimulate muscles in a paralyzed limb to enact the decoded movements, a procedure known as functional electrical stimulation. Many other prosthetic devices can be envisioned as we increasingly interact with the world around us elec-tronically (eg, smart phones, automobiles, and every-day objects that are embedded with electronics so that they can send and receive data—known as the “internet of things”).Finally, because the person can see the prosthetic device, she can alter her neural activity by thinking different thoughts on a moment-by-moment basis so as to guide the prosthetic device more accurately. This closed-loop feedback control system can make use of nonvisual sensory modalities as well, includ-ing delivering pressure and position information from electronic sensors wrapped on or embedded in a pros-thetic arm. Such surrogate sensory information can be transformed into electrical stimulation patterns that are delivered to proprioceptive and somatosensory cortex.The BMIs described above include motor and communication BMIs. Motor BMIs aim to provide natural control of a robotic limb or a paralyzed limb. In the case of upper-limb prostheses, this involves the Kandel-Ch39_0953-0974.indd 954 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 955Figure 39–1 Concept of motor and communication brain–machine interfaces.One or more electrode arrays are implanted in brain regions such as the primary motor cortex, dorsal and ventral premotor cortex, or intraparietal cortex. They record action potentials from tens to hundreds of neurons and local field potentials. The recorded neural activity is then con-verted by a decoding algorithm into (1) computer commands for controlling a computer interface or a prosthetic (robotic) arm, or (2) stimulation patterns for functional electrical stimula-tion of muscles in a paralyzed arm.precise movement of the arm along a desired path and with a desired speed profile. Such control is indeed an ambitious ultimate goal, but even intermediate steps toward this goal could improve quality of life by restoring some lost motor function and improving the patient’s ability to carry out “activities of daily living.” For example, numerous people with tetraplegia could benefit from being able to feed themselves.Communication BMIs are designed to provide a fast and accurate interface with a plethora of elec-tronic devices. The ability to move a computer cursor around an on-screen keyboard allows a patient to type commands for computers, smart phones, voice syn-thesizers, smart homes, and the “internet of things.” Ideally, communication BMIs would allow for a com-munication rate at which most people speak or type. Such BMIs would benefit people with amyotrophic lateral sclerosis (ALS), who often become “locked in” and unable to communicate with the outside world through any movements. Communication BMIs would also benefit people with other neurodegenerative dis-eases that severely compromise the quality of move-ment and speech, as well as those with upper spinal cord injury. The ability to reliably type several words per minute is a meaningful improvement in quality of life for many patients.Motor and communication BMIs build on basic neuroscientific research in voluntary movement (Chapter 34). The design and development of BMIs have so far depended on laboratory animal research, largely with nonhuman primates; recently, however, pilot clini-cal trials with humans with paralysis have begun.VisualcortexInjuryDecodingalgorithmNeuralsignalsNeuron 1Neuron 2Neuron 3ComputersignalsComputerinterfaceProstheticarmParalyzedarmFunctionalelectricalstimulationMotorcortexElectrodearrayRetinaKandel-Ch39_0953-0974.indd 955 14/12/20 9:44 AM956 Part V / MovementPathological Neural Activity Can Be Regulated by Deep Brain Stimulation and Antiseizure BMIsBMIs have been developed to help people with dis-orders involving pathological neural activity in the brain, such as Parkinson disease and epilepsy. People with Parkinson disease benefit by having hand and arm tremor reduced. At present, there is no cure for Parkinson disease, and many people become resistant to pharmacological treatments. A deep brain stimula-tor (DBS) can help these people by delivering electrical pulses to targeted areas in the brain to disrupt the aber-rant neural activity.DBS is controlled by a neurostimulator implanted in the chest, with wires to stimulating electrodes in deep brain nuclei (eg, the subthalamic nucleus). The nuclei are continuously stimulated with these elec-trodes in order to alter the aberrant neural activity. This method can often greatly reduce Parkinson disease–related tremor for years. A DBS applied to different brain areas can also help people with essential tremor, dystonia, chronic pain, major depression, and obsessive-compulsive disorder.Millions of people experiencing epileptic seizures are currently treated with antiseizure medications or neurosurgery, both of which often result in incomplete or impermanent seizure reduction. Antiseizure BMIs have shown considerable promise for further improv-ing quality of life. These fully implanted BMIs operate by continuously monitoring neural activity in a brain region determined to be involved with seizures. Theyidentify unusual activity that is predictive of seizure onset and then respond within milliseconds to disrupt this activity by electrically stimulating the same or a different brain region. This closed-loop response can be fast enough that seizure symptoms are not felt and seizures do not occur.Replacement Part BMIs Can Restore Lost Brain Processing CapabilitiesBMIs are capable of restoring more than lost sensory or motor capabilities. They are, in principle, capable of restoring internal brain processing. Of the four catego-ries of BMIs, this is the most futuristic. An example is a “replacement part” BMI. The central idea is that if enough is known about the function of a brain region, and if this region is damaged by disease or injury, then it may be possible to replace this brain region.Once the normal input activity to a brain region is measured (see next section), the function of the lost brain region could then be modeled in electronic hard-ware and software, and the output from this substitute processing center would then be delivered to the next brain region as though no injury had occurred. This would involve, for example, reading out neural activ-ity with electrodes, mimicking the brain region’s com-putational functions with low-power microelectronic circuits, and then writing in electrical neural activity with stimulating electrodes.This procedure might also be used to initiate and guide neural plasticity. A replacement part BMI that is currently being investigated focuses on restoring memory by replacing parts of the hippocampus that are damaged due to injury or disease. Another poten-tial application would be to restore the lost functional-ity of a brain region damaged by stroke.These systems represent the natural evolution of the BMI concept, a so-called “platform technology” because a large number of systems can be envisioned by mixing and matching various write-in, computa-tional, and read-out components. The number of neu-rological diseases and injuries that BMIs should be able to help address ought to increase as our understanding of the functions of the nervous system and the sophis-tication of the technology continue to grow.Measuring and Modulating Neural Activity Rely on Advanced NeurotechnologyMeasuring and modulating neural activity involves four broad areas of electronic technologies applied to the nervous system (so-called neurotechnology). The first area is the type of neural sensor; artificial neural sensors are designed with different levels of invasive-ness and spatial resolution (Figure 39–2). Sensors that are external to the body, such as an electroencephalogram (EEG) cap, have been used extensively in recent dec-ades. The EEG measures signals from many small metal disks (electrodes) applied to the surface of the scalp across the head. Each electrode detects average activ-ity from a large number of neurons beneath it.More recently, implantable electrode-array tech-niques, such as subdural electrocorticography (ECoG) and finely spaced micro-ECoG electrodes, have been used. Since ECoG electrodes are on the surface of the brain and are thus much closer to neurons than EEG electrodes, ECoG has higher spatial and temporal reso-lution and thus provides more information with which to control BMIs.Most recently, arrays of penetrating intracortical electrodes, which we focus on in this chapter, have been used. The intracortical electrode arrays are made of sil-icon or other materials and coated with biocompatible materials. The arrays are implanted on the surface of the brain, with the electrode tips penetrating 1 to 2 mm Kandel-Ch39_0953-0974.indd 956 14/12/20 9:44 AMChapter 39 / Brain–Machine Interfaces 957Figure 39–2 Brain–machine interfaces use different types of neural sensors.Electrical neural signals can be measured with various techniques ranging from electroencephalography (EEG) electrodes on the surface of the skin, to electrocorticography (ECoG) electrodes on the surface of the brain, to intracortical electrodes implanted in the outer 1 to 2 mm of cortex. The signals that can be measured range from the average of many neurons, to averages across fewer neurons, and finally to action potentials from individual neurons. (Adapted, with per-mission, from Blabe et al. 2015.)into the cortex. They have the ability to record action potentials from individual neurons, as well as local field potentials from small clusters of neurons near each electrode tip. The electrodes are able to record high-fidelity signals because they are inserted into the brain, bringing the electrode tips within micrometers of neurons. This is beneficial for BMI performance because individual neurons are the fundamental information-encoding units in the nervous system, and action potentials are the fundamental units of the digital code that carries information from the input to the output region of a neuron. Moreover, intracortical electrodes can deliver electrical microstimulation to either disrupt neural activity (eg, DBS) or write in sur-rogate information (eg, proprioceptive or somatosen-sory information).The second area of neurotechnology is scaling up the number of neurons measured at the same time. While one neuron contains some information about a person’s intended movement, tens to hundreds of neu-rons are needed to move a BMI more naturally, and even more neurons are needed to approach naturalis-tic levels of motor function. Although it is possible to place electrode arrays in many areas across the brain, thereby gaining more information from multiple areas, a key challenge is to measure activity from thousands of neurons within each individual brain area. Many efforts are underway to achieve this goal, including use of electrode arrays with many tiny shafts, each with hundreds of electrode contacts along its length; many tiny electrodes that are not physically wired together, but are instead inserted into the brain as stand-alone islands that transmit data outside of the head and receive power wirelessly; and optical imaging technol-ogies that can capture the activity of hundreds or more neurons by detecting how each neuron’s fluorescence changes over time.The third area is low-power electronics for sig-nal acquisition, wireless data communications, and wireless powering. In contrast to the BMI systems described above, which implant a passive electrode array in which each electrode is wired to the out-side world by a connector passing through the skin, future BMIs will be fully implanted like DBS systems. Electronic circuits are needed to amplify neural sig-nals, digitize them, process them (eg, to detect when EEGECoGIntracorticalelectrodesIntracortical electrodesECoGEEGKandel-Ch39_0953-0974.indd 957 14/12/20 9:44 AM958 Part V / Movementan action potential occurred or to estimate local field potential power), and transmit this information to a nearby receiver incorporated into a prosthetic arm, for example. Power consumption must be minimized for two reasons. First, the more power is consumed, the more power a battery or a wireless charging sys-tem would need to provide. Batteries would therefore need to be larger and replaced more often, and deliv-ering power wirelessly is challenging. Second, using power generates heat, and the brain can only tolerate a small temperature increase before there are deleterious effects. These trade-offs are similar to those of smart phones, which represent the current best technology available for low-power electronics.The final area is so-called supervisory systems. Software running on electronic hardware is at the heart of BMIs. Some software implements the math-ematical operations of the neural decoding, while other software must tend to aspects of the BMI’s over-all operation. For example, the supervisory software should monitor whether or not a person wishesto use the prosthesis (eg, if the person is sleeping); if neural signals have changed, thereby requiring recalibration of the decoder; and overall BMI performance and safety.Having discussed the range of different BMIs and neurotechnologies being developed, in the rest of this chapter we focus on motor and communication BMIs. We first describe different types of decoding algo-rithms and how they work. We then describe recent progress in BMI development toward assisting para-lyzed people and amputees. Next, we consider how sensory feedback can improve BMI performance and how BMIs can be used as an experimental paradigm to address basic scientific questions about brain function. Finally, we conclude with a cautionary note about ethi-cal issues that can arise with BMIs.BMIs Leverage the Activity of Many Neurons to Decode MovementsVarious aspects of movement—including position, velocity, acceleration, and force—are encoded in the activity of neurons throughout the motor system (Chapter 34). Even though our understanding of movement encoding in the motor system is incom-plete, there is usually a reliable relationship between aspects of movement and neural activity. This reli-able relationship allows us to estimate the desired movement from neural activity, a key component of a BMI.To study movement encoding, one typically con-siders the activity of an individual neuron across repeated movements (referred to as “trials”) to the same target. The activity of the neuron can be averaged across many trials to create a spike histogram for each target (Figure 39–3A). By comparing the spike histo-grams for different targets, one can characterize how the neuron’s activity varies with the movement pro-duced. One can also assess using the spike histograms whether the neuron is more involved in movement preparation or movement execution.In contrast, estimating a subject’s desired move-ment from neural activity (referred to as movement decoding) needs to be performed on an individual trial while the neural activity is being recorded. The activity of a single neuron cannot unambiguously provide such information. Thus, the BMI must moni-tor the activity of many neurons on a single trial (Figure 39–3B) rather than one neuron on many trials. A desired movement can be decoded from the neural activity associated with either preparation or execu-tion of the movement. Whereas preparation activity is related to the movement goal execution activity is related to the moment-by-moment details of move-ment (Chapter 34).Millions of neurons across multiple brain areas work together to produce a movement as simple as reaching for a cup. Yet in many BMIs, desired move-ments can be decoded reasonably accurately from the activity of dozens of neurons recorded from a single brain area. Although this may seem surprising, the fact is that the motor system has a great deal of redundancy—many neurons carry similar information about a desired movement (Chapter 34). This is reasonable because millions of neurons are involved in controlling the con-tractions of dozens of muscles. Thus, most of the neu-rons in regions of dorsal premotor cortex and primary motor cortex controlling arm movement are informa-tive about most arm movements.When decoding a movement, the activity of one neuron provides only incomplete information about the movement, whereas the activity of many neurons can provide substantially more accurate information about the movement. This is true for activity associ-ated with both movement preparation and execution. There are two reasons why using multiple neurons is helpful for decoding. First, a typical neuron alone can-not unambiguously determine the intended movement direction. Consider a neuron whose activity (during either preparation or execution) is related to move-ment direction via a cosine function, known as a tuning curve (Figure 39–4A). If this neuron fires at 30 spikes per second, the intended movement direction could be either 120° or 240°. However, by recording from a second neuron whose tuning curve is different from that of the first neuron, the movement direction can be Kandel-Ch39_0953-0974.indd 958 14/12/20 9:44 AMFigure 39–3 Movement encoding uses the activity of individual neurons averaged across experimental trials, whereas movement decoding uses the activity of many neurons on individual experimental trials.A.Activity of one neuron recorded in the dorsal premotor cortex of a monkey preparing and executing leftward arm movements (left) and rightward arm movements (right). Char-acterizing the movement encoding of a neuron involves deter-mining how the activity of the neuron on repeated leftward or rightward movements (each row of spike trains) relates to aspects of arm movement. Below is the spike histogram for this neuron for leftward and rightward movements, obtained by averaging neural activity across trials. This neuron shows a greater level of preparation activity for leftward movements and a greater level of execution activity for rightward movements. Many neurons in the dorsal premotor cortex and primary motor cortex show movement-related activity in both the preparation and execution epochs like the neuron shown.B.Neural activity for many neurons recorded in the dorsal premotor cortex for one leftward movement (left) and one rightward movement (right). The spike trains for neuron 1 corre-spond to those shown in part A. Spike counts are taken during the preparation epoch, typically in a large time bin of 100 ms or longer to estimate movement goal. In contrast, spike counts are taken during the execution epoch typically in many smaller time bins, each lasting tens of milliseconds. Using such short time bins provides the temporal resolution needed to estimate the moment-by-moment details of the movement.C.Neural decoding involves extracting movement information from many neurons on a single experimental trial. In the sub-ject’s workspace, there are eight possible targets (circles). Dis-crete decoding (see Figure 39–5) extracts the target location; the estimated target is filled in with gray. In contrast, continu-ous decoding (see Figure 39–6) extracts the moment-by-moment details of the movement; the orange dot represents the estimated position at one moment in time.Neuron 1Neuron 2Neuron 10Neuron 3A Single neuron, multiple trialsB Multiple neurons, single trialC Neural decodingTrial 1 Trial 11200 ms200 ms 200 mst=1 t=2t=1 t=2200 ms25 spikes/sTrial 1Preparation Execution Preparation ExecutionPreparation Execution Preparation ExecutionTrial 2Trial 10Trial 11DorsalpremotorcortexDorsalpremotorcortexTrial 12Trial 20Neuron 1Neuron 2Neuron 10t=1t=2Continuous decodingDiscrete decodingt=1t=2Continuous decodingDiscrete decodingTrial 3 Trial 13Neuron 3Spike histogramKandel-Ch39_0953-0974.indd 959 14/12/20 9:44 AM960 Part V / MovementFigure 39–4 More than one neuron is needed for accurate movement decoding.A.The tuning curve of one neuron defines how the neuron’s activity varies with movement direction. If this neuron shows activity of 30 spikes/s, it could correspond to movement in the 120° or 240° direction.B.A second neuron (green) with a different tuning curve shows activity of 5 spikes/s, which could correspond to movement in the 60° or 120° direction. The only movement direction consistent with the activity of both neurons is 120°, which is determined to be the decoded direction.C.Because neural activity is “noisy” (represented as a vertical displacement of the dashed lines), it is usually not possible to conclusively determine the movement direction from the activity of two neurons. Here, no one movement direction is consistent with the activity of both neurons.A One neuron B Two neurons (noiseless) C Two neurons (noisy)0 120 180 240 3601020