motor cortex in voluntary movements a distributed system for distributed functions

These cortical areas includethe primary motor cortex M1 and the six premotor areas that project directly to it.The results presented lead to an emerging view that motor commands can aris

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1 Motor cortex 2 Human locomotion I Riehle, Alexa II Vaadia, Eilon III Series QP383.15.M68 2005

Methods & New Frontiers

in Neuroscience

Our goal in creating the Methods & New Frontiers in Neuroscience series is topresent the insights of experts on emerging experimental techniques and theoreticalconcepts that are or will be at the vanguard of the study of neuroscience Books inthe series cover topics ranging from methods to investigate apoptosis to moderntechniques for neural ensemble recordings in behaving animals The series alsocovers new and exciting multidisciplinary areas of brain research, such as compu-tational neuroscience and neuroengineering, and describes breakthroughs in classicalfields such as behavioral neuroscience We want these to be the books every neuro-scientist will use in order to graduate students and postdoctoral fellows when theyare looking for guidance to start a new line of research

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Voluntary movement is undoubtedly the overt basis of human behavior Withoutmovement we cannot walk, nourish ourselves, communicate, or interact with theenvironment This is one of the reasons why the motor cortex was one of the firstcortical areas to be explored experimentally Historically, the generation of motorcommands was thought to proceed in a rigidly serial and hierarchical fashion Thetraditional metaphor of the piano presents the premotor cortex “playing” the uppermotoneuron keys of the primary motor cortex (M1), which in turn activate withstrict point-to-point connectivity the lower motoneurons of the spinal cord Years ofresearch have taught us that we may need to reexamine almost all aspects of thismodel Both the premotor and the primary motor cortex project directly to the spinalcord in highly complex overlapping patterns, contradicting the simple hierarchicalview of motor control The task of generating and controlling movements appears

to be subdivided into a number of subtasks that are accomplished through paralleldistributed processing in multiple motor areas Multiple motor areas may increasethe behavioral flexibility by responding in a context-related way to any constraintwithin the environment Furthermore, although more and more knowledge is accu-mulating, there is still an ongoing debate about what is represented in the motorcortex: dynamic parameters (such as specific muscle activation), kinematic param-eters of the movement (for example, its direction and speed), or even more abstractparameters such as the context of the movement Given the great scope of the subjectconsidered here, this book focuses on some new perspectives developed from con-temporary monkey and human studies Moreover, many topics receive very limitedtreatment

Section I, which includes the first two chapters, uses functional neuroanatomyand imaging studies to describe motor cortical function The objective of Chapter 1

is to describe the major components of the structural framework employed by thecerebral cortex to generate and control skeletomotor function Dum and Strick

focus on motor areas in the frontal lobe that are the source of corticospinal tions to the ventral horn of the spinal cord in primates These cortical areas includethe primary motor cortex (M1) and the six premotor areas that project directly to it.The results presented lead to an emerging view that motor commands can arise frommultiple motor areas and that each of these motor areas makes a specialized contri-bution to the planning, execution, or control of voluntary movement The purpose

projec-of Chapter 2 is to provide an overview of the contribution of functional magneticresonance imaging (fMRI) to some of the prevailing topics in the study of motorcontrol and the function of the primary motor cortex Kleinschmidt and Toni claimthat in several points the findings of functional neuroimaging seem to be in apparentdisagreement with those obtained with other methods, which cannot always beattributed to insufficient sensitivity of this noninvasive technique In part, it may

reflect the indirect and spatio-temporally imprecise nature of the fMRI signal, butthese studies remain informative by virtue of the fact that usually the whole brain

is covered Not only does fMRI reveal plausible brain regions for the control oflocalized effects, but the distribution of response foci and the correlation of effectsobserved at many different sites can assist in the guidance of detailed studies at themesoscopic or microscopic spatio-temporal level A prudently modest view mightconclude that fMRI is at present primarily a tool of exploratory rather than explan-atory value

Section II provides a large overview of studies about neural representations inthe motor cortex Chapter 3 focuses on the neuromuscular evolution of individuatedfinger movements Schieber, Reilly, and Lang demonstrate that rather than acting

as a somatotopic array of upper motor neurons, each controlling a single musclethat moves a single finger, neurons in the primary motor cortex (M1) act as a spatiallydistributed network of very diverse elements, many of which have outputs thatdiverge to facilitate multiple muscles acting on different fingers This biologicalcontrol of a complex peripheral apparatus initially may appear unnecessarily com-plicated compared to the independent control of digits in a robotic hand, but can beunderstood as the result of concurrent evolution of the peripheral neuromuscularapparatus and its descending control from the motor cortex Chapter 4 deals withsimultaneous movements of the two arms, as a simple example of complex move-ments, and may serve to test whether and how the brain generates unique represen-tations of complex movements from their constituent elements Vaadia and Cardoso

level of single neurons and at the level of neuronal populations (in local fieldpotentials) They further show that population firing rates and dynamic interactionsbetween the hemispheres contain information about the bimanual movement to beexecuted In Chapter 5, Ashe discusses studies with respect to the debate as towhether the motor cortex codes the spatial aspects (kinematics) of motor output,such as direction, velocity, and position, or primarily controls, muscles, and forces(dynamics) Although the weight of evidence is in favor of M1 controlling spatialoutput, the effect of limb biomechanics and forces on motor cortex activity is beyonddispute The author proposes that the motor cortex indeed codes for the mostbehaviorally relevant spatial variables and that both spatial variables and limb bio-mechanics are reflected in motor cortex activity Chapter 6 starts with the importantissue of how theoretical concepts guide experimental design and data analysis Scott

describes two conceptual frameworks for interpreting neural activity during ing: sensorimotor transformations and internal models He claims that sensorimotortransformation have been used extensively over the past 20 years to guide neuro-physiological experiments on reaching, whereas internal models have only recentlyhad an impact on experimental design Furthermore, the chapter demonstrates howthe notion of internal models can be used to explore the neural basis of movement

reach-by describing a new experimental tool that can sense and perturb multiple-jointplanar movements Chapter 7 deals with the function of oscillatory potentials in themotor cortex MacKay notes that from their earliest recognition, oscillatory EEGsignals in the sensorimotor cortex have been associated with stasis: a lack of move-ment, static postures, and possibly physiological tremor It is now established that

10-, 20-, and 40-Hz motor cortical oscillations are associated with constant, sustainedmuscle contractions, again a static condition Sigma band oscillations of about 14 Hzmay be indicative of maintained active suppression of a motor response The dynamicphase at the onset of an intended movement is preceded by a marked decrease inoscillatory power, but not all frequencies are suppressed Fast gamma oscillationscoincide with movement onset Moreover, there is increasing evidence that oscilla-tory potentials of even low frequencies (4–12 Hz) may be linked to dynamic episodes

of movement Most surprisingly, the 8-Hz cortical oscillation — the neurogeniccomponent of physiological tremor — is emerging as a major factor in shaping thepulsatile dynamic microstructure of movement, and possibly in coordinating diverseactions performed together In Chapter 8, Riehle discusses the main aspects ofpreparatory processes in the motor cortex Preparation for action is thought to bebased on central processes, which are responsible for maximizing the efficiency ofmotor performance A strong argument in favor of such an efficiency hypothesis ofpreparatory processes is the fact that providing prior information about movementparameters or removing time uncertainty about when to move significantly shortensreaction time The types of changes in the neuronal activity of the motor cortex, andtheir selectivity during preparation, are portrayed and compared with other corticalareas that are involved in motor behavior Furthermore, linking motor cortical activitydirectly to behavioral performance showed that the trial-by-trial correlation betweensingle neuron firing rates and reaction time revealed strong task-related corticaldynamics Finally, the cooperative interplay among neurons, expressed by precisesynchronization of their action potentials, is illustrated and compared with changes

in the firing rate of the same neurons New concepts including the notion of dinated ensemble activity and their functional implication during movement prepa-ration are discussed In the last chapter of Section II, Chapter 9, Jeannerod posesthe question of the role of the motor cortex in motor cognition The classical view

coor-of the primary motor cortex holds that it is an area devoted to transferring motorexecution messages that have been elaborated upstream in the cerebral cortex Morerecently, however, experimental data have pointed to the fact that the relation ofmotor cortex activity to the production of movements is not as simple as was thought

on the basis of early stimulation experiments This revision of motor cortical functionoriginated from two main lines of research, dealing first with the plasticity of thesomatotopic organization of the primary motor cortex, and second with its involve-ment in cognitive functions such as motor imagery

Section III is mainly concerned with motor learning Chapter 10 explores variousconditions of mapping between sensory input and motor output Brasted and Wise

claim that studies on the role of the motor cortex in voluntary movement usuallyfocus on standard sensorimotor mapping, in which movements are directed towardsensory cues Sensorimotor behavior can, however, show much greater flexibility.Some variants rely on an algorithmic transform between the location of the cue andthat of the target The well-known “antisaccade” task and its analogues in reachingserve as special cases of such transformational mapping, one form of nonstandardmapping Other forms of nonstandard mapping differ strongly: they are arbitrary Inarbitrary sensorimotor mapping, the cue’s location has no systematic spatial rela-tionship with the response The authors explore several types of arbitrary mapping,

with emphasis on the neural basis of learning In Chapter 11, Shadmehr, Donchin,

movement into a motor command When one moves the hand from one point toanother, the brain guides the arm by relying on neural structures that estimate thephysical dynamics of the task Internal models are learned with practice and are afundamental part of voluntary motor control What do internal models compute, andwhich neural structures perform that computation? The authors approach thesequestions by considering a task where the physical dynamics of reaching movementsare altered by force fields that act on the hand Many studies suggest that internalmodels are sensorimotor transformations that map a desired sensory state of the arminto an estimate of forces; i.e., a model of the inverse dynamics of the task If thiscomputation is represented as a population code via a flexible combination of basisfunctions, then one can infer activity fields of the bases from the patterns of gener-alization Shadmehr and colleagues provide a mathematical technique that facilitatesthis inference by analyzing trial-by-trial changes in performance Results suggestthat internal models are computed with bases that are directionally tuned to limbmotion in intrinsic coordinates of joints and muscles, and this tuning is modulatedmultiplicatively as a function of static position of the limb That is, limb positionacts as a gain field on directional tuning Some of these properties are consistentwith activity fields of neurons in the motor cortex and the cerebellum The authorssuggest that activity fields of these cells are reflected in human behavior in the waythat we learn and generalize patterns of dynamics in reaching movements In thelast chapter of Section III, Chapter 12, Padoa-Schioppa, Bizzi, and Mussa-Ivaldi

address the question of the cortical control of motor learning In robotic systems,engineers coordinate the action of multiple motors by writing computer codes thatspecify how the motors must be activated for achieving the desired robot motionand for compensating unexpected disturbance Humans and animals follow anotherpath Something akin to programming is achieved in nature by the biological mech-anisms of synaptic plasticity — that is, by the variation in efficacy of neural trans-mission brought about by past history of pre- and post-synaptic signals However,robots and animals differ in another important way Robots have a fixed mechanicalstructure and dimensions In contrast, the mechanics of muscles, bones, and liga-ments change in time Because of these changes, the central nervous system mustcontinuously adapt motor commands to the mechanics of the body Adaptation is aform of motor learning Here, a view of motor learning is presented that starts fromthe analysis of the computational problems associated with the execution of thesimplest gestures The authors discuss the theoretical idea of internal models andpresent some evidence and theoretical considerations suggesting that internal models

of limb dynamics may be obtained by the combination of simple modules or “motorprimitives.” Their findings suggest that the motor cortical areas include neurons thatprocess well-acquired movements as well as neurons that change their behaviorduring and after being exposed to a new task

The last section, Section IV, is devoted to the reconstruction of movements usingbrain activity For decades, science fiction authors anticipated the view that comput-ers can be made to communicate directly with the brain Now, a rapidly expandingscience community is making this a reality In Chapter 13, Carmena and Nicolelis

present and discuss the recent research in the field of brain–machine interfaces (BMI)conducted mainly on nonhuman primates In fact, this research field has supportedthe contention that we are at the brink of a technological revolution, where artificialdevices may be “integrated” in the multiple sensory, motor, and cognitive represen-tations that exist in the primate brain These studies have demonstrated that animalscan learn to utilize their brain activity to control the displacements of computercursors, the movements of simple and elaborate robot arms,and, more recently, thereaching and grasping movements of a robot arm In addition to the current researchperformed in rodents and primates, there are also preliminary studies using humansubjects The ultimate goal of this emerging field of BMI is to allow human subjects

to interact effortlessly with a variety of actuators and sensory devices through theexpression of their voluntary brain activity, either for augmenting or restoring sen-sory, motor, and cognitive function In the last chapter, Chapter 14, Pfurtscheller,

the human brain into commands that can control devices or applications BCIsprovide a new nonmuscular communication channel, which can be used to assistpatients who have highly compromised motor functions, as is the case with patientssuffering from neurological diseases such as amyotrophic lateral sclerosis (ALS) orbrainstem stroke The immediate goal of current research in this field is to providethese users with an opportunity to communicate with their environment Present-day BCI systems use different electrophysiological signals such as slow corticalpotentials, evoked potentials, and oscillatory activity recorded from scalp or subduralelectrodes, and cortical neuronal activity recorded from implanted electrodes Due

to advances in methods of signal processing, it is possible that specific featuresautomatically extracted from the electroencephalogram (EEG) and electrocortico-gram (ECoG) can be used to operate computer-controlled devices The interactionbetween the BCI system and the user, in terms of adaptation and learning, is achallenging aspect of any BCI development and application

It is the increased understanding of neuronal mechanisms of motor functions,

as reflected in this book, that led to the success of BCI Yet, the success in tappingand interpreting neuronal activity and interfacing it with a machine that eventuallyexecutes the subject’s intention is amazing, considering the limited understanding

we have of the system as a whole

Perhaps ironically, the proof of our understanding of motor cortical activity willstem from how effectively we, as external observers of the brain, can tap into it andmake use of it

Alexa Riehle Eilon Vaadia

to Hanns-Günther Riehle

microcir-cuitries in the frog retina) from the Free University, Berlin, Germany, in 1976, and

a Ph.D degree in neurophysiology (main topic: neuronal mechanisms of temporalaspects of color vision in the honey bee) from the Biology Department of the FreeUniversity in 1980

From 1980 to 1984, she was a postdoctoral fellow at the National Center forScientific Research (CNRS) in Marseille, France (main topic: neuronal mechanisms

of elementary motion detectors in the fly visual system) In 1984, she moved to theCognitive Neuroscience Department at the CNRS and has been mainly interestedsince then in the study of cortical information processing and neural coding in corticalensembles during movement preparation and execution in nonhuman primates

and joined the Department of Physiology at Hadassah Medical School after doctoral studies in the Department of Biomedical Engineering at Johns HopkinsUniversity Medical School in Baltimore, Maryland

post-Vaadia studies cortical mechanisms of sensorimotor functions by combiningexperimental work (recordings of multiple unit activity in the cortex of behavinganimals) with a computational approach He is currently the director of the Depart-ment of Physiology and the head of the Ph.D program at the Interdisciplinary Centerfor Neural Computation (ICNC) at HUJI, and a director of a European advancedcourse in computational neuroscience

James Ashe

Veterans Affairs Medical Center

Brain Sciences Center

Laboratory of Systems Neuroscience

National Institute of Mental Health

National Institutes of Health

Bethesda, Maryland

Simone Cardoso de Oliveira

German Primate Center

Cognitive Neuroscience Laboratory

Göttingen, Germany

Jose M Carmena

Center for Neuroengineering

Department of Neurobiology

Duke University Medical Center

Durham, North Carolina

Opher Donchin

Laboratory for Computational Motor

Control

Department of Biomedical Engineering

Johns Hopkins School of Medicine

Baltimore, Maryland

Richard P Dum

Department of NeurobiologyUniversity of Pittsburgh School of Medicine

Marc Jeannerod

Institute of Cognitive SciencesNational Center for Scientific Research (ISC-CNRS)

Bron, France

Andreas Kleinschmidt

Cognitive Neurology UnitDepartment of NeurologyJohann Wolfgang Goethe UniversityFrankfurt am Main, Germany

Catherine E Lang

University of Rochester Department of NeurologyRochester, New York

William A MacKay

Department of PhysiologyUniversity of TorontoToronto, Ontario, Canada

Ferdinando A Mussa-Ivaldi

Departments of Physiology,

Physical Medicine and Rehabilitation,

and Biomedical Engineering

Northwestern University

Chicago, Illinois

Christa Neuper

Ludwig Boltzmann Institute of Medical

Informatics and Neuroinformatics

Graz University of Technology

Graz, Austria

Miguel A.L Nicolelis

Department of Neurobiology

Duke University Medical Center

Durham, North Carolina

Columbia University Medical Center

Program in Physical Therapy

Stephen H Scott

Centre for Neuroscience StudiesDepartment of Anatomy and Cell Biology

Canadian Institutes of Health Research Group in Sensory-Motor SystemsQueen’s University

Peter L Strick

Veterans Affairs Medical Center for the Neural Basis of Cognition

Department of NeurobiologyUniversity of PittsburghPittsburgh, Pennsylvania

Steven P Wise

Laboratory of Systems NeuroscienceNational Institute of Mental HealthNational Institutes of HealthBethesda, Maryland

Table of Contents

Imaging

Chapter 1 Motor Areas in the Frontal Lobe: The Anatomical Substrate

for the Central Control of Movement

Richard P Dum and Peter L Strick

Cortex

Andreas Kleinschmidt and Ivan Toni

Motor Cortex

Chapter 3 Motor Cortex Control of a Complex Peripheral Apparatus: The

Neuromuscular Evolution of Individuated Finger Movements

Marc H Schieber, Karen T Reilly, and Catherine E Lang

Eilon Vaadia and Simone Cardoso de Oliveira

Chapter 5 What Is Coded in the Primary Motor Cortex?

James Ashe

Chapter 6 Conceptual Frameworks for Interpreting Motor Cortical Function:

New Insights from a Planar Multiple-Joint Paradigm

Stephen H Scott

Chapter 7 Wheels of Motion: Oscillatory Potentials in the Motor Cortex

William A MacKay

Chapter 8 Preparation for Action: One of the Key Functions of the Motor

Chapter 10 The Arbitrary Mapping of Sensory Inputs to Voluntary and

Involuntary Movement: Learning-Dependent Activity in the Motor Cortex and Other Telencephalic Networks

Peter J Brasted and Steven P Wise

Reza Shadmehr, Opher Donchin, Eun-Jung Hwang, Sarah E Hemminger, and

Ashwini K Rao

Chapter 12 Cortical Control of Motor Learning

Camillo Padoa-Schioppa, Emilio Bizzi, and Ferdinando A Mussa-Ivaldi

Brain Activity

Chapter 13 Advances in Brain–Machine Interfaces

Jose M Carmena and Miguel A.L Nicolelis

Gert Pfurtscheller, Christa Neuper, and Niels Birbaumer

Section I

Functional Neuroanatomy and Imaging

© 2005 by CRC Press LLC

1 Motor Areas in the

Frontal Lobe: The Anatomical Substrate for the Central Control

of Movement

Richard P Dum and Peter L Strick

CONTENTS

1.1 Introduction1.2 Functional Anatomy1.2.1 Primary Motor Cortex1.2.1.1 Organization Based on Intracortical Stimulation1.2.1.2 Output of Single Corticomotoneuronal Cells 1.2.1.3 Peripheral Input to M1

1.2.2 Premotor Areas1.2.2.1 Identification by Direct Projections to M11.2.2.2 Somatotopic Organization Based on Connections with

M11.2.2.3 Corticospinal Output1.2.2.4 Somatotopic Organization Based on Corticospinal

Output: Forelimb and Hindlimb Representation1.2.2.5 Somatotopic Organization Based on Corticospinal

Output: Proximal and Distal Arm Representation1.2.2.6 Organization Based on Intracortical Stimulation1.2.3 Corticospinal Terminations

1.2.3.1 Primary Motor Cortex1.2.3.2 Premotor Areas1.3 Cortical Inputs to the Motor Areas1.3.1 Primary Motor Cortex1.3.1.1 Frontal Cortex1.3.1.2 Parietal Cortex1.3.2 Premotor Areas

1.3.2.1 Interconnections among the Motor Areas1.3.2.2 Parietal Cortex

1.3.2.3 Pre-Premotor Cortex1.3.2.4 Prefrontal Cortex 1.3.2.5 Limbic Cortex1.3.3 Summary of Cortical Connections 1.4 Subcortical Inputs

1.5 Summary and Conclusions

In this chapter, we will describe some of the relevant anatomical and physiologicalevidence that has led to this viewpoint

Given the breadth of the subject considered here, our review will focus on newperspectives developed from contemporary primate studies Even with this focus,many topics will receive limited treatment For instance, the physiological andbehavioral studies that provide evidence of differential involvement of each motorarea in the generation and control of movement are beyond the scope of this chapter.For further insight into the historical development of this field and a broader coverage

of related issues, numerous reviews on this and related topics are available.1–11 Inaddition, the corticospinal system has been the subject of a recent book.12

1.2 FUNCTIONAL ANATOMY

1.2.1 P RIMARY M OTOR C ORTEX

The primary motor cortex (M1) owes its name to the fact that thresholds for evokingmovement with electrical stimulation are lower here than in any other corticalregion.13–15 (For historical review, see Reference 12.) Anatomically, M1 corresponds

to cytoarchitectonic area 4, which is identified by the presence of giant pyramidalcells in cortical layer V.16–18 Based on these definitions, M1 is located in the anteriorbank of the central sulcus and on the adjacent caudal portion of the precentral gyrus(Figure 1.1) (For more complete reviews, see References 4,5,9,12.)

FIGURE 1.1 Identification of cortical areas in the macaque monkey The cingulate sulcus (CgS), lateral sulcus (LS), and intraparietal sulcus (IPS) are unfolded and each fundus is

dotted lines. M1 and the premotor areas are shaded Abbreviations: AIP, LIP, MIP, VIP: anterior, lateral, medial, and ventral intraparietal areas; ArS: arcuate sulcus; CGp: posterior cingulate gyrus; CMAd, CMAv, CMAr: dorsal, ventral, and rostral cingulate motor areas; CS: central sulcus; F1 to F7: cytoarchitectonic areas in the frontal lobe according to Matelli

OFC: orbital frontal cortex; PMd: dorsal premotor area; PMv: ventral premotor area; PrCO: precentral opercular cortex; prePMd: pre-premotor area, dorsal; preSMA: presupplementary motor area; PS: principal sulcus; SEF: supplementary eye field; SI: primary somatosensory cortex; SII: secondary somatosensory cortex; SMA: supplementary motor area; PE, PEc, PEci,

V6 PEip

24a,b 9m

V6A PEci

PrCO

46d 46v

Ig

PFGop

V6

LS PS

SMA (F3)

(F4)

(F5)

(F6)

prePMd (F7)

1.2.1.1 Organization Based on Intracortical Stimulation

Our view of the organization of M1 as based on electrical stimulation has evolvedwith advances in stimulation techniques Classically, surface stimulation suggestedthat M1 contained a “motor map” that was a single, contiguous representation ofthe body.14,15 (For reviews, see References 4 and 12.) In this map, the leg, trunk,arm, and face formed a medial to lateral procession across M1 with the distalmusculature of each limb located in the central sulcus Electrical stimulation withmicroelectrodes inserted into the cortex lowered the amount of current necessary toevoke movement by a factor of 100.19 Although this advance allowed a much moredetailed exploration of the cortex, intracortical stimulation confirmed the overallsomatotopy of leg, arm, and face representation described by surface stimulation.19–32

Thus, electrical stimulation of M1 generated a somatotopic motor map with relativelysharp boundaries between major body parts

The organization of movements generated by intracortical stimulation withineach major body part, however, was more complex than that produced by surfacestimulation (Color Figure 1.2).* A consistent observation was that the same move-ment could be evoked at multiple, spatially separate sites.22–32 Although this obser-vation precluded an orderly somatotopy, the general features of this map werereproducible Within the arm representation of macaque monkeys, distal limb move-ments (fingers and wrist) tended to form a central core that was surrounded by ahorseshoe of proximal limb movements (elbow and shoulder) (Color Figure1.2A).22,33 Some intermingling of distal and proximal limb movements occurred atthe borders This organizational structure has been confirmed with single-pulse,stimulus-triggered averaging (Color Figure 1.2B).34 The presence of multiple repre-sentations of an individual movement/muscle in M1 has been proposed as an arrange-ment that allows a muscle to engage in multiple synergies with other muscles acting

at the same or different joints (See Reference 35.)

Other studies utilizing intracortical stimulation20,26,28,32 reported even more plex patterns of muscle activation For example, stimulation at some sites in M1evoked reciprocal activation of wrist antagonists, whereas at other sites it causedtheir co-contraction.26 Some stimulus locations evoked movements of several joints

com-at barely differing thresholds Thus, multiple-joint movements could also be evoked

by relatively localized stimulation These more complex relationships may allow

“automatic” coordination of postural stabilization of the proximal limb during objectmanipulation by the distal limb musculature

More recently, long trains (0.5 to 1.0 sec) of supra-threshold intracortical ulation have been reported to evoke coordinated forelimb movements in the awakeprimate (Color Figure 1.2C).36 Each stimulation site produced a stereotyped posture

stim-in which the arm moved to the same fstim-inal position regardless of its posture at theinitiation of stimulation In the most complex example, the monkey formed a frozenpose with the hand in a grasping position in front of the open mouth The map offinal hand location in the workspace in front of the monkey included both M1 andthe premotor cortex (Color Figure 1.2C) In many respects, these results were a more

* Please see color insert following page 170.

detailed equivalent of observations made initially by Ferrier37 who reported that inM1 “long-continued stimulation brings the hand to the mouth, and at the same timethe angle of the mouth is retracted and elevated.” The interpretation of these complexmovements is limited by the fact that intracortical stimulation primarily activatesneurons trans-synaptically, and thereby enlarges its sphere of activation.38,39 (Seealso References 40,41.) At the extreme, long stimulus trains and high stimulusintensities open the route for interactions at multiple levels, including local, cortical,subcortical, and spinal Thus, intracortical stimulation is unable to determine the

FIGURE 1.2 (see color figure) Intracortical stimulation maps of M1 in macaque monkeys.

(Adapted with permission from Reference 22.) (B) Summary map of muscle representation

shading, those that influenced only distal muscles by dark shading, and those sites that

6 S.D levels above pre-trigger level baseline activity) (Adapted with permission from erence 34.) (C) Summary of hand and arm postures produced by long train (0.5 sec), high

received visual input and stimulation moved the arm into a defensive posture See text for further explanation (Adapted with permission from Reference 36.)

A

Area 3a

Area 4 Area 6

Digits Elbow

Elbow

Shoulder

Elbow Wrist

Digits

Shoulder Wrist

Wrist

Wrist

Digits + Wrist Digits + Wrist

Shoulder

Ce ntra

Wrist

output structure of M1 unambiguously or to ascertain the functional organization of

a cortical motor area

1.2.1.2 Output of Single Corticomotoneuronal Cells

A more focused approach to examining the output structure of M1 has been todetermine the axonal branching patterns of single corticospinal neurons Both phys-iological and anatomical studies provide evidence that single corticospinal neuronsmay have a rather widespread influence in the spinal cord A substantial proportion

of corticospinal neurons (43%) innervates several segments of the spinal cord.42

Reconstruction of individual corticospinal axons filled with an intracellular tracerreveals terminal arbors located in as many as four separate motor nuclei.43 Thus, asingle corticospinal axon can directly influence several muscles

These anatomical observations are consistent with the results of studies ing the spike-triggered averaging technique to examine the divergence of singlecorticomotoneuronal (CM) cells.44–49 (For review see Reference 6.) In this technique,electromyographic (EMG) activity of a sampled muscle was averaged followingeach action potential of a single CM cell Averaged muscle activity exhibitingfacilitation or suppression at a short latency after the spike was considered to indicate

employ-a connection between the CM cell employ-and the muscle’s motoneurons Most CM cells(71%) produced post-spike effects in two or more muscles (mean = 3.1, maximum

10 of 24.49 Many of the post-spike effects were confined to distal muscles (45%)and some were found in proximal muscles (10%) Remarkably, the remaining 45%

of CM neurons produced post-spike effects in both distal and proximal muscles.This result strongly suggests that single CM neurons can influence muscles at bothproximal and distal joints

FIGURE 1.2 (continued)

Fundus

Trunk T

0 5

10

5

10

15 Face

C

EDC BIS Distal Distal + Proximal Proximal

CS ArS

2 mm

Hand to Mouth Hand + arm Bimodal/defensive

Arm Hindlim

The size of the branching patterns of individual CM cells appears to be related

to the muscles they innervate CM cells that influence both proximal and distalmuscles have wider branching patterns than those that project to either proximal ordistal muscles.49 In addition, half of the CM cells that facilitate intrinsic hand musclestargeted just one of the muscles sampled.48 These observations suggest that CM cellshave more restricted branching to distal muscles than they do to proximal muscles.Lemon and colleagues50–52 have emphasized, on the basis of electrophysiologicaldata from macaque and squirrel monkeys, that direct CM projections are importantfor the control of grasp Although Schieber35 has argued that restricted branching isnot a requirement for producing individuated finger movements, the restrictedbranching of some CM cells suggests that they may be specialized to controlindividual finger muscles

The limited branching patterns of some CM neurons as well as the observationthat small clusters of CM neurons tend to innervate the same motoneuron pool42,46

may explain why intracortical stimulation can evoke contractions of a single muscle

at threshold.19 This raises the possibility that a framework for muscle representationexists at the level of small clusters of neurons On the other hand, the highly divergentprojections of many CM neurons are consistent with some of the more complex,multiple-joint movements observed with other variations of the intracortical stimu-lation technique.26,36 Thus, adjustment of the parameters of intracortical stimulationmay promote access to different structural features of the output organization of M1

as well as other portions of the motor system

1.2.1.3 Peripheral Input to M1

Another type of map within M1 concerns the responses of its neurons to peripheralsomatosensory stimulation In both New and Old World primates, neurons in thecaudal part of the forelimb representation of M1 were activated by peripheral inputpredominantly from cutaneous afferents.25,53–55 In contrast, neurons in the rostral part

of the M1 forelimb representation were driven by peripheral afferents originatinglargely from muscles or joints A similar segregation of peripheral input has beenobserved in the hindlimb representation of M1 in the macaque.24 Strick and Preston54

have proposed that the segregation of peripheral inputs within M1 may represent afunctional specialization designed to solve tasks demanding high levels of sen-sory–motor integration For example, the portion of the hand representation in M1that receives largely cutaneous input may be specialized to control finger coordina-tion during object manipulation Thus, the internal organization of M1 is quitecomplicated and may include multiple, overlapping maps of sensory input and motoroutput

1.2.2 P REMOTOR A REAS

The identification and characterization of the premotor cortex has been the subject

of some controversy and considerable revision over the last century.2,9,15,56–61 Theterm “premotor cortex” was originally applied to the portion of agranular cortex(area 6) located anterior to M1 (Figure 1.1).56,62 However, this cytoarchitectonically

1.2.2.1 Identification by Direct Projections to M1

A more recent approach for determining the location of premotor cortex has beenbased on its neuroanatomical connections The premotor cortex in non-human pri-mates has been operationally defined as consisting of those regions in the frontallobe that have direct projections to M1 (For review see References 9,59,60,64–66.)According to this definition, the frontal lobe contains at least six spatially separatepremotor areas (Figures 1.1 and 1.3A) For example, the arm representation of M1receives projections from two rostrally adjacent regions on the lateral surface: theventral premotor area (PMv) and the dorsal premotor area (PMd) (Figure 1.3A).The PMv is located in the portion of area 6 that is lateral to the arcuate spur andextends rostrally into the posterior bank of the inferior limb of the arcuate sulcus.The PMd occupies the portion of area 6 that is medial to the fundus of the arcuatespur and caudal to the genu of the arcuate sulcus Its caudal extent typically includesthe cortex within the superior precentral sulcus (Figures 1.1, 1.3A, and 1.4).Four premotor areas are located on the medial wall of the hemisphere (Figures 1.1,1.3A, and 1.4) These premotor areas include the SMA and three motor areas locatedwithin the cingulate sulcus: the rostral, dorsal, and ventral cingulate motor areas(CMAr, CMAd, and CMAv) The SMA is confined to the portion of area 6 on themesial surface of the superior frontal gyrus that lies between the arcuate genurostrally and the hindlimb representation in M1 caudally The CMAr is located withinarea 24c on the dorsal and ventral banks of the cingulate sulcus at levels largelyanterior to the genu of the arcuate sulcus The CMAd occupies area 6c on the dorsalbank of the cingulate sulcus at levels caudal to the genu of the arcuate sulcus TheCMAv lies on the ventral bank of the cingulate sulcus in area 23c, mostly at thesame levels as the CMAd Thus, the premotor cortex, as defined by its anatomicalconnections to M1, is more complicated than previously recognized (for review seeReferences 2,3,8,15,57,62) and is composed of multiple, spatially separate premotorareas (Figures 1.1, 1.3, and 1.4).59,60,67–69 (See also References 70–76.)

The portion of area 6 (area 6aB)17 that lies dorsal and anterior to the genu ofthe arcuate sulcus can no longer be considered as part of the premotor cortex because

it lacks direct connections with M1 In fact, the connections of these rostral portions

of area 6 suggest that they are more properly considered regions of the prefrontalcortex (see below) On the medial wall, this rostral portion of area 6 (area F677,78)has been recognized as a separate functional region and termed the preSMA (Figures1.1 and 1.4).65,79,80 Similarly, on the lateral surface, the rostral portion of area 6 (areaF777,78) has been termed the prePMd (Figures 1.1 and 1.4) (For review see Reference

66.) Thus, the current definition of premotor cortex includes multiple premotor areaslocated in the caudal half of area 6 as well as in additional regions within the cingulatesulcus that were historically considered part of the limbic cortex.9

1.2.2.2 Somatotopic Organization Based on Connections with M1

The somatotopic organization of the premotor areas has been evaluated based oftheir projections to the arm, leg, and face representations of M1.59,60,64,67–69,71–76,81,82

A number of general conclusions have come from these studies Some premotor

FIGURE 1.3 Identification of premotor areas in the frontal lobe (A) Premotor areas project

to M1 An unfolded map of the frontal lobe depicts the density of labeled neurons after WGA–HRP injections into the physiologically identified digit representation of M1 in the macaque monkey (For details of the unfolding and the determination of cell density, see Dum

arcuate sulcus and have been projected to the surface This projection to the surface artificially increases the displayed density (B) Premotor areas project to the spinal cord An unfolded map of the frontal lobe shows the density of labeled corticospinal neurons after injections of

a fluorescent tracer into the C7–T1 segments of the spinal cord Abbreviations: CC: corpus callosum; CgSd: dorsal bank of the cingulate sulcus; CgSv: ventral bank of the cingulate sulcus; SGm: medial superior frontal gyrus (Reproduced with permission from Reference 64.)

5 mm

PS ArS

PS

LS

CS Midline

SGm CgSd CgSv CgG

areas lack a complete representation of the body (e.g., the PMd lacks a face area).Indeed, complete maps of the body can only be defined for the SMA, CMAv, andCMAr On the other hand, the arm has the most widespread and robust representationwithin each of the premotor areas Overall, the major representations within eachpremotor area originate from distinct, non-overlapping regions

FIGURE 1.4 Somatotopy of corticospinal projections In this map, the location of the arm representations in M1 and the premotor areas are based on the origin of neurons that project

to upper and lower cervical segments The location of the leg representations in each cortical area is based on the origin of neurons that project to lower lumbosacral segments For

ArSs: arcuate sulcus, superior limb (Adapted with permission from Reference 84 Also adapted with permission from Reference 85.)

PMd

PMv

PS ArSs

1.2.2.3 Corticospinal Output

Russell and DeMyer83 first demonstrated that area 6 contributes about the same

number of axons to the pyramids as does area 4 However, the importance of

corticospinal projections from the premotor areas has only been appreciated recently

With the advent of retrograde and anterograde neuronal tracing techniques, numerous

authors were able to demonstrate that each premotor area has direct access to the

spinal cord (Figures 1.3B and 1.4).59,60,84,85 (See also References 86–93.) The

distri-bution of corticospinal neurons in the premotor areas that projected to cervical

segments of the spinal cord corresponded remarkably well to the distribution of

neurons in the premotor areas that projected directly to the arm representation in

M1 (Figures 1.3A and 1.3B) These results suggest that each premotor area has the

potential to influence the generation and control of movement directly at the level

of the spinal cord, as well as at the level of the primary motor cortex

Numerically, the overall contribution of the premotor areas to the corticospinaltract is equivalent to or greater than that of M1 This is most apparent for corticospinal

projections to the cervical segments of the spinal cord After tracer injections

con-fined to the cervical segments (arm representation), the percentage of the total

number of corticospinal neurons in the frontal lobe that originated in the premotor

areas was always equal to or greater than the percentage of corticospinal neurons

in M1 (premotor mean = 56%, range 50–70%, n = 6).60,84,85 For tracer injections

confined to the lumbosacral segments (leg representation), the percentage of

corti-cospinal neurons in the frontal lobe that originated in the premotor areas was less

than the percentage of corticospinal neurons in M1 (premotor mean = 43%, range

39–46%, n = 2).85 These observations reinforce the view that the arm representation

within the premotor areas is more robustly developed than is the leg representation

In other measures of the relative strength of corticospinal projections, M1 clearlydominates but the premotor areas still make significant contributions For example,

each premotor area had some localized regions in which the density of corticospinal

neurons was equivalent to that found in M1 In fact, the relative density of

corti-cospinal neurons in the SMA, CMAd, CMAv and PMd was similar to that found in

M1.60 (See also References 84,85.) With respect to the distribution of large and small

corticospinal neurons, most large corticospinal neurons (79%) were concentrated in

M1.60 The remaining large corticospinal neurons were located in the PMv, PMd,

SMA and CMAd.60 Large corticospinal neurons, which comprise less than 20 percent

of the total,60,88,94,95 are thought to be especially important for mediating

corticomo-toneuronal synapses (See Reference 11.) Taken together, the observations on the

number, density, and size of corticospinal neurons indicate that the premotor areas

make a substantial contribution to the corticospinal system

1.2.2.4 Somatotopic Organization Based on Corticospinal

Output: Forelimb and Hindlimb Representation

Because cervical segments of the spinal cord are known to control arm movements

and lumbosacral segments are known to control leg movements, the “arm” and the

“leg” representations of a cortical area also can be identified on the basis of the

origin of their projections to the cervical or lumbosacral segments of the spinal cord,

respectively This is possible because only 0.2% of corticospinal neurons branch and

innervate both the cervical and lumbosacral levels of the spinal cord.85 Corticospinal

projections from all of the premotor areas displayed a high degree of topographic

organization The origin of corticospinal neurons in the premotor areas that projected

to cervical or to lumbar segments of the spinal cord corresponded remarkably well

to the origin of neurons in the premotor areas that projected directly to the M1 arm

or to the M1 leg representations, respectively (Figures 1.3A, 1.3B, and 1.4).59,60,76,84,85

Thus, the origins of corticospinal and cortico-cortical projections to M1 are in the

somatotopic register

Five premotor areas projected to the cervical and to the lumbosacral segments

of the spinal cord (Figure 1.4) In the PMd, SMA, CMAd, and CMAv, the origin of

projections to cervical segments did not overlap with the origin of projections to the

lumbosacral segments In the CMAr, the arm and leg representations were not as

clearly separated, whereas in the PMv, most of the corticospinal neurons projected

only to the upper cervical segments.84 Thus, at least four premotor areas contained

arm and leg representations that appear to be as distinct as those found in M1

1.2.2.5 Somatotopic Organization Based on Corticospinal

Output: Proximal and Distal Arm Representation

The topography of the “proximal” and “distal” arm representations has been

exam-ined by injecting different fluorescent tracers into upper cervical and lower cervical

segments of the spinal cord.84,85 In general, lower cervical segments are primarily

involved in the control of the hand and wrist muscles, whereas upper cervical

segments are largely involved in the control of the neck, elbow, and shoulder muscles

(He et al.84 have discussed the topographic organization of the spinal cord motor

nuclei.) All of the premotor areas projected to upper and lower cervical segments,

but only 5% of corticospinal neurons innervated both the upper and lower cervical

segments.85 In each premotor area, the densest concentrations of corticospinal

neu-rons that projected to upper cervical segments were separate from the densest

concentrations of neurons that projected to lower cervical segments.84,85 This same

pattern was also evident in M1 These results suggest that some of the premotor

areas have proximal and distal representations of the arm that are as distinct as those

in M1

One measure of the importance of each premotor area in the control of distalversus proximal arm movements is the relative amount of cortex projecting to the

lower versus upper cervical segments.84,85 Within M1, the region that projects to

lower cervical segments is equal in size to the region that projects to upper cervical

segments This result suggests that the hand representation in M1 is expanded relative

to the actual physical proportion of the arm that is occupied by the hand The

expansion of the hand representation has been viewed as a reflection of the special

role that M1 retains in the generation and control of highly skilled hand

move-ments.12,15,96,97

1.2.2.6 Organization Based on Intracortical Stimulation

The anatomical framework outlined above firmly establishes that the premotor areasare important components in the central mechanisms of skeletomotor control Intra-cortical stimulation with microelectrodes has been used to assess the potential ofeach premotor area to generate movements and to construct a map of the body partsrepresented in each area Significantly, intracortical stimulation has evoked move-ment in each of the premotor areas Typically, the average threshold for evokingmovement with intracortical stimulation in a premotor area is somewhat higher thanthat in M1, and the probability of evoking movement at any given site is lower inthe premotor areas than in M1.64,76,98–101 In most respects, the body maps produced

by intracortical stimulation within the premotor areas are congruent with the graphic organization revealed by anatomical methods

topo-Electrical stimulation of the SMA generated a complete map of the body with

a rostral to caudal orientation of its face, arm, and leg representations (Figure1.5).63,80,89,98,99,102,103 Overall, this somatotopy was consistent with the body map based

on the SMA’s projections to M1 and on corticospinal projections to different segmental

FIGURE 1.5 Intracortical stimulation map of the medial wall of the hemisphere The medial

wall is unfolded and reflected upward to display the medial wall in an “upside down”

orientation The boundaries between cytoarchitectonic areas (dotted lines), the fundus of the cingulate sulcus (dashed line), and the lips of the cingulate sulcus (solid lines) are indicated.

Movements were evoked by short- or long-train intracortical stimulation in a macaque monkey All movements were contralateral to the stimulated hemisphere For conventions and abbre-

Fgc: frontal granular cortex; Skc: somatic koniocortex (Adapted from Reference 99.)

F1 F2

F3 F6

F7

Midline

SGm CgSd CgSv CgG

E y e Face Arm Leg

Lower Trunk & Tail Upper Trunk Neck &

No Response Penetration Site Arm- Long Train

levels (Figures 1.4 and 1.5) (see above).67,75,76,84,85 The reported organization of bodyparts within the face, arm, and leg representations has been less consistent, perhapsdue to the fact that complex movements involving multiple joints or noncontiguousjoints were evoked at some sites in the SMA Nevertheless, sites within the armrepresentation of the SMA that evoked movements of distal joints tended to belocated ventral to sites where movements of proximal joints were evoked.80,89,98,99

Correspondingly, the origin of corticospinal neurons projecting to lower cervicalsegments tended to be located ventral to the origin of corticospinal neurons projecting

to upper cervical segments.85

Intracortical stimulation reinforced the distinction between the SMA and thepreSMA Intracortical stimulation with parameters that were effective in the SMAdid not evoke movement in the preSMA which lies just rostral to the SMA on themedial wall of the hemisphere (Figures 1.1 and 1.5).79,80,99,104–107 Movements of thearm and rarely the face were evoked at some sites within the preSMA when highercurrents and longer pulse trains were applied.80,99,102,106 The movements were alsodifferent in character from those evoked in the SMA Movements elicited in thepreSMA were typically slow, involved multiple joints, and resembled natural posturalmovements PreSMA neurons often responded to visual but not to somatosensorystimuli, whereas SMA neurons had the opposite characteristics, responding to somato-sensory but not visual stimuli.79,80 The requirement for higher currents and longerstimulus trains is consistent with the fact that the preSMA lacks direct projections

to the spinal cord60,85 and to M1.59,60,74,78,79

The major features of the body maps generated with intracortical stimulation inthe cingulate motor areas are in many respects consistent with anatomically definedsomatotopy (compare Figures 1.3, 1.4, and 1.5) The intracortical stimulation maps,however, are more fractured, are punctuated with nonresponsive areas, and reflect alower sampling frequency than in the anatomical experiments Movements of thearm and leg were elicited in each cingulate motor area, but face movements wereevoked only, and infrequently, in the CMAr (Figure 1.5).98,99,101–103 In addition,proximal and distal arm movements have been evoked within the arm representation

of each cingulate motor area.99 The evoked movements, like those elicited in M1,were usually limited to fast, brief contractions at a single joint

Longer pulse trains and higher currents were required to evoke movementswithin the CMAr This observation is congruent with the relatively low density ofcorticospinal neurons found in this area (Figure 1.3B) Thorough exploration of theCMAr was limited to one animal, where arm and leg movements were found to besomewhat intermingled.99 Similarly, the origins of corticospinal projections to thecervical and lumbar segments are somewhat overlapping in the CMAr.85 In the regioncorresponding to the CMAd on the dorsal bank of the cingulate sulcus, leg and trunkmovements were found rostrally, just ventral to the arm representation in theSMA.99,103 Thus, the orientation of the body map in the CMAd is reversed compared

to the one in the SMA, just as was predicted by the origin of corticospinal projections

to the cervical and lumbar segments (Figure 1.4).85,108 Arm movements were consistently

evoked in the rostral portion of the region corresponding to the CMAv (Figure 1.5)(see also Reference 109), but few penetrations have been made in the caudal portion

of the CMAv where a leg representation was reported to be located.72,76,82,85,108 Thus,there is a reasonable correspondence between the maps generated by intracorticalstimulation and those generated using anatomical methods

Systematic mapping of the PMd with intracortical stimulation has been limited

to one study,101 although numerous studies have reported the results of partialexplorations of this region.22,36,76,110 In general, leg movements were evoked in theregion of the PMd that was medial to the superior precentral sulcus (dimple) andarm movements were evoked in the region that was lateral to this sulcus.101 Distaland proximal arm movements were evoked within this region.22,101,110 Within thePMd, the threshold for evoking movements is highest rostrally and decreases cau-dally.101,111,112 These results parallel the increase in the density of corticospinalneurons in the caudal portion of the PMd.60,84 Eye movements were evoked bystimulation in the prePMd which lies just rostral to the PMd.112 Thus, here again,the border between the prePMd and the PMd defined by intracortical stimulationcorresponds to the border defined using connections to M1 and the spinal cord.60,64,76,84

Intracortical stimulation has defined arm and face representations within thePMv.101 Distal arm movements dominated the portion of the arm representation thatwas buried medially within the inferior limb of the posterior bank of the arcuatesulcus (Figure 1.6).64,100,101 This portion of the PMv projected almost exclusively toupper cervical segments of the spinal cord.60,84,113 The distal movements evoked bystimulation at this site must therefore be mediated either by propriospinal connec-tions from upper to lower cervical segments (for discussions see References84,114–116) or through connections with the hand area of M1.117,118 Proximal armmovements tended to be evoked on the surface near the arcuate spur.100,101 The PMvface representation was located lateral to the arm representation both on the surfaceand within the posterior bank of the arcuate sulcus (not shown in Figure 1.6).101

Information regarding the internal organization of the face area is limited, althoughlaryngeal muscles appear to be represented laterally along the inferior limb of thearcuate sulcus.119

In summary, intracortical stimulation evokes body movements from each motor area These stimulation effects could be mediated directly via corticospinalefferents from each premotor area or indirectly by projections from each premotorarea to M1 and henceforth via the corticospinal efferents from M1 Examination ofthis issue is limited to a short report.120 In this study, the arm and vibrissae repre-sentations in the SMA and M1 of the owl monkey were mapped with intracorticalstimulation Following removal of M1, intracortical stimulation of the SMA couldstill evoke movements with stimulus currents that were in the range of prelesionvalues This observation suggests that electrical activation of corticospinal efferents

pre-in the SMA is sufficient to generate muscle contraction This conclusion repre-inforcesthe view that independent and parallel pathways for motor control originate in theSMA and M1

1.2.3 C ORTICOSPINAL T ERMINATIONS

1.2.3.1 Primary Motor Cortex

The pattern of corticospinal terminations is one indicator of a cortical area’s potentialinfluence on different spinal mechanisms (A complete discussion of this issue isprovided by Kuypers.1) Corticospinal efferents from M1 project to the intermediatezone (laminae V–VIII) of the spinal cord where interneurons that innervate moto-neurons are located as well as directly to the portions of the ventral horn wheremotoneurons are located (Figure 1.7).1,97,121–129 On the other hand, corticospinalprojections from somatosensory and posterior parietal cortex terminate primarily inthe dorsal horn.1,121,122,124–126 Evidence from physiological studies suggests that thesecorticospinal efferents modulate neural processing in ascending somatosensory path-ways (For review, see References 12,130.) Thus, both anatomical and physiological

FIGURE 1.6 Intracortical stimulation map of the arm representation of the PMv A

cross-section from a macaque brain (Macaca nemestrina) illustrates the location of electrode

penetrations and the movements evoked at each stimulation site within the posterior bank of the inferior limb of the arcuate sulcus Thresholds for evoking movement are indicated by

permission from Reference 64.)

30 32 33 34 35 36

2 mm

29

Thumb Fingers Wrist Elbow, Shoulder Orofacial Upper Trunk Eye Blink

evidence suggest that the pattern of corticospinal terminations reflects the differentialinvolvement of these cortical areas in motor output or in somatosensory processing.The extent of M1 terminations within the motor nuclei of the spinal cord changesduring development129,131,132 and varies between different species.1,133 This variationappears to correlate with an animal’s manual dexterity.127,132–136 For example, cebusmonkeys, which grasp small objects and manipulate tools with a modified “precisiongrip,”137–139 have abundant direct projections from M1 to spinal motor nuclei.127 Incontrast, squirrel monkeys, which pick up small items with all fingers grasping inconcert,139,140 have sparse monosynaptic corticospinal terminations that are locatedremotely on motoneuron dendrites.50,127 Thus, the extent of monosynaptic projectionsfrom M1 to spinal motoneurons appears to be part of the neural substrate necessary

to make highly skilled and relatively independent movements of the fingers.50,127,129

(For review, see References 1,12.)

1.2.3.2 Premotor Areas

The relationship between the terminations of corticospinal efferents and the motor,sensory, and interneuronal systems of the spinal cord has been studied only forpremotor areas on the medial wall of the hemisphere.97,128,141,142 In general, the pattern

of corticospinal terminations from the SMA was quite similar to that of M1 (Figure1.7).97,128 The densest terminations of efferents from the SMA and M1 were located

FIGURE 1.7 Corticospinal terminations in C7 of a macaque monkey Digital

photomicro-graphs of spinal cord sections viewed under dark-field illumination with polarized light The

gray matter and spinal laminae are outlined (A) SMA efferents terminate densely in mediate zone of the gray matter of the cervical spinal cord Arrow points to terminations in

inter-the dorsolateral part of lamina IX that contains motoneurons (B) M1 efferents terminate in the same regions as do SMA efferents Compared to SMA terminations, M1 terminations are denser and more extensive in lamina IX, and extend further into the base of the dorsal horn (Adapted with permission from Reference 9.)

A

1 mm

in the intermediate zone (laminae V–VIII) of the cervical spinal cord Terminationshere were concentrated at three locations: (1) the dorsolateral portion of laminaeV–VII; (2) the dorsomedial portion of lamina VI at the base of the dorsal columns;and (3) the ventromedial portion of lamina VII and adjacent lamina VIII Thecingulate motor areas (CMAr, CMAd, CMAv) also terminated most densely withinthe intermediate zone.128,142 However, the density of their terminations was noticeablylower than those from the SMA In addition, terminations from the CMAr and CMAdwere concentrated in the dorsolateral portions of the intermediate zone whereasCMAv terminations were most dense in the dorsomedial portions.128,142 This differ-ential pattern of terminations suggests that the CMAr, CMAd, and CMAv innervatespecific sets of spinal interneurons and thereby influence different spinal mechanismsfor controlling forelimb movements.

All of the medial wall premotor areas, like M1, had terminations that overlappedmotor nuclei in the ventral horn of the cervical segments (Figure 1.7).97,128,141,142

Although the terminations from the premotor areas were less dense over lamina IXthan were those from M1, all of these studies had a consistent result: the terminations

of premotor areas that do overlap lamina IX were concentrated over the motor nucleiinnervating muscles of the fingers and wrist Furthermore, the presence of mono-synaptic projections onto motoneurons innervating muscles of the distal forelimbhas been confirmed electrophysiologically for the SMA.97 This result implies thatthe presence of anterogradely labeled terminations over spinal motoneurons is anindication of direct corticomotoneuronal connections Thus, not only the SMA butalso the CMAd, CMAv, and CMAr appear to project directly to motoneurons con-trolling the distal forelimb In summary, these results suggest that the premotor areashave the anatomical substrate required to influence the generation and control oflimb movement, particularly of the hand This influence is mediated by pathwaysthat are parallel to and independent of those originating in M1

1.3 CORTICAL INPUTS TO THE MOTOR AREAS

The recognition that the premotor areas as well as M1 project to the spinal cordsuggests that motor commands may arise from multiple cortical areas We haveproposed that each cortical area in the frontal lobe that projects to the spinal cordcould operate as a separate efferent system for the control of specific aspects of motorbehavior.59 Obviously, identification of the cortical and subcortical inputs to thesemotor areas could provide some insight into their functional contributions to motorcontrol

Analysis of inputs to M1 and the premotor areas is complicated by severalfactors First, the characterization of the premotor areas is still evolving and thus,their precise borders remain controversial.60,77,82 (For review, see Reference 66.) Forinstance, some initial examinations of the inputs to the SMA actually studied therostrally adjacent region that is now termed the preSMA Second, the representations

of the face, arm, and leg within a cortical area may receive different sets of corticalinputs.73,75,76,78,82,143–146 For example, the arm representations of M1 and the SMAhave robust connections with the PMv whereas their leg representations do not.75,76,78

Thus, discrepancies between studies may result from differences in the body

repre-sentation actually injected Third, the boundaries and identification of the corticalareas projecting to the motor areas are still evolving For instance, area PE in theparietal lobe projects to several premotor areas, but these projections tend to originatefrom separate portions of this parietal area.81,146,148,149 These results suggest that PEmay not be a single homogeneous area Thus, precise localization and identification

of the cortical areas injected with tracers and the cortical areas containing labeledneurons are essential for valid comparisons between different experiments.Another aspect of comparing the inputs to each motor area is judging the relativeimportance of various inputs A small cortical region may receive input from 40 to

70 cytoarchitectonically recognized cortical areas in the ipsilateral hemispherealone.82,144,150,151 However, quantitative analysis of all of the inputs to a single corticalsite has rarely been attempted

To minimize the problems of cortical identification and strength of input, wefocused our analysis on studies that examined the inputs to the arm representation

of motor areas in macaque monkeys We then transformed the results of these studiesonto a standarized map of the frontal and parietal lobes (Figure 1.1) Next, we pooledthe results from recent publications and assigned a “strength” to specific connectionsbased on the relative number of labeled neurons and the consistency with which aprojection was observed in all studies (Tables 1.1 and 1.2) Even with these con-straints, we found considerable variation in the results among studies Consequently,our synthesis of these results reflects our consensus derived from multiple studiesand may not always fit with the data reported in an individual study

1.3.1 P RIMARY M OTOR C ORTEX

1.3.1.1 Frontal Cortex

Cortical input to M1 is entirely confined to cortical regions in the frontal and parietallobes that, like M1, are the origin of projections to the spinal cord (Figure 1.8, Table1.1; see Figure 1.1 for area identification) These corticospinal tract (CST) projectingareas include all the premotor areas in the frontal lobe (defined above) and portions

of the superior parietal lobe (SPL) M1 has no substantial connections with theprefrontal, pre-premotor or limbic cortex

1.3.1.2 Parietal Cortex

The densest and most extensive of projections from the parietal lobe to M1 originate

in the posterior portions of the SPL (Figure 1.8, Table 1.2; see Figure 1.1 for areaidentification) This input arises in area PE on the lateral surface of the postcentralgyrus and area PEip in the lateral portion of the dorsal bank of the intraparietalsulcus.59,68,71,73,76,147,152–155 M1 also receives strong inputs from the primary (SI) andsecondary (SII) somatosensory cortices The origin of SI projections to M1 issurprisingly widespread although their density is more modest than those from area

PE (Table 1.2) The strength of projection from the subdivisions of SI is greater forthose regions (e.g., areas 1 and 2) that are at a “later” stage in processing of thecutaneous and proprioceptive afferent information than area 3b, which is at an

“earlier” stage of processing Nevertheless, area 3a does have substantial input to

M1.71,73,154–156 SII has heavy projections to M1 in most studies,68,71,73,154,155 but theseprojections were less substantial when injections were confined to the surface of theprecentral gyrus.59,76

As noted earlier, neurons in M1 exhibit short latency responses to activation ofcutaneous and proprioceptive receptors However, the route by which this soma-tosensory input reaches M1 remains controversial Lesion of the dorsal columns, amajor ascending pathway to the parietal cortex, extinguishes the responsiveness of

SMA

Pre-Motor

M1 Inj Site xxx xxx xxx xx xx x

PMd xxx Inj Site xx xxx xx x x xxx xx PMv xxx x Inj Site xxx x x xx x xx SMA xxx xxx xxx Inj Site xxx xxx xx x x CMAd xx xxx x xxx Inj Site xxx xxx

CMAv xx xxx xx xxx xxx Inj Site xxx ?

CMAr xx xx xx xxx xxx xxx Inj Site xxx xxx

Pre-Premotor

PreSMA xx x xx ? x xx xxx Inj Site

Note: xxx = major input, xx = moderate input, x = weak input, ? = weak input that was less than 1% of

total input and/or not observed in every case.

M1 neurons to peripheral input.157 Removal of the primary and secondary sensory areas, as well as removal of the cerebellum, does not.5,158 Some authors haveproposed that M1 receives input directly from a thalamic region innervated by aportion of the dorsal column pathway (for references and discussion, see Reference 5),but firm anatomical evidence for such a neural circuit remains elusive.159 Althoughthe major route by which short latency somatosensory information reaches M1 has

somato-TABLE 1.2

Ipsilateral Cortical Input from the Parietal Lobe to M1, the Premotor Areas and the Pre-Premotor Areas

Cortical

Area M1 PMdc PMv SMA CMAd CMAv CMAr Pre-PMd Pre-SMA

Superior Parietal Lobule

Note: xxx = major input, xx = moderate input, x = weak input, ? = weak input that was less than 1%

of total input and/or not observed in every case.

not been determined, the interconnections between SI and M1 may be necessary for

an animal to learn a new motor skill under the guidance of somatosensory cues.5,160

1.3.2 P REMOTOR A REAS

1.3.2.1 Interconnections among the Motor Areas

In general, the premotor areas are richly interconnected (Figure 1.8, Table 1.1).Several features of the connections among the premotor areas stand out First, theSMA, of all the premotor areas, has the densest and most balanced reciprocal

FIGURE 1.8 Major ipsilateral cortical inputs to M1, the premotor areas and the pre-premotor

areas in macaque monkeys The premotor areas (gray shading) have reciprocal connections with M1 and project to the spinal cord, whereas pre-premotor areas (no shading) do not All

25 of the major cortical inputs are grouped into 8 categories, reflecting morphological location

divided into cortical regions that project to the spinal cord (gray shading) and those that do not (no shading) Note that each of the profiled cortical areas receives a unique signature of

extrinsic cortical inputs.

PMd

PEip MIP PEc i

pSM A pPM d

PE PEip

PMv

AI P PF SII Ig

46v PrCO

SII Ig

24a, b

2 3a, b 46d 46v

pSM A

pP Md PrC O

PFop

CMAr

PEi p

PFop SII Ig

CMAd

PE PEip

M1

3a 2 1

SII

PMd

Pre-PE c V6A PG m CGp

46d 9m pSM A

SMA

Pre-24a, b 46v 9m pPMd

PE PEi p MIP

CMAv

PFG PFop

24a, b 46d pPMd

2

SMA

PE PEi p PEci

pS MA

Premotor

Pre-Prefront al

Limbic

Medial Posterio r Pariet al

Primary Somato- sensory

Superior P ariet al

L obule

Inferior Pariet al Lobule Later al Sulcus

Target Cortical Area

3a 2

PE PEi p MI P PEci

AI P PF G

P Fop

SII Ig

PreSMA PrePMd PrCO

Project to the Spinal Cord

No Spinal Projections

connections with every other premotor area as well as with M1 Second, the connections among the cingulate motor areas (CMAd, CMAv, CMAr) on the medialwall are dense and equal Third, the PMd and the PMv on the lateral surface havestrong, reciprocal connections with M1 and the SMA On the other hand, the con-nections between the PMd and PMv are more limited The PMv is connected to thecaudal portion of the PMd,58,59,68,72,81 but only sparsely to its rostral portions.58,161,162

inter-The restricted connections between the PMd and the PMv may reflect differences

in the body representation in each area The PMd was reported to project mainly tothe shoulder representation of M1, whereas the PMv projected largely to the digitrepresentation in M1.73 Fourth, the projections from the lateral motor areas (PMd,PMv, M1) to the cingulate motor areas, particularly the CMAv and the CMAr, tend

to be relatively weak.82,163,164 These patterns of connectivity suggest that the PMd andPMv are fundamentally distinct from each other and from the motor areas on themedial wall The SMA with its broad, balanced connectivity is ideally situated tocoordinate and integrate information flowing among the motor areas in the frontal lobe

1.3.2.2 Parietal Cortex

Parietal lobe input to the premotor areas appears to follow a general trend Most ofthe parietal lobe input to the premotor areas originates from posterior portions of theparietal lobe including the SPL (area 5, as described by Brodmann16), the inferiorparietal lobule (area 7, as described by Brodmann16) and the secondary somatosen-sory cortex (SII) (Figure 1.8, Table 1.2) These areas are thought to be concernedwith the highest levels of somatosensory processing and to participate in multimodalsensory integration, spatial attention, or visuomotor control.165 Every premotor area

in the frontal lobe is richly interconnected with parts of at least one of these posteriorparietal areas On the other hand, only the SMA receives dense input from any ofthe subdivisions of the primary somatosensory cortex This input to the SMA orig-inates in area 2, which is thought to be at an intermediate stage of somatosensoryprocessing (Figure 1.8, Table 1.2).59,68,70,72,78,81,146,148,155,161–163

Portions of the superior parietal lobule project to all the premotor areas exceptfor the CMAr On the postcentral gyrus, the lateral portion of area PE targets thePMv, whereas its more medial portions project heavily to the SMA and CMAv Inthe most caudal portion of the postcentral gyrus, area PEc supplies dense input tothe PMd Laterally within the intraparietal sulcus, area PEip has the most widespreadprojections Area PEip targets five premotor areas, including the PMd, PMv, SMA,CMAd, and CMAv (Figure 1.8, Table 1.2) Despite this apparently broad divergence,the origin of projections from PEip to the PMv and PMd as well as M1 tend to arisefrom separate location.59,147,149,162 Medially in the intraparietal sulcus, area MIPprojects densely to the PMd and the CMAv In the caudal portion of the cingulatesulcus, area PEci provides strong input to the SMA and the PMd.59,78,146,148,149,166

Thus, although the premotor areas are broadly targeted by SPL projections, eachpremotor area can be distinguished by its unique mixture of inputs from the SPL(Figure 1.8, Table 1.2)

Projections from subdivisions of area 7 (AIP, PF, PFG, PFop) are primarilyrestricted to the PMv and the three cingulate motor areas (Figure 1.8, Table 1.2)

Subdivisions of area 7 are characterized by more complex forms of somatosensoryprocessing and the presence of multimodal information that integrates visual andsomatosensory inputs.167–169 Area PFop is the only IPL subdivision with strong links

to more than one premotor area It has heavy projections to the CMAd, CMAv, andCMAr AIP in the anterior portion of the ventral bank of the intraparietal sulcus andarea PF on the adjacent IPL provide dense input to the PMv.59,68,81,149,161,162 Area PFG,located just caudal to area PF, projects to the CMAv.82,163,170 Within the lateral sulcus,SII projects densely to the PMv, CMAd, and CMAr, as well as M1.58,59,70,149,162,163,171–174

Taken together, these observations indicate that each premotor area receives a uniquepattern of input from the various subdivisions of the parietal lobe and providesanother basis for differentiating the individual premotor areas

The outputs from the medial posterior parietal cortex to the frontal motor areasarise from regions that are one to two synapses removed from the primary visualcortex These regions include the PEc on the most caudal portion of the superiorparietal gyrus, area V6A buried on the anterior bank of the parietal occipital sulcus,area PGm on the medial wall just rostral to the parietal occipital sulcus and theposterior cingulate gyrus (CGp) (Figure 1.1) The projections from these regions arerestricted to the prePMd and PMd The differential distribution of the projectionsfrom this posterior parietal region to regions of the PMd and prePMd suggests thatthese frontal lobe areas may require further parcellation This is likely to be especiallyevident as more physiological studies are designed to explore the visual–spatialcapabilities of these regions.146,148,175

In general, the density of projections from these “visual areas” in posteriorparietal cortex increases as one proceeds from the caudal border of the PMd to theprePMd.146–149 Some have argued that these projections provide a neural substratefor the visual guidance of reaching movements to objects in extrapersonalspace.146–149 It is unclear, however, whether the visual information provided by theseregions is sufficient for the accurate localization of targets For instance, area V6Ahas the most direct visual input to the motor areas in the frontal lobe V6A neuronshave large receptive fields located in the periphery of the visual field Such fieldsseem better suited to alert the motor system and shift attention to a particular quadrant

of space176–178 than to drive the visuomotor transformation required to reach out andgrasp an object

1.3.2.3 Pre-Premotor Cortex

Three cortical areas — the preSMA, the prePMd, and the precentral opercular cortex(PrCO)179 — reside at the junction between the prefrontal cortex and the premotorareas in the frontal lobe (Figure 1.1) All three areas are located in subdivisions ofarea 6 The prePMd and preSMA are part of area 6a.17 The PrCO is part of area6b.17 At one time or another, each of them has been considered to be a motor areaand part of the broad term — premotor cortex (For prePMd, see Reference 66 forreview; for preSMA, see Reference 8; for PrCO, also known as motor proisocortex[ProM], see Reference 58) None of these areas projects directly to M1, and therefore

we do not consider any of them to be a premotor area.9,59,64,163 Instead, the prePMd,

preSMA, and PrCO are one step removed from M1 and have connections with atleast one premotor area (Figure 1.8, Table 1.1) For example, all of these frontallobe areas are interconnected with the CMAr.58,78,82,107,144,164,180 Each area is alsoconnected with the adjacent premotor area — PrCO with the PMv, prePMd withthe PMd, and preSMA with the SMA.78,107,148,161,162,180 However, the significance ofthe preSMA–SMA connection and the prePMd–PMd connection is unclear Onlyimmediately adjacent regions in these cortical areas appear to be interconnected and

at times these interconnections do not appear especially dense The organization ofthese connections clearly requires further investigation

1.3.2.4 Prefrontal Cortex

Only three premotor areas — the PMv, the CMAr, and the CMAv — receivesubstantial input from the dorsolateral prefrontal cortex (Walker’s area 46181) Thevast majority of these projections originate in the dorsal (area 46d) and ventral (area46v) banks of the principal sulcus (Figures 1.1 and 1.8; Table 1.1).58,59,74,81,82,143,162

The PMv is the target of dense prefrontal projections that originate from area 46v

in a topographic manner.59,74,81,162,182,183 The CMAv and the CMAr are the targets ofprojections from both the dorsal and ventral banks of principal sulcus (areas 46dand 46v) Additional projections to the CMAr arise from the medial and lateralportions of area 9.82,166 These observations indicate that specific portions of theprefrontal cortex selectively target just three of the seven motor areas in the frontallobe These projections of area 46 to the premotor areas link the prefrontal cortex

to cortical regions with direct access to the primary motor cortex and spinal anisms of motor control Connections of the prefrontal cortex with the motor systemappear to be tightly focused and designed to provide specialized information aboutparticular aspects of cognitive and executive functions

mech-1.3.2.5 Limbic Cortex

Limbic input provides a route for emotional and affective influences over motorbehavior Such influences may include the direction of attention toward sensorystimuli and the expression of the motivational–affective response to noxious stimuli,

as well as the potential integration of autonomic responses.184,185 Strong projectionsfrom various portions of the limbic cortex are limited to the cingulate motor areasand the PMv (Figures 1.1 and 1.8; Tables 1.1 and 1.2) The insular cortex providesthe most widespread projections to the premotor areas The granular insular cortextargets the PMv, CMAd, CMAv, and CMAr58,59,68,81,144,149,162,163,166,186 and the dysgran-ular insular cortex targets the CMAv and CMAr.144 From the cingulate gyrus,areas 24a,b and 23a,b send robust projections to the CMAv and the CMAr, whereasarea 24b has additional weak projections to the SMA and CMAd.78,82,107,163,164 TheCMAr and to a lesser degree the CMAv are also the target of weak, scatteredprojections from a wide variety of cortical areas including cingulate (e.g., areas 25,

29, 30), orbitofrontal (POdg, OFdg, OFg), and temporal (e.g., TPdg, TF, areas 28and 35) cortex.143,144 Thus, widespread regions of the limbic cortex target the CMAr