Movement and Basal Ganglia.pdf

The Movement System(Behavior)

Schedule for the Week

Read Chapter 9: Organization of the Motor System & Chapt 27 (pp 786-796)

Wed Watch ETV (“Brain Transplant”)

Four Brain SystemsSensory System

e.g. vision, audition, somatosensation, etc

Cognitive System

Cortex

Motor System

e.g. basal nuclei,cerebellum,

corticospinal

Behavioral StateSleep-Waking Cycles

arousalmidbrain areas

Anterior Cortex & Actionplan for the subsequent movement and send a corresponding message to muscles, wassimply too long to permit piano playing. Lashley suggested that movements must beperformed as motor sequences, with one sequence being held in readiness while anongoing sequence was being completed. According to this view, all complex behaviors,including playing the piano, painting pictures, and playing basketball, would requirethe selection and execution of multiple sequences of movements. As one sequence is

being executed, the next sequence is being prepared so that the secondcan follow the first smoothly. Interestingly, Lashley’s view seems to beborne out in how we execute speech. When people use complex se-quences of words, they are more likely to pause and make “umm” and“ahh” sounds, suggesting that it is taking them more time than usualto organize their word sequences.

The frontal lobe of each hemisphere is responsible for planningand initiating sequences of behavior. The frontal lobe is divided into anumber of different regions, including the three illustrated in Figure10-3. From front to back, they are the prefrontal cortex, the premotorcortex, and the primary motor cortex.

A function of the prefrontal cortex is to plan complex behaviors.Such plans might be deciding to get up at a certain hour to arrive atwork on time, deciding to stop at the library to return a book that isdue, or deciding what kind of picture to paint for an art class. The pre-frontal cortex does not specify the precise movements that should bemade. It simply specifies the goal toward which movements should bedirected.

To bring a plan to completion, the prefrontal cortex sends in-structions to the premotor cortex, which produces complex sequencesof movement appropriate to the task. If the premotor cortex is dam-aged, such sequences cannot be coordinated and the goal cannot beaccomplished. For example, the monkey in Figure 10-4 has a lesion inthe dorsal part of its premotor cortex. It has been given the task of ex-

tracting a piece of food wedged in a hole in a table (Brinkman, 1984). If it simplypushes the food with a finger, the food will drop to the floor and be lost. The monkeyhas to catch the food by holding a palm beneath the hole as the food is being pushedout. This animal is unable to make the two complementary movements together. It canpush the food with a finger and extend an open palm, but it cannot coordinate theseactions of its two hands.

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Motor sequence. A sequence of move-ments preprogrammed by the brain andproduced as a unit.

Figure 10-3

The prefrontal cortex of the frontal lobeplans movements. The premotor cortexorganizes sequences of movements. Themotor cortex executes specificmovements. Information flow is fromprefrontal to premotor cortex and thento motor cortex.

Figure 10-4

A unilateral lesion in the premotorcortex impairs performance by a monkeyon a task requiring both hands. Thenormal monkey can push the peanut outof a hole with one hand and catch it inthe other, but the experimental monkeyis unable to do so.Adapted from “Supplementary Motor Areaof the Monkey’s Cerebral Cortex: Short - andLong-Term Effects After Unilateral Ablationand the Effects of Subsequent CallosalSection,” by C. Brinkman, 1984, Journal ofNeuroscience, 4, p. 925.

Prefrontal cortex plans movements.

Motor cortex produces specific movements.

Premotor cortex organizes movement sequences.

Prefrontalcortexplans

Premotorcortex

sequences

Motor cortexexecutes actions

5 monthsafter lesion

Premotor cortex(area of lesion)

Primary motorcortex

Prefrontalcortex

Normal animal

Motor Cortex

evidence that the neocortex could control movement. Later researchers confirmed thefinding by using a variety of animals as subjects, including primates such as monkeys.

Then, in the 1950s, Wilder Penfieldused electrical stimulation to map thecortex of conscious human patients whowere about to undergo neurosurgery. (Seethe discussion of Penfield’s techniques inChapter 9.) He and his colleagues foundthat movements were triggered mainly inresponse to stimulation of the primarymotor cortex (also known as Brodmann’sarea 4 or the precentral gyrus). Penfieldsummarized his results by drawing car-toons of body parts to represent the areasof the primary motor cortex that producemovement in those parts. The result was ahomunculus (little person) that could bespread out across the motor cortex, as il-lustrated in Figure 10-9. Because the bodyis symmetrical, an equivalent motor ho-munculus is represented in the cortex ofeach hemisphere. Penfield also identifiedanother smaller motor homunculus inthe dorsal premotor area of each frontallobe, a region sometimes referred to asthe supplementary motor cortex.

The most striking feature of themotor homunculus is the disproportion-ate relative sizes of its body parts com-pared with the relative sizes of actualparts of the body. This distinctive featureis even more clearly illustrated in some of

the artistic renditions of the homunculus that others scientists have made, one ofwhich is shown in Figure 10-10. As you can see, the homunculus has very large handswith an especially large thumb. It also has very large lips and a large tongue. In con-trast, the trunk, arms, and legs, which constitute most of the area of a real body, aremuch smaller in relative size. These size distortions illustrate the fact that large parts ofthe motor cortex regulate the hands, fingers, lips, and tongue, giving us precise motorcontrol over these body parts. Areas of the body over which we have much less motorcontrol have a much smaller representation in the motor cortex.

Another distinctive feature of the homunculus when it is laid out across themotor cortex is that the body parts are arranged somewhat differently than in an ac-tual body. For instance, the area of the cortex that produces eye movements is lo-cated in front of the homunculus’s head. The head is oriented with the chin up andthe forehead down, with the tongue located below the forehead. But such detailsaside, the homunculus is still a useful concept for understanding the topographic organization (functional layout) of the primary motor cortex. It shows at a glancethat relatively larger areas of the brain control the parts of the body that are able tomake the most skilled movements.

The discovery of the topographical representation of the motor cortex suggestedhow movements might be produced. Information from other regions of the neocortexcould be sent to the motor homunculus, and neurons in the appropriate part of thehomunculus could then execute the movements called for. If finger movements are

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Go to the area on the primary motorcortex in the module on the Control ofMovement on your C D for a more de-tailed analysis of the motor homunculus.Notice the exaggerated body parts associ-ated with fine motor control.

Figure 10-9

Penfield’s homunculus. Electricalstimulation, in conscious human patients,of the motor cortex (precentral gyrus, or

Brodmann’s area 4) elicits movement of

the body parts corresponding to the map

of the body. Movements aretopographically organized so that

stimulation of the dorsal medial regionsof the cortex produces movements in thelower limbs, and stimulation in ventralregions of the cortex producesmovements in the upper body, hands,and face.

Figure 10-10

An artistic representation of the corticalhomunculus illustrates thedisproportionate areas of the sensoryand motor cortex that control different

parts of the body.

Movement ofbody parts

Motor cortex

Electrical stimulation of the motor cortex…

…elicits movements of body parts corresponding to the map of the body.

Stimulatingelectrode

Homunculus

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Motor Cortex

Corticospinal Tract

needed, for example, messages could be sent to the finger area of the motor cortex,triggering the required activity there. If this model of how the motor system works iscorrect, damage to any part of the homunculus would result in loss of movements inthe corresponding part of the body.

Although the general idea underlying this model is right, more detailed mappingof the motor cortex and more detailed studies of the effects of damage to it indicatethat the picture is a bit more complex. When researchers investigated the motor cortexin nonhuman primates, with the use of smaller electrodes than those used by Penfieldto examine his patients, they discovered as many as 10 motor homunculi (Galea &Darian-Smith, 1994). As many as 4 representations of the body may exist in the pri-mary motor cortex, and a number of other representations may be found in the pre-motor cortex. What each of these different homunculi does is still unclear. Perhapseach is responsible for a particular class of movements. Whatever the functions turnout to be, they will have to be determined by future research.

The Corticospinal TractsThe main pathways from the motor cortex to the brainstem andspinal cord are called the corticospinal tracts. (The term corti-cospinal indicates that these tracts begin in the neocortex andterminate in the spinal cord.) The axons of the corticospinaltracts originate mainly in layer-V pyramidal cells of the motorcortex, although axons also come from the premotor cortex andsensory cortex. The axons from the motor cortex descend intothe brainstem, sending collaterals to a few brainstem nuclei andeventually emerging on the brainstem’s ventral surface, wherethey form a large bump on each side of that surface. Thesebumps, known as pyramids, give the corticospinal tracts theiralternate name, the pyramidal tracts. At this point, some of theaxons descending from the left hemisphere cross over to theright side of the brainstem, and some of the axons descendingfrom the right hemisphere cross over to the left side of the brain-stem. The rest of the axons stay on their original sides. This divi-sion produces two corticospinal tracts entering each side of thespinal cord. Figure 10-11 illustrates the division of axons for thetract originating in the left-hemisphere cortex. The dual tractson each side of the brainstem then descend into the spinal cord.

HOW DOES THE BRAIN PRODUCE MOVEMENT? ! 367

p

Homunculus. The representation of thehuman body in the sensory or motor cor-tex; also any topographical representationof the body by a neural area.

Topographic organization. A neuralspatial representation of the body or areasof the sensory world perceived by a sen-sory organ.

Figure 10-11

The corticospinal (from cortex to spinal cord) tracts descend from themotor cortex to the brainstem. Their location in the lower brainstem

produces a protrusion (a pyramid) on the ventral surface of the brain. A

tract from each hemisphere (only that from the left hemisphere is shown)divides into a lateral spinothalamic tract, which crosses the midline to theother side of the spinal cord, and a ventral spinothalamic tract, which

remains on the same side. Fibers in the lateral spinothalamic tract arerepresented by the limbs and digits of the cortical homunculus and aredestined to move muscles of the limbs and digits. Fibers of the ventralspinothalamic tract are represented by the midline of the homunculus’sbody and are destined to move muscles of the midline of the body.Photo of spinal cord reproduced from The Human Brain: Dissections of the RealBrain by T. H. Williams, N. Gluhbegovic, and J. Jew, on CD-Rom. Published byBrain University, brain-university.com 2000.

motor cortex

Left-hemisphere

Brainstem

Spinal cord

Pyramidal protrusion

Left-hemispherecorticospinal tract

Ventral corticospinal tract moves muscles of midline of the body.

Lateral corticospinal tract moves limbs and digits.

In looking at the cross section of the spinal cord in Figure 10-12, you can see thelocation of the two tracts on each side. Those fibers that cross to the opposite side ofthe brainstem descend the spinal cord in a lateral position, giving them the name lat-eral corticospinal tract. Those fibers that remain on their original side of the brain-stem continue down the spinal cord in a ventral position, giving them the nameventral corticospinal tract.

The Motor NeuronsThe spinal-cord motor neurons that connect to muscles are located in the spinal cord’sventral horns. Interneurons lie just medial to the motor neurons and project ontothem. The fibers from the corticospinal tracts make synaptic connections with boththe interneurons and the motor neurons, but all nervous system commands to themuscles are carried by the motor neurons. Figure 10-12 shows that the more laterallylocated motor neurons project to muscles that control the fingers and hands, whereasintermediately located motor neurons project to muscles that control the arms andshoulders. The most medially located motor neurons project to muscles that controlthe trunk. The lateral corticospinal tract axons connect mainly with the lateral motorneurons, and the ventral corticospinal tract axons connect mainly to the medial motorneurons.

To picture how the motor homunculus in the cortex is related to motor neurons inthe spinal cord, imagine placing your right index finger on the index-finger region ofthe motor homunculus on the left side of the brain and then following the axons of thecortical neurons downward. Your route takes you through the brainstem, across itsmidline, and down the lateral corticospinal tract, ending on interneurons and motor

368 ! CHAPTER 10

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Figure 10-12

The interneurons and the motor neuronsof the ventral spinal cord aretopographically arranged so that themore lateral neurons innervate the moredistal parts of the limbs and the moremedial neurons innervate the moreproximal muscles of the body.

Fingers

Arms

Shoulders

Trunk

The interneurons and motor neurons of the spinal cord are envisioned as a homunculus representing the muscles that they innervate.

Interneurons project to motor neurons.

Motor neurons project to muscles of the body.

Lateral corticospinal tract synapses with interneurons and motor neurons that innervate muscles of the limbs and digits.

Ventral corticospinal tract synapses with interneurons and motor neurons that innervate the trunk (midline of the body).

Ventral hornof spinal cord

Click on the area on descendingmotor tracts in the module on the Controlof Movement on your C D for a visualoverview of the corticospinal tracts.

Giacomo Rizzolatti

• Born in Kiev

• Studied Medicine in University of Padua

• Professor of Human Physiology, University of Parma

• Studied the role of the motor system in cognition

Primate Area F5

Rizzolatti found F5neurons specific

to particular movements, e.g.

grasping, reaching, tearing

TINS Vol. 21, No. 5, 1998 189

the function of mirror neurons? The proposal thatwe7,8 and others9 have advanced is that their activity‘represents’ actions. This representation can be usedfor imitating actions and for understanding them. By‘understanding’ we mean the capacity that individualshave to recognize that another individual is perform-ing an action, to differentiate the observed actionfrom other actions, and to use this information to actappropriately. According to this view, mirror neuronsrepresent the link between sender and receiver thatLiberman postulated in his motor theory of speechperception as the necessary prerequisite for any typeof communication1,10,11.

What is area F5?

Although doubts have been expressed12, mostauthors share the view that the rostral part of themonkey ventral premotor cortex (area F5) is the mon-key homolog of Broca’s area in the human brain. Thereasons for this view are: that both F5 and Broca’s area are parts of inferior area 6 (Refs 13!15) and theirlocation within the agranular frontal cortex is similar(Box 1); and cytoarchitectonically, there are strongsimilarities between area 44 (the caudal part of Broca’sarea) and F5 (Refs 14,16,17).

Functionally, a difference between Broca’s area andF5 is that Broca’s area is most commonly thought of asan area for speech, whereas F5 is often considered asan area for hand movements. F5 is somatotopicallyorganized – its dorsal part contains a representation ofhand movements2,3,18 and its large ventral part con-tains a representation of mouth and larynx move-ment19,20; a similar organization is present in the ven-tral premotor cortex of other primates21. Similarly, themotor properties of human Broca’s area do not relateonly to speech: recent PET data indicate that Broca’sarea might also become active during the execution ofhand or arm movements22,23, during mental imageryof hand grasping movement (mostly area 44)24,25, andduring tasks involving hand–mental rotations (areas44 and 45)26. Finally, Broca’s area becomes active inpatients who have recovered from subcortical infarctionswhen they are asked to use their paralyzed hand27.

It is intriguing that the area, which in the monkeycontains a system that links action recognition andaction production, is precisely that area that, for com-pletely different reasons, has been proposed as thehomologue of Broca’s area. Is this a mere coincidence?

Or, on the contrary, has the mirror system been fun-damental for the development of speech and, beforespeech, of other forms of intentional communication?Before discussing these points, we examine the evidencefor a mirror system in humans.

G. Rizzolatti and M.A. Arbib – Language and mirror neurons VI E W P O I N T

Fig. 1. An example of a mirror neuron. The behavioral situation isschematically represented in the upper part of each panel. Theresponses of the neuron are shown in the middle and lower parts ofeach panel. The responses are shown as discharges using ten individualbehavioral trials (each short vertical line corresponds to an actionpotential) and expressed as relative-response histograms. (A) Theexperimenter grasps a piece of food with his hand then moves it towardthe monkey, who, at the end of the trial, grasps it. The neuron dis-charges during observation of the grip, ceases to fire when the food isgiven to the monkey and discharges again when the monkey grasps it.(B) The experimenter grasps the food with a tool. The subsequentsequence of events is as in (A). Note the lack of response of the neuronwhen the food is grasped with the tool. (C) The monkey grasps food indarkness. In (A) and (B) the rasters are aligned with the moment whenthe food is grasped by the experimenter (vertical line). In (C) the align-ment is with the approximate beginning of the grasping movement.Each small vertical line in the rasters corresponds to a spike. Histogrambin width: 20 ms. Reproduced with permission from Ref. 7.

TINS Vol. 21, No. 5, 1998 189

the function of mirror neurons? The proposal thatwe7,8 and others9 have advanced is that their activity‘represents’ actions. This representation can be usedfor imitating actions and for understanding them. By‘understanding’ we mean the capacity that individualshave to recognize that another individual is perform-ing an action, to differentiate the observed actionfrom other actions, and to use this information to actappropriately. According to this view, mirror neuronsrepresent the link between sender and receiver thatLiberman postulated in his motor theory of speechperception as the necessary prerequisite for any typeof communication1,10,11.

What is area F5?

Although doubts have been expressed12, mostauthors share the view that the rostral part of themonkey ventral premotor cortex (area F5) is the mon-key homolog of Broca’s area in the human brain. Thereasons for this view are: that both F5 and Broca’s area are parts of inferior area 6 (Refs 13!15) and theirlocation within the agranular frontal cortex is similar(Box 1); and cytoarchitectonically, there are strongsimilarities between area 44 (the caudal part of Broca’sarea) and F5 (Refs 14,16,17).

Functionally, a difference between Broca’s area andF5 is that Broca’s area is most commonly thought of asan area for speech, whereas F5 is often considered asan area for hand movements. F5 is somatotopicallyorganized – its dorsal part contains a representation ofhand movements2,3,18 and its large ventral part con-tains a representation of mouth and larynx move-ment19,20; a similar organization is present in the ven-tral premotor cortex of other primates21. Similarly, themotor properties of human Broca’s area do not relateonly to speech: recent PET data indicate that Broca’sarea might also become active during the execution ofhand or arm movements22,23, during mental imageryof hand grasping movement (mostly area 44)24,25, andduring tasks involving hand–mental rotations (areas44 and 45)26. Finally, Broca’s area becomes active inpatients who have recovered from subcortical infarctionswhen they are asked to use their paralyzed hand27.

It is intriguing that the area, which in the monkeycontains a system that links action recognition andaction production, is precisely that area that, for com-pletely different reasons, has been proposed as thehomologue of Broca’s area. Is this a mere coincidence?

Or, on the contrary, has the mirror system been fun-damental for the development of speech and, beforespeech, of other forms of intentional communication?Before discussing these points, we examine the evidencefor a mirror system in humans.


Fig. 1. An example of a mirror neuron. The behavioral situation isschematically represented in the upper part of each panel. Theresponses of the neuron are shown in the middle and lower parts ofeach panel. The responses are shown as discharges using ten individualbehavioral trials (each short vertical line corresponds to an actionpotential) and expressed as relative-response histograms. (A) Theexperimenter grasps a piece of food with his hand then moves it towardthe monkey, who, at the end of the trial, grasps it. The neuron dis-charges during observation of the grip, ceases to fire when the food isgiven to the monkey and discharges again when the monkey grasps it.(B) The experimenter grasps the food with a tool. The subsequentsequence of events is as in (A). Note the lack of response of the neuronwhen the food is grasped with the tool. (C) The monkey grasps food indarkness. In (A) and (B) the rasters are aligned with the moment whenthe food is grasped by the experimenter (vertical line). In (C) the align-ment is with the approximate beginning of the grasping movement.Each small vertical line in the rasters corresponds to a spike. Histogrambin width: 20 ms. Reproduced with permission from Ref. 7.

Rizzolatti

Alvin Liberman, 1993

VI E W P O I N T

Language within our graspGiacomo Rizzolatti and Michael A. Arbib

In monkeys,the rostral part of ventral premotor cortex (area F5) contains neurons that discharge,both when the monkey grasps or manipulates objects and when it observes the experimentermaking similar actions.These neurons (mirror neurons) appear to represent a system that matchesobserved events to similar, internally generated actions, and in this way forms a link between theobserver and the actor. Transcranial magnetic stimulation and positron emission tomography(PET) experiments suggest that a mirror system for gesture recognition also exists in humans andincludes Broca’s area. We propose here that such an observation/execution matching systemprovides a necessary bridge from ‘doing’ to ‘communicating’,as the link between actor and observerbecomes a link between the sender and the receiver of each message.Trends Neurosci. (1998) 21, 188–194

‘In all communication, sender and receiver mustbe bound by a common understanding aboutwhat counts; what counts for the sender mustcount for the receiver, else communication doesnot occur. Moreover the processes of productionand perception must somehow be linked; theirrepresentation must, at some point, be the same.’

WHAT IS SAID HERE by Alvin Liberman1 forspeech where individuals have an explicit intent

to communicate, must apply also for ‘communi-cations’ in which such an overt intention is absent. Weunderstand when one individual is attacking anotheror when someone is peacefully eating an apple. Howdo we do it? What is shared by the (involuntary)sender and by the receiver? Is this mechanism the pre-cursor of willed communications? The present reviewaddresses these questions.

The mirror system

Neurons located in the rostral part of monkey inferior area 6 (area F5) discharge during active move-ments of the hand or mouth, or both2–4. Some yearsago we found that in most F5 neurons, the dischargecorrelates with an action, rather than with the indi-vidual movements that form it3. Accordingly, we clas-sified F5 neurons into various categories correspond-ing to the action associated with their discharge. Themost common are: ‘grasping with the hand’ neurons,‘holding’ neurons and ‘tearing’ neurons3,5. Furtherstudy revealed something unexpected: a class of F5neurons that discharge not only when the monkeygrasped or manipulated the objects, but also when themonkey observed the experimenter making a similar

gesture6–8. We called the neurons endowed with thisproperty ‘mirror neurons’ (Fig. 1).

The response properties of mirror neurons to visualstimuli can be summarized as follows: mirror neuronsdo not discharge in response to object presentation; inorder to be triggered they require a specific observedaction. The majority of them respond selectivelywhen the monkey observes one type of action (such asgrasping). Some are highly specific, coding not onlythe action aim, but also how that action is executed.They fire, for example, during observation of graspingmovements, but only when the object is grasped withthe index finger and the thumb.

All mirror neurons show visual generalization: theydischarge when the agent of the observed action (typi-cally a hand) is far away from or close to the monkey.A few neurons respond even when the object isgrasped by the mouth. The actions most representedare: grasp, manipulate, tear, and put an object on aplate. Mirror neurons also have motor properties thatare indistinguishable from those of F5 neurons that donot respond to action observation. In this review, theywill be referred to collectively and regardless of theirother properties, as ‘canonical neurons’. Typically,mirror neurons show congruence between theobserved and executed action. This congruence can beextremely strict, that is, the effective motor action (forexample, precision grip) corresponds with the actionthat, when seen, triggers the neuron (that is, precisiongrip). For other neurons the congruence is broader:the motor requirements (for example, precision grip)are usually stricter than the visual ones (for example,any type of hand grasping). An example of a highlycongruent mirror neuron is shown in Fig. 2. What is

Giacomo Rizzolattiis at the Istituto diFisiologia Umana,

Università diParma, Via

Gramsci 14,43100 Parma,

Italy, andMichael A. Arbib

is at the USCBrain Project,University of

SouthernCalifornia,

Los Angeles, CA 90089-2520,

USA.

G. Rizzolatti and M.A. Arbib – Language and mirror neurons

What is Area F5 in the human?

• Broca’s Area?

• Brodmann’s area 44 & 45?

TINS Vol. 21, No. 5, 1998 191

system will allow a brief prefix of the movement to beexhibited. This prefix will be recognized by the otherindividual. This fact will affect both the actor and theobserver. The actor will recognize an intention in theobserver, and the observer will notice that its invol-untary response affects the behavior of the actor. Thedevelopment of the capacity of the observer to controlhis or her mirror system is crucial in order to emit(voluntarily) a signal. When this occurs, a primitivedialogue between observer and actor is established.This dialogue forms the core of language. The capacityto notice that one has emitted a signal and associatingit with changes of the behavior of others might ormight not have developed simultaneously. However,there is no doubt that, once established, this new

association should have yielded enormous benefits ofadaptive value for the group of individuals that startedto make use of it, providing the selective pressure forthe extension of communicative capacities to largergroups.

This new use of the mirror system, at both individualand species levels, marks the beginning of intentionalcommunication. What actions were used for this newfunction in primates? Hand gestures or oro-facialmovements? Before examining this issue, it is necess-ary to examine whether or not a ‘prelinguistic gram-mar’ can be assigned to the control and observation ofactions. If this is so, the notion that evolution couldyield a language system ‘atop’ of the action systembecomes much more plausible.


Figure A shows parcellation of prearcuate cortexa andagranular frontal cortexb of the macaque monkey and Fig.B shows parcellation of the region of the human frontalcortex defined as ‘intermediate precentral cortex’ byCampbellc. The terminology of Foersterd and Vogt andVogte has been adopted for the human cortex. Similar colors in A and B indicate areas with anatomical andfunctional homologies. Brain regions colored yellow areareas with anatomical and functional homologies, mostlyrelated to orienting behavior; areas colored red also share anatomical and functional homologies and aremostly related to interactions with the external worlde–h.

The homology is based on cytoarchitectonics, electricalstimulationi and sulci embryologyj.

The superior frontal sulcus (SF) and the superior pre-central sulcus (SP) of human brain are drawn in dark greenas the superior limb of the monkey arcuate sulcus (AS).The inferior frontal sulcus (IF) and the ascending branchof the inferior precentral sulcus (IPa) of human brain aredrawn in blue as the inferior limb of the monkey arcuatesulcus (AI). The descending branch of the inferior pre-central sulcus (IPd) of human brain is drawn in pale greenand is labeled as the inferior precentral dimple (ipd) ofthe monkey brain Fig. A. The reasons for these hom-ologies are the following. The precentral sulcus developsfrom two separate primordia. Both of them have, duringdevelopment, a horizontal branch representing the pri-mordia of SF and IF, respectively. Typically, in the adultbrain, the precentral sulcusj is formed by two separate segments. Thus, we suggest that the human homolog ofthe monkey arcuate sulcus is formed by SF plus SP (darkgreen) and by the IF plus IPa (blue). The descendingbranch of inferior precentral sulcus (IPd, pale green)corresponds, in this view, to the inferior precentral dimple of the monkey. In humans it abuts IF. The pro-posed sulcal equivalence fits well the available data onthe anatomical and functional organization of the pre-motor cortices in the two species. The equivalencebetween human IPd and monkey ipd is well supported bythe fact that this sulcus marks the border between F4 andF5 in monkey and the border between inferior area 6 (inf. 6) and area 44 in humans. Abbreviations: 4, corticalarea 4; C, central sulcus; F1, cortical area F1; P, principal sulcus; spd, superior precentral dimple.

Referencesa Walker, A.E. (1940) J. Comp. Neurol. 262, 256–270b Matelli, M. , Luppino, G. and Rizzolatti, G. (1985) Behav.

Brain Res. 18, 125–137c Campbell, A.W. (1905) Histological Studies on the Localisation

of Cerebral Function, Cambridge University Pressd Foerster, O. (1936) Brain 59, 135–159e Vogt, C. and Vogt, O. (1926) Naturwissenschaften 14,

1190–1194f Bruce, C.J. (1988) in Neurobiology of Neocortex (Rakic, P. and

Singer, W., eds), pp. 297–329, Wileyg Suzuki, H. and Azuma, M. (1983) Exp. Brain Res. 53,

47–58h Matelli, M. and Luppino, G. (1992) Exp. Brain Res. (Suppl.)

22, 85–102i Preuss, T.M., Stepniewska, I. and Kaas, J.H. (1996) J. Comp.

Neurol. 371, 649–676j Ono, M., Kubik, S. and Abernathey, C.D. (1990) Atlas of

the Cerebral Sulci, Thieme

Box 1. Cytoarchitectonic map of the caudal part of the monkey frontal lobeand possible homologies with human frontal cortex

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F5

F7

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The ability to infer others’ mental states (e.g. intentions) may depend on the Mirror Neuron System

• Superior temporal sulcus

• visual object recognition

• Inferior posterior paritetal cortex

• somatosensory information

• Inferior premotor cortex

• motor action

Research report

EEG evidence for mirror neuron dysfunction in autismspectrum disorders

Lindsay M. Obermana,b,T, Edward M. Hubbarda,b, Joseph P. McCleeryb, Eric L. Altschulera,b,c,Vilayanur S. Ramachandrana,b,d, Jaime A. Pinedad,e

aCenter for Brain and Cognition, UC San Diego, La Jolla, CA 92093-0109, USAbDepartment of Psychology, UC San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0109, USA

cDepartment of Rehabilitation Medicine, Mt. Sinai School of Medicine, New York, New York 10029, USAdDepartment of Neurosciences, UC San Diego, La Jolla, CA 92093-0662, USA

eDepartment of Cognitive Science, UC San Diego, La Jolla, CA 92093-0515, USA

Accepted 13 January 2005

Available online 9 March 2005

Abstract

Autism spectrum disorders (ASD) are largely characterized by deficits in imitation, pragmatic language, theory of mind, and empathy.Previous research has suggested that a dysfunctional mirror neuron system may explain the pathology observed in ASD. Because EEGoscillations in the mu frequency (8–13 Hz) over sensorimotor cortex are thought to reflect mirror neuron activity, one method for testing the

integrity of this system is to measure mu responsiveness to actual and observed movement. It has been established that mu power is reduced(mu suppression) in typically developing individuals both when they perform actions and when they observe others performing actions,reflecting an observation/execution system which may play a critical role in the ability to understand and imitate others’ behaviors. This study

investigated whether individuals with ASD show a dysfunction in this system, given their behavioral impairments in understanding andresponding appropriately to others’ behaviors. Mu wave suppression was measured in ten high-functioning individuals with ASD and tenage- and gender-matched control subjects while watching videos of (1) a moving hand, (2) a bouncing ball, and (3) visual noise, or (4)moving their own hand. Control subjects showed significant mu suppression to both self and observed hand movement. The ASD group

showed significant mu suppression to self-performed hand movements but not to observed hand movements. These results support thehypothesis of a dysfunctional mirror neuron system in high-functioning individuals with ASD.

D 2005 Elsevier B.V. All rights reserved.

Theme: Disorders of the nervous system

Topic: Developmental disorders

Keywords: Mirror neurons; Autism spectrum disorders; EEG; Mu rhythm

1. Introduction

Disorders on the autism spectrum are characterized bydeficits in social and communicative skills, such as imi-tation, pragmatic language, theory of mind, and empathy[7,19,20]. Elucidating the underlying neural bases of thesedeficits has been a challenge because the behavioral

manifestations of this disorder vary both in severity (low-and high-functioning) as well as in expression (autisticdisorder, Asperger’s disorder, pervasive developmentaldisorder—not otherwise specified). The recent discoveryof bmirror neuronsQ in macaque monkeys by Rizzolatti andcolleagues [16], however, may provide a basis for explain-ing some of the behavioral deficits seen in individuals withautism spectrum disorders (ASD). Mirror neurons areprimarily thought to be involved in perception andcomprehension of motor actions [46], but they may alsoplay a critical role in higher order cognitive processes such

0926-6410/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.cogbrainres.2005.01.014

T Corresponding author. 9500 Gilman Drive, La Jolla, CA 92093-0109,

USA. Fax: +1 858 534 7190.

E-mail address: [email protected] (L.M. Oberman).

Cognitive Brain Research 24 (2005) 190–198

www.elsevier.com/locate/cogbrainres

conditions for both groups (Figs. 1A, B). Although datawere obtained from electrodes across the scalp, mu rhythmis defined as oscillations measured over sensorimotorcortex, thus only data from C3, Cz, and C4 are presented.

The control group (Fig. 1A) showed significant suppres-sion from baseline in mu oscillations at each electrode duringboth the self-initiated hand movement condition (C3 t(9) =!3.97, P b 0.002; Cz t(9) = !2.85, P b 0.01; C4 t(9) =!4.00, P b 0.002) and observed hand movement condition(C3 t(9) =!3.99, P b 0.002; Cz t(9) =!3.21, P b 0.005; C4t(9) = !2.78, P b 0.01). The ASD group (Fig. 1B) alsoshowed significant mu suppression during the self-initiatedhand movement condition (C3 t(9) = !2.27, P b 0.03; Czt(9) = !1.91, P b 0.05; C4 t(9) = !2.50, P b 0.02). Unlikecontrols, the ASD group did not show significant suppres-sion during the observed hand movement condition (C3t(9) = !0.64, P N 0.25; Cz t(9) = !0.98, P N 0.15; C4t(9) = !0.74, P N 0.20). The failure to find suppression inthe ASD group was not due to differences in baseline mupower (C3 t(9) = !0.99, P N 0.30; Cz t(9) = !0.69, P N0.50; C4 t(9) = !0.47, P N 0.50). Lastly, neither groupshowed significant suppression from baseline during thenon-biological motion (bouncing balls) condition (ASD:C3 t(9) = !0.73, P N 0.20; Cz t(9) = 0.49, P N 0.65; C4t(9) = !.25, P N 0.40; Control: C3 t(9) = !1.45, P N 0.08;Cz t(9) = !0.54, P N 0.30; C4 t(9) = 0.00, P N 0.50).1

Additional ratios were calculated comparing the powerduring the observed hand movement and self hand move-ment conditions to that of the ball condition for both groups.Results were consistent with the baseline ratios. The controlgroup still showed significant suppression in the self handmovement condition (C3 t(9) = !2.84, P b 0.01; Cz t(9) =!2.14, P b 0.03; C4 t(9) = !2.93, P b 0.009), and observedhand movement condition (C3 t(9) = !1.80, P b 0.05; Czt(9) = !2.05, P b 0.04; C4 t(9) = !2.67, P b 0.02). TheASD group again showed suppression in the self handmovement condition (C3 t(9) = !3.97, P b 0.002; Cz t(9) =!2.85, P b 0.01; C4 t(9) = !4.00, P b 0.002) but not in theobserved hand movement condition (C3 t(9) = 0.40, P N0.65; Cz t(9) = !1.38, P N 0.1; C4 t(9) = !0.44, P N 0.3).

Since the mu frequency band overlaps with the posterioralpha frequency band (recorded from O1 and O2) and thegenerator for posterior alpha is stronger than that for mu, itis possible that recordings from C3, Cz, and C4 might beaffected by this posterior activity. As all conditions involvedvisual stimuli and the eyes were open throughout the study,we would not expect a systematic difference betweenconditions in posterior alpha activity. Additionally, byeliminating the first and last 10 s of each block, we reducedthe possibility of alpha modulations due to attentionaffecting our mu power results. Consistent with this, otherthan C3, Cz, and C4, no electrodes showed a consistentpattern of suppression in the frequency band of interest.These results indicate that the modulations of mu activitywe observed in C3, Cz, and C4 were not mediated byposterior alpha activity.

In order to rule out the possibility that our results wereinfluenced by the large age range, a Pearson r correlationcoefficient was calculated for each log ratio at each electrodesite. Neither group showed a significant correlation betweenmu suppression and age in any condition or electrode site.

Fig. 1. Mu suppression in control and ASD participants. Bars represent the mean log ratio of power in the mu frequency (8–13 Hz) during the watching balls

condition (light gray), watching hand movement condition (medium gray), and moving own hand condition (dark gray) over the power in the baseline

condition for scalp locations C3, CZ, and C4 for typically developing individuals (A) and individuals with ASD (B). Error bars represent the standard error of

the mean. For all values, a mean log ratio greater than zero indicates mu enhancement; a mean log ratio less than zero indicates mu suppression. Significant

suppression is indicated by asterisks, *P b 0.05, **P b 0.01, ***P b 0.005.

1 The control group had a significantly greater amount of clean data;

hence, the analysis was reconducted using equal length segments. Segments

from the control group were recut through random removal of small epochs

of the EEG resulting in a total amount of clean data that was equal to that of

the ASD group. In these analyses, the same main findings held: self-

initiated hand movement condition (C3 t(9) = !3.51, P b 0.004; Cz t(9) =

!2.77, P b 0.02; C4 t(9) = !3.88, P b 0.002) and observed hand

movement condition (C3 t(9) = !4.03, P b 0.002; Cz t(9) = !3.19, P b0.006; C4 t(9) = !2.97, P b 0.008).

L.M. Oberman et al. / Cognitive Brain Research 24 (2005) 190–198194

Cerebellum

Cerebellum

Aristotle distinguished the “little brain” from the “large brain” (cerebrum)

Muscle coordination

Equilibrium, posture, timing and accuracy of movements

movement learning

Ataxialack of muscle coordination when performing voluntary movement

e.g. when tracking an object with finger

movements become uncoordinated and inaccurate

Implies that the cerebellum is involved in sequencing of muscle contractions in voluntary movements

Sep 25: International Ataxia Awareness Day

Cortex

Three layers

Deep Nuclei

Input

Receives sensory information from spinal cord & brainstem via climbing fibers

indirectly from cerebral cortex via mossy fibers

Intrinsic CircuitryExcitatory input to deep nuclei via mossy and climbing fibers

Excitatory input to cerebellar cortex via mossy and climbing fibers

Purkinje cortical cells inhibit Deep nuclei

OutputDeep nuclei contain output neurons via cerebellar peduncles

Project to motor system of the brainstem and spinal cord

and the cerebral hemisphere cognitive system via thalamus

Implications Circuitry set up to perform comparison of inputs from cortex (via mossy fibers)and brainstem and spinal cord (via climbing fibers)

if excitatory input occurs at same time, large excitation of deep nuclei occurs

followed by inhibitory input from cerebellar cortex

Implications

Also, Synaptic strength can be increased or decreased by coincident activation of mossy and climbing fibers

Classical ConditioningTone produces no eye response (neutral stimulus)

Puff of air to the eye (US) produces an eye blink (UR)

Pair Tone (CS) followed by puff of air (US)

Results in tone alone(CS) producing eyeblink (CR)

Classical Conditioning

Climbing fibers transmit the tone (CS) to deep cerebellar nuclei (DCN)

Climbing fiber input of tone is insufficient to drive the DCN

Mossy Fibers transmit airpuff (uS) to deep cerebellar nuclei

After pairings, synaptic strength is altered to the point that climbing fiber alone can drive DCN

The Basal Ganglia

Diseases of the Basal Ganglia

Tend to produce involuntary movements

John Hughlings Jackson (1835-1911)

Negative signs-loss of normal function (e.g. paralysis)

Positive signs-caused by the emergence of an abnormal patter of action (e.g. tremor) may result from loss of inhibition.

James Parkinson (1817)

“involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.”

Parkinson’s Disease Rhythmical tremor at rest

Increase in muscle tone-rigidity

Difficulty in initiating movement and paucity of spontaneous movement (akinesia)

Slowness in execution of movement (bradykinesia)

Parkinson’s Disease

Arvid Carlsson, (1959) observed that 80% of dopamine in brain is localized in BG, which makes up .5% of total brain weight

Oleh Hornykiewicz (1966) discovered that monoamines (DA, NE & serotonin) were low in patients who had died of PD (DA lowest)


Loss of neurons in two pigmented areas of the brain-locus coeruleus and substantia nigra

Noradrenergic


Degree of loss of SN neurons correlated with degree of pathology

But, only after the onset of symptoms, which only occur after loss of about 85-90% of SN neurons

PD Treatments: drugs Suggested that

replacement of lost DA may improve symptoms of PD.

L-DOPA is highly effective in relieving symptoms of PD (temporarily!).

Birkmayer & Hornykiewicz (1976)

Why doesn’t L-DOPA stop progression of PD?

Aging

MAOb increases with aging

associated with production of H2O2, a catalysis for oxidative stress (production of toxic peroxides and free radicals)

Etiology of Parkinson’s Disease

Tanner et al. (1999)

Comprehensive study of over 19,000 white male twins suggests genetic heritability is not basis for PD

Genetic origin in 5% of cases


MPTP (1-methyl-4-phenyl-1,2,3,6-

tetrahydropyridine) toxicity produces symptoms and pathology similar to that found in PD (Langston et al. 1983)

MPTP induced toxicity in laboratory animals provides an animal model of PD

Etiology of PD MPTP is converted to MPP+ by MAOb, which

is found in high concentrations in basal ganglia. MPP+ binds to melatonin and an increase in MPP+ concentration causes damage to these neurons (i.e. SN and locus coeruleus)

MAO inhibitors may protect against damage caused by MPTP (Langston et al. 1984)


Herbicide paraquat is structurally similar to MPP+

Paraquat crosses the blood-brain barrier

Occupational exposure associated with Parkinsonism (Hertzman et al. 1990; Liou et al. 1997)

inhibit mitochondrial functioning, leading to cell death

Buhmann et al. (2003)

Akinesia shown to be correlated with decrease in supplementary and primary motor cortex

L-Dopa shown to increase activity of supplementary and primary motor cortex as measured by fmri

PD Treatments: transplants

Fetal transplants of SN cells into basal ganglia show increase of BG activity and improvement of symptoms

Olanow et al. (2003)

Patients can develop dyskinesias

troublesome involuntary movements

Stem cell transplants may not have this side-effect?

The Basal Ganglia

Caudate nucleus

Putamen

Globus Pallidus

Subthalamic nucleus

Substantia Nigra

Two Basal Ganglia Loops

Direct

excitatory influence on sensorimotor output

Indirect

inhibitory influence on sensorimotor cortex

Substantia Nigra & DA

Facilitates excitation of direct excitatory loop

Inhibits indirect inhibitory loop

results in facilitation of sensorimotor output

PD Treatments: lesions

Lesion of globus pallidus internal segment increases metabolic activity in the premotor and supplementary motor areas (Grafton et al. 1995)

Increase in cortical activation by reduction of the inhibitory influence of GPi

PD Treatments: Deep Brain Stimulation

Play video

Stimulation of subthalamus reduces tremor

The End

Connie SainzL-dopa had been discontinued in 1990 due to “terrifying hallucinations”

Unable to move her hands, arms and legs

Langston suspected that she was cognitively intact

Would laugh to a joke

Could moan “yes” or “no”

Connie SainzApril 4, 1994, flew to Lund with funds raised by a local columnist

Since she was the most severe, her case served as a test of whether treatment could benefit the most severe patients

Changed her mind about the operation but her family back home convinced her to go ahead with it.

Connie SainzDeveloped a temperature, but subsided before postponing the surgery

April 8, tissue from 4.5 fetuses was implanted into her left putamen

Two weeks later, tissue implanted into right putamen

Returned home May 2

Connie SainzFive months later, langston examined Connie

She was alert, smiled and had facial expressions

Speech was easier to understand and she could answer questions

Still would not initiate dialogue

Connie Sainz

Much of muscle stiffness was gone

Could raise and lower arms

Could walk with some assistance

Bill Silvey

Died November 29, 1994

Been in poor health with a chronic intestinal disorder

Autopsy revealed SN almost completely gone; also evidence that nerve cells in the area had recently degenerated, suggesting exposure to neurotoxin could have long-term degenerative effects

The End

Basal Ganglia

B.G. receives input from cortex and projects back to cortex via the thalamus

Afferents (inputs) Almost all of the afferent connection to

the B.G. terminates in the neostriatum (caudate and putamen)

Most important input comes from the cortex and contains input from all parts of cortex

Topographically organized

sensorimotor input to putamen

association cortext to caudate

Internal Connections Putamen projects to globus pallidus

(internal & external segments)

Subthalamus receives output of the external segment of GP and projects to GP internal segment

Putamen receives dopamine input from SN.

Efferent Connections (outputs)

Major output comes from internal segment of GP

Projects to ventral anterior (VA) and ventral lateral (VL) thalamus

VA/VL projects to sensorimotor cortex

Caudate & Putamen

Isocortex(neocortex)

Globus Pallidus

Thalamus, Brainstem & Spinal Cord

Glutamate (+)

GABA (-)

GABA (-)

GLU +

GABA -

How does L-DOPA improve symptoms?

DA acts directly on DA receptors in neostriatum

L-DOPA taken up by remaining DA neurons and released in greater amounts

Taken up by non-DA neurons and released in BG (e.g. NE,serotonin cells, & glial cells?)

Insecticides paraquat and rotenone can cause symptoms of PD

inhibit mitochondrial functioning, leading to cell death

PD Treatments: more drugs

Deprenyl, a MAO inhibitor, has been found to slow the progression of PD in human patients (Tetrud & Langston, 1989).

But, results are conflicting

May also have the potential to delay progressive loss of SN neurons due to normal aging

Kumar & Andersen (2004)

Found an age-related increase in MAOb

breakdown of DA by intracellular MAOb produces hydrogen peroxide, which can damage neurons

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