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NEURAL PLASTICITY VOLUME 10, NO. 1-2, 2003 Cerebellar Involvement in Clumsiness and Other Developmental Disorders Richard B. Ivry Department of Psychology, University of California, Berkeley, California, USA ABSTRACT Cerebellar abnormalities have been linked to a number of developmental disorders. Much evidence is based on the analysis of high- resolution MRI scans. Imaging and behavioral studies have led researchers to consider functional contributions of the cerebellum beyond that associated with motor control. I review this literature, providing an analysis of different ways to consider the relation between cerebellar abnormalities and developmental disorders. Interestingly, although clumsiness is a problem of coordination, the contribution of cerebellar dysfunction to this developmental problem has received little attention. Select studies indicate that some clumsy children have difficulties on tasks requiring precise timing, similar to that observed in adult patients with cerebellar lesions. I suggest that the underlying neural bases of clumsiness are heterogeneous, with cerebellar dysfunction likely a major contributor for a subpopulation of such children. INTRODUCTION Problems with motor coordination are a common feature of neurologic disorders, consistent with the observation that a substantial proportion Reprint requests to: Richard B. Ivry, Department of Psychology, MC 1650, University of California, Berkeley, California 94720, USA; e-mail: [email protected] of the central nervous system is associated with the control of movement. Parkinson’s disease and Huntington’s disease are examples of degenerative disorders of the brain having prominent motor disturbances. Syndromes like hemiplegia or apraxia are often present following stroke, although persistence is dependent on the extent and location of the resultant neuropathology. Developmental disorders affecting coordination have received modest attention in the cognitive neuroscience literature. This situation likely reflects many factors, such as difficulty in defining appropriate populations, unique laboratory demands involved in testing children, and that coordination problems, at least for some children, become less pronounced with maturation. For example, many children who exhibit delayed development in reading eventually catch up with their peers as young adults, or at least acquire a sufficient skill level so that the problem does not interfere with their education or careers (Demb et al., 1998). The idea that certain developmental disorders can be linked to specific neurologic abnormalities has only recently taken firm hold in the neuro- science community. This paradigm shift is driven not only by new methodologies for analyzing brain function, but also by the application of sophisticated behavioral tests for assaying cognitive and motor abilities. Rather than focusing on standardized tests that provide useful descriptions of performance, the methods of cognitive psychology are designed to isolate the set of specific mental operations that are invoked in the performance of complex skills. Whether this new approach will (C) 2003 Freund & Pettman, U.K. 141

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NEURAL PLASTICITY VOLUME 10, NO. 1-2, 2003

Cerebellar Involvement in Clumsiness and OtherDevelopmental Disorders

Richard B. Ivry

Department ofPsychology, University ofCalifornia, Berkeley, California, USA

ABSTRACT

Cerebellar abnormalities have been linked toa number of developmental disorders. Muchevidence is based on the analysis of high-resolution MRI scans. Imaging and behavioralstudies have led researchers to considerfunctional contributions of the cerebellumbeyond that associated with motor control. Ireview this literature, providing an analysis ofdifferent ways to consider the relation betweencerebellar abnormalities and developmentaldisorders. Interestingly, although clumsiness is aproblem of coordination, the contribution ofcerebellar dysfunction to this developmentalproblem has received little attention. Selectstudies indicate that some clumsy children havedifficulties on tasks requiring precise timing,similar to that observed in adult patients withcerebellar lesions. I suggest that the underlyingneural bases of clumsiness are heterogeneous,with cerebellar dysfunction likely a majorcontributor for a subpopulation of such children.

INTRODUCTION

Problems with motor coordination are a

common feature of neurologic disorders, consistentwith the observation that a substantial proportion

Reprint requests to: Richard B. Ivry, Department ofPsychology, MC 1650, University of California, Berkeley,California 94720, USA; e-mail: [email protected]

of the central nervous system is associated withthe control of movement. Parkinson’s disease andHuntington’s disease are examples of degenerativedisorders of the brain having prominent motordisturbances. Syndromes like hemiplegia or apraxiaare often present following stroke, althoughpersistence is dependent on the extent and locationof the resultant neuropathology.

Developmental disorders affecting coordinationhave received modest attention in the cognitiveneuroscience literature. This situation likely reflectsmany factors, such as difficulty in definingappropriate populations, unique laboratory demandsinvolved in testing children, and that coordinationproblems, at least for some children, become lesspronounced with maturation. For example, manychildren who exhibit delayed development inreading eventually catch up with their peers as

young adults, or at least acquire a sufficient skilllevel so that the problem does not interfere with

their education or careers (Demb et al., 1998).The idea that certain developmental disorders

can be linked to specific neurologic abnormalitieshas only recently taken firm hold in the neuro-science community. This paradigm shift is drivennot only by new methodologies for analyzing brainfunction, but also by the application of sophisticatedbehavioral tests for assaying cognitive and motorabilities. Rather than focusing on standardizedtests that provide useful descriptions ofperformance, the methods of cognitive psychologyare designed to isolate the set of specific mentaloperations that are invoked in the performance ofcomplex skills. Whether this new approach will

(C) 2003 Freund & Pettman, U.K. 141

142 RICHARD B. IVRY

prove fruitful in the study of clumsiness remains tobe seen.

The term ’clumsiness’ describes a rather broadset of behaviors. Establishing a defining set ofcriteria has been difficult and the subject of muchdebate (Henderson & Henderson, 2003). Thegeneral consensus is that this label refers to aheterogeneous constellation of coordinationproblems. Such heterogeneity can be viewed in atleast two different ways. One interpretation is thatthe diversity arises from diffuse neurologicabnormalities. Altematively, heterogeneity mightreflect the use of a term in a generic way, eventhough subtypes exist that result from more focalneural dysfunction.

This paper focuses on the relation of cerebellarfunction to clumsiness. The cerebellum is a primestructure to consider when discussing the role ofspecific neural systems in coordination problems.The most prominent symptom observed in patientswith acquired cerebellar disorders is a loss ofcoordination. Similar to the behavior of clumsychildren, such patients generally have a good senseof the appropriate action for a given context; theirproblems arise when trying to execute: themovements in a coordinated manner. The term’cerebellar ataxia’ is used to describe the break-down in patterns of muscular activation that causethe limb to follow a wobbly trajectory or fail toend at a target location.

Another reason to consider the relationbetween the cerebellum and clumsiness comesfrom the recent association of this structure to anumber of disparate developmental disorders. Thisassociation has led to new perspectives oncerebellar function--perspectives that emphasizenon-motor capabilities (see Schmahmann & Harris,1997). The first section of this paper provides abrief review of recent literature, addressing theissue of how we should interpret these correlations.Following this, I explore the more specific questionof whether cerebellar dysfunction is apparent in

clumsy children, and whether such deficits areubiquitous in this population or restricted to

subgroups.

CEREBELLAR ASSOCIATION WITHDEVELOPMENTAL DISORDERS

Evaluating causal brain-function relationshipsis a tricky business. Neuropsychological researchis primarily correlational. In the best-case scenario,functional inferences are made about neuralstructures based on the observation that consistentbehavioral impairments arise following neuro-pathology restricted to a well-localized region. Inmore typical situations, the damage spansrelatively large areas. Moreover, it remainspossible that the behavioral changes are due toindirect alterations in the function of intact tissue.With developmental disorders, the challenge iseven greater. Neural abnormalities can be subtleand/or relatively diffuse. In addition, as discussedin various papers in this special edition, there arehigh degrees of co-morbidity of many syndromes.For example, clumsiness has been reported to bemore prevalent in both children with attentiondeficit and hyperactivity disorder (ADHD) anddyslexia.

When considering the relation of thecerebellum to clumsiness, it is instructive toexamine other developmental disorders that havebeen linked to this structure. Much of this work isbased on neuroanatomic analyses made possiblewith magnetic resonance imaging (MRI). Thistechnique allows for the in vivo analysis of brainstructure with remarkable spatial resolution.Measurements are made to determine if particulardisorders are associated with structural abnormalities,usually in terms of volumetric deviations Althoughthe application of this technique using largesamples of clumsy children is just emerging(Mercuri & Barnett, 2003), MRI has been used to

CEREBELLUM IN CLUMSINESS AND DEVELOPMENTAL DISORDERS 143

study a number of psychiatric and developmentaldisorders. A striking result in this literature hasbeen the surprising degree of cerebellar pathologyobserved in disorders that would seem, a priori, tohave little connection to cerebellar function.

Perhaps best studied with this approach isautism. In 1988, Courchesne and colleagues(1988) reported pronounced cerebellar hypoplasiain a study that included 18 autistic individuals and12 age-matched controls (mean age 20.9 yearsranging from 6 to 30 years old). Interestingly, noother brain region showed a difference betweenthe two groups. Subsequent studies involvinglarger sample sizes have confirmed that cerebellarabnormalities are consistently associated withautism, although the initial report has beenqualified in two significant ways. First, a sub-population of autistic individuals was found tohave cerebellar hyperplasia (Courchesne et al.,1994). Second, the structural differences are notrestricted to the cerebellum. Several MRI studieshave shown reduced volume in the parietal lobe,limbic regions, and white matter tracts such as thecorpus callosum (reviewed in Courchesne, 1997).Although the latter results suggest diffusedevelopmental abnormalities, apparently a reducedcerebellar volume is the most consistent structuralmarker of autism, at least in terms of macroscopicmeasurements of the central nervous system.

Cerebellar hypoplasia has been associated withtwo other psychiatric conditions, ADHD (Berquin etal., 1998; Mostofsky et al., 1998) and schizophrenia(Nopoulos et al., 1999). Even more so than withautism studies, MRI evidence with ADHD andschizophrenia indicates that cerebellar abnormalitiesco-exist with structural differences in the cerebralcortex. For example, children with ADHD showapproximately 10% reduction in surface area ofcerebellar lobules VIII to X and a 10% reduction intotal volume of the cerebrum (Berquin et al., 1998).Although the last point emphasizes that theanatomic abnormalities are not restricted to the

cerebellum, noteworthy is that the evidence to dateargues for some degree of specificity. The regionswithin the cerebellar cortex showing a significantdegree of hypoplasia differ for autism, ADHD,schizophrenia (see Fig. 1). Indeed, when standarddivisions of the cerebellar cortex are used, theabnormalities associated with these syndromesform non-overlapping groups. This result arguesagainst the idea that the cerebellum is genericallysensitive to some sort of neural insult duringdevelopment. A reasonable alternative is that thetime course of neural development within theseregions varies in a systematic manner (Altman &Bayer, 1985), and that pathology-inducing events(genetic or environmental) have time sensitivewindows of opportunity.

Fig. 1. Sagittal section ofthe cerebellum showing the foliaof the vermis. MRI studies have revealedcerebellar hypoplasia associated with autism,schizophrenia, and ADHD. Interestingly, theregions showing hypoplasia differ for thesedisorders with the focus being in (1) Lobules toV in schizophrenia; (2) Lobules VI to VII inautism; (3) Lobules VIII to X in ADHD.

144 RICHARD B. IVRY

Researchers have also used behavioral methodsto study the relation of cerebellar function todevelop-mental disorders. One notable example isthe recent work on developmental dyslexia. Childrenwith severe reading problems have marked impair-ments on tests of coordination, and their problemsresemble those exhibited by neurology patients withacquired cerebellar lesions (Fawcett et al., 1996).Moreover, on various motor and non-motor testsspecifically designed to evaluate cerebellar function,dyslexic children perform in a manner similar tothat of patients with cerebellar insults (Fawcett &Nicolson, 1999; Nicolson et al., 2001).

To summarize this brief review, cerebellarabnormalities, either anatomically or behaviorallydefined, have now been linked to developmentaldisorders like autism, ADHD, and dyslexia. Theresults are surprising in that motor problems havenot been traditionally associated with any of thesesyndromes. As with all correlational results, wemust give careful thought to our interpretation ofthese relations, how we assess potential cause-and-effect relations.

At one extreme, the correlations betweencerebellar pathology and these developmentaldisorders may have no causative relation. Forexample, problems in development that can result inautism might independently produce hypoplasia ofcerebellar lobules VI and VII. Or the underlyingmechanisms could be very different but covary.

Alternatively, there may be causal relationsbetween the cerebellar abnormalities and some orall of these developmental disorders. Over the past10 years, well-articulated hypotheses have beenoffered about how cerebellar pathology could becentral to the development of autism (Courchesne &Allen, 1997), schizophrenia (Wiser et al., 1998), anddyslexia (Nicolson et al., 2001). These hypothesesbuild on more traditional notions concerning howthe cerebellum might contribute to motor control.Andreassen et al. (1996) coined the term ’cognitivedysmetria’ to describe the breakdown of thought

pattems in schizophrenia. In this view, the cerebellumcoordinates mental activity across regions of thecerebral cortex, similar to how it has beenhypothesized to coordinate activity across differentmuscular groups for skilled movement. Courchesneand Allen (1997) proposed a more specific versionof this idea with respect to a causal account of thecerebellum and autism. In his theory, thecerebellum is responsible for coordinating rapidshifts of attention. An inability to engage incoordinated attentional focus is seen as afundamental deficit in the development of normalsocial relationships. With respect to dyslexia,Nicolson and Fawcett (2001) hypothesize thatreading is one form of a skilled behavior, and thatthe cerebellum is essential for the automatizationof skills.

At present, such causal accounts are

speculative, yet can be subjected to rigorousempirical evaluation. The devil is in the details andthe hypotheses will surely become more explicit(and thus testable) as terms like mental coordinationor automatization become operationalized.Traditional neurology would encourage skepticismwith respect to accounts in which cerebellarpathology is causally related to such disparatedisorders such as autism, ADHD, and dyslexia.

First, there are marked differences betweenthese developmental disorders and it is notobvious why they would be related to a

common neural system.Second, these theories tend to focus on theidea that a fundamental and localizedpathology underlies the syndromes. Althoughthis position may be useful for challengingtraditional views, it is also likely to besimplistic.Third, patients with acquired cerebellardisorders do not appear to develop problemssimilar to those evident in autism, ADHD, ordyslexia. Patients with focal, unilateral lesionsor widespread bilateral cerebellar degeneration

CEREBELLUM IN CLUMSINESS AND DEVELOPMENTAL DISORDERS 145

do not have pronounced, if indeed, any deficitsin coordinating rapid shifts of attemion (Helmuthet al., 1997; but see Townsend et al., 1999).

The last point, though, must be qualified.Disturbing a system during development couldhave very different long-term consequences thanwould a similar disruption in a mature system. Thestudy of infants who incur severe brain injuries hasshown that massive functional reorganization ispossible. The degree of recovery in such infantsfar exceeds that possible in adults who suffersimilar injuries.

On the other hand, the dysfunctional operationof a system early in life can prevent thedevelopment of certain abilities, whereas thoseabilities can remain undisturbed if the same systemis damaged late in life. Consider one of thehypotheses proposed to account for the putativerelationship between cerebellar dysfunction anddyslexia (Ivry et al., 2001). In this hypothesis, thecerebellum is conceptualized to be part of aninternal articulatory loop, contributing to covertarticulation in a manner similar to how it

participates in overt articulation. Building on theidea that our phonological knowledge develops byreference to the motor events that produce thesesounds, one would expect that artic,ulatory skill isessential for developing robust phonologicalrepresentations. If cerebellar pathology disruptsthe articulatory system, then normal developmentof phonological skills might be impacted. Learningto read would prove challenging, given the need tolearn the mapping between orthography andphonology (Studdert-Kennedy & Mody, 1995).Damage to the cerebellum in the adult, however,might have no effect on reading skills. With suchindividuals, the mapping between orthography andphonology should be well established. Moreover,skilled readers can directly access lexical repre-sentations from orthography without mediation

through phonology (e.g., Coltheart et al., 2001).

This last hypothesis emphasizes one additionalimportant issue concerning causal models of brainfunction and behavior. Causality can vary in termsof the degree of directness. In the hypothesis justdiscussed, the causal relation between the cerebellumand dyslexia is indirect. The cerebellum, through itsrole in articulation, is hypothesized to be essentialfor the development of phonological knowledge.But the phonological representations themselves,once established can be accessed without involvingthe cerebellum. A more direct relation is assumedby the proposal that dyslexia is a specific mani-festation of a failure of skill automatization(Nicolson et al., 2001), assuming that suchautomatized skills entail the consolidation ofrepresentations within the cerebellum.

THE CEREBELLUM AS AN INTERNALTIMING SYSTEM

We have sought to identify basic componentoperations that, in combination, might underlie a

general human competence the ability to

produce coordinated movements. Using an

individual difference approach, we found that theability to produce well-timed movements was

highly correlated across different effectors like the

finger and foot (Keele et al., 1985). In contrast, a

much lower correlation was found betweentemporal control and response speed, as well as

between temporal control and force control (Keeleet al., 1987), even when the correlations involved

performance with the same effector. The results ofthese studies suggest the existence of a specificsystem devoted to controlling the timing ofmovements, or what might be called an ’internal

clock’. Further support for this hypothesis came

from studies looking at correlations between these

motor tasks and perceptual tasks. A significantcorrelation was found between motor and

perceptual timing (Keele et al., 1985)" Individuals

146 RICHARD B. IVRY

who were good at controlling the timing of theirmovements also exhibited fine acuity in judgingtemporal differences between stimulus events.This ability was specific to the temporal domain;for example, motor timing and loudness perceptionwere not correlated.

To examine the neural structures involved ininternal timing, we tested various neurology patientson our tests of motor and perceptual timing. Forthe motor task, we used the repetitive tapping taskintroduced by Wing and Kristofferson (1973). Inthis task, the participant taps on a response keywith the index finger, attempting to match thetarget rate set by an auditory metronome (forexample, 550 ms). After 10 responses, the metro-nome is terminated, and the task of the participantis to continue tapping at the same rate for another30 responses. The analysis focuses on the standarddeviation of the unpaced inter-tap intervals. Thisdependent variable serves as an indicator of theconsistency of an internal timing system. Wingand Kristofferson had shown that the auto-covariance of the time series of responses could beused to decompose this measure into twoindependent sources of variability. One source isassociated with central processes determiningwhen the next response should be produced, orwhat is referred to as ’clock variability’ (but seeIvry & Hazeltine, 1995); the other source isassociated with response implementation, or whatWing termed ’motor delay’. In brief, the modelassumes that an internal clock determines wheneach response is to be emitted, and this commandmust then be translated into a movement. Eachprocess makes an independent contribution,resulting in the total variability of the inter-

response intervals.For the perceptual task, we used an adaptive

psychophysical procedure to determine thedifference threshold on a duration discriminationtask. Four tones are presented on each trial, with

the first two separated by a standard interval (forexample, 400 ms) and the second two separated bya variable interval. The participant judged whetherthe variable interval was shorter or longer than thestandard interval. Based on this response, theduration of the variable interval is adjusted. Forexample, if the variable interval is longer than thestandard yet the response was "shorter", then thevariable interval for the next trial would be madelonger. After a fixed number of trials, the durationof the variable interval provides an estimate of thedifference required for performance at a pre-determined criterion. A stable estimate of thisdifference threshold is obtained after about 30trials. In this way, perceptual temporal acuity is

measured; for example, a noisy internal clockwould lead to a higher difference threshold. Thesame stimulus configuration is also used in a controltask, but here the loudness of the second pair oftones is varied. This control task allows us to

determine if someone has generic problems on

perceptual tasks or whether the impairment is

specific to one task or the other.Three groups of patients were tested in our

first study (Ivry & Keele, 1989): (1) a group witheither focal or degenerative cerebellar lesions, (2)a group with cortical lesions resulting incoordination problems, and (3) a group withParkinson’s disease. We assumed that the lattergroup was representative of basal gangliadysfunction. The results showed that the integrityof the cerebellum was essential for accurate

timing. The patients with cortical or cerebellarlesions were more variable on the tapping task,and this increase was primarily associated with theclock component (but see also Ivry et al., 1988).Moreover, only patients with cerebellar lesionswere impaired on the duration discrimination task.Their difference threshold was about 50% greaterthan either of the other two patient groups and age-matched controls. The deficit of these patients was

CEREBELLUM IN CLUMSINESS AND DEVELOPMENTAL DISORDERS 147

specific to the time perception task; theirperformance was comparable to that of the controlson the loudness discrimination task. Interestingly,the Parkinson’s patients were unimpaired on boththe motor and the perceptual tasks (but seeHarrington et al., 1998). This result was also foundin a subset of patients tested both on and off theirnormal medication regimen. In the latter condition,their motor symptoms were exacerbated, yetremained comparable to controls on the timingtasks.

The results of these studies led us to postulatethat the cerebellum plays a critical role in theprecise representation of temporal information. Asreviewed elsewhere (Ivry, 1997), this hypothesis isin accord with many of the prominent coordinationproblems associated with cerebellar dysfunctionincluding intentional tremor, dysmetria, and speechdysarthria. The timing hypothesis also provides a

computational account of the role of the cerebellumin certain types of sensorimotor learning likeeyeblink conditioning. By this view, the cerebellumis essential for those tasks in which the learnedresponse is adaptive only when the temporalrelation between different environmental eventsmust be extracted. In eyeblink conditioning, theanimal must learn not only to anticipate an

aversive stimulus like an air puff but also mustlearn exactly when that stimulus will occur so thatthe conditioned response is timed to maximallyattenuate the aversive consequences of the air puff.

Subsequent research has supported the role ofthe cerebellum in temporal processing, althoughconsiderable debate continues about whether thisstructure is uniquely suited for this form ofrepresentation. Much remains to be learned at amechanistic level. Nonetheless, the timing hypothesisprovides a functional account of the cerebellarcontribution to coordination and has offered novelinsight into non-motor functions of this subcorticalstructure.

ASSESSING CEREBELLAR FUNCTION INCLUMSY CHILDREN

As noted previously, it seems reasonable toask if clumsiness is related, at least in part, tocerebellar dysfunction. First, the defining featuresof clumsiness are problems of coordination, thecardinal symptoms observed in patients withcerebellar ataxia. Second, the recent links betweenvarious developmental disorders and cerebellarabnormalities suggests that this structure may beespecially vulnerable during early brain develop-ment. Nonetheless, few studies have focused onthe question of whether clumsy children exhibitsigns of cerebellar dysfunction. In this section,review two studies that were published on thistopic over a decade ago. Surprisingly, a literaturesearch failed to reveal more recent papers thathave pursued this issue, suggesting that a cognitiveneuroscientific approach to the study of clumsinesshas yet to be vigorously pursued.

The logic of our studies was quite simple dochildren diagnosed as clumsy show deficits on t4motor and perceptual timing tasks similar to thosein adult patients with cerebellar lesions? In thefirst study (Williams et al. 1992), fifty childrenwere recruited, based on referrals from theirteachers concerning possible motor coordinationproblems. The children were given a short form ofthe Bruininks-Oseretsky Motor Proficiency Scale

(Bruininks, 1978) and a clinical battery developedby one of the authors to assess perceptual-motordevelopment problems (Williams, 1973). Thechildren were categorized as clumsy if they werebetween the 40t and 50t percentile on theBruininks-Oseretsky test and scored between 0.5and 1.5 SD below normal on at least 6 of the 9items in the clinical battery. The control groupconsisted of individuals who were at or above the50t percentile on the Bruininks-Oseretsky test andscored above 0.4 SD below the mean on at least 6

148 RICHARD B. IVRY

of the 9 items in the clinical battery. Thus, thedefinition of the groups was conservative. Severelyuncoordinated children were excluded, and thechildren in the control group showed some motorproblems based on teacher observation, yet failed tomeet the clinical criterion for clumsiness. Based onthese selection criteria, 12 children were assigned tothe clumsy group and 13 to the control group.

Both groups were relatively proficient inmaintaining the target interval during the unpacedphase ofthe tapping task, showing a slight hasteningover the 30 taps. The clumsy children, however,exhibited greater overall variability, and when thedata were analyzed with the Wing-Kristoffersonmodel (Fig. 2a), only the estimate of clockvariability was significant (p < 0.05 vs. p 0.61for the motor implementation estimate). Theperception tasks also suggested a selective timingdeficit (Fig. 2b). The mean difference threshold onthe duration discrimination task was 54% higherfor the group of clumsy children when compared

with that of the control group (p < 0.05). The two

groups performed comparably on the loudnessdiscrimination task (p 0.66).

The results of Williams et al. (1992) show thatchildren classified as clumsy on standard clinicalassessment instruments are impaired on tasks thatrequire precise timing. We hypothesize that theirdeficits on the two timing tasks reflect cerebellardysfunction, given the similarity of theirperformance profiles to that exhibited by adultpatients with acquired cerebellar lesions. Wecannot, of course, claim on the basis of theseresults that cerebellar dysfunction is directlycausal for the clumsiness of these children. Indeed,as with single dissociations in neuropsychology,the results are of limited value in evaluating thespecificity of the neural correlates of clumsiness.The normal performance of the clumsy children onthe loudness task demonstrates that this group doesnot perform poorly on all tasks: on the taskemployed, their impairments are restricted to those

Ao

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Fig. 2: Performance of normal and clumsy children on motor and perceptual timing tasks used to assess cerebellarfunction, a) Estimates of component sources of variability during repetitive finger tapping. The total variabilityof the inter-tap intervals during the unpaced phase of the trial is assumed to reflect independent contributionsfrom central processes (CLOCK) determining when a response should be initiated and motor implementationprocesses (MOTOR DELAY), involved in executing the central commands, b) Difference thresholds on twoperceptual discrimination tasks, duration (left axis) and loudness (right axis). The values indicate the differencerequired between the standard and comparison stimuli for the participants to be correct on 75% ofthe trials.Adapted from Williams et al. (1992).

CEREBELLUM IN CLUMSINESS AND DEVELOPMENTAL DISORDERS 149

that evaluate the operation of an internal timingsystem. But it may well be that these childrenwould also be impaired on tasks that assess othercomponents of coordination, not just timing. Theremay be a general deficit in the function of theentire motor system, with the (cerebellar) timingproblems just one particular manifestation of thisgeneric impairment

As noted by many researchers, the term’clumsiness’ is applied to a heterogeneous popu-lation. This practice raises the possibility thatcerebellar dysfunction might be present in one

subgroup of clumsy children and absent in othersubgroups. Such a result would suggest thatdevelopmental movement disorders might mirrorthose in patients with acquired neurologic lesions.Similar to how these acquired lesions producesystem-specific impairments, subtypes of clumsi-ness might reflect the dysfunctional operation oflimited sets of neural systems. Alternatively, thecluster of symptoms that define clumsiness mightarise only when there is widespread depression ofneural function or may not pinpoint specific neuralabnormalities with such heterogeneity.

Laurie Lundy-Ekman addressed this specificityquestion in her dissertation studies (Lundy-Ekmanet al., 1991). The design of her study was similarto that of Williams et al. (1992). The selectionprocedure, however, was modified to include a

neurologic exam that was created to assess thepresence of soft neurologic signs of basal gangliaor cerebellar dysfunction (Touwen, 1979). Theterm ’soft signs’ is used when evidence of a

neurologic disorder is absent (for example, reflexabnormality or known brain injury), yet whengiven a neurologic exam, the performance issimilar to that seen in patients with knownneurologic disorders. For basal ganglia function,the assessment was for signs associated with

Huntington’s disease. Such signs included testingfor choreiform and athetoid movements, or thepresence of synkinesis (for example, when

children spread their fingers with arms out-stretched, small jerky movements were rated aschoreiform, those with slow writhing movementswere rated as athetoid). Cerebellar function wasassessed by tests for dysdiadokinesis (for example,smoothness of repetitive wrist pronation andsupination), intentional tremor, and dysmetria.

A total of 155 7- and 8-year olds were giventhe neurologic exam. Of these, 60 exhibited softneurologic signs. Twenty were excluded becausethey presented both soft basal ganglia and softcerebellar signs. The others were given theBruininks-Oseretsky test and selected for the studyif they scored below the 40t’ percentile. The finalgroups consisted of 11 children with soft signs ofbasal ganglia dysfunction and 14 children with softsigns of cerebellar dysfunction. Fourteen controlparticipants were selected from the pool ofcandidates who did not present any soft neurologicsigns and scored above the 40t’ percentile on theBruininks-Oseretsky test (mean of 79th percentile).

The task battery included the tapping task, theduration and loudness discrimination tasks, and aforce control task. The latter was chosen becausepatients with Parkinson’s disease are impaired inthe ability to modulate force output (Hallett &Khoshbin, 1980; Ivry & Corcos, 1993; Wing, 1988).For this task, isometric movements were madewith the index finger on a strain gauge. Targetforce levels were indicated by the vertical positionof a line appearing on the computer monitor (forexample, for a large target force, the line was

positioned near the top of the screen). The same

target was used for 12 consecutive responses.Feedback was provided for the first six responses.No feedback was given for the last six. As with thetapping task, the focus was on the consistency(standard deviation) with which the participantsproduced a series of responses without feedback.

The results revealed a striking dissociationbetween the performances of children with softcerebellar or soft basal ganglia signs. In terms of

150 RICHARD B. IVRY

total variability on the tapping task, children withsoft cerebellar signs were significantly morevariable than both the controls and children withsoft basal ganglia signs (Fig. 3a). When the datawere analyzed with the Wing-Krisotofferson model,the only reliable difference was between thecontrols and the soft cerebellar group in estimatesof clock variability (p<0.05). A similardissociation was also observed in the perceptiontasks (Fig. 3b). The difference in the threshold on

the duration discrimination task was much largerfor the children with soft cerebellar signs than forthe other two groups (p < 0.05). No differenceswere observed on the control loudness discrimi-nation task. A very different picture emerged on theforce control task. Here, the children with basalganglia soft signs were more variable than were theother two groups (Fig. 3c). Note that the childrenwith soft cerebellar signs tended to producesmaller forces than did the other two groups.

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Fig. 3:Performance of normal and clumsy children on motor and perceptual tasks used to assess subcortical function.Based on an independent clinical exam, the clumsy children were divided into two groups, those with soft signsof cerebellar dysfunction and those with soft signs of basal ganglia dysfunction. (a) As in Figure 2, estimates ofcomponent sources of variability during repetitive finger tapping, and (b) difference thresholds on two perceptualdiscrimination tasks. (c) Variability of force pulses produced without feedback is plotted as a function of meanforce produced. Adapted from Lundy-Ekman et al. (1991).

CEREBELLUM IN CLUMSINESS AND DEVELOPMENTAL DISORDERS 151

When a normalized measure of variability wasused (SD divided by mean force), the groupdifference was only marginally significant. Evenwith this adjustment, however, the normalizedmeasure of variability remained highest for thechildren with soft basal ganglia signs (p < 0.05).

In su..nary, the results of the Lundy-Ekmanstudy (1991) suggest that some degree ofspecificity, in terms of the underlying neurologicdysfunction, may be associated with clumsiness, atleast for subpopulations of children. A group ofclumsy children was identified who presented softneurologic signs of cerebellar dysfunction. Similarto adults with acquired cerebellar lesions, thesechildren were selectively impaired on tasks thatrequired precise timing. In contrast, the childrenwith soft basal ganglia signs performed normallyon the tapping and duration discrimination tasks.The soft basal ganglia group, however, wasimpaired on the force control task. Thus, theirmotor problems, in terms of both clinicalassessmert and behavioral performance, aresimilar to that found in patients with basal gangliadysfunction.

As interesting as the patterns of impairmentare, noteworthy is that the clumsy children did notperform more poorly than the controls on all motortasks. The basal ganglia group was unimpaired onthe tapping task, and the performance of thecerebellar group, at least on measures ofvariability, was similar to that of the control groupon the force control task. The results argue againstthe hypothesis that clumsiness reflects ageneralized dysfunction across the motor system.For at least some children, the syndrome mayreflect dysfunction in a particular neural system.Of course for others, the problems can be morewidespreaa, as indicated by the significantpercentage of children exhibiting both soft cerebellarand soft basal ganglia signs. We would predict thatthese children would have performed poorly onboth the timing and force control tasks.

CONCLUSIONS

The studies reviewed in this paper provide an

example of the bidirectional nature of cognitiveneuroscience research. At the behavioral level, a

primary endeavor within the field is to specify thecomputations that allow for different aspects ofmental competence. Tasks used in clinicalassessments prove to have good utility fordiscriminating between normal and abnormalpopulations, but the complexity of many of thesetasks, limits their utility for evaluating specificfunctional hypotheses. The focus of cognitiveneuroscience research is on the computationallevel. The finding that clumsy children are morevariable than age-matched controls in producingregularly timed intervals is not surprising. Theconclusion, however, that some of these childrenhave a problem representing temporal informationis bolstered by the observation of a correspondingimpairment on a perceptual timing task. Asimportant, the finding that other children, rated as

equally clumsy on standard clinical assessmentbatteries, are not impaired on the timing tasksprovides stronger evidence that a timing problemmay be present in a subpopulation of clumsychildren.

At the neural level, it remains to be seen ifdevelopmental disorders like clumsiness reflectabnormal function in a single or a limited set ofneural structures or whether they result from diffuseabnormalities. Given that the clinical picture isheterogeneous, it is likely that a multitude ofneurologic profiles are also associated withclumsiness. The results of the study of Lundy-Ekman et al. (1991) demonstrate that distinctsubpopulations of clumsy children have behavioralproblems similar to those of patients with eithercerebellar or basal ganglia dysfunction. Thus, forthese subgroups, there may be some neuralspecificity. On the other hand, the story that hasemerged in the search for the neural basis of autism

152 RICHARD B. IVRY

may be instructive here. In the initial high-resolution MRI studies, the only region showingstructural abnormalities was the cerebellum. Thisfinding led to considerable effort to determine howcerebellar dysfunction would cause autism.Subsequent studies, however, have shown thatneural abnormalities are quite widespread inautism, with reduced volume reported in limbic,cortical, and white matter regions (Courchesne,1997). Although a link between cerebellardysfunction and autism might still exist, a simplemapping between neural pathology and behavioralsyndrome seems very unlikely.

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