cerebelum_it's about time, but time isn't eveything

8/3/2019 cerebelum_it's about time, but time isn't eveything

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Topical Review

The Cerebellum: It 's About Time! But Timiug Is NoEverythiugNew Iusights Iuto the Role of theCerebellum iu Timiug Motor aud Coguit ive Tasks

Michael S. Salman, MSc, MRCP

ABSTRACT

Converging evidence from different research studies supports a role for the cerebellum in timing neural processes. T

cerebellum is part of a distributed system for motor contro l. The timing hypothes is provides a specific functional rolethe unique contribution of the cerebellum. The timing capabilities of the cerebellum appeal- to extend beyond motor cirol into tasks focusing on perceptual processing tliat require the precise representation of temporal information sensorimo tor learning. Behavioral and m odeling studies suggest that the cerebellar timing system is best characterizeproviding a near-infmite set of interval-type timers rather than as a single clock with pacemaker or oscillatory propertbut this is controvei-sial. In addition to learning precisely thiied m otor res pon ses, th e cerebellum is involved in on-line cessing using feed-forward systems for which sensory input is used prior to movem ent execution to improve move maccuracy. This would be a mechamsm for triggering accurate "time." The cerebellum continues to fascinate scientists, although sur\ival is possible without the cerebellum, tl^e resultant quality of lile is significantly compromised with cl.siness, ataxia, hypotonia, dysarthria, slowing of various cognitive perceptual processes, and impaired fine motor ocular-motor coordination. The last tliree decades have seen the development of research that has focused on how (erebellum functions. Further neurophysiologic research in cerebellaj- cortical neuroLransniission is likely to furtherunderstanding of the cerebellar contribution to timing sensorimotor p rocesse s.(J Child Neural 2002; 17:1-9).

The foiuth dimension of our world, time, has tended to beforgotten in many theories of perception and m otor contrcjl.Yet actions and events take place overtim e. It is not manda-tory to postulate that temporal information is representedexplicitly. Variation in the speed and durat ion of a reachingmovement might be an emergent property of the rate at

which miLscle units are recruited . Therefore, tem pora l reg-ularities in sequential actions m ay not reflect direct controlprocesses. Nonetheless, many phenomena suggest the exis-tence of an internal timing system in which temp oral infor-mation is explicitly represented. For example, hum ans caii

Received June 15,2001. Accepted for publication Juty17,2001,

From tlie Division of Neurology, Hospital for Sick Cliildien, Toron to, ON,

'Hie author is finimc'ially s upp orted by a resea rch traiiun g fellowship awaixiedby the Hospital for Sick t'hildren's Research Institute.

Addiess correspondence to Dr Michael S, Salman, Divisions of Neurology;md Psychology, Hospital forSick Children, 55ii University Avenue, Toron to,ON M5(J 1X8. Tel: 416-813-6918; fax: 416-813-6334; e-mail:

easily discriminate among intervals between event-s separated by 400 or 425 msec or show high sensitivity to peturbations in a stream of rhythmic events. ' It has beehypothesized that the cerebellum opera tes as a specializemodule for timing.

in this review, the evidence is presented for and again

this hypothesis. The evidence is based on a sensitive but nospecific literature search strategy. This approacth was takein order not to miss important and relevant studies in tharea. The initial MEDLINE search identified over 500 stuies; 52 we re initially selected based on the relevance of thtitle and abstract. Twenty-two studies were then retrievein full aiid review ed in de tail.A fuither 12 relevant referencethat w ere mentioned in important studies w ere also retrieveto verify some of the quoted "facts." Animal and humastudies in health and disease w ere included to ensure adquate coverage of the topic. Different lines of evidencwere reviewed (eg, theoretical, physiologic, neuropsychlogic, and neuroradiologic) to enrich the discussion. Thcerebellum's role in oculomotor co ntrol is not discussed hi i i


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2 Journal of Child Neurology I Volume 17, Number 1, January2002

NEUROBIOLOGY OF TEMPORAL PROCESSING

Tlie passage of time can be estimated by means of (I) stim-ulus duration by verbal estimation, for which subjects arer equired to evalu ate verbally the dui-adon of either filled (eg,a tone is heard) or empty intervals; (2) temporal discrimi-nation tests, for which subjects are presented with two

stimulus durations and are asked to determine w hether thesecond one is shorter or longer than the first stimulus; (3)tem poral produ ction, for wliich the subject is asked to pro-duce a certain interval (eg, by pressing a button); and (4)temporal repro duction, for which the subject is presentedwith specific stimulus duration and is asked to producethat duration. In temporal orientation, the subject is asked

10 identify the h our of the day, the day of the week, and themonth of Uxe year. This task is different and not corre latedto time estimation, although both requ ire tlie optimal use ofm em oiy It is specula ted that bniin mecha nism s involved intlie c:onect estimation of slioit duration s (mse c) are differentfirom tluise involved in long durations (sec); in the fonner,the subject is unable toluse cues such as counting.- The cere-bellum and the basal ganglia are considered to be ca ndidateregions within the brain for intenial clock representation.Other aj eas include the prefrontal co rtex and tem poral andparietal lobes, but the eviden ce for this is scanty and not con-vincing .' The circadian rhythm is ano ther exa mp le of a bio-logic clock (~ 24 hours). It is located in the hypothalamlcsuprachiasmatic nucleus.

There are many factors that are thought to influencetime estimation in noniial sub jects. Tliese factors have been

discussed in detail- and include (a) isolation from obvioustemporal markers (eg, day/night, cycle), (b) attention, (c)short term memory (hypothesized but not proven), (d)aiousal, (e) development (adult levels are reached around11 year s of age), (f) type of stimu lus (aud itory stimuli arejudged to be longer than visual stimuh of equivalent dura-tions), and (g) cognitive strategies (eg, counting silently).

FUNCTIONAL ROLE OF THE CEREBELLUM

The cerebellum constitutes only10% of the brain by weight;md volume' bu t contains ~ 5X 10'" neiu-ons, which is in thesame range as tbe numb er of neurons in the whole cerebralcortex, ' ' estimated to be 22 X 10'". Most of the brain'sinhibitoi-y neurotransmitter, 7-aminobutyric acid (GABA),is located in the cerebellum.

Tiaditionally, the cerebellum wa s thought to b e devotedentirely to the quality of movement, particularly the coor-dination of skilled volimtary m oveme nt including eye move-ments and c ontrol of motor tone, posture, and gait (ie, thecerebellum is concerned no t with movem ent per se but thequality of movement). This popularized \iew states thatthe principal role of the cerebellum is tlie acquisition and.storage of the plastic changes underlying learned and con-ditioned motor behaviors.

An alternative view proposes that, although the cere-

contribution to regulating motor behavior relates totime on-line processing it performs to optimize the outthe motor system ciuring the performance of coordiajid novel m ovem ents." Over tlie last decade , functionaroimaging studies have implicated the cerebellum in dhigher cognitive and behavioral functions including etive function (jilaiming. abstj-act reasoning, working mem

spatial cognition (visuospatial organization, memory)guage (fluency, prosody), and emotional regulation.'" Tnot surprising given the substantial input to the cerebfrom alm ost all levels oftlie centi'al nei-voussystem.'* In eral terms, these inpu ts are via vestibulocerebe llar (ging body equilibrium and eye movements), spinocere(controlling execution of limb movements), and cercerebellar (through the p ontine nuclei; implicated in ttiation, planning, and timing of mov emen ts) pathw ays

The cerebellum plays a cnicial piu1 in the visual giiidof movement. The m idline cerebellumis concern ed withibrating reflex m ovem ents of tlie eyes, wherea s the celar hem ispheres are conc erned with the voluntaiy conteye movements." The main contribution of the cerebelltlie control of these systemsis predictio n, the ability to aipate events and thus adapt movements fluenlly torequired goal.'" This may be regarded as on e aspec t othe cerebellum controls the quality of movement.

More recently, mo lecular and g enetic stutlies havetified m any genes and mutatio ns in cerebellar ion cha(eg, the Ca-* channel in episodic ata xia tyjie 2) and dtive proteins in diseases causing spinocerebellar degation (eg, mitochondrial iron transport protein in Friedr

ataxia). These advances have added another angle t(j bellar reseai'ch tliat will help us understand and adv ancbasic mechanism s underlyingcerebellai-function and, in ticular, its contribution to timing.

ANATOMY AND PHYSIOLOGY OF THECEREBELLUM

The internal structure of the cerebellum se em s simplsurprisingly consistent throug hou t the different cerebregions."* It is also highly con serve d acr oss spe cies .I'his sgests that the cerebellmn performs the same general putation for many different tasks. However, imporegional heterogeneities within the cerebellum in cchemistry or physiology ex ist Forexample,it was found the cerebellar polypeptides, zebiiiisI an d II, are Purkiiyespecific within the cerebellum .' ' The m^jor anatom ic partments of the cerebellum are the cortex and the nuclei. Purkir\ie cells, the only outputs from the cerehcortex, project through inhibitory conne ctions to the cerebeUar nuclei, which provide the ou tput to oth er regi(3ns. Inputs are traiismitted to tlie cerebellum over cing fibers and mo ssy fibere, two path wa ys with funda

tally different physiology and anatomy (Figure 1).The inferior o lives give rise to climbing fibers. Cing fibers project to Purkinje cells. Each Purkinjc


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The C erebellmn / Salvian

Cerebellar cortex

Purtunje cli

Climbing fiber

Excitation

Inhibition

25-msec cycle

I Oeep cerebeilar nucleus

Interior olive

Figure 1. Schematic of the basic cerebellar circuit, which is iteratedhroughout the structure. A mossy fiber - granule ceil * parallel fibernput. An inferior olive -- climbing fiber input and some, but not all,

of the intricate connections of the inhibitory interneurons are shown.Arrows indicate direction of impulse transmission. (Reprinted with per-mission fr om Raymond JL, Lisberger SG, Mauk MD:The cerebel lum:A neural learning machine? Science 1996;272:n26-1131. Copyright 1996American Association for the Advancement of Science.)

wliich mak es it emit complex sp ikes, occiuiingat 1 or a fewIlz. Complex spikes occur infrequentlyand hence are nothought to code for infoniiation transfer. This led to the sug-

t*estion that climbing fibers-Purkinje cellsare involved inkeeping time for coordination.The mossy fiber inputs aiise froma variety of pontine

nuclei and spinal cord. They influence Purkinje cell firingthrough their comiection with granule cells. Granule cellsform parallel fibers thai make excitatory connections withnumerous Purkirge cellsand inhibi tory connectionsoninterneurons. Inhibitory intenie uron s synapse on Purkii\jecells aiifl also provide inhibitory feedback to th e granule cells.This airangement offers many opportmiities for spatial andtemporal integration. Mossy fibers,via the granule celLs,cause Purkinje cells to emit simple spikesat rates of up to

100 Hz. TM s is probably compatible witha frequency codefor information transfer. Thereare also direct axonalcol-laterals between mossyand climbing fibers and the deepcerebellar n uclei. '-

Climbing fiber input is capable of producing a long-term depression of Purkii\ie cell responsive ness to parallelfiber inp uts. ' ' Long term depression had been observed inde-)endently in different laboratories usingthe conjunctive

stimulation paradigms in which long-term de pression is pro-duced by pairing the stimuli tliat activatethe parallelandclimbing fiber inputs to the same population of Purkin.jeneurons. However, the sustained high rates of climbing fiberactivation that are needed to produce long-term depressionliave not been observed under more behavioral conditions.

= 300 msec

= 400 msec

Counter

B

300 msec 400 msec 500 msecO 1B96 Current Opinion In Neurobmlogv

Figure 2. Two mechanisms for representing temporal information.A, Clock-counter models postulate a pacemaker that produces outputto a counter. Longer intervals are represented by increases in the num-ber of pacemaker outputs that accumulate in the counter B, Interval-based models assume that different intervals are represented bydistinct elements, each corresponding to a specific duration. (Reprintedfrom Current Opinion in Neurobiology, Vol. 6, Ivry RB.The represen-tation of temporal information in perception and motor control,851-857, Copyright 1996, with permission from Elsevier Science.)

term depression-related phenomenon.In addition, long-term depression is usually not a reversible experimentalphenomenon. ' ' " This aigues againstthe cerebellum as astorage site.

G A I N C H A N G E A N D D Y N A M I C S E L E C T I O N

H Y P O T H E S E S

Interestingly, it has been show n that short-term en hanc eme ncan occur in Purkirye cells in respo nse to lnossy-parallel fibeinput. In the gain change hyjiothesis, this occurs whenclimbing fiber activation tak es place within a critical perioprior to the arrival of other synaptic inputs to Purkii\jecells. These observations have been incorpo rated intothedynamic selection hypothesis, which proposesa mecha-nism by which the climbing fiber inputs can actto specifyspecific spatial distributionsof Purkinje cells that willbemost responsive and hence most highly modulated by combinations of mossy fiber inputs originating from manysources. The well-characterized oscillatory activityof th eolivary neurons (6-10 Hz)is postulated to provide a pace-making signal and lo restiict the control proc ess to particu lar moments in t ime (Figure 2). This view requires atask-specific, behaviorally dependent activation of specif


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Journal of Child Neurology IVolume 17, Number 1, Janiiary 2002

of converging inputs (ie, muscle synergies) to the inferiorolive."'' The theo ry e mp hasizes the Involvement of the olivo-cerebe llar system in on-line, real-time processing, allowingmovements to be executed rapidly in a feed-forward man-ner with minimum sensory guidance and feedback ratherthan in processes involved in establishing memoi-y in thecerebellum." This process is not easily observed by record-

ing the activity of individual Purkin.je cells, one at a time,as this may not appear to be significantly related to partic-ular instances of movement. However, tlie activity of groupsof olivary neuron s, producing distributed but synchron ousactivity within sets of Purkirye cells, is clearly related tomovement.'^

There does not seem to be any shortage of theoriesexplaining the function of the cerebellum. In one theory,"'it was proposed that the different speeds of conductionthrough parallel fibers, together with the simultaneousinput from climbing fibers, cause increased synaptic dis-charge in a previously facilitated Purkinje cell synapsehence, Purkinje cell output codes for specific temporalinformation. In a more recent theory,'^ it was proposedtliat Golgic ells fulfill a gating tas k by forming sho rt, and well-defmed time window s within which granule cells can reachfiring threshold, thus organizing neural activity in discrete"time slices." In this theory, the climbing fiber's spikes actas synchronization and as a teaching signal, not as an en orsignal.

ATAXIA TELANGIECTASIA AND TIMEPERCEPTION

Ataxia telangiectasia is an autosomal-recessive progress ivedisorder, with an early childliood onset of around age 2 to3 yeai\s. It presents with ataxia. extrapyramidal movementdisorder, and c utaneous telangiectasia. Tliereis an increasedsusceptibility to chromosomal breakage with failure in itsrepair mechanism s. Ataxia telangiectasia cau ses acquiredcereboliai' cortical deg eneration affecting Purkirye andg!"an-ular cell layers. In an expe riment using a test of judgmen tof duration, '" 17patien ts with this disease were comp aredwith 21 control subjects. The age range was 7 to 21 yearein both groups, with significantly more girls in the controlgrou p. The W echsler Verbal IQ w as significantly higher inthe controls (107 versus 74). Fi'equency perception of soundwas used as a control task.

For judgment of duration (perception task), subjectscomp ared successive time intervals generated by two pairsof (73-dB) tones tha t were 50 mse c in duration and 1 kHzin frequency. The first pair of tones was separated by 550msec ; the seco nd pair, presente d 1 sec later, had va riableintervals that w ere either shorter or longer than 550 msec;10 prac tice trials for each task we re offered before the startof the experim ent. A fter statistically controlling for Verbal

IQ, children and adolescents with this disease performedsignificantly wo rse than contro ls on judg me nt of duration(P = .01) but not of pitch, suggesting that the ce rebelliun may

In this study, only seven participants in the telangiectasia group had evidence of cerebellar atropbrain imaging (magnetic resonance imaging [MRIIput ed tomog raphy [CT]). Imaging was no niial in fourand not available for the rest. It is not cleai- when thewere done . This ma tters becaiLse the disease is progreand the results may be biased as other abnormalit

this disease are repo rted in the basal ganglia, albeit umonly. Also, ataxia telangiectasia causes increasedceptibi l i ty to infect ions and brain lymphoma lacliiidhood and early adulthood that may be silent inithis can further bias the results. Although age was mathe age range chosen w as wide, and, as mentioned ethere is developmental influence on time estimatioreaches adult values around the age of11 years, this chave confound ed the results, albeit in both gro ups. Intion, the study w as not blinded and had a small niuusubjects.

CEREBELLAR TUMORS AND TIME ESTIMATIO

CerebeUar lesions in childhood a re not rare. The po sfossa is the site of half of all< hildhood tumors, of wmedulloblastoma and astrocytomas are the most comtypes. They displace the cerebellum but rarely infiltrIn a study done on long-tenn survivors with these tumfew timing functions were studied , including short-tiuperception and long-duration estimation. The paiiicincluded 40 controls, 20 subjects with cerebellar astoma, and 20 subjects with medullobiastoma. The

age of diagnosis was 8 years. The mean age of testindon e 14 years after diagno sis. Wechsler Verbal or Pman ce IQ was greater tha n 70 in all participants.

In the first experiment, short-duration and freqpercep tion w ere measured using a two-alternative fchoice proce dure. The ability to discriminate am ongvals in the 400-msec range was tested. The particmade their choices by pressing on a left or right baccording to their abi l i ty to discriminate betweenempty intervals marked by a 1-kHz tone of 50-nisec tion. Participants were instructed to press the left bif they thought that the first duration was longer anright button if they thought that the second duratiolonger. The tumor group was less able to discrimamong durations in the 400-msec range (P = .006)two g roups did not differ in their ability to discrim inaquency differences In the3-kHz range.

In the second ex perimen t, a retrospe ctive estimat60-minute duration w as assessed by asking the subjeestimate the duration of time passed in the waiting without the aid of external cu es. Prospective time estion was assessed by asking the subjects to tell the iner when they believed that 30 minutes had elapsed

two groups did not differ significantly in their abilestim ate long durations , althougli timior-relatf d pros pmem ory deficits interfered with the ability to pro duc e


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The Cerebeilimi / Salman

The results of the experimen ts were the same regard-ess of the pathology or treatm en ts used . The re was no evi-

dence of functional recovery of short-duration perception.However, this study is not longitudinal, and the ability tostimate short d urations close to the time of diagnosis is

unkno wn. The two tumo r groups were affected similarlydespite the more extensive lesions associated with the

medulloblastoma group. Possible bias may have arisenrom the wide age range at the time of diagno sis(1 '/i2-15^/i2years) . The wide age range assu m es that the effect of hav-ng tumo r and treatme nt, including surgery and radiation,n early childho od is similar to having it in late ch ildhood .

Many studie s have show n this not to be the case; for exam-ple, radiation effects on the developing brain are particu-arly harmful below the age of 3 to 4 years. Overall, tl\istudy was well designed and show ed that ch ildhood lesions

of the cerebellum produced enduring deficits in short-duration percep tion. i

CEREBELLAR MOTOR CONTROL AND TIMING

Motor control can be defined as the process of restrictinghe outpu t of the m otor nervo us system so tliat meaningful

and co ordinated b eh a\io r ensue s. Timing is a critical aspectof movement. This is not surprising as controlling move-me nts inlierently involves activating mo tor units at the cor-ect times. Accurate anii movement requires correct time

courses in the command for force generation in each mus-cle, as well as suitable am plitude of the force crea ted by eachcontraction. There are overGOO skeletal muscles in thehuman body, each having many motor units. Complexmovement sequences often involve many muscles, result-ng in an astronom ical num ber of simultaneous and sequen-ial muscle contractions. Continuous control through time

has extremely high computational overload for which notenough neurons are present. The stereotypical and time-ocked performance of multiple and clearly independent

muscles suggests that they are activated by a single com-mand and controlled as a functional g roup (ie, musc le syn-ergies). It may be nece ssary to use m otor learning to regulatehe timing of motor commands to produce coordinatedmooth movements'^-*^ that meet motor demands under

various circumstances, but real-time, on-line processinghas also been suggested."'

Defective motor coordination is a principal feature ofdiseases of tlie cerebellum, m anifested by a lack of smooth-ness dining movem ent execution. One possible explanationevolves aroimd the d isruption in the timing of the no rmal

patterning of agonist and antago nist m uscle activity inth ecourse of the m ove me nt^ '- '

In supp ort of this idea, people with cerebe llar disea sehave excessive am oun ts of agonist-antagonist co-con tractionat movement onset, improper timing of phasic bursts ofactivity in agonist and antagonist muscle pairs causing adelay in move men t initiation. This is cause d by a delay in tlieonset of phasic motor cortex neural discharge owing to

results from abn onn al timing and the intensity of the antagonist burst necessary to break the movement. In additionthe time delay in tracking mov emen ts is increased, possiblbec ause of an increase in reaction time for movement initiation.-^ Dysdiadochokinesia is slowing and abnormal performance of rapid, al ternating movements. I t may beexplained by slowness at the turning points caused by delay

in movement initiation and/or dysmetria at the end of thmovement,-' ' compounded by delay or absence of agonispause . This results in abnormalities of movem ent velocityacceleration, and dece leration.''-'' The cerebellum is involvedin sequencing agonist and antagon ist activity; henc e, timinmay be faulty in cerebellar disease.

In addition to timing, the cerebellum has been shownto be involved in other as pects of movement c ontrol including modulating reflex gain (eg, long latency reflexes),^'thereby maintaining effective joint compliance; compensating for inlierent m echan ical instability, controlling movements requiring multiplejoints,^"and updating motor actsto correct for any mismatch between the current and thedesired limb position. In an interestingsi udy on the effectof weight on cerebellar hypennetria,-' it was found thaadding w eight to a rapidly n\oving limb increased the overshoot in patients with cerebellar disease and reduced it innonnal controls.

This contrasts with previous studies showing a reduction in kinetic tremor w ith added weiglit to the hm b. It wapostulated that kinetic tremor and hypermetila in cerebellar disease seem to have different pathophy siologic m echanisms. The authors suggested that the lateral cerebella

cortex is involved not only in programming the time onsefor the antagonist muscle con traction but also the am plitudand inten sity of the co nti action b ased on Ihe initial positionof the limb, the position of the target, and the inertia to beovercom e. Hence, the cerebellum is iTsponsible for providinmore than jus t timing function.

Physiologic, anatomic, and clinical studies-^ have alsoassociated the lateral cerebellum with movement planninand programming, whereas the intermediate and mediaregions were associated with movement execution. Basedon the se fmdings and th e Wing and Kristofferson model-'" othe two processes involved in periodic behavior, namely

timekeeper and implementation systems (Figiu'e 3),^ anexperiment was designed to m easure movem ent timing anmovement execution using rhythmic tiipping in patientwith localized cerebellar damage.

Seven patients aged19 to 66 years were tested. Fo ur ofthem had predom inantly lateral cerebellar lesions, where ain three the lesions were ce ntered in the m edial zone of thcerebellum. This was only an ^p rox ima tion , however, baseon clinical, surgical, and CT scan reports. The lesions w ereither caused by vascular strokes including hemorrhage oexcised tumo rs. Tiie authors did not give details on the etiology of the h em onh age (eg, traum a). This is relevant a s theffects of concussion may not show up on clinical or radiologic exam ination but may, nevertheless, ii\fiuence th e sub


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6 Journal of Child Neurology I Volume 17, Number 1, January 2002

Centralsignal

Peripherolfesponse

Central

signat

PeripherotresponseB

Figure 3. Hypothetical series of inter-response intervals resulting fromthe two-process model o f Wing and K ristofferson.^"A, Series of inter-vals in which the only va riability is introduced on the third responseresulting from added implem entation (motor delay) time. S, Series ofintervals in which the only va riability is introduced by the long clocktime on the th ird interval. C = clock; I = interval; D - motor imple-mentation (delay). (Reprinted with permission from ExperimentalBrain Research, Dissociation of the lateral and m edial cerebellum inmovement timing and movement execution, IvryRB, Keete SW, DienerHC, Vol. 73, 167-180, Figures I A and IB , 1988, Copyright notice ofSpringer-Verlag.)

Germany, others in the United States. Hence, the evaluationwas not identical, and. in some ca ses, the examin er was no tblinded Io the outcome of the tapping performance.

Tlie subjec ts w ere instructed to tap a microsw itch firstwith and then without (65-dB) tones of 50-msec durationprese nted at sufficiently slow regular intew als of550 msec.The index fmger of either the normal or impaired hand

was chosen randomly and put on a mit roswitch. mou ntedon a wooden block, and linked to a computer. The co mp uterrecorded th e subjects' respons e to the nearest millisecondafter a few pract ice t r ials . Control subjects were notincluded in the experimental design as the authors chiimedthat in a pre\'iously published stud y on nom ial subjects, n odifference in the same task proficiency w as found b ased onhand dominance. All of the patients were found to haveincreased variability in performing rhythmic tapping withthe impaired hand (ipsilateral to the lesion) compared withthe ctjntrol hand. Further analysis, biised on the Wing andKristofferson model, which assumes that the timing and

motor implementation processes operate independently,each witli its normal variance (ie, open-loop mode only),revealed that the poor perform ance of patie nts with the lat-eral lesion could be attribu ted to a deficit in the central tim-ing process. Pat ients with medial lesions were able toaccurately determine w hen to make a response but w ereunable to implement the respo nse at the desired time. Afterlaking th e pro blem s (higliliglited ab ove) in tJie design of tJiisstudy into account, the con clusions of the study are inter-esting and a{id furtlier weight to th e involvem ent of the cere -bellum in temporal processing. Many studies, in additionto this study, have suggested that the cerebellum can oper-ate in an open-loop (feedback free) system but that timingis unlikely to be the sole function of the lateral cerebellar

d d l

CEREBELLUM AND EYELID CONDITIONING

The temporal specificity of cerebellar motor learnibeen revealed most clearly from analysis of eyelid tioning. Eyelid conditioning provides a relatively direcat the temporal specificity of cerebellar learning. Intraining involves a relatively netitral stimuliLs such as an

tory tone followed by a reinforcing stimulus such aulation aroimd the eye (eg, air puff). The air puff ac tunconditioned stimulus, eliciting a reflex eyelid c(retraction of the eyeball aiid closure of the nictitatingbr


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The Cerebellum /Salman

nto a brief, short-latency response. Thus, the tone afterlie lesion had the sam e sho rt latency independ ent of its tim-ng before the lesion.

In both condit ioning experiments, deep cerebellarnuclear lesions abolished tliis learned response, presumablybec ause the se lesions destroy all of the ou tput from the cere-bellum."' The interpretation of tliis experiment was that

he cerebellar cortex is required for the expression ofemTied and timed resp on ses that a re delayed relative to thetimuli tliat elicit them . The cerebellar corte x may therefo re

be the site in which the m emory of learned timing is stored.The cerebellum not only lean is but also learns to change

ts output at the coiTect time, hi eyelid con ditioning, whe na mossy fiber input repeatedly predicts a climbing fibernput, there will be an increase in cerebellar outi^ut timedo peak Just prior to the arrival time of the climbing fibernput. The learning capa city that eyelid cond itioning revealss consistent with a classic feed-foi'ward use of sensorynput to improve movement accuracy. Feedback of sen-

ory infomiation is used during the execution of moveme nto produce accurate movement, but it is inherently hmited

hy its sluggishness and tendency to oscillate when forcedo opera te quickly. Feed-forward control obv iates this prob-em by using sensory information available prior to move-

ment execution to make decisions about ensuing motorcommands.

FUNCTIONAL NEUROIMAGING AND TIMING

Relatively little timing resea rch has been cond ucted using

unctional imaging techniqu es. An adva ntage of this methods that the im portan ce of a neural site relative to othe rs canbe examined more readily than in lesion or phannacologict udy. Activation of a particular system can also providensight into the cognitive processes underlying behavior,

w hen the re is a general agreem ent ab out the sys tem's ftuic-ion. In a controlled study using positron emission tomog-aphy (PET) to localize cerebeUar timing function,^' six

healthy adu lts aged 23 to41 years compared a test intervaleither 200- or 400-msec du ration), defined by two ton es of

50-msec duration and1 kHz, with a stand ard 300-msec inter-val. The subjec ts use d their right index finger if they though t

hat the test interval wa s shorte r or the right middle fingerf they thought that the tes t interval was longer to m ake the irchoices. In the con trol task, the two intervals had identicalduration, and subjects were instructed to make alternativechoices with their right index and middle fingers. Regionalcerebnil b lood flow using the C'''O, inhalation techniqu e w asexamined. For anatomic reference, T,-weighted MRI wasobtained.

A significant in crea se in blood flow w as found in thenferior parts of the ipsilateral cerebeUar hem isphere reflect-ng finger movem ents when the control task was com pared

with rest conditions. Bilateral activation of the temporalobes, donsolatenil prefrontal cortex, anterior cingulate cor-ex, and right caudate nucleus was seen during the control

thning task in the cerebeUar vemiis and hemisphere bilaterally. On average, subjects correctly identified97% of testintervals presented in the timing condition. The authorconcluded that the cerebellum is involved in time perception. However, an alternative interp retation of the resu lts habeen suggested,'- whereby activation of the cerebellar hem ispheres may have been the result of their involvement insequential stimulus discrimination, a possible nonmotocerebeUar function.

In another study using PET,-^' both auditoiy (li-kllz)tones and visual stimuli (white squares appearing sequentially on a computer screen) were presented to 12 normasubjects aged 20 to30 years in a set of expe riments tiiat hada similar design to the exp eriments m entioned above. Thsubjects, however, had to reproduce the sequences presented during a pause by tapping on a computer keyboarusing their right index finger. The sequences presentedwere (1) isosynchronous short (250-msec) or long (750msec) duration or (2) novel (ie, a mixture of 250- or 750

msec) duration. Regional cerebral blood flow using thC'-la bele d H,,O bolus technique wa s exam ined. In additioto the basal ganglia and modality-specific activation in thsen soty asso ciation and frontal co rtices, the results revealeda supramodal contribution of the lateral cerebellar cortexand cerebellai' vennis to the production of a timed motorespo nse, paiticiUarly when it is com plex a nd/or novel.

Tlie authors suggested that the cerebellum may contribute in two ways: (1) in computing the temporal parame ters of incoming sensory stimuli and outgoing movem entand (2) in learn ing novel , tempora l ly prec ise motoresponses. The results also gave suppoil to the involvemen t of the basal gangUa struc tures in mo tor timing that mabe more directly related to implementation of the motoresponse than to timing per se. The role of the cerebellumin timing is conceptualized not as a clock or cou nter bu t simply as the structure that provides the nec essary circuitry fothe sensory system to extract temporal information andfor the m otor system to learn to prod uce a precisely timedresponse. The impUcit assumption in tliis study that thtiming requirements increased across tasks, with the fixeinterval sequence being the easiest and tlie novel sequ encewith mixed intervals being the most difficult to time, wa

not verified by the be havioral data.Experimental manipulations of a cognitive function

may alter brain activity in many sites; hence, it is difficulto directly associate brain activity in a specific- aiea witli onbut not another behavioral measure. Additionally, functional imaging cunvntly relies heavily on the subtractivlogic, wherein the subtraction of two tasks is assumed toreflect functional activity associated with a mental operation in one but not the other task. This may not be tenablor difficult to test These limitations can seriously obscurinterpretations of causal linkages between brain structurand function.' The results of functional neu roimaging fromstudies of motor timing are discrepant, particularly withregard to the role of the cerebellum and basal ganglia. Thi


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8 Journal of Child Ntjuroloyy I Vuhuiie 17, Number 1, Januaiy 2002

In recent years , functional MRI has emerged as apromising and noninvasive technique that m ay helpin thefunctional loca lization of variou s brain regions.It does notinvolve the use of radioactive isotopes thataie used inPET studies. The assumption underlyingthe use of func-tional MRI is that during a specific task, blood tlowto theprocessing region increases with consequent increasein

oxygen delivery, extraction,and

use. Hence,by

subtract-ing the resting image from the image acquired duringthetask, the result should bea functional, task-specific m ap ofthe brain. In a study on memory-timed finger movementt;isk.'^ functional MRI was usedto measure regional cere-bral hemodynamic responses.The subjects were eighthealthy male volunteers aged 19to 27 years. All su bjectsperfonned the following four tasks: (1) memory-timedfin-ger movement (using the right index finger to click on amouse every 1500 msec w ithout any precedingcue), (2) visu-ally cued finger movement(by clicking on a mouse asabove when the br ightness of light at a fixation point

changes randomly between 500and 2500 msec , (3) silentarticula tion (saying "pi" silently every 1500 ms ec w ithoutany cue), and (4) resting baseline.

The results showed that niomory-timed fmger niove-nieuts significantly activatedthe anterior lobe of the cere-bellum bilaterally (lobulesIV and V), the contralateralprimary m otorarea, the dorsal premotor areabUateraUy, tliesupp lem entary m otor area, the inferior frontal corte x bUat-erally, the left intraparietal cortex,and the right inferiorpaiietal lobe conipai ed with the contro l resting conditions.The same are as inthe ipsilateral right anterior cerebellum,

contralateral primary motor area, bilateral dorsal prem otorarea, left intraparietal cortex,and right inferior parietalcorte x we re also significantly activated during the visuaUycued movement task. The supplementary motor areawasactivated in a more posterior location compared withthememory task . Additional areas were also activated, includ-ing the ipsilateral ventral pre mo tor area , right middle frontalcoriex, left inferior parietal cortex, right superior temporalcortex, left insula,and right thalamu s. In the silent articu-lation task, the supplementary motor area and the left infe-rior frontiil cortex w ere activated com pared with the controlresting conditions and in the same are as as the first task. The

anterior lobe of the cerebellum w as only minimally activatedin the silent articulation task.

It is known that ipsilateral activationof the anteriorcerebellum is associated with the index finger movement.However, the autho rs postulate that b ilateral activationofthe anterior lobesof the cerebellum, supplementary motorarea, and left prefrontal c ortex w ere probably involvedinthe generat ion of accurate timing, functioningas a clockin the central nervous system.The left prefrontal cortexis associated with language processingin t e rms of per-ception, production , and mem ory; hence, its activation maybe involved in the subvocalization associated with chrono-metric counting. Similar reasoning was postulated by theauthors to explain supplementary motor area act ivat ion

Memory

DedsloQ

Figure 4. Diagram of the information-processing mode!of intervaing derived fro m scalar theory. The clock stage compone nt conof a pacemaker that discharges pulses, which are gated by a swand then passed into an accumulator to be counted. Accumupulses are encoded into working mem ory on each trial and stor

reference memory over trials.The decision process compares pcounts from the accumulator with those in memory to deterho w or when to respond. Attention can influence the clock procedelaying (or hastening) the onset of the switch or changing the pcount in the accum ulator. Attention and strategic processes influthe decision stage by biasing response thresholds. (Reprinted Harrington DL. Haaiand KY: Neural underpinnings of temporacessing: A review of focal lesions, pharmacological, and functimaging research. flev/Veu/-osc/1999;10:91-n6,by permission ofund Publishing House Ltd.)

supporting the role of the supplementary motor area insequence generation from memory that fit into a precisetiming plan. The absence of basal ganglia activation in thisstudy was blamed on susceptibility artifacts, hi a functionalMRI study investigating explicit time estimation,''"' par-ticipants were given time intervals (12-24 sec) and wereasked to indicate when it elapsed without external clockcues. Compared to control tasks (counting backwjird orforward), lateral cerebellar and inferior lobe activation wasseen. This study implicated the involvement of the cere-bellum in estimating longer time intervals (in the order of

seconds) compared with other studies that implicatedthe cerebellum in timing tasks in the order of milliseconds.The above studies show that multiple neural systems

support temporal processing, consistent with the scalartiming theory, which assumes tJiat the scalar property of tim-ing is att ributable o multiplicative variance mechjinisms thatcan be influenced by the clock, memory, and decisionprocesses (Figure 4). Isolating these processes and, in par-ticular, expUcit timing from those involved in nontemporalprocesses in functional neuroimaging studies is compli-cated, with many limiting factors as described earlier.

AcknouiledgmenlI w


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R^erences1. Ivry RB: The rep resentationof temporal informationin percep-

tion aiid m otor con trol.Ctirr Opin NeuroMol1996;6:851-857.:;. I^lo nde R, Hiuineqiiin I): The neiirobiolog iral basis of time esti-

mation aiui temponil order.Rev Nrum.sci lf)99;10:l.'Jl-17;i.'!. HaiTiiigtonDL, Haaiand KY: Neural underpinnings of temporal pro-

cessing:A review of focal lesion s, phamiacologic:al, and fimctionalimaging research.Rev Ncumsci 1999;10:91-116.

1. Dolari RI: A cogn itive affective rolefor the cerebellum.BrainIi)fi8;121:545-546.5. Robinson FR: Roleof Ihe cerebellum in movement control and

adaptation.Curr Opin Neurobiot1995;5:755-762.G. Bloedel JR. Bracha V, I^^rson PS: Real time op eratio nsof tlie

cerebeUar cortex.Can J Neurol Sci 1993;20(StippI 3):S7 -Si8.7. Schmahinitnn JD, Sherm aJC : The cerebellar cognitive affective

syndrome.Brain 1998;121:561-57f).8. Honi AKE, Buttner U, Buttner-E nnever JA: Brainstem and cere-

beUar stnicturesfor eye movement generation.Adv Otorhino-Inryngol im?l;55:l-2B.

9. I^eigliR(j, Zee DS: Tlie proiwrtJes and netiral su tratrate of eye n iove-menls, in Leigh RG, Zee DS (eds):The Neurologyof Eye Move-

ments, 3rd ed. New York, Oxford University Press, 1999,:J-15.10. Stein JF, Giickstein MG: Role of cerebeUum in visual guidance ofmovement.Physiol Rev 1992;72:968-1017.

11. Hawkes R, Blytli S, Chockkan V. e( al: Structural and molecularc o m p a r t m e n t a t i o n in the ce rebe l lum. Can J Neurol Set

12.

13.

14.

15.

17,

18,

Raymond JL, Lisberger SG, MaukMD: The cerebeUum:A neuralleamuig machine? Sfr;ni.rPl996;272:1126-1131.Ito M: Synaptic plasticity in the cerebeUar cortex and its roleinmotor learning.Can J Neurol Sci 1993;20(Suppl 3):S70-S74.Llinas R, W elshJP : On Ihe cerebelltmi and motor learning.CurrOpin Biol 1993;3:958-965.WeLshJP, LlinasR: Some organizing principles for the control of

movement based on olivocerebellar physiology.Pivg Brain Res

1997;1I4:449-461.SlrehlerBL: A new th eoiy of cerebellar function: Movement con-trol through phase-dependent recognitionof identities betweentime-based neural inrormational symbols.Synap.'ie19{)0;5:l-32.Kisder WM, Henimen JL: Delayed reverberation tlirough timew i n d o w s as a key to ce rebe l l a r f unc t ion .Biol Cybern1999:81:373-380.Mostofsky SH, Kunze JC, Cutting LE: Judgementof durationinindiv iduals wi th a taxia te langiec tas ia .Dev Neuropsychol2000;!7(1 ):63-74.

The Cerebellum! Salimin

19. HetheringtonR, Dennis M, SpieglerB: Perc eption and estimatioof time in long-term surv ivors of childhood pos terio r fossa tum./ hU Ncn rapnycbol Sor200();6:682-()92.

20. MaukMD , MedinaJF . Noies WL,OhyainaT: CerebeUar fimcUoCoordination, learning or timing?Cmr Biol 2000;10:R522-R525.

21. Dichgans J: Clinical symptomsof cerebellar dysfunctionandt h e i r t o p o d i a g n o s t i c a l s i g n i f i c a n c e .Hum Neurobiol1984;2:269-279.

22. Diener HC, DichgansJ: Pathophysiologyof cerebellar ataxiaMov D isord 1992;2:95-109,

23. Gilman S: Cerebe l l a r con t ro lof m o v e m e n t , Ann Neurol1994;;i5(l):3-4.

24. Hallet M, Massaquoi SG: Physiologic studiesof dysmelriainpatie nts with cereb ellar deficit.s.Can J Neuwl Sci 1993;20(Suppl3):S83-S92.

25. DienerHC ,Hore J, Ivry R, Dichg ans J: Cerebellar dysftmctionmovement and percept ion .Can J Neurol Sci 1993;20(SuppI3):S62-Sfi9.

26. Be cke r W,I, Mo rrice BL, Clark AW, Lee RG: Mu lti-joint rea* hmovem ents and eye-himd tracking in cerebeUar incoordinatInvestigation of a patient wilh complete loss of Purkirijecells.Can

J Neurol Sci 1991;18:476-487.27. MacK i^ WA, Muri)hy JT CerebcUar modulation of refiex gain. P

Neurobiol 1979;13:361^17.28. Ivry RB, Keele SW, Diener HC: Dissociationof Ihe lateral and

medial cej-ebellum in movement timing and movem ent ex ecutE3i:p Brain Res 1988;73:167-180.

29. Wing A, KristoffersonA: Response d elays and the timing ofdis-crete motor responses.Percept Psycliopfty.s1973; 14:5-12.

30. IvryRB: Cerebeilai timing systems, inSchm ;dim aimJ D(ed ):TheCerebeUum and Cognition. Inlernationat Revien' of Neurobiology, vol.41 . San Diego, Academy Press, 1997;41:565-573.

31 . Jue ptn er M, Rijnt,jes M, Weiller C, etal: Localization of a cerebeUliming pro cess u.sing PET.Neurology 1995:45:1540-1545.

32. Seitz RJ: CerebeUar timing pr oce ss.Neurology 1996;47:306-a07.33 . Penhtine VB, Zatorre RJ, Evans AC: Cerebellar contributionto

mo tor timing: A PET stn dy of audit ory and visual i hyl hni reductio n. /Cogn NeunKsciI998;10:752-7f>5.

34. Kawashinia R, Okuda J, Umetsu A, etal: Human cerebellum playan important rolein memory-timed finger movement: An fMR

35. TracyJI , Faro SH, Mohamed FB, etal : Functional localization oa "time keeper" fimction separate from attentJonal resources task strategy.Neuroimagc 2000;ll:22S-242.

AnnouncementBernard L. Maria, MD, MBA, Chair, Department of Child Health, and Pediatrician-in Chief

Congratulations to Bernard L. Maria, MD, MBA, a long-termmember of the Editorial Board of the Journal of ChildNeurology, for having joined a select group of childneurologists who have ascended to the position of chairmanof a department of pediatrics. On September 1, 2001, DrMaria was named Chair of the Department of Child Healthat, the University of Missouri-Columbia School of Medicineand Pediatrician-in-Chief at Children's Hospital. Dr Maiiareceived his medical degree in 1981 from the Universite deSherbrooke (Sherbrooke, Quebec, Canada). He thencompleted a residency in pediatrics at McGill University

neurology at Johns Hopkins Hospital (Baltimore, Maryland)in 1986, and a fellowship in neiiro-oncology at the M. D.Anderson Cancer Center (Houston, Texas) in 1988. Hereturned to Canada as the country's first pedialric neuro-oncologist. Later he Joined the University of Florida Collegeof Medicine (Gainesville, Florida), where he founded theneuro-oncology program and was professor and chief ofpediatric netirology. He also received a master's degree inbusiness administration with honors from the University ofFlorida in 1995. The Editorial Staff and Publisher of theJournal of Child Neuwlogy compliment Dr Maria on this


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cerebelum_it's about time, but time isn't eveything

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