A preliminary transcranial magnetic stimulation study of corticalinhibition and excitability in high-functioning autism and Aspergerdisorder

PETER G ENTICOTT1,2 | NICOLE J RINEHART2 | BRUCE J TONGE2 | JOHN L BRADSHAW2 |PAUL B FITZGERALD1

1 Monash Alfred Psychiatry Research Centre, School of Psychology and Psychiatry, Monash University and The Alfred, Melbourne, Australia. 2 Centre for DevelopmentalPsychiatry and Psychology, School of Psychology and Psychiatry, Monash University, Clayton, Australia.

Correspondence to Dr Peter G Enticott at Monash Alfred Psychiatry Research Centre, Level 1, Old Baker Building, The Alfred, Melbourne, Victoria, 3004, Australia.E-mail: peter.enticott@med.monash.edu.au

PUBLICATION DATA

Accepted for publication 2nd February 2010.Published online 29th March 2010.

LIST OF ABBREVIATIONSGABA Gamma-aminobutyric acidHFA High-functioning autismppTMS Paired-pulse transcranial magnetic

stimulationTMS Transcranial magnetic stimulation

AIM Controversy surrounds the distinction between high-functioning autism (HFA) and

Asperger disorder, but motor abnormalities are associated features of both conditions. This study

examined motor cortical inhibition and excitability in HFA and Asperger disorder using transcra-

nial magnetic stimulation (TMS).

METHOD Participants were diagnosed by experienced clinicians strictly according to DSM-IV

criteria. Participants with HFA (nine males, two females; mean age 16y 8mo, SD 4y 5mo) or

Asperger disorder (11 males, three females; mean age 19y 1mo, SD 4y 2mo) and neurotypical

participants (eight males, three females; mean age 19y 0mo, SD 3y 1mo) were administered a

paired-pulse TMS paradigm intended to assess motor cortical inhibition and excitability.

Responses to TMS were recorded by electromyography.

RESULTS Cortical inhibition was significantly reduced in the HFA group compared with both the

Asperger disorder (p<0.001) and neurotypical (p<0.001) groups, suggesting disruption of activity

at gamma-aminobutyric acid A (GABAA) receptors. There was no group difference in cortical excit-

ability.

INTERPRETATION Cortical inhibition deficits may underlie motor dysfunction in autism, and per-

haps even relate to specific clinical symptoms (e.g. repetitive behaviours). These findings provide

novel evidence for a possible neurobiological dissociation between HFA and Asperger disorder

based on GABAergic function.

Both autism and Asperger disorder involve social, communica-tive, motor, and behavioural disturbances (including stereo-typed and repetitive behaviours), but there is controversysurrounding their clinical distinction,1 coupled with a rela-tively limited neurobiological understanding of the disorders.These conditions are primarily differentiated on the basis oflanguage and communication delay, which must be present inautism but, by definition, is absent in Asperger disorder.2 Inaddition, although intelligence in individuals with Aspergerdisorder is typically within the average range, the majority ofindividuals with autism have intellectual disability. However,clinical research has demonstrated that the psychosocialprofile of typical intelligent individuals with autism (i.e. high-functioning autism [HFA]) is convergent with that of individu-als with Asperger disorder.3 Such findings form the basis ofthe argument that autism and Asperger disorder are not clini-cally distinct disorders, but are clinical labels that can be usedinterchangeably. By contrast, others have argued that the ini-tial significant language delays that characterize autism (but

not Asperger disorder) place the two disorders on separateneurodevelopmental trajectories.4 The hypothesis that autismand Asperger disorder are clinically separate disorders withdistinct neurobiological underpinnings has been supported byneuropsychological and neurophysiological research thatshows dissociations in visual perception, language, attention,executive function, and motor function.5

The neural circuitry involved in motor control is reasonablywell defined; accordingly, studies of motor dysfunction in par-ticular can further inform the debate concerning a possibleneurobiological dissociation between autism and Asperger dis-order. Although motor impairments are common to bothautism and Asperger disorder, there is evidence to suggest thatthese impairments are neither behaviourally nor neurophysio-logically equivalent. For example, analysis of gait functionindicates that individuals with autism, compared with thosewith Asperger disorder and healthy individuals, show anincreased variability in stride length, whereas those withAsperger disorder (but not autism) display significantly more

ª The Authors. Journal compilation ª Mac Keith Press 2010 DOI: 10.1111/j.1469-8749.2010.03665.x e179

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

head and trunk posturing abnormalities than comparison indi-viduals.6 Movement dysfunction differences between autismand Asperger disorder have also been described in early child-hood.7 Other studies, however, have found no differencebetween autism and Asperger disorder on standardized motorassessments8 and tests of coordination.9 Thus, although theremay be behavioural differences in motor function, this area iscontroversial.

In relation to biology, recent brain imaging and neurophysi-ological studies of autism suggest dysfunction in both the basalganglia ⁄ frontostriatal and cerebellar regions, but it is less clearwhether this also extends to Asperger disorder. For example,Rinehart et al.10 and Enticott et al.11 report electroencepha-lographic (EEG) abnormalities over the supplementary motorarea (similar to that found in Parkinson disease) in HFA butnot in Asperger disorder, indicating a possible frontostriataldissociation between the two disorders. Further, Mulleret al.,12 in their functional magnetic resonance imaging (fMRI)study of autism, found decreased activation of motor-relatedneural circuitry (e.g. thalamus, basal ganglia, supplementarymotor area), whereas subsequent fMRI research also foundcerebellar abnormalities in a simple motor task in autism.13

Motor deficiencies in autism may, therefore, be underpinnedby insufficient control of the basal ganglia ⁄ frontostriatalmotor loop, perhaps attributable to reduced cortical inhibitionarising from dysfunction in gamma-aminobutyric acid(GABA)-mediated processes. Indeed, there is some evidencefor GABAergic abnormalities in autism.14,15 It is unclear,however, whether in vivo GABA impairments exist in autismand, if so, whether these impairments also extend to Aspergerdisorder (which is often considered a milder form of autisticdisorder).

Aside from EEG investigations, and despite some neuro-behavioural support for a frontostriatal dissociation, to datethere have been no direct studies of motor cortical function(including GABAergic cortical inhibition) in autism andAsperger disorder. Transcranial magnetic stimulation (TMS)offers a unique tool with which to investigate motor corticalfunction in autism and Asperger disorder. To our know-ledge, only one group has conducted a TMS study of themotor cortex in autism; Theoret et al.16 compared motorcortical function in 10 adults with ‘autism spectrum disorder’(autism and Asperger disorder combined) and 10 comparisonindividuals, but found no between-group differences incortical inhibition. HFA and Asperger disorder were notcompared.

Using a well-established and validated paired-pulse TMS(ppTMS) paradigm, the aim of this study was to investigatecortical inhibition and excitability in individuals with HFAand Asperger disorder. By varying the time interval betweenpulses, ppTMS allows investigation of inhibitory (GABAer-gic)17 and excitatory (glutamatergic) cortical processes.18

Based on the body of experimental research indicating a disso-ciation in the nature of basal ganglia ⁄ frontostriatal dysfunctionin autism and Asperger disorder, it was predicted that corticalinhibition would be more reduced in autism and relativelyspared in Asperger disorder.

METHODParticipantsParticipants included 11 individuals with HFA, 14 with Asper-ger disorder, and 11 neurotypical individuals (see Table I).Clinical participants were recruited via letters sent to parentsof patients of one of the authors, while neurotypical partici-pants were recruited via advertisements in the local commu-nity. All participants were diagnosed by experienced cliniciansstrictly according to DSM-IV criteria (autistic disorder [with-out intellectual disability] or Asperger disorder), while historyof language development (delayed in HFA but not Aspergerdisorder) was also confirmed with a parent at the time of theTMS experiment. Participants were excluded if they had anyadditional psychiatric or neurological conditions. Seven partic-ipants with HFA were receiving low-dosage medication (oneclomipramine 12.5mg, one risperidone 0.5mg, one quetiapine100mg, one venlafaxine 150mg, two fluoxetine 20mg, and onevalproate 600mg), and two participants with Asperger disorderwere receiving medication (both fluoxetine 40mg). This studywas approved by the ethics committees of The Alfred, MonashUniversity, and Southern Health. Participants aged 18 yearsand over provided written informed consent. A parent orguardian provided written informed consent for participantsaged below 18 years.

ProcedureTMS was administered to the motor cortex via a hand-held,70mm figure-of-eight coil positioned over the scalp. Single-pulse TMS was administered using a Magstim 200 stimulator(Magstim Company Ltd., Carmarthenshire, Wales, UK);ppTMS was administered using two Magstim 200 stimulatorslinked with a bistim device. The coil was held tangential tothe scalp, with the handle angled backwards and 45 degreesaway from the midline. Electromyographic activity wasrecorded from the abductor pollicis brevis muscle, contralat-eral to the hemisphere receiving TMS, using self-adhesiveelectrodes.

Table I: Demographic variables for all groups

HFA AD NT p value

n 11 14 11 –Age, mean(SD)

16y 8mo(4y 4mo)

19y 1mo(4y 2mo)

19y (3y1mo)

0.289(ANOVA)

Sex (M:F) 9:2 11:3 8:3 0.873 (v2)

HFA, high functioning autism; AD, Asperger disorder; NT,neurotypical.

What this paper adds• In vivo evidence for possible GABAergic dysfunction in autism (using TMS).• Evidence for a neurobiological dissociation between autism and Asperger dis-

order based on GABAergic function.• Further understanding of the neuropathophysiology of motor impairments and

repetitive behaviours in autism.• Indication that possible neurochemical abnormalities beyond the motor cortic-

es might underlie social and language impairments in autism.

e180 Developmental Medicine & Child Neurology 2010, 52: e179–e183

Participants’ resting motor threshold and active motorthreshold were determined for each hemisphere. Restingmotor threshold was defined as the minimum stimulationintensity required to evoke a peak-to-peak motor-evokedpotential (MEP) of more than 50lV in at least three out of fiveconsecutive trials, whereas active motor threshold was definedas the minimum stimulation intensity required to produce anMEP of 100lV in at least one out of five trials during volun-tary abductor pollicis brevis muscle contraction.

ppTMS involved the administration of a subthreshold (90%of active motor threshold) conditioning stimulus followed by asuprathreshold (115% resting motor threshold) test stimulus.The ppTMS paradigm was administered to each hemisphere,and involved a randomized sequence of 60 trials, comprising20 of each of the following three conditions: single-pulseTMS, ppTMS with a 2ms interstimulus interval, and ppTMSwith a 15ms interstimulus interval. There was a 5 secondinterval between each trial. This ppTMS protocol is widelyused, and its effects are well established.19 Among healthychild and adult populations, a 2ms interval between the condi-tioning and test pulses produces an inhibitory effect (i.e.reduced MEP amplitude), reflecting GABAA function.17 Bycontrast, a 15ms interval results in a facilitatory effect (i.e.enhanced MEP amplitude), reflecting glutamatergic func-tion.18 MEPs recorded for each ppTMS condition (2 and15ms) were compared with MEPs recorded during single-pulse TMS.

Data analysesMixed-model analyses of variance (ANOVA; i.e. combinedwithin- and between-individual data) were used to investigatedifferences in motor thresholds (resting and active) and MEPamplitudes. For motor thresholds, this involved two 2 (‘later-ality’: left hemisphere vs right hemisphere) · 3 (‘group’:HFA vs Asperger disorder vs neurotypical) mixed-modelANOVAs (i.e. one for resting motor threshold, one for activemotor threshold). For MEP amplitudes, there was an addi-tional within-individual factor (i.e. TMS condition); thus, thisinvolved a 2 (laterality: left hemisphere vs right hemisphere)· 3 (‘TMS’: single pulse vs 2ms ppTMS vs 15ms ppTMS)· 3 (group: HFA vs Asperger disorder vs neurotypical)mixed-model ANOVA. Least significant (LSD) post-hocanalyses were used to examine main effects. In addition, theresponse to ppTMS expressed as a percentage of theresponse to single-pulse TMS was calculated for eachppTMS condition (2 and 15ms), and compared betweengroups using a mixed-model ANOVA (with laterality as thewithin-individual factor, and LSD post-hoc testing whereappropriate). For short-interval cortical inhibition (2msppTMS), a value below 100% is expected, whereas for corti-cal facilitation (15ms ppTMS) a value above 100% isexpected. Data were analysed using SPSS version 16.0.1(SPSS Inc., Chicago, IL, USA). Data were inspected toensure adherence to the assumptions of ANOVA; violationsof homogeneity of variance were noted for some analyses,and corrected values are reported. An alpha-level of 0.05 wasadopted for all analyses.

RESULTSMotor thresholdsResting and active motor thresholds are presented in Table II.For resting motor thresholds, the main effect of groupapproached significance (F2,33=3.21, p=0.053). Post-hoc analy-ses indicated that the HFA group displayed a significantlygreater threshold than the neurotypical group (p=0.018).There was no effect of laterality (F1,33=0.01; p=0.907), nor wasthere an interaction effect of laterality–group (F2,33=2.15;p=0.133). For active motor threshold, there was no effect ofgroup (F2,33=2.44; p=0.103), laterality (F1,33=0.16; p=0.688), orlaterality–group (F2,33=1.76; p=0.187).

Cortical inhibition and excitabilityMEP amplitudes are presented in Table II. TMS analysesfailed Mauchley’s test of sphericity, and a Greenhouse–Geissercorrection was used. There was an effect of TMS (F2,53=59.89;p<0.001) and a significant TMS–group interaction (F3,53=3.44;p=0.021). In relation to cortical inhibition, post-hoc analysesrevealed no significant difference between single-pulse TMSand 2ms ppTMS among participants with HFA (p=0.311). Bycontrast, there was a significant difference between single-pulse TMS and 2ms ppTMS in both the Asperger disorder(p=0.001) and neurotypical (p=0.001) groups. In relation tocortical excitability (i.e. facilitation), there was a significant dif-ference between single-pulse TMS and 15ms ppTMS in theHFA (p=0.014), Asperger disorder (p<0.001), and neurotypical(p=0.004) groups.

The cortical inhibition effects described above are furtherdemonstrated when inspecting 2ms ppTMS MEP amplitudesexpressed as a percentage of single-pulse TMS MEP ampli-tudes (per cent of reflecting short-interval cortical inhibition;see Table II). Mixed-model ANOVA revealed an effect of

Table II: Mean results for transcranial magnetic stimulation variables forall groups

HFA AD NT p

Resting motor threshold, %Left hemisphere 50.9 (9.0) 49.6 (12.2) 42.7 (4.4) 0.104Right hemisphere 53.1 (10.5) 47.6 (10.8) 42.2 (4.1) 0.030

Active motor threshold, %Left hemisphere 42.4 (7.9) 41.2 (12.4) 35.1 (5.2) 0.158Right hemisphere 43.7 (9.2) 39.2 (10.7) 34.8 (3.6) 0.068

Motor-evoked potentials – left hemisphere, mVSingle pulse 0.5 (0.3) 0.8 (0.7) 0.6 (0.4) 0.2842ms paired pulse 0.5 (0.4) 0.2 (0.2) 0.3 (0.2) 0.15815ms paired pulse 0.8 (0.4) 1.1 (0.8) 0.9 (0.6) 0.510

Motor-evoked potentials – right hemisphere, mVSingle pulse 0.5 (0.3) 0.8 (0.5) 0.7 (0.5) 0.3242ms paired pulse 0.4 (0.2) 0.3 (0.2) 0.3 (0.1) 0.21815ms paired pulse 0.8 (0.7) 1.2 (0.8) 1.0 (0.6) 0.498

Short-interval cortical inhibition, %Left hemisphere 101 (51) 39 (22) 46 (28) 0.000Right hemisphere 90 (41) 43 (34) 41 (23) 0.002

Cortical facilitation, %Left hemisphere 212 (149) 180 (104) 159 (91) 0.561Right hemisphere 185 (87) 162 (63) 150 (48) 0.457

Standard deviations in parentheses, unless otherwise indicated. HFA,high functioning autism; AD, Asperger disorder; NT, neurotypical.

TMS in Austism and Asperger Disorder Peter G Enticott et al. e181

group (F2,33=15.28; p<0.001). Post-hoc analyses indicated thatthe per cent of short-interval cortical inhibition was signifi-cantly greater (i.e. less inhibition) in the HFA group than ineither the Asperger disorder (p<0.001) or the neurotypical(p<0.001) group. There was no significant difference betweenthe Asperger disorder group and the neurotypical group(p=0.788). There was no effect of laterality (F1,33=0.33;p=0.568) and no laterality–group interaction (F2,33=0.40;p=0.677). In relation to cortical facilitation, in which 15msppTMS amplitudes are expressed as a percentage of single-pulse TMS MEP amplitudes (reflecting cortical facilitation %;see Table II), there was no effect of group (F1,33=0.81;p=0.453), or laterality, (F1,33=1.26; p=0.270) and no group–laterality interaction (F2,33=0.10; p=0.903).

DISCUSSIONMotor dysfunction is apparent in both HFA and Asperger dis-order, yet we have relatively little understanding of the motorcortical aspects of these disorders, and much controversysurrounds their separation in DSM-IV Text Revision (DSM-IV-TR).2 Reduced cortical inhibition during ppTMS in autismstrongly suggests dysfunction of GABAergic circuits (specifi-cally, impaired activity at GABAA receptors17) and supportsthe hypothesis that this disorder is associated with reducedcontrol of the basal ganglia ⁄ frontostriatal motor loop.20 Thisis consistent with DSM-IV-TR accounts of motor dysfunctionin autism (including stereotyped body movements, whichseem to imply a deficit in inhibitory control), and empiricalstudies of the control of motor activity (including gait vari-ability6) and motor-related brain activity.10–12 By contrast,cortical inhibition appears to be intact in Asperger disorder,suggesting that motor abnormalities (including clumsiness,reduced coordination, and impaired gait) may not be attribut-able to reduced motor cortical control. Cortical facilitation,largely reflecting glutamatergic processes,18 appears largelyundifferentiated between HFA and Asperger disorder (andgenerally similar to neurotypical individuals, with the excep-tion of right hemisphere resting motor threshold), despiteevidence for cortical glutamatergic dysfunction in autism.21.

These findings represent perhaps the first direct functionalbrain evidence for a neurobiological dissociation between aut-ism and Asperger disorder, and one presumably based onGABAergic function. Asperger disorder is frequently consid-ered a ‘mild’ form of autism because of similarities in clinicalpresentation, but these findings instead provide support forthe current clinically based distinction made in DSM-IV-TR.2

Based on these findings, it is conceivable that Theoret et al.16

did not detect differences in cortical inhibition between adultswith autism spectrum disorder and comparison individualsbecause they were combining a group with normal (i.e. Asper-ger disorder) and abnormal (i.e. autism) cortical inhibition,which when combined would result in a ‘normal’ pattern offindings.

Although providing a more specific pathophysiologicalaccount of motor dysfunction, these results are also consistentwith genetic and neurochemical research suggesting impairedGABAergic function in autism.14,15 Widespread abnormalities

in GABAA receptor activity was recently demonstrated in post-mortem brain tissue samples from individuals with autism,with affected regions including parietal and frontal corticesand the cerebellum.22 These findings are also consistent withneural connectivity studies suggesting a reduction of inhibitorycells in autism,23,24 which operate as ‘GABA-gated pacemakersfor neocortical oscillatory activity’ (Wilson et al.24 p 195).

Reduced cortical inhibition in the motor cortex may under-lie some of the disorder-specific movement abnormalities seenin autism (e.g. an inability to anticipate when a movement isrequired25), but such cortical inhibitory deficits could alsocontribute to the specific executive function deficits that havebeen shown for autism (e.g. lower-level repetitive behaviouralpatterns), but not Asperger disorder. For example, repetitivebehaviours in autism may result from impaired inhibition,26

whereas such behaviour in Asperger disorder could result froma failure to ‘spontaneously generate novel behaviour withoutprompting’27 (p 843) (reflecting higher-level repetitive behav-iours, including circumscribed interests), although thishypothesis requires further investigation (see Rinehart et al.5

for a review).This study is limited by a relatively small sample size, and

its results should, therefore, be considered preliminary. A fail-ure to include clinical measures to examine in relation to corti-cal inhibition is also a limitation and would have been ofadditional value. It might also be argued that standardizedclinical measures should also have been included to differenti-ate HFA from Asperger disorder; however, we took theutmost care in reaching a diagnosis strictly according toDSM-IV criteria. Several HFA participants were receivinglow-dose medication, but evidence suggests that the effect ofthese medications on GABAergic activity, if any, would bepositive (i.e. increasing GABA-mediated cortical inhibition28).Theoretically, therefore, these medications limit our ability todetect GABAergic abnormalities in autism. Future investiga-tions in this area should broaden the scope of TMS paradigmsto include 100ms interstimulus interval ppTMS and a corticalsilent period, both thought to involve GABAB function. Thisis particularly crucial given recent evidence of post-mortemGABAB abnormalities in autism.10 Larger sample sizes willalso allow further exploration of cortical excitability and asso-ciations with clinical characteristics (e.g. repetitive behaviours,motor dysfunction), which should be measured in future stud-ies. Nevertheless, the current findings represent a promisingnew direction for in vivo research elucidating the functionalneuropathophysiology of autism and Asperger disorder.

ACKNOWLEDGEMENTSThe authors thank Dr Robin Laycock, Dr Sally Herring, and Mrs

Hayley Kennedy for their assistance with data collection, and are

extremely grateful to Ms Pamela Williams, Mr Dennis Freeman, and

Wesley College Melbourne for assistance with participant recruit-

ment. Funding was provided by Monash University (Small Grant

Scheme) and the Cure Autism Now Foundation (Treatment-related

Grant). Equipment funding was provided in part by Neurosciences

Victoria (Clinical Neurobiology of Psychiatry Platform). PGE was

supported by a NARSAD Young Investigator Award.

e182 Developmental Medicine & Child Neurology 2010, 52: e179–e183

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TMS in Austism and Asperger Disorder Peter G Enticott et al. e183