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Using transcranial magnetic stimulation to investigate

the cortical origins of motor overflow: a study inschizophrenia and healthy controls

K A T E E . H O Y 1,2*, N E L L I E G E O R G I O U-K A R I S T I A N I S 2 , R O B I N L A Y C O C K 1,3

A N D P A U L B. F I T Z G E R A L D 1

1 Alfred Psychiatry Research Centre, The Alfred and Monash University School of Psychology, Psychiatryand Psychological Medicine, Melbourne, Australia ; 2 Experimental Neuropsychology Research Unit,

School of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton, Victoria,Australia ; 3 School of Psychological Science, La Trobe University, Bundoora, Victoria, Australia

ABSTRACT

Background. Previous research has confirmed the presence of increased motor overflow in schizo-phrenia. There are essentially two theories regarding the cortical origins of overflow. Recent re-search suggests that both may be correct, and that the cortical origin of overflow is highlydependent upon the population in which it presents. Motor overflow, due to an abnormally activeipsilateral corticospinal tract, may indicate a potentially severe brain abnormality arising in earlydevelopment. In contrast, bilaterally active corticospinal tracts accounting for overflow probablyrepresent a naturally occurring response during fatiguing contractions.

Method. The cortical origins of motor overflow in 20 participants with schizophrenia and 20normal controls were investigated through the use of a number of transcranial magnetic stimulation

(TMS) protocols.

Results. Each of the experimental protocols employed independently supported the contention thatoverflow was originating in the hemisphere contralateral to the involuntary movement.

Conclusions. Results indicated that the origins of overflow in schizophrenia are the same as thoseseen in the normal control group, i.e. motor overflow seems to be due to the presence of bilaterallyactive corticospinal tracts. Potential explanations for greater motor overflow seen in schizophreniaare discussed.

INTRODUCTION

Motor overflow refers to involuntary movementthat sometimes accompanies voluntary move-ment; it is exhibited in various populations andunder certain conditions (Armatas et al. 1994).Overflow presenting in children before the ageof 10 years has been a consistent finding (Cohenet al. 1967; Wolff et al. 1983; Reitz & Muller,1998; Mayston et al. 1999), while overflow in

adults is usually only seen under effortful con-ditions and during fatiguing voluntary contrac-tions (Armatas et al. 1996; Aranyi & Rosler,2002; Bodwell et al. 2003). Where uninduced orclinical motor overflow persists into adulthoodin the presence of a congenital neurologicaldeficit it is termed congenital mirror movement(CMM). CMMs are essentially defined asoccurring as a manifestation of a hereditarydisorder or in the presence of some otherneurological disorder either congenital oracquired (Schott & Wyke, 1981). Finally, there

is some evidence that overflow represents aneurological soft sign (NSS) in a number of

* Address for correspondence to: Ms Kate Hoy, AlfredPsychiatry Research Centre, The Alfred and Monash University

School of Psychology, Psychiatry and Psychological Medicine,Commercial Rd, Melbourne 3004.

(Email: k.hoy@alfred.org.au)

Psychological Medicine, Page 1 of 14. f 2007 Cambridge University Pressdoi:10.1017/S0033291706009810 Printed in the United Kingdom

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psychiatric and neurological disorders. Thepresence of exaggerated motor overflow in dis-orders such as schizophrenia, Huntingtonsdisease (HD), and Parkinsons disease (PD) hasbeen noted in a number of studies (Meyer, 1942;

Hertzig & Birch, 1966; Marcus et al. 1985;Rogers, 1985; Vrtunski et al. 1989; Ismail et al.1998; Neumann & Walker, 1999; van denBerg et al. 2000; Vidal et al. 2003; Georgiou-Karistianis et al. 2004; Hoy et al. 2004 b). Theorigins of motor overflow appear to be depen-dent upon the population exhibiting the invol-untary movement. Uninduced or clinical motoroverflow persisting into adulthood in conjunc-tion with a congenital neurological deficit (i.e.CMMs) appears to be predominately due to an

active ipsilateral corticospinal tract (Hoy et al.2004a). According to the ipsilateral activationtheory (IAT) of motor overflow, subjects dis-playing this form of overflow have a function-ally active ipsilateral corticospinal projection,whereby movements produced by the con-tralateral hemisphere result in a degree of ipsi-lateral movement (see Appendix Fig. 1 in onlineversion of the paper). While the IAT appearsto be the principal mechanism of overflow inCMM, it is an unlikely explanation for the

presence of overflow in other adult populationsas there is considerable evidence that in adultsthe ipsilateral tract predominantly innervatesproximal and axial muscles (Brinkman &Kuypers, 1972; Ziemann et al. 1999). Therefore,according to IAT, only the presence of abnor-mal ipsilateral corticospinal tracts would ac-count for the production of motor overflow indistal muscles. Such tracts have been identifiedin patients with CMMs in the presence ofKlippelFiel syndrome, Kallmanns syndrome,and/or severe hemispheric lesions (Konagayaet al. 1990; Kanouchi et al. 1997; Maystonet al. 1997, 2001). No such syndromes or lesionsare known to be associated with schizophrenia.Therefore, the increased motor overflow seenin this patient group would most likely beexplained by the alternate theory of motoroverflow ; that is bilateral activation theory(BAT) (see Appendix Fig. 1 in online version).

Transcallosal facilitation (TCF) and trans-callosal inhibition (TCI), the processes thoughtto occur during unilateral voluntary move-

ments, are central to the BAT of motor over-flow. Initially during voluntary movement there

appears to be, via transcallosal mechanisms,an early facilitation of the contralateral motorcortex (Ferbert et al. 1992; Meyer et al. 1995;Salerno & Georgesco, 1996 ; Hanajima et al.2001). When the degree or spread of the cortical

activation increases, this facilitation appearsto be replaced by inhibition (Ferbert et al. 1992;Ugawa et al . 1993; Salerno & Georgesco,1996; Meyer et al. 1998; Mayston et al. 1999;Hanajima et al. 2001). This conscription of TCIis believed to occur as increasingly complexor forceful movements will be detrimentallyaffected by bilateral activity; inhibition actsto therefore ensure unilateral movements inthese situations. There is also evidence that ifthe unilateral voluntary contraction, and thus

the cortical activation, continues to increase instrength, inhibition is itself replaced by TCF(Hess et al. 1986; Meyer et al. 1995; Stedmanet al. 1998; Muellbacher et al. 2000). Therefore,there are two possible scenarios which may leadto the bilateral activation of corticospinal tractsduring voluntary movement: (1) lack of TCIpreventing suppression of the initial period ofTCF, and/or (2) strong voluntary contractionsleading to secondary facilitation, throughincreased TCF or decreased TCI.

Therefore, according to BAT the ability of thecortex ipsilateral to voluntary movement tomediate facilitatory influences (both inter- andintra-cortical) will influence the productionof motor overflow. Mediation of such processesrequires effective inhibitory control both withinand between motor cortices (Hammond et al.2004). Schizophrenia has been repeatedly as-sociated with various cortical inhibitiondeficits, including impaired sensorimotor gating(Swerdlow & Koob, 1987), reduced inhibitionof event-related potentials (Griffith et al. 1995)and most recently impaired motor cortical inhi-bition (Puri et al . 1996; Boroojerdi et al .2000; Daskalakis et al. 2002; Fitzgerald et al.2002b, c). Motor abnormalities in schizo-phrenia, including in coordination, agitationand catatonia, are believed to be a consequenceof disruption of cortical inhibitory neuro-transmission (Walker, 1994). A number oftranscranial magnetic simulation (TMS) studies,allowing direct investigation of motor corticalinhibition, have revealed deficits in both intra-

and inter-cortical inhibition in patients withschizophrenia (Puri et al. 1996 ; Boroojerdi et al.

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2000; Daskalakis et al. 2002; Fitzgerald et al.2002 b, c). Therefore, theoretically, the presenceof increased motor overflow in schizophreniacould be explained by bilaterally active cortico-spinal tracts as a consequence of impaired

cortical inhibition. Despite these suggestions,currently no studies have demonstrated exper-imentally that BAT is responsible for excessiveoverflow in schizophrenia.

TMS is a non-invasive method of stimulatingthe brain (Fitzgerald et al. 2002a). TMS in-volves passing a brief high-current alternatingelectric pulse through an insulated coil, whichinduces a rapidly changing magnetic field; thecoil is placed against the scalp and the magneticfield passes through the skull, inducing an

electrical current in the cortex (Geddes, 1991).There are a number of properties of TMS whichmake it ideal for investigating the corticalorigins of motor overflow. Applying TMS to aninactive motor cortex will induce activity (i.e. amotor-evoked potential; MEP), while stimu-lation to an active motor cortex will initiallyinduce a facilitated response followed by a sup-pression of tonic activity (i.e. a silent period)(Thompson et al. 1991). These central principlesof motor cortex stimulation formed the theor-

etical basis of the experimental paradigms usedin the current study (see Appendix Fig. 2 in on-line version). Unilateral application of TMS tothe motor cortex and bilateral recording of re-sultant MEPs is a commonly used methodologyto establish the presence of active ipsilateralcorticospinal tracts (Konagaya et al . 1990;Kanouchi et al . 1997; Muller et al . 1997;Mayston et al. 1999; Maegaki et al. 2002). Thepresence of a single contralateral MEP is theexpected finding, while bilateral MEPs (at simi-lar or slightly shorter latencies) would indicatean active ipsilateral corticospinal tract. Theinduction of these has only been found in adultpopulations to date in the presence of CMMs(Hoy et al. 2004 a). The second paradigm used inthis study involves applying TMS to the hemi-sphere contralateral to voluntary movementduring the induction of motor overflow.As previously stated, TMS during an activemovement will initially induce a facilitated MEPcontralateral to the site of stimulation, followedby momentary inhibition of tonic contraction

as well as TCI resulting in inhibition of anyipsilateral motor activity. Therefore, in this

paradigm stimulation will induce a facilitatedcontralateral MEP (cMEP) during voluntarymovement and an ipsilateral silent period (iSP)of the motor overflow. Measurement of thelatencies of these responses will provide an in-

dication of whether or not overflow is originat-ing in the same hemisphere as the voluntarymovement. If the cMEP and the iSP occur atessentially the same time this would suggest thatoverflow is originating in the same hemisphereas voluntary movement, since simultaneous re-sponses to stimulation would not allow enoughtime for the transcallosal conduction of inhi-bition necessary for the generation of the iSP ifoverflow originated in the opposite hemisphereto that of voluntary movement. If the iSP occurs

only after enough time to allow for the trans-callosal conduction of inhibition (i.e. y12 ms)(Muller et al. 1997), this would then providesupport for the theory that overflow is indeedoriginating in the hemisphere opposite to that ofvoluntary movement. Finally, the presence ofcortical activation can be inferred via the sizeof the cMEP produced following unilateralstimulation, whereby a facilitated MEP in-dicates cortical activation. Therefore in thefinal paradigm, during overflow induction, TMS

is applied to the hemisphere contralateral tooverflow production (and the site of proposedexcessive overflow-related activation), and theresultant MEP is measured. TMS is then appliedto the hemisphere opposite a voluntary con-traction (made to a similar degree to the over-flow produced), and the resultant MEP is againmeasured. By comparing the sizes of theseMEPs, the presence or absence of cortical acti-vation can be inferred. If the MEPs are ap-proximately the same size this would indicatebilateral cortical activation during overflow.However, if the MEP produced following TMSduring motor overflow was not facilitated tothe same degree this would indicate a lack ofcontralateral cortical activation. In addition toexamining facilitated MEPs, the above para-digm also allows investigation of silent periodsinduced during motor overflow production.Measurement of these silent periods may pro-vide information regarding the ability of thehemisphere contralateral to voluntary move-ment to mediate transcallosal processes, a

central tenet of the BAT of motor overflow.A significant discrepancy in the magnitude of

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the silent periods produced by patients andcontrols during overflow could indicate dis-crepant abilities to inhibit TCF resultingfrom voluntary movement; this may contributeto the greater overflow seen in this patientgroup.

While there is considerable evidence ofgreater overflow in people with schizophrenia,direct experimental investigation of its originsis lacking. The increased overflow seen inschizophrenia is unlikely to be due to an activeipsilateral corticospinal tract, as the instanceswhere this is the case have generally involvedmore gross structural neuropathologies. Theor-etically, increased overflow in schizophreniais likely to be due bilaterally active corticospinaltracts. The current study aims to provide ex-

perimental evidence for this contention.

METHODS

Participants

The study included 20 out-patients with adiagnosis of schizophrenia or schizoaffectivedisorder and 20 controls. All participants wererecruited via local area newspaper advertise-ments. The two groups differed significantlyin age [t(38)=3.95, p0.05]. Patient diagnoseswere confirmed on the Mini International

Neuropsychiatric Interview (MINI; Sheehanet al. 1998) and clinical interview. Informedconsent was obtained from all participants.Patients were only included if they were eitherunmedicated, or on types or doses of anti-

psychotic medication unlikely to occupy dopa-mine D2 receptors to a degree that wouldproduce direct effects in nigrostriatal pathwayseffecting motor activity (i.e. low occupancyatypical antipsychotics or higher occupancydrugs at low dose). Three patients were notreceiving antipsychotic medication. Of the pa-tients currently receiving antipsychotics, sevenwere on olanzapine (doses ranged from 10 to30 mg), three were on clozapine (doses rangedfrom 350 to 850 mg), six were on amisulpride

(doses ranging from 100 to 400 mg) ; the re-maining medicated patients were on apripipra-zole (30 mg), chloropromazine (100 mg), andquetiapine (75 mg). Five patients were receivingan antidepressant (venlafaxine, and fluoxetine)and three a mood stabilizer (sodium valproate).(See Table 1 for demographic data.)

Questionnaires

Both patients and controls were initially as-sessed on the MINI (Sheehan et al. 1998). The

MINI was designed as a brief structured clinicalinterview for the major Axis I psychiatric dis-orders in DSM-IV and ICD-10. In the currentstudy the MINI was used to confirm patientdiagnosis and as a psychopathology screen forcontrols. Patients then underwent a series ofclinical interviews in order to determine theirsymptom severity. The Positive and NegativeSyndrome Scale (PANSS) interview was con-ducted with all patients (Kay et al. 1987). TheMontgomeryAsberg Depression Rating Scale(MADRS) (Montgomery & Asberg, 1979) andthe Beck Depression Inventory (BDI) were alsoadministered to patients, in order to investigatedepressive symptomology. The SimpsonAngusScale (SAS; Simpson & Angus, 1970) andthe Abnormal Involuntary Movement Scale(AIMS) assessed the immediate presence andseverity of any extrapyramidal side-effects.Patients were to be excluded if they exhibitedsignificant extrapyramidal side-effects, definedby an overall SAS score >5 and/or an AIMSscore >10. None were excluded on this basis,

however. (See Table 1 for psychopathologydata.)

Table 1. Sample demographics and psycho-pathology measures ; means and standard devi-ations (S.D.) for patients with schizophrenia andcontrols

Patients Controls

SignificanceMean S.D. Mean S.D.

Age (yr) 42.21 8.92 30.00 1.95 SignificantSex (M/F) 9/11 6/14 Not significantMADRS 12.76 1.97BDI 12.68 2.34PANSS

Total 55.32 2.63General 28.47 1.24Positive 13.21 1.01Negative 13.63 1.01

SAS 2.68 0.46AIMS 4.36 0.85

MADRS, MontgomeryAsberg Depression Rating Scale; BDI,Beck Depression Inventory; PANSS, Positive and NegativeSyndrome Scale; SAS, SimpsonAngus Scale; AIMS, AbnormalInvoluntary Movement Scale.

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Apparatus

Isometric force recording

Isometric force was recorded using two linearvariable differential transformer (LVDT) units

(Lucas Schaevitz model FTD-G-5K), whichproduce measures of absolute force (measuredin g wt). Participants were required to sustaineither a maximum voluntary contraction or aspecific target force depending on the require-ments of the individual experiment. The LVDTwas connected to a laptop with an in-houseprogram, designed specifically for the currentstudy, which provided participants with a real-time force display and thus visual feedback.

Electromyographic (EMG) recordings

EMG was recorded bilaterally from the abduc-tor digiti minimi (ADM) muscle using self-adhesive electrodes. One electrode was placedover the ADM muscle bulk and another on thedorsal aspect of the small metacarpophalangeal

joint. An earth electrode was placed on themid-forearm. All EMG signals were amplifiedand filtered (bandpass 10 Hz2.4 kHz). Theywere sampled (rate 10 Hz) using a Digidata1320A Data Acquisition board and PLCAMP8.0 software (Axon Technologies, Melbourne,

Australia).

TMS

Participants were seated in a reclining chair witha headrest allowing for stabilization of the headthroughout the procedures. Focal TMS wasadministered with a figure-of-eight coil (diam-eter of each wing 70 mm, peak magnetic field2.2 T) using a Magstim 200 magnetic stimulator(Magstim Co., Whitland, Dyfed, UK). The coilwas held tangential to the scalp with the midline

at 45 degrees. The current flow in the junction ofthe figure-of-eight coil was anteriorposteriorproducing posterioranterior flow in the cortexperpendicular to the line of the central sulcus.All subjects were tested according to the fol-lowing protocol.

Procedure

Resting motor threshold (RMT)

The coil was placed on the scalp at the estimatedposition of the motor cortex (5 cm lateral to and

2 cm anterior to the vertex). Stimulation wasprovided with an intensity that produced a

consistent motor response in the ADM muscleand the coil moved until the position was

located that produced the largest MEP responseat this intensity. This position was marked andused throughout the experimental procedure.The RMT was then determined with the ADMmuscle completely at rest (monitored with con-tinuous EMG recording). The RMT was de-fined as the minimum stimulator intensity thatevoked a peakpeak amplitude MEP of>50 mVin at least three out of five consecutive trials.

Experiment 1 : Unilateral stimulation ; bilateralMEP recording

The participant was instructed to remain com-pletely at rest (monitored with continuous EMGrecording) whilst stimulation was applied at afrequency of 0.2 Hz. TMS was applied in asingle run of 10 stimulations. The stimulusintensity was set at 140% of the RMT. EMGwas recorded bilaterally for the entire durationof the experiment. The magnitude of the cMEPwas calculated as the peakpeak amplitude ofthe response in the hand contralateral to thehemisphere being stimulated, while the iMEPwas defined as the peakpeak amplitude of anyresponse occurring at the same time-point in theipsilateral hand.

Experiment 2 : Measuring latencies of cMEPsand iSPs during motor overflow production

Participants were asked to perform a maximumvoluntary contraction using either their left orright ADM muscle. Muscle activity in bothhands was monitored using EMG. When theparticipant began to exhibit overflow (i.e.

defined as an EMG response in the passivehand) 10 single TMS pulses were applied at a

Table 2. Means and standard deviations (S.D.)of resting motor thresholds for patients withschizophrenia and controls

Group

Session 1 Session 2

Right Left Right Left

PatientsMean 46.09 44.72 43.63 45.09S.D. 11.32 8.83 10.83 9.33

ControlsMean 45.63 46.27 46.45 46.36S.D. 8.72 8.18 9.19 7.18

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frequency of 0.2 Hz. The stimulus intensity wasset at 140% of the RMT. EMG was recordedbilaterally for the entire duration of the exper-iment. Measurements were subsequently madeoffline. The latency of the cMEP was calculatedas the time from stimulation to the onset of theMEP. The onset of the iSP was defined as thetime- point where the EMG trace fell persist-ently below the baseline. The iSP latency wascalculated as the time from stimulation to theonset of the iSP.

Experiment 3 : Facilitated MEPs and silentperiods during voluntary movement and motoroverflow

Participants were asked to perform a maximum

voluntary contraction using either their leftor right ADM muscle. Muscle activity in both

hands was monitored using EMG. When theparticipant began to exhibit overflow (i.e. de-fined as a distinct EMG response in the passivehand) single TMS pulses were applied at a fre-quency of 0.2 Hz to the hemisphere contralateralto the passive hand. The stimulus intensity wasset at 140% of the RMT.

After a period of rest, participants were thenrequired to make a voluntary contraction ofan intensity equivalent to the motor overflowproduced in the passive hand. Stimulation was

then applied to the hemisphere contralateral tothe passive hand at a frequency of 0.2 Hz. TMSwas applied in a single run of 10 stimulations.The stimulus intensity was set at 140% of theRMT.

The magnitudes of the cMEPs were cal-culated as the peakpeak amplitude of theresponse in the hand contralateral to the hemi-sphere being stimulated. In addition, the mag-nitude of the silent period produced duringmotor overflow was calculated for each group.The cortical silent period duration was thetime from the MEP onset to the return of anyvoluntary EMG activity.

A series of repeated-measures ANOVAswere used to analyse the data. All analysis wascompleted using SPSS version 14 (SPSS Inc.,Chicago, IL, USA).

RESULTS

RMTs

The results did not reveal a significant main

effect of group, session or hemisphere (seeTable 2).

Table 4. Means, and standard deviations (S.D.),for patients and controls, of the latencies for theiSP and the cMEP during motor overflow pro-duction (measured in ms)

Group

Left hemispherestimulation

Right hemispherestimulation

cMEP iSP cMEP ISP

PatientsMean 23.318 41.204 24.886 45.386

S.D. 3.653 3

.485 4

.29 7

.72

ControlsMean 27.818 40.250 26.523 42.045S.D. 4.451 7.973 4.73 6.65

cMEP, Contralateral motor-evoked potential; iSP, ipsilateral si-lent period.

Table 5. Means, and standard deviations (S.D.),for patients and controls, of the facilitated motor-evoked potentials during voluntary movement andmotor overflow (measured in mV)

Group

Left hemispherestimulation

Right hemispherestimulation

Voluntary Overflow Voluntary Overflow

PatientsMean 1.423 1.539 1.443 1.463S.D. 1.040 0.9913 0.833 0.820

ControlsMean 1.728 1.767 1.443 1.462S.D. 0.661 0.689 0.833 0.820

Table 3. Means, and standard deviations (S.D.),for patients with and controls, of bilateral MEPresponses following unilateral stimulation (mea-sured in mV)

Group

Left hemispherestimulation

Right hemispherestimulation

cMEP iMEP cMEP iMEP

PatientsMean 0.879 0.021 1.135 0.025S.D. 0.524 0.018 0.615 0.019

ControlsMean 0.940 0.013 0.773 0.018S.D. 0.735 0.011 0.535 0.023

cMEP, Contralateral motor-evoked potential ; iMEP, ipsilateralmotor-evoked potential.

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Experiment 1 : Unilateral stimulation, bilateralMEP recordings

All participants produced contralateral MEPsto stimulation, however, no significant ipsilat-eral responses were found (see Table 3).Therefore, there was a significant main effectof measure [F(1, 37)=174.361, p

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latencies. Finally, there was no significant dif-ference between MEP facilitation during volun-tary movement and during motor overflow,suggesting the presence of an active con-tralateral corticospinal tract in both instances.

Therefore, the current study indicates thatmotor overflow in patients and controls is due tobilaterally active corticospinal tracts; thus im-

plicating the BAT of motor overflow. Addition-ally, in a finding which has implications forelucidation of the specific processes by whichbilateral activation results in motor overflow,there was no significant difference in silentperiod duration during overflow betweenpatients and controls.

The lack of bilateral response to unilateral

stimulation was not an unexpected finding. Thepresence of bilateral MEPs is considered to bestrongly indicative of an active ipsilateral corti-cospinal tract (Konagaya et al. 1990; Kanouchiet al. 1997; Muller et al. 1997; Mayston et al.1999 ; Maegaki et al. 2002), and there is littleevidence that this is the case in either schizo-phrenia or normal adults. Support for thepresence of a fast conducting ipsilateral corti-cospinal tract has been found in children, how-ever, these direct projections are thought to be

gradually withdrawn during normal develop-ment (Carson, 2005). The vast majority of re-search examining motor overflow has focusedon distal muscles (i.e. hand and finger move-ments), yet there is considerable evidence thatin adults the ipsilateral tract predominantlyinnervates proximal muscles (Brinkman &Kuypers, 1972; Ziemann et al. 1999). As suchthe presence of active ipsilateral corticospinaltracts projecting distally in adults would beconsidered pathological. Such tracts have beenidentified in patients with CMMs in the presenceof KlippelFiel syndrome, Kallmanns syn-drome, and/or severe hemispheric lesions.Schizophrenia has not been associated with anysuch disorders and/or lesions. Therefore, thelack of an active ipsilateral corticospinal tractinnervating distal muscles, and the subsequentabsence of bilateral MEPs, in this population isnot unexpected. The IAT of motor overflow wasnot supported by this finding.

Stimulation of the hemisphere contralateralto voluntary movement during motor overflow

also failed to support an ipsilateral corticalorigin of overflow, and in doing so generated

some interesting findings. Comparison of thelatencies of responses following stimulation,that is cMEP during voluntary movement andiSP during motor overflow, revealed a signifi-cant delay between the onset of these measures

for both patients and controls. If the iSP hadoccurred at approximately the same time as thecMEP it could have been argued that the sup-pression of overflow was due to inhibition ofcortical activity in the same hemisphere respon-sible for the production of the cMEP (i.e. thehemisphere contralateral to the voluntarymovement); thus indicating an ipsilateral originfor motor overflow. However, the significantlylater onset of the iSP, on average 16.58 ms,suggests that the mechanism of inhibition was

in fact transcallosal. Transcallosal conductiontime has been estimated aty12 ms, allowing forthe TMS-induced inhibition to be transmitted,via the corpus callosum, to the contralateralhemisphere (Muller et al. 1997). Therefore thedelay of approximately 16 ms for the iSP onsetwould indicate that inhibition of the hemispherecontralateral to overflow was responsible forthe suppression of activity, indicating a con-tralateral cortical origin of motor overflow.

While both groups exhibited equivalent iSP

onset latencies, the patient group revealed asignificantly earlier cMEP onset than controlparticipants. This is an unexpected finding andits significance is unclear; a possible explanationis as follows. The earlier cMEP seen in patientscould be attributed to the cortical inhibitiondeficits which have been consistently reported inschizophrenia (Puri et al. 1996 ; Boroojerdi et al.2000; Daskalakis et al. 2002; Fitzgerald et al.2002b, c). Patients with schizophrenia may pro-duce an earlier cMEP due to reduced corticalexcitation requirements, that is when activetheir motor cortex is potentially more excit-able than that of controls. Therefore, the in-duction of the cMEP may occur more quickly inschizophrenia thus resulting in reduced cMEPlatency. The inhibition deficits in schizophreniamay also explain the subsequent catching upof the iSP response. According to BAT duringnormal voluntary movement there are a seriesof transcallosal processes whereby the activemotor cortex (i.e. the hemisphere contralateralto voluntary movement) is able to exert influ-

ence on the opposite hemisphere resulting in anet increase in activation (Hoy et al. 2004 a). In

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patients with schizophrenia this facilitation isproposed to be exacerbated, possibly due toinhibition deficits, and this is ultimately thoughtto be responsible for the increased motor over-flow seen in this group. The induction of the iSP

in the current study was thought to involve thetranscallosal transmission of inhibition fromthe active motor cortex to the hemispherecontralateral to the overflow production; ahigher degree of facilitation in this hemispherecould delay the induction of the iSP, potentiallyallowing the response to catch up withthe control group. While purely speculative innature these processes may explain the com-parative iSP latencies despite the significantlyearlier onset of cMEP in the patient group.

The final paradigm employed the premisethat when TMS is applied to an active cortex theresultant MEP is facilitated (Thompson et al.1991). Through the application of TMS to thehemisphere contralateral to voluntary move-ment and then to the hemisphere contralateralto motor overflow we were able to compare thedegree of facilitation in the responses. The lackof a significant difference in the facilitated MEPssuggests that in both instances the hemispherecontralateral to the movement (i.e. voluntary

movement and motor overflow) was active. Ifthe MEP induced during motor overflow wasnot facilitated, then one could have postulated alack of activity in the contralateral hemisphere.This was not the case, however, and theresults clearly implicate a common contralateralcortical origin for both normal voluntarymovement and motor overflow. This paradigmalso allowed investigation of the magnitude ofthe contralateral silent period produced duringmotor overflow. By measuring the duration ofthe silent period occurring during motor over-flow, we were able to more directly investigatethe ability of the cortex contralateral to volun-tary movement to mediate the transcallosalprocesses (i.e. facilitation) thought to resultin activation and thus overflow production.Patients with schizophrenia exhibited a shortersilent period duration than controls, butthis difference was not statistically significant.These results indicate that the ability of thecontralateral hemisphere to mediate incomingfacilitation alone may not account for the

greater overflow in schizophrenia. Therefore,it may be that significantly greater TCF or

reduced TCI, rather than deficient intra-corticalprocesses, contributes to the greater overflowseen in patients with schizophrenia.

There are a number of potential limitations tothe current research which need to be addressed.

It is not possible to entirely exclude the poten-tially confounding effect of antipsychoticmedication on the production of motor over-flow. However, this potential confound wasminimized by only including patients withoutsignificant extra-pyramidal side-effects. In ad-dition, medicated patients were on medicationor doses known to be associated with few motorside-effects (Anon, 1998 ; Anath et al. 2001;Glick et al. 2001). The effects of medication oncortical excitability as measured by TMS must

also be considered, and there have been a num-ber of studies which have directly investigatedthese effects. Ziemann et al. (1996) studied theeffect of a single oral dose of lorazepam onmotor cortical excitability in normal controls.They found no change with respect to measuresof resting and active motor thresholds, but theresults did indicate that lorazepam had someeffect on inhibitory processes. The cortical silentperiod duration was found to be prolonged fol-lowing drug administration, and corticocortical

inhibition was said to be increased while corti-cocortical facilitation was considerably sup-pressed (Ziemann et al. 1996). Daskalakis et al.(2002) found similar effects of antipsychoticmedication when investigating cortical inhi-bition deficits in schizophrenia. Unmedicatedpatients exhibited significant cortical inhibitiondeficits when compared to healthy controls,while medicated patients did not. It wasconcluded that antipsychotic medications mayactually act to increase cortical inhibition inpatients with schizophrenia (Daskalakis et al.2002). These investigations indicate that themedications appear to decrease motor corticalexcitability (through either suppression of fa-cilitation or enhancement of inhibition). Thesefindings further support the conclusions madein the current study motor overflow is beingproduced due to either an increase in facilitationor a decrease in inhibition resulting in bilateralactivation of contralateral corticospinal tracts.If medication was having the predicted effect ofincreasing inhibition, this makes the current

findings of greater activation more robust. Inaddition, a study directly investigating the

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effects of antipsychotic medication on the EMGresponses of thenar muscles to TMS of themotor cortex in schizophrenia found few medi-cation effects (Davey et al . 1997). Patientstaking antipsychotics showed equivalent cMEP

latencies, motor thresholds and total silentperiod durations to those exhibited by drug-naive patients. The only significant effect wasthe presence of an early component of weakersuppression of EMG activity in the silent periodof medication patients. Therefore, in light of thepotential effects of medication on motor corticalexcitability, the current findings indicatingbilaterally active corticospinal tracts in schizo-phrenia are considered to be particularly strong.Finally, the two groups differed significantly

in age. A number of studies investigating theeffects of age on TMS responses have largelyrevealed that in the elderly there is a tendencytowards hypoexcitability, or a decreased re-sponsiveness to TMS (Rossini et al . 1992;Oliviero et al. 2006). The older group in thecurrent study (mean age 42 years) is consider-ably younger than the defined elderly groupsin which these findings were reported, and infact the older group essentially exhibited op-posite findings showing increased cortical excit-

ability. Finally, a recent study by Wassermann(2002) examined the variation in response toTMS in the general population in a sample of151 individuals with an age range of 1876years. It was concluded that age was not directlyrelated to cortical excitability as measured viaMEP amplitudes (Wassermann, 2002). There-fore, it is felt that the significant difference in agedid not contribute to findings of the currentstudy.

Taken independently the results of these threeexperiments are suggestive of bilateral corticalactivation as the mechanism of motor overflow;however, when viewed as a series of confirma-tory findings they become considerably moreconvincing. The initial paradigm indicates thelack of an active ipsilateral corticospinal tract,the second experiment suggests that inhibitionof the activity in the hemisphere contralateralto the motor overflow production generatedthe iSP, and the final study revealed thatstimulation of the motor cortex contralateral tomovement (both voluntary movement and

motor overflow) produces comparative degreesof MEP facilitation. Taken together these

findings strongly indicate that the motor over-flow produced, in both patients and controls, isdue to the presence of bilaterally active cortico-spinal tracts. Therefore, increased overflow inpatients with schizophrenia does not seem to be

due to a pathological mechanism of overflowproduction per se. Overflow in schizophreniaappears to be produced via the same mechanismseen in adults under effort-induced conditions,but to a significantly greater degree. BATessentially posits that an imbalance in thetranscallosal inhibitory and excitatory processesinvolved in voluntary movement is responsiblefor motor overflow production; a more pro-nounced imbalance is likely to be responsible forthe greater overflow in schizophrenia.

ACKNOWLEDGEMENTS

This work was conducted as part of a doct-oral qualification through Monash University(K.H.), and all funds were provided by MonashUniversity.

DECLARATION OF INTEREST

None.

NOTE

Supplementary information accompanies thispaper on the Journals website (http://journals.cambridge.org).

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a

1. Ipsilateral Activation Theory of Motor

Overflow2. Bilateral Activation Theory of Motor

Overflow

Normal

Voluntary

Movement

Normal

Voluntary

Movement

Motor Overflow Motor Overflow

APPENDIX FIG. 1. Theories of Motor Overflow Production.a) The Ipsilateral Activation Theory (IAT) production theory proposes the presence of functionally active ipsilateral corticospinal projections(a), where movements produced by the contralateral hemisphere result in a degree of ipsilateral movement. b) The Bilateral Activation Theory(BAT) suggests that during voluntary movement disruption to transcallosal processes, TCI and TCF, results in bilateral activation of corti-cospinal tracts thus resulting in a degree of overflow.

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iMEP cMEPb

a

Experiment One

cMEP

f Normal VoluntaryMovement

Motor overflow

e Normal VoluntaryMovement

Motor overflow

Experiment Three

c

d cMEPiSP

Experiment Two

cMEPiSP

TCI

APPENDIX FIG. 2. TMS Experimental Protocols.The first panel depicts the potential findings from experiment one; a) following unilateral TMS stimulation a contralateral MEP is obtained

indicating the absence of an active ipsilateral corticospinal tract, alternatively b) following unilateral TMS stimulation bilateral MEPs areobtained indicating an active ipsilateral corticospinal tract. The middle panel indicates the possible findings from the second experiment; c) asignificant difference in the latency between the iSP and the facilitated cMEP would suggest bilateral activation was responsible for overflow,while d) the iSP and facilitated cMEP occurring at essentially the same time would suggest an ipsilateral origin of motor overflow. The finalpanel shows the alternative findings from experiment three; e) if TMS to the hemisphere contralateral to overflow production is able tofacilitated the resultant MEP to the same degree as TMS to the hemisphere contralateral to voluntary movement bilateral activation issupported, however f) if the MEP induced during motor overflow is not facilitated to the same degree as that induced during voluntarymovement then bilateral activation is not supported.

14 K. E. Hoy et al.