Psychological Medicine, Page 1 of 14. f 2007 Cambridge University Press doi:10.

1017/S0033291706009810 Printed in the United Kingdom

Using transcranial magnetic stimulation to investigate the cortical origins of motor overow : a study in schizophrenia 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 1 A N D P A U L B. F I T Z G E R A L D
1

Alfred Psychiatry Research Centre, The Alfred and Monash University School of Psychology, Psychiatry and 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 conrmed the presence of increased motor overow in schizophrenia. There are essentially two theories regarding the cortical origins of overow. Recent research suggests that both may be correct, and that the cortical origin of overow is highly dependent upon the population in which it presents. Motor overow, due to an abnormally active ipsilateral corticospinal tract, may indicate a potentially severe brain abnormality arising in early development. In contrast, bilaterally active corticospinal tracts accounting for overow probably represent a naturally occurring response during fatiguing contractions. Method. The cortical origins of motor overow in 20 participants with schizophrenia and 20 normal 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 that overow was originating in the hemisphere contralateral to the involuntary movement. Conclusions. Results indicated that the origins of overow in schizophrenia are the same as those seen in the normal control group, i.e. motor overow seems to be due to the presence of bilaterally active corticospinal tracts. Potential explanations for greater motor overow seen in schizophrenia are discussed.

INTRODUCTION Motor overow refers to involuntary movement that sometimes accompanies voluntary movement ; it is exhibited in various populations and under certain conditions (Armatas et al. 1994). Overow presenting in children before the age of 10 years has been a consistent nding (Cohen et al. 1967 ; Wol et al. 1983 ; Reitz & Muller, 1998 ; Mayston et al. 1999), while overow in
* Address for correspondence to : Ms Kate Hoy, Alfred Psychiatry Research Centre, The Alfred and Monash University School of Psychology, Psychiatry and Psychological Medicine, Commercial Rd, Melbourne 3004. (Email : k.hoy@alfred.org.au)

adults is usually only seen under eortful conditions and during fatiguing voluntary contractions (Armatas et al. 1996 ; Aranyi & Rosler, 2002; Bodwell et al. 2003). Where uninduced or clinical motor overow persists into adulthood in the presence of a congenital neurological decit it is termed congenital mirror movement (CMM). CMMs are essentially dened as occurring as a manifestation of a hereditary disorder or in the presence of some other neurological disorder either congenital or acquired (Schott & Wyke, 1981). Finally, there is some evidence that overow represents a neurological soft sign (NSS) in a number of
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psychiatric and neurological disorders. The presence of exaggerated motor overow in disorders such as schizophrenia, Huntingtons disease (HD), and Parkinsons disease (PD) has been 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 den Berg et al. 2000; Vidal et al. 2003; GeorgiouKaristianis et al. 2004 ; Hoy et al. 2004b). The origins of motor overow appear to be dependent upon the population exhibiting the involuntary movement. Uninduced or clinical motor overow persisting into adulthood in conjunction with a congenital neurological decit (i.e. CMMs) appears to be predominately due to an active ipsilateral corticospinal tract (Hoy et al. 2004 a). According to the ipsilateral activation theory (IAT) of motor overow, subjects displaying this form of overow have a functionally active ipsilateral corticospinal projection, whereby movements produced by the contralateral hemisphere result in a degree of ipsilateral movement (see Appendix Fig. 1 in online version of the paper). While the IAT appears to be the principal mechanism of overow in CMM, it is an unlikely explanation for the presence of overow in other adult populations as there is considerable evidence that in adults the ipsilateral tract predominantly innervates proximal and axial muscles (Brinkman & Kuypers, 1972; Ziemann et al. 1999). Therefore, according to IAT, only the presence of abnormal ipsilateral corticospinal tracts would account for the production of motor overow in distal muscles. Such tracts have been identied in patients with CMMs in the presence of KlippelFiel syndrome, Kallmanns syndrome, and/or severe hemispheric lesions (Konagaya et al. 1990 ; Kanouchi et al. 1997; Mayston et al. 1997, 2001). No such syndromes or lesions are known to be associated with schizophrenia. Therefore, the increased motor overow seen in this patient group would most likely be explained by the alternate theory of motor overow ; that is bilateral activation theory (BAT) (see Appendix Fig. 1 in online version). Transcallosal facilitation (TCF) and transcallosal inhibition (TCI), the processes thought to occur during unilateral voluntary movements, are central to the BAT of motor overow. Initially during voluntary movement there

appears to be, via transcallosal mechanisms, an early facilitation of the contralateral motor cortex (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 appears to 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 TCI is believed to occur as increasingly complex or forceful movements will be detrimentally aected by bilateral activity; inhibition acts to therefore ensure unilateral movements in these situations. There is also evidence that if the unilateral voluntary contraction, and thus the cortical activation, continues to increase in strength, inhibition is itself replaced by TCF (Hess et al. 1986 ; Meyer et al. 1995; Stedman et al. 1998; Muellbacher et al. 2000). Therefore, there are two possible scenarios which may lead to the bilateral activation of corticospinal tracts during voluntary movement : (1) lack of TCI preventing suppression of the initial period of TCF, and/or (2) strong voluntary contractions leading to secondary facilitation , through increased TCF or decreased TCI. Therefore, according to BAT the ability of the cortex ipsilateral to voluntary movement to mediate facilitatory inuences (both inter- and intra-cortical) will inuence the production of motor overow. Mediation of such processes requires eective inhibitory control both within and between motor cortices (Hammond et al. 2004). Schizophrenia has been repeatedly associated with various cortical inhibition decits, including impaired sensorimotor gating (Swerdlow & Koob, 1987), reduced inhibition of event-related potentials (Grith et al. 1995) and most recently impaired motor cortical inhibition (Puri et al. 1996 ; Boroojerdi et al. 2000 ; Daskalakis et al. 2002 ; Fitzgerald et al. 2002 b, c). Motor abnormalities in schizophrenia, including in coordination, agitation and catatonia, are believed to be a consequence of disruption of cortical inhibitory neurotransmission (Walker, 1994). A number of transcranial magnetic simulation (TMS) studies, allowing direct investigation of motor cortical inhibition, have revealed decits in both intraand inter-cortical inhibition in patients with schizophrenia (Puri et al. 1996 ; Boroojerdi et al.

Using TMS to investigate motor overow in schizophrenia

2000 ; Daskalakis et al. 2002 ; Fitzgerald et al. 2002 b, c). Therefore, theoretically, the presence of increased motor overow in schizophrenia could be explained by bilaterally active corticospinal tracts as a consequence of impaired cortical inhibition. Despite these suggestions, currently no studies have demonstrated experimentally that BAT is responsible for excessive overow in schizophrenia. TMS is a non-invasive method of stimulating the brain (Fitzgerald et al. 2002 a). TMS involves passing a brief high-current alternating electric pulse through an insulated coil, which induces a rapidly changing magnetic eld ; the coil is placed against the scalp and the magnetic eld passes through the skull, inducing an electrical current in the cortex (Geddes, 1991). There are a number of properties of TMS which make it ideal for investigating the cortical origins of motor overow. Applying TMS to an inactive motor cortex will induce activity (i.e. a motor-evoked potential ; MEP), while stimulation to an active motor cortex will initially induce a facilitated response followed by a suppression of tonic activity (i.e. a silent period) (Thompson et al. 1991). These central principles of motor cortex stimulation formed the theoretical basis of the experimental paradigms used in the current study (see Appendix Fig. 2 in online version). Unilateral application of TMS to the motor cortex and bilateral recording of resultant MEPs is a commonly used methodology to establish the presence of active ipsilateral corticospinal tracts (Konagaya et al. 1990; Kanouchi et al. 1997; Muller et al. 1997; Mayston et al. 1999 ; Maegaki et al. 2002). The presence of a single contralateral MEP is the expected nding, while bilateral MEPs (at similar or slightly shorter latencies) would indicate an active ipsilateral corticospinal tract. The induction of these has only been found in adult populations to date in the presence of CMMs (Hoy et al. 2004 a). The second paradigm used in this study involves applying TMS to the hemisphere contralateral to voluntary movement during the induction of motor overow. As previously stated, TMS during an active movement will initially induce a facilitated MEP contralateral to the site of stimulation, followed by momentary inhibition of tonic contraction as well as TCI resulting in inhibition of any ipsilateral motor activity. Therefore, in this

paradigm stimulation will induce a facilitated contralateral MEP (cMEP) during voluntary movement and an ipsilateral silent period (iSP) of the motor overow. Measurement of the latencies of these responses will provide an indication of whether or not overow is originating in the same hemisphere as the voluntary movement. If the cMEP and the iSP occur at essentially the same time this would suggest that overow is originating in the same hemisphere as voluntary movement, since simultaneous responses to stimulation would not allow enough time for the transcallosal conduction of inhibition necessary for the generation of the iSP if overow originated in the opposite hemisphere to that of voluntary movement. If the iSP occurs only after enough time to allow for the transcallosal conduction of inhibition (i.e. y12 ms) (Muller et al. 1997), this would then provide support for the theory that overow is indeed originating in the hemisphere opposite to that of voluntary movement. Finally, the presence of cortical activation can be inferred via the size of the cMEP produced following unilateral stimulation, whereby a facilitated MEP indicates cortical activation. Therefore in the nal paradigm, during overow induction, TMS is applied to the hemisphere contralateral to overow production (and the site of proposed excessive overow-related activation), and the resultant MEP is measured. TMS is then applied to the hemisphere opposite a voluntary contraction (made to a similar degree to the overow produced), and the resultant MEP is again measured. By comparing the sizes of these MEPs, the presence or absence of cortical activation can be inferred. If the MEPs are approximately the same size this would indicate bilateral cortical activation during overow. However, if the MEP produced following TMS during motor overow was not facilitated to the same degree this would indicate a lack of contralateral cortical activation. In addition to examining facilitated MEPs, the above paradigm also allows investigation of silent periods induced during motor overow production. Measurement of these silent periods may provide information regarding the ability of the hemisphere contralateral to voluntary movement to mediate transcallosal processes, a central tenet of the BAT of motor overow. A signicant discrepancy in the magnitude of

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Table 1. Sample demographics and psychopathology measures ; means and standard deviations (S.D.) for patients with schizophrenia and controls
Patients Mean Age (yr) Sex (M/F) MADRS BDI PANSS Total General Positive Negative SAS AIMS 42.21 9/11 12.76 12.68 55.32 28.47 13.21 13.63 2.68 4.36
S.D.

Controls Mean 30.00 6/14

S.D.

Signicance Signicant Not signicant

8.92 1.97 2.34 2.63 1.24 1.01 1.01 0.46 0.85

1.95

MADRS, MontgomeryAsberg Depression Rating Scale ; BDI, Beck Depression Inventory ; PANSS, Positive and Negative Syndrome Scale ; SAS, SimpsonAngus Scale ; AIMS, Abnormal Involuntary Movement Scale.

the silent periods produced by patients and controls during overow could indicate discrepant abilities to inhibit TCF resulting from voluntary movement ; this may contribute to the greater overow seen in this patient group. While there is considerable evidence of greater overow in people with schizophrenia, direct experimental investigation of its origins is lacking. The increased overow seen in schizophrenia is unlikely to be due to an active ipsilateral corticospinal tract, as the instances where this is the case have generally involved more gross structural neuropathologies. Theoretically, increased overow in schizophrenia is likely to be due bilaterally active corticospinal tracts. The current study aims to provide experimental evidence for this contention. METHODS Participants The study included 20 out-patients with a diagnosis of schizophrenia or schizoaective disorder and 20 controls. All participants were recruited via local area newspaper advertisements. The two groups diered signicantly in age [t(38)=3.95, p<0.05], but not sex [ x2(1, 40)=0.96, p>0.05]. Patient diagnoses were conrmed on the Mini International

Neuropsychiatric Interview (MINI; Sheehan et al. 1998) and clinical interview. Informed consent was obtained from all participants. Patients were only included if they were either unmedicated, or on types or doses of antipsychotic medication unlikely to occupy dopamine D2 receptors to a degree that would produce direct eects in nigrostriatal pathways eecting motor activity (i.e. low occupancy atypical antipsychotics or higher occupancy drugs at low dose). Three patients were not receiving antipsychotic medication. Of the patients currently receiving antipsychotics, seven were on olanzapine (doses ranged from 10 to 30 mg), three were on clozapine (doses ranged from 350 to 850 mg), six were on amisulpride (doses ranging from 100 to 400 mg) ; the remaining medicated patients were on apripiprazole (30 mg), chloropromazine (100 mg), and quetiapine (75 mg). Five patients were receiving an antidepressant (venlafaxine, and uoxetine) and three a mood stabilizer (sodium valproate). (See Table 1 for demographic data.) Questionnaires Both patients and controls were initially assessed on the MINI (Sheehan et al. 1998). The MINI was designed as a brief structured clinical interview for the major Axis I psychiatric disorders in DSM-IV and ICD-10. In the current study the MINI was used to conrm patient diagnosis and as a psychopathology screen for controls. Patients then underwent a series of clinical interviews in order to determine their symptom severity. The Positive and Negative Syndrome Scale (PANSS) interview was conducted with all patients (Kay et al. 1987). The MontgomeryAsberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 1979) and the Beck Depression Inventory (BDI) were also administered to patients, in order to investigate depressive symptomology. The SimpsonAngus Scale (SAS ; Simpson & Angus, 1970) and the Abnormal Involuntary Movement Scale (AIMS) assessed the immediate presence and severity of any extrapyramidal side-eects. Patients were to be excluded if they exhibited signicant extrapyramidal side-eects, dened by an overall SAS score >5 and/or an AIMS score >10. None were excluded on this basis, however. (See Table 1 for psychopathology data.)

Using TMS to investigate motor overow in schizophrenia

Apparatus Isometric force recording Isometric force was recorded using two linear variable dierential transformer (LVDT) units (Lucas Schaevitz model FTD-G-5K), which produce measures of absolute force (measured in g wt). Participants were required to sustain either a maximum voluntary contraction or a specic target force depending on the requirements of the individual experiment. The LVDT was connected to a laptop with an in-house program, designed specically for the current study, which provided participants with a realtime force display and thus visual feedback. Electromyographic (EMG) recordings EMG was recorded bilaterally from the abductor digiti minimi (ADM) muscle using selfadhesive electrodes. One electrode was placed over the ADM muscle bulk and another on the dorsal aspect of the small metacarpophalangeal joint. An earth electrode was placed on the mid-forearm. All EMG signals were amplied and ltered (bandpass 10 Hz2.4 kHz). They were sampled (rate 10 Hz) using a Digidata 1320A Data Acquisition board and PLCAMP 8.0 software (Axon Technologies, Melbourne, Australia). TMS Participants were seated in a reclining chair with a headrest allowing for stabilization of the head throughout the procedures. Focal TMS was administered with a gure-of-eight coil (diameter of each wing 70 mm, peak magnetic eld 2.2 T) using a Magstim 200 magnetic stimulator (Magstim Co., Whitland, Dyfed, UK). The coil was held tangential to the scalp with the midline at 45 degrees. The current ow in the junction of the gure-of-eight coil was anteriorposterior producing posterioranterior ow in the cortex perpendicular to the line of the central sulcus. All subjects were tested according to the following protocol. Procedure Resting motor threshold (RMT ) The coil was placed on the scalp at the estimated position of the motor cortex (5 cm lateral to and 2 cm anterior to the vertex). Stimulation was provided with an intensity that produced a

Table 2. Means and standard deviations (S.D.) of resting motor thresholds for patients with schizophrenia and controls
Session 1 Group Patients Mean S.D. Controls Mean S.D. Right 46.09 11.32 45.63 8.72 Left 44.72 8.83 46.27 8.18 Session 2 Right 43.63 10.83 46.45 9.19 Left 45.09 9.33 46.36 7.18

consistent motor response in the ADM muscle and the coil moved until the position was located that produced the largest MEP response at this intensity. This position was marked and used throughout the experimental procedure. The RMT was then determined with the ADM muscle completely at rest (monitored with continuous EMG recording). The RMT was dened as the minimum stimulator intensity that evoked a peakpeak amplitude MEP of >50 mV in at least three out of ve consecutive trials. Experiment 1: Unilateral stimulation ; bilateral MEP recording The participant was instructed to remain completely at rest (monitored with continuous EMG recording) whilst stimulation was applied at a frequency of 0.2 Hz. TMS was applied in a single run of 10 stimulations. The stimulus intensity was set at 140% of the RMT. EMG was recorded bilaterally for the entire duration of the experiment. The magnitude of the cMEP was calculated as the peakpeak amplitude of the response in the hand contralateral to the hemisphere being stimulated, while the iMEP was dened as the peakpeak amplitude of any response occurring at the same time-point in the ipsilateral hand. Experiment 2: Measuring latencies of cMEPs and iSPs during motor overow production Participants were asked to perform a maximum voluntary contraction using either their left or right ADM muscle. Muscle activity in both hands was monitored using EMG. When the participant began to exhibit overow (i.e. dened as an EMG response in the passive hand) 10 single TMS pulses were applied at a

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Table 3. Means, and standard deviations (S.D.), for patients with and controls, of bilateral MEP responses following unilateral stimulation (measured in mV )
Left hemisphere stimulation Group Patients Mean S.D. Controls Mean S.D. cMEP 0.879 0.524 0.940 0.735 iMEP 0.021 0.018 0.013 0.011 Right hemisphere stimulation cMEP 1.135 0.615 0.773 0.535 iMEP 0.025 0.019 0.018 0.023

Table 5. Means, and standard deviations (S.D.), for patients and controls, of the facilitated motorevoked potentials during voluntary movement and motor overow (measured in mV)
Left hemisphere stimulation Group Patients Mean S.D. Controls Mean S.D. Voluntary 1.423 1.040 1.728 0.661 Overow 1.539 0.9913 1.767 0.689 Right hemisphere stimulation Voluntary 1.443 0.833 1.443 0.833 Overow 1.463 0.820 1.462 0.820

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

Table 4. Means, and standard deviations (S.D.), for patients and controls, of the latencies for the iSP and the cMEP during motor overow production (measured in ms)
Left hemisphere stimulation Group Patients Mean S.D. Controls Mean S.D. cMEP 23.318 3.653 27.818 4.451 iSP 41.204 3.485 40.250 7.973 Right hemisphere stimulation cMEP 24.886 4.29 26.523 4.73 ISP 45.386 7.72 42.045 6.65

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

frequency of 0.2 Hz. The stimulus intensity was set at 140% of the RMT. EMG was recorded bilaterally for the entire duration of the experiment. Measurements were subsequently made oine. The latency of the cMEP was calculated as the time from stimulation to the onset of the MEP. The onset of the iSP was dened as the time- point where the EMG trace fell persistently below the baseline. The iSP latency was calculated as the time from stimulation to the onset of the iSP. Experiment 3 : Facilitated MEPs and silent periods during voluntary movement and motor overow Participants were asked to perform a maximum voluntary contraction using either their left or right ADM muscle. Muscle activity in both

hands was monitored using EMG. When the participant began to exhibit overow (i.e. dened as a distinct EMG response in the passive hand) single TMS pulses were applied at a frequency of 0.2 Hz to the hemisphere contralateral to the passive hand. The stimulus intensity was set at 140% of the RMT. After a period of rest, participants were then required to make a voluntary contraction of an intensity equivalent to the motor overow produced in the passive hand. Stimulation was then applied to the hemisphere contralateral to the passive hand at a frequency of 0.2 Hz. TMS was applied in a single run of 10 stimulations. The stimulus intensity was set at 140 % of the RMT. The magnitudes of the cMEPs were calculated as the peakpeak amplitude of the response in the hand contralateral to the hemisphere being stimulated. In addition, the magnitude of the silent period produced during motor overow was calculated for each group. The cortical silent period duration was the time from the MEP onset to the return of any voluntary EMG activity. A series of repeated-measures ANOVAs were used to analyse the data. All analysis was completed using SPSS version 14 (SPSS Inc., Chicago, IL, USA). RESULTS RMTs The results did not reveal a signicant main eect of group, session or hemisphere (see Table 2).

Using TMS to investigate motor overow in schizophrenia

Table 6. Means, and standard deviations (S.D.), for patients and controls, of the duration of contralateral silent periods during motor overow (measured in ms)
Group Patients Mean S.D. Controls Mean S.D. Left hemisphere stimulation 168.33 27.73 175.68 31.28 Right hemisphere stimulation 166.50 29.92 178.07 33.19

4500

4000 Latency (ms)

3500

3000

Experiment 1: Unilateral stimulation, bilateral MEP recordings All participants produced contralateral MEPs to stimulation, however, no signicant ipsilateral responses were found (see Table 3). Therefore, there was a signicant main eect of measure [F(1, 37)=174.361, p<0.01] ; the contralateral MEPs (mean=0.932) were signicantly greater than the ipsilateral response (mean=0.19). These results are highly suggestive of an inactive ipsilateral tract in both groups. Experiment 2: Latency dierences Data was available from 19 patients and 18 controls for analysis. Results revealed a signicant overall dierence between the onset latency of the cMEP and that of the iSP [F(1, 20)= 335.17, p<0.00] ; the latency of the iSP was signicantly later (mean=42.22) than the contralateral response (mean=25.64) (see Table 4). The mean dierence in latency (16.58 ms) indicates that overow was probably suppressed via inter-hemispheric inhibition in both groups. There was also a grouprmeasure interaction [F(1, 20)=3.06, p<0.01], explaining 29.3 % of the variance. Patients exhibited a signicantly earlier cMEP than controls, resulting in a greater latency dierence overall (see Fig. 1). Experiment 3: Facilitated MEPs and silent periods Neither patients nor controls showed a signicant dierence between MEPs facilitated during voluntary movement and MEPs facilitated during motor overow (see Table 5). The duration of the contralateral silent period occurring

2500 cMEP iSP

FIG. 1. Contralateral motor-evoked potential (cMEP) and ipsilateral silent period (iSP) latencies as a function of group. , Control ; , patient.

following stimulation during motor overow also failed to reveal any signicant dierences (see Table 6). CONCLUSIONS The results of the current study consistently implicate bilaterally active corticospinal tracts in the production of motor overow, in both patients with schizophrenia and controls. All three experiments independently support the contention that overow originates in the hemisphere contralateral to the involuntary movement. The absence of bilateral MEPs following unilateral stimulation is a strong indication of the lack of an active ipsilateral corticospinal tract, thus making an ipsilateral origin of motor overow unlikely. The second experiment revealed a signicant time delay between the onset of the cMEP (during voluntary movement) and the iSP (during involuntary movement) ; this suggests that the overow was not inhibited via the ipsilateral corticospinal tract, but was rather suppressed via TCI acting on the hemisphere contralateral to the involuntary movements. A signicant interaction also revealed that while patients exhibited a signicantly earlier cMEP response than controls, there was no signicant dierence in iSP

K. E. Hoy et al.

latencies. Finally, there was no signicant difference between MEP facilitation during voluntary movement and during motor overow, suggesting the presence of an active contralateral corticospinal tract in both instances. Therefore, the current study indicates that motor overow in patients and controls is due to bilaterally active corticospinal tracts ; thus implicating the BAT of motor overow. Additionally, in a nding which has implications for elucidation of the specic processes by which bilateral activation results in motor overow, there was no signicant dierence in silent period duration during overow between patients and controls. The lack of bilateral response to unilateral stimulation was not an unexpected nding. The presence of bilateral MEPs is considered to be strongly indicative of an active ipsilateral corticospinal tract (Konagaya et al. 1990; Kanouchi et al. 1997 ; Muller et al. 1997 ; Mayston et al. 1999 ; Maegaki et al. 2002), and there is little evidence that this is the case in either schizophrenia or normal adults. Support for the presence of a fast conducting ipsilateral corticospinal tract has been found in children, however, these direct projections are thought to be gradually withdrawn during normal development (Carson, 2005). The vast majority of research examining motor overow has focused on distal muscles (i.e. hand and nger movements), yet there is considerable evidence that in adults the ipsilateral tract predominantly innervates proximal muscles (Brinkman & Kuypers, 1972 ; Ziemann et al. 1999). As such the presence of active ipsilateral corticospinal tracts projecting distally in adults would be considered pathological. Such tracts have been identied in patients with CMMs in the presence of KlippelFiel syndrome, Kallmanns syndrome, and/or severe hemispheric lesions. Schizophrenia has not been associated with any such disorders and/or lesions. Therefore, the lack of an active ipsilateral corticospinal tract innervating distal muscles, and the subsequent absence of bilateral MEPs, in this population is not unexpected. The IAT of motor overow was not supported by this nding. Stimulation of the hemisphere contralateral to voluntary movement during motor overow also failed to support an ipsilateral cortical origin of overow, and in doing so generated

some interesting ndings. Comparison of the latencies of responses following stimulation, that is cMEP during voluntary movement and iSP during motor overow, revealed a signicant delay between the onset of these measures for both patients and controls. If the iSP had occurred at approximately the same time as the cMEP it could have been argued that the suppression of overow was due to inhibition of cortical activity in the same hemisphere responsible for the production of the cMEP (i.e. the hemisphere contralateral to the voluntary movement) ; thus indicating an ipsilateral origin for motor overow. However, the signicantly later onset of the iSP, on average 16.58 ms, suggests that the mechanism of inhibition was in fact transcallosal. Transcallosal conduction time has been estimated at y12 ms, allowing for the TMS-induced inhibition to be transmitted, via the corpus callosum, to the contralateral hemisphere (Muller et al. 1997). Therefore the delay of approximately 16 ms for the iSP onset would indicate that inhibition of the hemisphere contralateral to overow was responsible for the suppression of activity, indicating a contralateral cortical origin of motor overow. While both groups exhibited equivalent iSP onset latencies, the patient group revealed a signicantly earlier cMEP onset than control participants. This is an unexpected nding and its signicance is unclear ; a possible explanation is as follows. The earlier cMEP seen in patients could be attributed to the cortical inhibition decits which have been consistently reported in schizophrenia (Puri et al. 1996 ; Boroojerdi et al. 2000 ; Daskalakis et al. 2002 ; Fitzgerald et al. 2002 b, c). Patients with schizophrenia may produce an earlier cMEP due to reduced cortical excitation requirements, that is when active their motor cortex is potentially more excitable than that of controls. Therefore, the induction of the cMEP may occur more quickly in schizophrenia thus resulting in reduced cMEP latency. The inhibition decits in schizophrenia may also explain the subsequent catching up of the iSP response. According to BAT during normal voluntary movement there are a series of transcallosal processes whereby the active motor cortex (i.e. the hemisphere contralateral to voluntary movement) is able to exert inuence on the opposite hemisphere resulting in a net increase in activation (Hoy et al. 2004 a). In

Using TMS to investigate motor overow in schizophrenia

patients with schizophrenia this facilitation is proposed to be exacerbated, possibly due to inhibition decits, and this is ultimately thought to be responsible for the increased motor overow seen in this group. The induction of the iSP in the current study was thought to involve the transcallosal transmission of inhibition from the active motor cortex to the hemisphere contralateral to the overow production ; a higher degree of facilitation in this hemisphere could delay the induction of the iSP, potentially allowing the response to catch up with the control group. While purely speculative in nature these processes may explain the comparative iSP latencies despite the signicantly earlier onset of cMEP in the patient group. The nal paradigm employed the premise that when TMS is applied to an active cortex the resultant MEP is facilitated (Thompson et al. 1991). Through the application of TMS to the hemisphere contralateral to voluntary movement and then to the hemisphere contralateral to motor overow we were able to compare the degree of facilitation in the responses. The lack of a signicant dierence in the facilitated MEPs suggests that in both instances the hemisphere contralateral to the movement (i.e. voluntary movement and motor overow) was active. If the MEP induced during motor overow was not facilitated, then one could have postulated a lack of activity in the contralateral hemisphere. This was not the case, however, and the results clearly implicate a common contralateral cortical origin for both normal voluntary movement and motor overow. This paradigm also allowed investigation of the magnitude of the contralateral silent period produced during motor overow. By measuring the duration of the silent period occurring during motor overow, we were able to more directly investigate the ability of the cortex contralateral to voluntary movement to mediate the transcallosal processes (i.e. facilitation) thought to result in activation and thus overow production. Patients with schizophrenia exhibited a shorter silent period duration than controls, but this dierence was not statistically signicant. These results indicate that the ability of the contralateral hemisphere to mediate incoming facilitation alone may not account for the greater overow in schizophrenia. Therefore, it may be that signicantly greater TCF or

reduced TCI, rather than decient intra-cortical processes, contributes to the greater overow seen in patients with schizophrenia. There are a number of potential limitations to the current research which need to be addressed. It is not possible to entirely exclude the potentially confounding eect of antipsychotic medication on the production of motor overow. However, this potential confound was minimized by only including patients without signicant extra-pyramidal side-eects. In addition, medicated patients were on medication or doses known to be associated with few motor side-eects (Anon, 1998; Anath et al. 2001 ; Glick et al. 2001). The eects of medication on cortical excitability as measured by TMS must also be considered, and there have been a number of studies which have directly investigated these eects. Ziemann et al. (1996) studied the eect of a single oral dose of lorazepam on motor cortical excitability in normal controls. They found no change with respect to measures of resting and active motor thresholds, but the results did indicate that lorazepam had some eect on inhibitory processes. The cortical silent period duration was found to be prolonged following drug administration, and corticocortical inhibition was said to be increased while corticocortical facilitation was considerably suppressed (Ziemann et al. 1996). Daskalakis et al. (2002) found similar eects of antipsychotic medication when investigating cortical inhibition decits in schizophrenia. Unmedicated patients exhibited signicant cortical inhibition decits when compared to healthy controls, while medicated patients did not. It was concluded that antipsychotic medications may actually act to increase cortical inhibition in patients with schizophrenia (Daskalakis et al. 2002). These investigations indicate that the medications appear to decrease motor cortical excitability (through either suppression of facilitation or enhancement of inhibition). These ndings further support the conclusions made in the current study motor overow is being produced due to either an increase in facilitation or a decrease in inhibition resulting in bilateral activation of contralateral corticospinal tracts. If medication was having the predicted eect of increasing inhibition, this makes the current ndings of greater activation more robust. In addition, a study directly investigating the

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eects of antipsychotic medication on the EMG responses of thenar muscles to TMS of the motor cortex in schizophrenia found few medication eects (Davey et al. 1997). Patients taking antipsychotics showed equivalent cMEP latencies, motor thresholds and total silent period durations to those exhibited by drugnaive patients. The only signicant eect was the presence of an early component of weaker suppression of EMG activity in the silent period of medication patients. Therefore, in light of the potential eects of medication on motor cortical excitability, the current ndings indicating bilaterally active corticospinal tracts in schizophrenia are considered to be particularly strong. Finally, the two groups diered signicantly in age. A number of studies investigating the eects of age on TMS responses have largely revealed that in the elderly there is a tendency towards hypoexcitability, or a decreased responsiveness to TMS (Rossini et al. 1992 ; Oliviero et al. 2006). The older group in the current study (mean age 42 years) is considerably younger than the dened elderly groups in which these ndings were reported, and in fact the older group essentially exhibited opposite ndings showing increased cortical excitability. Finally, a recent study by Wassermann (2002) examined the variation in response to TMS in the general population in a sample of 151 individuals with an age range of 1876 years. It was concluded that age was not directly related to cortical excitability as measured via MEP amplitudes (Wassermann, 2002). Therefore, it is felt that the signicant dierence in age did not contribute to ndings of the current study. Taken independently the results of these three experiments are suggestive of bilateral cortical activation as the mechanism of motor overow ; however, when viewed as a series of conrmatory ndings they become considerably more convincing. The initial paradigm indicates the lack of an active ipsilateral corticospinal tract, the second experiment suggests that inhibition of the activity in the hemisphere contralateral to the motor overow production generated the iSP, and the nal study revealed that stimulation of the motor cortex contralateral to movement (both voluntary movement and motor overow) produces comparative degrees of MEP facilitation. Taken together these

ndings strongly indicate that the motor overow produced, in both patients and controls, is due to the presence of bilaterally active corticospinal tracts. Therefore, increased overow in patients with schizophrenia does not seem to be due to a pathological mechanism of overow production per se. Overow in schizophrenia appears to be produced via the same mechanism seen in adults under eort-induced conditions, but to a signicantly greater degree. BAT essentially posits that an imbalance in the transcallosal inhibitory and excitatory processes involved in voluntary movement is responsible for motor overow production ; a more pronounced imbalance is likely to be responsible for the greater overow in schizophrenia. ACKNOWLEDGEMENTS This work was conducted as part of a doctoral qualication through Monash University (K. H.), and all funds were provided by Monash University. DECLARATION OF INTEREST None. NOTE Supplementary information accompanies this paper on the Journals website (http://journals. cambridge.org). REFERENCES
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Using TMS to investigate motor overow in schizophrenia

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13

1. Ipsilateral Activation Theory of Motor Overflow

2. Bilateral Activation Theory of Motor Overflow

Motor Overflow

Normal Voluntary Movement

Motor Overflow

Normal Voluntary Movement

APPENDIX FIG. 1. Theories of Motor Overow 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 corticospinal tracts thus resulting in a degree of overow.

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Experiment One

Experiment Two TCI

Experiment Three

cMEP

iSP

cMEP

Motor overflow

Normal Voluntary Movement

iMEP

cMEP

iSP

cMEP

Motor overflow

Normal Voluntary Movement

APPENDIX FIG. 2. TMS Experimental Protocols. The rst panel depicts the potential ndings 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 are obtained indicating an active ipsilateral corticospinal tract. The middle panel indicates the possible ndings from the second experiment; c) a signicant dierence in the latency between the iSP and the facilitated cMEP would suggest bilateral activation was responsible for overow, while d) the iSP and facilitated cMEP occurring at essentially the same time would suggest an ipsilateral origin of motor overow. The nal panel shows the alternative ndings from experiment three; e) if TMS to the hemisphere contralateral to overow production is able to facilitated the resultant MEP to the same degree as TMS to the hemisphere contralateral to voluntary movement bilateral activation is supported, however f) if the MEP induced during motor overow is not facilitated to the same degree as that induced during voluntary movement then bilateral activation is not supported.