Abnormal premovement brain potentials in schizophrenia

Schizophrenia Research, 8 (1992) 31-41 u 1992 Elsevier Science Publishers B .V . All rights reserved 0920-9964/92/$05 .00

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SCHIZO 00247

Abnormal premovement brain potentials in schizophrenia Jaswinder Singh', Robert T . Knight`', N . Rosenlicht`, Joan M . Kotun`, D .J . Beckleyb and D .L . Woods b 'Department of Psychulogv, Northwestern University and ° Department of Neurology and 'Psychitnrr. Veterans Administration Medical Center, University of Caliifornia, Davis, CA . USA

(Received 4 December 1991 ; revision received 14 April 1992 : accepted 20 April 1992) We assessed scalp-recorded movement related potentials (MRPs) generated prior to voluntary movements in chronic, medicated schizophrenics (n=9) and age matched normal controls (n=9) . M RPs were recorded in a self-paced button press task in which subjects pressed a button with either their right, left or both thumbs (experimental condition I, IT and III respectively), Controls generated a slowly rising readiness potential (RP) at about 1000 ms, a negative shift (NS') at about 450 ms and a motor potential (MP) at about 100 ms prior to movement . The initial MRP components (RP and NS') were reduced in schizophrenics indicating an impairment of the voluntary preparatory process in schizophrenia . Results of the present study indicate a similarity of MRP findings in schizophrenics and reported MRPs (Singh and Knight, 1990) in patients with unilateral lesions of the dorsolateral prefrontal cortex . These findings provide further support for frontal lobe dysfunction in schizophrenia . Key wards: Movement-related potentials ; Readiness potential ; Schizophrenia ; Frontal lobes : Voluntary movements : (Schizophrenia)

INTRODUCTION

Movement related potentials (MRPs) provide an electrophysiological measure of motor preparatory processes assessed with voluntary movement (Kornhuber and Deecke, 1964 ; Vaughan et al ., 1968 ; Singh et al ., 1990) . Three premovement MRP components (the readiness potential, RP ; the negative shift, NS' and the motor potential, MP) and a post motion component (P2) of MRPs have been reliably reported (Neshige et al ., 1989 ; Shibasaki et al ., 1980 ; Singh and Knight, 1990) . Movement related disturbances in schizophrenics have been described in literature . For example, Kraepelin described movement disturbances in his initial definition of schizophrenia (Crow ct al ., 1984) . In addition to abnormal saccadic eye moveCorrespondence to : Present address: J . Singh . The Franklin McLean Institute. Department of Radiology . The University of Chicago, 5841 S . Maryland Avenue, Box MC1037 Chicago . IL 60637, USA .

ments (Holzman et al ., 1974 ; Stevens. 1978), Manschreck (1986) showed that schizophrenics were unable to tap their fingers in synchrony with rhythmically occurring auditory stimuli . Schizophrenics also have difficulty in shifting attentional set from one visual field to another, possibly due to an impaired ability to shift motor programming (Rizzolatti, 1987) . MRP recordings can provide an electrophysiological measure of such voluntary movements, and can index motor preparatory processes associated with voluntary movements in schizophrenia . Recent studies have implicated neuroanatomical changes in schizophrenia . For example, schizophrenics show decreased brain weight and volume reduction of the hippocampus, amygdala, parahippocampal gyrus and pallidum internum in addition to left temporal lobe abnormalities (Flor Henry, 1969 ; Bogerts et al ., 1985; Brown et al ., 1986) . Computed tomography (Farkas et al ., 1984 ; Weinberger, 1984) and postmortem studies (Stevens, 1988 ; Benes et al ., 1986) have further revealed that

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schizophrenics have larger ventricular area than the general psychiatric population (Owens et al ., 1985 ; Kelsoe and Cadet, 1988) . The literature also suggests frontal lobe dysfunction in schizophrenia (Levin, 1984a, 1984b ; Goldberg et al ., 1982 ; Goldberg, 1985 ; also see Weinberger, 1988) supported by regional Cerebral Blood flow (rCBF) (Weinberger et al ., 1985 ; Berman et al . . 1985) . assessment (Kolb and neuropsychological Whishaw, 1983), and EEG studies (Morihisa and McAnulty, 1985), The neural origin of slow movement related potentials is not fully understood . However, evidence provided by scalp topography (Vaughan et al . . 1968 ; Shibasaki et al ., 1980), intracranial (Neshige cL al ., 1989), and MRP studies on brain damaged patients (Deecke et al ., 1977, 1987 ; Deccke and Kornhuber, 1978 ; Singh et al ., submitted) indicate that primary sensori-motor cortex, supplementary, premotor, and prefrontal cortex (Singh and Knight . 1990) form elements of a neural network necessary for MRP generation . MRP recordings in schizophrenics might provide further clectrophysiological data on the involvement of anterior cortical regions in schizophrenia . Prior studies of MRPs in schizophrenia are equivocal . For example, Timsit-Berthier et al, (1973) recorded MRPs in psychiatric patients and reported that the potentials recorded in psychotics were characteristically different from that of neurotics . Kornhuber (1983) also reported reduction of the Readiness potential in medicated schizophrenics . Similar results have been obtained by others (Kornhuber et al ., 1982 : Westphal et al ., 1985, 1986 ; Chiarenza ct al ., 1985) . However, Adler et al . (1989) reported normal RPs in chronic, medicated schizophrenics and significantly enhanced MRPs in schizophrenics with tardive dyskinesia (TD) . Thus, there is some disagreement concerning MRP findings in schizophrenia . The present study was designed to provide MRP data from multiple scalp sites in stable schizophrenics in a self-paced voluntary task .

male ; mean age= 49 .3 y ears. S D =13 .6) followed on an ongoing basis in a V .A . outpatient clinic participated in the study . A consensual agreement with regard to the clinical diagnosis, severity symptom rating and current mental status of each of the patients was reached between two psychiatrists (N .R . and J .M . K .) . Eight of the patients had active psychotic symptoms including auditory hallucinations (3 patients), and delusions (5 patients) . All were receiving neuroleptic treatment (mean= 431 mg per day in chlorpromazine equivalents, range 20 to 1000, SD=255) . All patients had histories of multiple prior hospitalizations and an onset of psychotic symptoms at least five years prior to the study (mean duration of illness= 24 .77, SD =10 .56 years) . Patients were rated for global severity of symptoms (mild-moderatesevere) by clinical history and mental status examination, with one patient rated as mild and eight patients rated as moderate . Patients with severe symptoms were screened out due to potential difficulties in following study protocol . Patients with TD . drug-induced parkinsonism, history of significant medical illness, head injury, stroke or primary diagnosis of substance abuse were also excluded . All subjects underwent a neurological examination at the time of testing . None of the patients had lateralized motor deficits, apraxia or signs of extrapyramidal dysfunction . All patients were right handed according to the Edinburgh Handedness Inventory (Oldfield, 1971) . All participants gave informed consent and were paid for their participation . Controls

Nine neurologically normal subjects (8 male ; mean age= 50 .3 years, SD 10 .25), with no family history of schizophrenia or movement disorder and not receiving any medication constituted the normal control group . Subjects with history of substance ahusc, and psychiatric or medical disorders were excluded . All subjects were right handed . Recording

METHOD Patient Population

Nine chronic, medicated schizophrenics diagnosed according to DSM-IIIR (APA, 1987) criteria (all

of MRPs

MRPs were recorded according to methods described before (Singh and Knight . 1990 : Singh et al ., 1990) . Briefly, recording was conducted in a dimly lit, electrically and acoustically shielded room . The subject was seated in a comfortable reclining armchair and given a pushbutton (two

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pushbuttons in the bimanual condition) mounted atop a cycle handle grip . Each subject was instructed to loosely grasp the handle in his or her palm and briskly press and release the button with his or her thumb . Subjects were instructed to press the button at their own pace without any external cue or control . They were warned against pressing the button too rapidly to minimize problems from overlapping of MRP epochs . Thus, the button press was self-initiated and self-paced with an inter-movement interval (I MI) ranging between 3 to 10 s in both control and schizophrenic groups (Table 1) . MRPs were recorded with Ag/AgCl electrodes placed at FPI, FPZ, FP2 (overlying superior frontal gyrus), F3 . FZ, F4 (mid frontal gyrus, near superior frontal cortex), C3, CZ, C4 (precentral gyrus) and P3 and P4 (superior parietal lobule) . Three additional electrodes C3a, CZa and C4a were placed over precentral areas (Homan et al ., 1987) . These were located 2 cm anterior to C3, CZ, and C4, respectively (between precentral and superior frontal gyrus) . Multiple electrodes were used to obtain a detailed MRP scalp topography including precentral and central sites . All electrodes were referenced to linked earlobes, A ground electrode was placed on the forehead and EOG was recorded from an electrode below and slightly lateral to the inferior orbit of the eye . Individual trials with excessive muscle activity (peak to peak amplitude of 80 MV) or eye blinks (peak to peak amplitude of 80 µV) were excluded from the average . EMG responses were recorded from a pair of electrodes placed on the thenar TABLE

I

Mean inter-movement interval between groups Group

RHP Mean ( .SD)

LHP Mean (SD)

BMP Mean ISDj

Control Schizophrenic Significance

3 .10 (0 .50) 4 .23 (0 .43)

3 .22 (0 .40) 4 .20 (0 .34)

3 .04 (0 .50) 4.13 (0 .51)

*

*

*

Table showing mean interpress interval differences during selfpaced task between control and schizophrenic . Schizophrenic patients tend to have prolonged Ms. *p< 0 .05

RHP=Right hand press LI4P=Left hand press BMP=Bimanual press

muscle and first metacarpal-phalangeal joint of the hand involved in the task . Electrode impedances were less than 5 kOhms . EEG, EOG, and EMG were recorded using Grass P511 amplifiers . EEG and EOG were amplified (50K) and bandpass filtered from 0 .01-100 Hz (time constant=5 s) . EMG activity was amplified (10K) and filtered from 10-100 Hz . Signals were digitized at a sampling rate of 128Hz,tchannel by a PDPI 1/73 minicomputer . Digitized single trial epochs were stored on magnetic tape for off-line averaging and analysis . The stored data was averaged from epochs of raw EEG beginning 1400 nis prior to the trigger and continuing for 600 ms post-motion . Trials contaminated by eye blinks, excessive EMG activity or amplifier blocking were rejected by the computer algorithms prior to averaging . Sums of 150 to 200 (total trials-200) artifact free trials were obtained for each subject in each condition . Mean trials obtained from control and experimental groups after artifact rejection (percentage of artifact rejection : schizophrenia= 23% ; control= 26%) were not significantly different (mean number of trials averaged : controls= 148 (RHP), 149 (LHY), 152 (BMP), schizophrenics- 154 (RHP), 142 (LHP), 149 (BMP)) . Behavioral measures

The mean inter-movement interval was examined between control and patient groups . All schizophrenics were subjected to Mini-mental State Examination (MMSE ; Folstein, 1975) . Data reduction and analysis

Measurements of MRPs were made according to the method described previously (Singh and Knight, 1990; Singh et at., 1990) . Four MRP components were identified based on individual and group mean averages . A regression line was fitted to these MRP phases . The RP was identified as the initial portion of the premovement negativity . The onset of the second component NS' (or N2a), occurred at 450 ms prior to the switch closure . The third component MP (or N2b) refers to the additional negativity generated immediately (about 100 ins) preceding the movement (Vaughan et al ., 1968) . The fourth component, post motion positivity (P2) was measured 180 to 220 ms postmotion . Measurements were made on the individual records using a computer assisted cursoring

34 program . Mean MRP amplitudes were calculated in restricted windows (i .e . RP : --1000 to - 500 ins ; NS' : -500 to - 100 ins ; MP : - 100 to 0) . The MP is superimposed on the NS' and the NS' in turn is superimposed on the RP . In order to obtain relatively isolated measures of the Wand MP components, we also used the subtraction method (Kutas and Donchin, 1980) . The NS' was computed as the potential difference between the N2a and N1 . The MP was calculated as the potential difference between N2b and the sum of NI and N2a components . Isopotential maps were constructed from the normalized voltages for each subject . The electrode site values were first normalized to allow comparisons of the maps across groups and conditions with all scales ranging between 0 and 100 percent . An automated interpolation algorithm was then used to calculate the contribution of each electrode to each inter-electrode point on the map, with the contribution from each inversely weighed as a function of the cube of the inter-electrode distance . Data were analyzed using ANOVA with a between-group design . Each of the three components (RP, NS' and MP) were analyzed separately for the two groups . T-tests were used to make specific electrode comparisons for each condition independently . Possible relationships between duration of illness and MRP amplitudes, IM Is and MRP amplitudes and drug dosage and MRP amplitude were examined by correlation methods .

Electrophysiological Data Control Group

Controls generated a slowly increasing negativity beginning at about 1000 ms (CZ: mean= 1023) prior to switch closure (RP) . The RP was symmetrical, widely distributed and maximal at frontocentral midlinc electrodes (CZ and CZa, Figs . 1, 2) . The NS' began at about 450 ms (CZ : Mean= 412) prior to the switch closure and was maximal over fronto-central regions contralateral to movement in controls (R H P : C3 vs C4, F =4 .2, p<0 .01) . This effect was not significant in the LHP condition . The MP peaked at the trigger point and was maximal over contralateral sites in unimanual conditions (RHP : C3 vs C4, F=3 .57 . p<0 .02) . During the bimanual condition MRPs were symmetrically distributed over the scalp and there was no contralateral enhancement (C3 vs C4, F=0 .98, n .s ., also see Table 2) . Schizophrenic group

A clear RP beginning at about 1000 ms (CZ : mean : 821 ins) prior to the button press was observable only in 2 schizophrenic patients . An NS' starting at about 400-300 ms (CZ : Mean= 340) prior to the switch closure was observed in only 3 patients . An MP was observable in most patients . The MP

TABLE 2 .Mean amplitude to Uc:BMP

RESULTS Behavioral Data Interinovement Interval . The mean IM I in controls and schizophrenics was not significantly different . However, schizophrenics tended to have a prolonged IMI relative to controls (Table I) . Mini-Menial State Examination (MMSE) .

Most schizophrenics performed well on the M MSE (Range of score : 27 to 29 ;30) . Correlational Analysis . No relationship could be established between duration of symptoms and MRP amplitudes (RP : r=0 .29 ; NS' : r=0 .21 ; MP : r=0 .19), IMIs and MRP amplitudes (RP : r= 0 .19 ; NS' : r=0 .29 ; MP : r=0 .16) and drug dosage and MRP amplitudes (RP : r=0 .17 ; NS' : r=0 .11 ; MP : r=0 .23).

Electrodes

Control

Schizophrenic

F3 FZ

4 .6 (SE=0 .82) 4 .0 (SE 1 .02) 4 .5 (SE 0 .0) 5 .7 (SE=0 .97) 5 .6 (SE=0 .80) 6 .4 (SE=0 .97) 6 .1 (SE=0 .65) 5 .1 (SE=0 .80) 5 .7 (SE=1 .02)

2 .8 (SE=0 .82) 2 .1 (SE=1_05) 2 .3 (SE= 1,30) 2 .3 (SE=1 .02) 2 .4 (SE=0 .89) 2 .5 (SE=0 .99) 3 .2 (SE=0 .97) 1 .8 (SF.-0 .77) 3 .0 (SE=0.88)

F4 C3 C3a CZ

CZa C4 C4a

Sig .

Table showing mean amplitude (in pV) of the MP component during the bimanual button press condition in controls and schizophrenics over precentral and central leads . Significantly larger potentials were recorded in controls . The overall difference was also noted on the frontal leads. Absence of lateralization of the MP component is also evident . ** •p <0 .001 . P<0 .01

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started at about 100 ms before the button press and peaked at the trigger point (e .g ., F3- C3, C3a) . Inspection of the Fig . I shows a nonsignificant trend toward contralateral enhancement of the MP (RHP: C3 vs C4 : F(df= l, 16)= 1 .3, n .s .) and NS'

(RHP : C3 vs C4 : F(df= 1, 16)= 1 .43, n .s .) during RHP and LHP conditions in this group . During the BMP, no differences were noted between ipsilateral and contralateral leads (C3 vs C4, F= 1 .02, n .s .) .

SCHIZOPHRENIC

Fig . l . Overlapped group grand-averaged waveforms from control (solid) and schizophrenic (dotted) subjects in a self-paced right hand button press . Note the contralateral enhancement of MRPs in controls as well as in schizophrenics (all subjects in both groups were right handed) and the decrement or absence of RP and NS components in schizophrenics with relative preservation of the MP component over some leads . Also note that there is clear MRP reduction at frontal leads (F3 and F4) in schizophrenics . Arrow indicates the trigger point from which back-averaging was done . HE=below eye .

36 Control versus Schizophrenics MRP scalp topography, onset latency and amplitude

In contrast to controls, the premovement negativity in schizophrenics did not onset until about 400 ms before the button press . Despite marked

amplitude reductions, the scalp topographical distribution of the MP component was similar to that of normal controls (Figs . 1, 2, 3) . The early and late MRP components were significantly reduced in all experimental conditions in schizophrenics . A statistically significant difference in mean amplitude was found between the two groups for the

SCI-IZOPHRENC

Fig . 2 . Overlapped group grand averages from control (solid) and schizophrenic (dotted) subjects in a self-paced left hand switch closure . Note the contralateral enhancement of MRPs in both the groups . The RP and NS' components are either reduced or absent on most scalp sites . The MP is somewhat preserved . Also note a frontal decrement of MRPs (F3 and F4) .

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CONTROL

SCHIZOPHRENIC

RP

NS'

100 .0

75 .0

MP

50 .0

25 .0

0 .0

Fig . 3 . Scalp topographical maps of the RP, NS' and MP components in the left hand button press condition . The maps reveal symmetrical distribution of the RP and eontralateral preponderance of the NS' and MP components in controls and schizophrenics . A marked reduction of the RP and NS' components is evident . The MP component is relatively preserved .

38 TABLE 3 Statistical comparisons : RP Groups

Control versus Schizophrenic

F

Significance

7 .91

NS' Groups

Control versus Schizophrenic

F

Significance

18 .72

as

F

Significance

6 .78

3

MP Groups

Control versus Schizophrenic

Mean group comparisons between controls and schizophrenics for the RP, NS' and MP components . ** <0 .01 * <0A5

RP, NS' and MP components (see Table 3) . The MRP reduction can be seen on the frontal leads in schizophrenic group (F3, FZ and F4, see Figs . 1, 2) . Specific group comparisons with respect to each of the conditions also showed a significant difference between the two groups (RHP : F=6 .95, p<0 .01 ; LHP : F=9 .90, p<0 .01 ; BMP: F=8 .80, p<0 .01) . However, isolated measures of the MP component obtained by the subtraction method (Kutas and Donchin, 1980), showed no statistically significant difference between control and schizophrenic groups (LHP : F - 1 .63, p=0 .55, n .s .) . Thus, the schizophrenic group showed a reduction of RP and NS' components with relative preservation of the MP (F3, FZ, F4, C3a, C4a . CZa ; see Figs . 1, 2, 3) . The P2 component was variable in both the patient and normal control group and no significant difference emerged between the two groups (F=2 .8, n .s .) .

DISCUSSION

Three premovement (RP, NS' and MP) and a postmotion (P2) component of the MRPs were generated in normal controls . The onset of premotion negativity was markedly delayed in schizophrenics and the amplitude of the RP and NS' components

was either reduced or abolished in a majority of schizophrenics at frontal and central scalp sites (Figs . 1, 2) . The MP component, although reduced, was observable in most subjects . MRP reduction was observed in unimanual as well as himanual experimental conditions . Despite amplitude reduction, the scalp topographical distribution of late component in schizophrenics was similar to those of controls (Fig . 3) . Like those in controls, the NS' and MP components were maximal contralaterally in unimanual conditions, and were symmetrical in the bimanual experimental condition . No difference between side of the press (RHP vs LHP) was noted both with respect to IMIs and laterality of MRPs in schizophrenics . Further, no relationship could be established between duration of symptoms and MRP amplitudes, IMIs or drug dosage and MRP amplitudes . Despite differences in experimental design, our results in schizophrenics are consistent with the findings of other investigators (Timsit-Berthier et al ., 1973 ; Kornhuber, 1983 ; Westphal ct al ., 1985, 1986 ; Chiarenza et al ., 1985) who showed abnormal MRPs in schizophrenics . However, our results are opposite to the findings of Adler et al . (1989) who reported normal RPs in chronic, medicated schizophrenics and significantly enhanced MRPs in schizophrenics with TD . Differences of results may be due to the differences in the task employed and patient population studied . Our group of patients (8/9) had active psychotic symptoms which might have contributed to the impairment of the RP component in these patients . In addition, the extent of the influence of antipsychotic medication on MRPs in the current and previously reported studies needs further investigation . In the current study, no significant difference emerged between the performance of control and schizophrenics on the experimental task . However, schizophrenics had a trend to prolonged interpress interval relative to controls, consistent with problems of initiation and slowness observed in these patients (Levin . 1984a,b) . Schizophrenic patients showed no clinical evidence of apraxia, sequencing difficulties or elementary motor disturbances . In addition, none of the patients had muscle weakness or difficulty in pressing the button so MRP reductions are not likely due to decreased button press force . Moreover, force is reported to

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affect the late MP component with early components (RP and NS') largely unaffected by force variations (Kristeva et al ., 1990) . Abnormality of MRPs cannot he attributed to attentional deficits in these patients because of high scores obtained by these individuals on MMSE which do not indicate severe attcntional problems in these patients . However, the possibility of reduced motivation (this variable has been shown to affect MRPs, McAdam and Seal, 1971) in these patients cannot be ruled out . Furthermore, schizophrenics show lack of planning, initiation, (Levin, 1984a) and problems with temporal organization (Klonoff et at., 1970 : DePue et al ., 1975) on behavioral tasks . M RPs have been associated with psychological constructs such as readiness, preparation, initiation, planning, volition and intention to act (Kornhuber and Deecke, 1964 ; Libet et al ., 1982 ; Kutas and Donchin, 1980) . Abnormal MRPs in schizophrenics might relate to deficits in these processes in schizophrenia . The frontal cortex is involved in initiation, planning and regulation of voluntary movements (Fuster, 1980 ; Luria, 1980) . Frontal lobe dysfunction has been reported in neuropsychological studies of schizophrenia (Kolb and Whishaw, 1983 ; Heatan et al ., 1978) . Also, frontal EEG abnormalities (Morihisa and McAnulty, 1985) and hypofrontality of glucose metabolism has been observed in schizophrenics (Farkas et al ., 1984) . Recent rCBF studies have found reduced activity in the dorsolateral frontal cortex in medicated and medicationfree schizophrenics engaged in the frontal lobe mediated Wisconsin Card Sorting Test (Weinberger et al,, 1985 ; Berman et al ., 1985) . These findings are supported by studies showing decrease in the frontal lobe volume in schizophrenia (Andreasen et al ., 1989, 1990) . Intracranial recordings and human lesion data have indicated discrete MRP sources in pre- and postcentral gyrus with additional contribution from supplementary and premotor cortices . Further, abnormal MRPs recorded from patients with Parkinson's disease are interpreted as dysfunction of supplementary area (SMA) in these patients primarily because the SMA derives its major input from the basal ganglia (Deecke et al ., 1977 ; Deecke and Kornhuher, 1978) . In addition . MRP recordings from patients with prefrontal cortex lesions have reported significant MRP decrement in these patients . This

indicates that in addition to supplementary, motor and premotor areas, prefrontal cortex areas 8, 9 and 46 are involved in MRP generation (Singh and Knight, 1990) . The MP component was partially preserved in schizophrenics as well as in patients with prefrontal lesions . The similarity of MRP findings in schizophrenics and prefrontal lesioned subjects provide further support for frontal lobe dysfunction in schizophrenia . MRP reductions in frontal sites could be due to direct loss of prefrontal or premotor generators or to decrease in prefrontal modulation of MRP generators in distant sites . Additional concurrent measures of frontal activity such as rCBF or PET would be needed to address this issue .

ACKNOWLEDGEMENTS

This work was carried out at the Department of Neurology and Psychiatry, University of California, Davis, Veterans Administration Medical Center . Support was provided by NIH Grant NS21135 and the VA Research Service . We are thankful to Clay Clayworth for technical assistance in all phases of the project . Special thanks to Kalyani Gopal for her help . We would also like to thank Irwin Feinberg, M .D . for his helpful suggestions .

REFERENCES

Adler, L .E ., Pecevich, M . and Nagamoto, H . (1989) Bereitschaftspotential in Tardive Dyskinesia . Movement Dis . 4, 105-112 .

American Psychiatric Association (1987) Diagnostic and Statistical Manual for Mental Disorders led 3) . Washington, D .C. American Psychiatric Press . Andreasen, N., Ehrhardt, J .C ., Swayze, V .W .T ., Alliger, R .J ., Yuh . W .T .C ., Cohen, G . and Zeibell, S . (1990) Magnetic Resonance Imaging of the brain in schizophrenia . The pathophvsiological significance of structural abnormalities . Arch . Gen. Psychiat . 47, 35-44 . Andreasen, N ., Nasarallah, H .A ., Drum, V ., Olson, S .C . . Grove . W .M ., Ehrhardt, J .C_ Colfman, .LA. and Crossett, J .H .W. (1989) Structural abnormalities in the frontal system in schizophrenia . A Magnetic Resonance Imaging study . Arch . Gen . Psychiat 43, 136-144 . Benes, F ., Davidson, 7F and Bird, F .D . (1985) Quantitative

40 cytoarchitectural studies of the cerebral cortex of schizophrenics . Arch . Gen . Psychiat . 43, 126-135 . Berman, K .F ., Zec, R .F . and Weinherger, D .R . (1985) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia : 11 . Role of neuroleptic treatment, attention, and mental effort. Arch . Gen . Psychiat. 43, 126-135 . Bogerts, B ., Meertz, E . and Schonfteld-Bausch, R . (1985) Basal ganglia and limbic system pathology in schizophrenia : a morphometric study brain volume and shrinkage . Arch . Gen . Psychiat.43, 784-791 . Brown, R ., Colter, N ., Corsellis . J .A .N ., Crow, T .J., Frith, C .D ., Jagoe, R . and Marsh, L . (1986) Postmortem evidence of structural brain changes in schizophrenia : differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder . Arch . Gen . Psychiat . 43, 36-42. Chiarcnza, G .A ., Papkostopoulos, D ., Dini, M . and Cazzullo, C .L . (1985) Neurophysiological correlates of psychomotor activity in chronic schizophrenics . Electroencephal . Clin . Neurophysiol . 61 . 218-228 . Crow, T .J ., Cross, A .J ., Johnstone . E .C ., Owen, F ., Owens, D .G .C:- and Waddington, J .L . (1982) Abnormal involuntary movements in schizophrenia : are they related to the disease process or its treatment? Are they associated with changes in dopamine receptors? J . C1in . PsychopharmacoL 2, 336-340 . Deecke, L_. Englitz, G ., Kornhubcr, H .H . and Schmitt, G . (1977) Cerebral potentials preceding voluntary movements in patients with bilateral or unilateral akinesia . In : 1 .E. Desmcdt (Ed .), Progress in Clinical Neurophysiology . Vol I, Attention, Voluntary Contraction and Event-related Cerebral Potentials. Basel. Karger, pp . 151-163 . Deecke, L . and Kornhuber, H .H . (1978) An electrical sign of participation of the mesial `Supplementary Motor Cortex' in human voluntary finger movement . Brain Res . 159, 473 476 . Decckc, L., Lang, W ., Helfer, H .J ., Hufnagl, M . and Kornhuber, H .H . (1987) Bereitsehaftspotential in patients with unilateral lesions of the supplementary motor a rea . J . Neurol . Neurosurg . Psychiat . 50 . 1430-143 4 . Deecke, L ., Scheid, P . and Kornhuber, H .H . (1969) Distribution of Readiness potential, premotion positivity, and motor potential of the human cerebral cortex preceding voluntary finger movement . Exp . Brain Res. 7, 158-168. DePue, R .A . . Dubicki, M .D . and McCarthy, T . (1975) Differential recovery of intellectual, associational, and psychophysiological functioning in withdrawal and active schizophrenics . J . Abnormal Psychol. 84, 325 -330 . Farkas, T ., Wolf, A .P ., Jaeger, J ., Brodie, J .D ., Christman, D .R . and Fowler, L.S . (1984) Regional brain glucose metabolism in chronic schizophrenia : A positron emission transaxial toniographic study . Arch . Gen . Psychiat . 41 . 293-300 . Flor-Henry . P. (1969) Psychosis and temporal lobe epilepsy : a controlled investigation . Epilcpsia 10, 363-395 . Folstein, M .F ., Folstein, SE . and McHugh, P .R . (1975) Minimenial state . A practical method for grading the cognitive state of patients for the clinician . J . Psychiat. Res . 12 . 189-198 . Faster, J .M . (1980) The Prefrontal Cortex . Raven Press, New York .

Goldberg, E . (1985) Akinesia, tardive dysmentia, and frontal lobe disorder in schizophrenia . Schizophrenia Bull . 11, 255 . Goldberg, E ., Mattis, S ., Hughes, J .E .O . and Antin, P . (1982) Frontal lobe syndrome without a frontal lesion : A case study . Paper presented at Fifth European Meeting of the International Neuropsychological Society Deauville, France . Ileaton, R .K ., Baade . L .E . and Johnson, K .L . (1978) Neuropsychological test results associated with psychiatric disorders in adults . Psychol . Bull . 85, 141-162 . Holzman, P.S ., Proctor, L.R ., Levy, G .L., Yasillo, N .J ., Meltzer, H .Y . and Hurt, S .W . (1974) Eye tracking dysfunc tions in schizophrenic patients and their relatives . Arch. Gen. Psychiat . 31, 143-151 . Homan, R .W . Herman, J ., Deecke, L . and Purdy, P . (1987) Cerebral location of 10-20 system electrode placement . Electroencephal . Clin . Neurophysiol . 66, 376-382 . Kelsoe, J . R ., Cadet, J .L ., Pickar. 1) . and Weinberger, D .R . (1988) Quantitative neuroanatomy in schizophrenia-a controlled magnetic resonance imaging study . Arch. Gen . Psych. 45, 533-541 . nat Klonotf. H ., Fibiger . C . and Hutton . G .H . (1970) Neuropsychological pattern in chronic schizophrenia . J . Nerv . Ment . Dis . 150, 291-300 . Kolh, B . and Wishaw, I .Q . (1983) Performance of schizophrenic patients on tests sensitive to left or right frontal temporal parietal function in neurological patients . J . Nerv, Ment . Dis . 171, 435-443 . Kornhuber, H .H . (1983) Chemistry . physiology and neuropsychology of schizophrenia : towards an earlier diagnosis of schizophrenia . Arch . Psychiatr. Nervenkrankheit . 233, 415-422 . Kornhuber, H .H . and Deeckc, L . (1964) Hirnpotentialanderungen heim Menschen Nor and nach Willkurbewegungen . dargestellt mit Magnetband Speichcrung and Ruckwartsanalyse. Pfliigers Arch. 281, 52 . Komhuher, H .H . and Deecke, T . . (1965) Hirnpotential$nderungen, lei Willkurbewegungen and passiven Bewegungen des Menschen : Bereitschafsputential and reafferente Potentiale . Pfliigers Arch . 284, 1-17 . Kornhuhcr, H .H ., Deecke, L .. Diekman, V ., Grozinger . B ., Hufnagel, M., Kornhuber, M . and Westphal, K .P. (1982) Bet eitschaftspotential, Directed Attention Potential and Related Potentials : Children, Attention and Schizophrenia. In: A . Rothenberger (Ed .), Event-related Potentials in Children . Elsevier . Amsterdam, pp. 231-242 . Kristeva, R ., Cheyne, W, Lang, W ., Lindinger, GG and Deecke, L . (1990) Movement-related potentials accompanying unilateral and bilateral finger movements with different inertial loads. Electroencephal . Clin . Neurophysiol . 75 . 410-418 . Kutas, M . and Donchin, E . (1980) Preparation to respond as manifested by movement related brain potentials. Brain Res. 202, 95-115 . Levin, S . (1984) Frontal lobe dysfunction in schizophreniaEye movement impairments. J . Psychiat . Res . 18, 27-55 . Levin, S . (1984) Frontal lobe dysfunction in schizophrenia-11 . Impairment of psychological and brain functions . J . Psychiat. Res . 18, 57-72 . Libel . B ., Gleason, C .A . . Wright, E .W ., Jr . and Pearl . D .K . (1983) 'Time of conscious intention to act in relation to onset

41 of cerebral activities (readiness potential) : The unconscious initiation of a freely voluntary act . Brain 106, 623-642 . Luria, A .R . (1980) Higher Cortical Functions in Man . Basic Books, New York . Manschreck, T .C . (1986) Motor abnormalities in schizophrenia . In : H .A . Nasrallah (series Ed .), Handbook of Schizophrenia . Vol . I : H .A . Nasrallah and D .K . Weinberger (Eds .), The Neurology of Schizophrenia . Elsevier, Amsterdam, pp . 65-90, Matsue . Y ., Okuma, T ., Sano, H ., .Aneha, S ., Ueno . T ., Chiba, H . and Matsuoka . H . (1986) Saccadic eye movements in tracking. fixation, and rest in schizophrenic and normal subjects . Biol . Psychiat . 21, 382 389 . McAdam, D .W . and Seal, D .M . (1969) Bercitschaftspotential enhancement with increased level of motivation . Electroencephal . Clin . Neurophysiol . 27, 73-75 . Morihisa, J .M . and McAnulty . G .B . (1985) Structure and function : brain electrical activity mapping and computed tomography in schizophrenia . Biol . Psychiat . 20, 3-19 . Neshige . R. . Luders, H ., Friedman, L . and Shibasaki, H . (1988) Recording of movement-related potentials from the human cortex . Brain 24, 439-445 . Oldfield. R .C . (1971) The assessment and analysis of handedness . The Edinburgh Inventory . Neuropsychologia 9, 97-113 . Owens . D .G .G . Johnstone, E .C ., Frith, C .D ., Jagoe, J .R . and Kreel, L. (1985) lateral ventricle size in schizophrenia : relationship to the disease process and its clinical manifestation . Psychol. Med . 15, 27-41 . Rizzolatti, G ., Riggio, L ., Dascola . 1 . and Umilta, C. (1971) Reorienting attention across the horizontal and vertical meridians : evidence in favor of a premotor theory of attention . Neuropsychologia 25, 31 40 . Shibasaki, H ., Barret, G ., Halliday, F . and Halliday, A .M . (1980) Components of the movement-related cortical potentials and their scalp topography . ElectroencephaL Clin . Neurophysiol . 49,213-2_26 . Singh, L . Woods . D.L . and Knight . R .T . (submitted) Psychophysiology of Movement Related Potentials : Task dependence and neural generators .

Singh, J . and Knight . R.T . (1990) Frontal lobe contribution to voluntary movements in humans . Brain Res . 531, 45-54 . Singh, J ., Knight, R .T . Woods. D .L ., Beckley, D .J . and Clayworth . C . (1990) Lack of age effects on human brain potentials preceding voluntary movements . Ncurosei . Lett. 119, 27-31 . Stevens . J .R . (1978) Disturbances of ocular movements and blinking in schizophrenia . J . Neural . Neurosurg . Psychiat . 41,1024-1030 . Stevens, J .R . (1988) Quantitative study of gliosis in schizophrenia . Biol . Psychiat . 24, 697-700 . Stuss, D .T . (t986) The frontal lobes. Raven Press, New York . Timsist-Berthier, M . . Delaunoy, J ., Koninckx, W . and Rousseau, J .C . (1968) Slow potential changes in psychiatry )I . Motor potentials . Electroencephal . Clin . Neurophysiol . 35, 363-367 . Vaughan, ILG . . Costa, L .D . and Ritter, W-(1968) Topography of the human motor potential . Electroencephal . Clin . Neurophysiol . 25, 1-10 . Weinberger, D .R . (1984) CAT scan findings in schizophrenia : Speculation on the meaning of it all . 1 . Psychiat. Res . 18, 477-499 . Wcinberger, D .R . (1988) Schizophrenia and the frontal lobe . Tr. Neurosci . 11, 367-370 . Weinberger, D .R ., Berman, K .F . and Zec . R .F . (1985) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia : 1 . Regional cerebral blood flow (rCBF) evidence . Arch . Gen . Psychiat . 43, 114-124 . Westphal, K .P ., Grozinger, B ., Andersen, C ., Scherh, W ., Nitsch, J ., Frech . M .M . and Kornhuber, H .H . (1985) Different movement-related EEG-spectra in schizophrenics and normals . IV World Congress of Biological Psychiatry, Abstr . 130 .11 . Westphal, K .P ., Grozinger, B ., Andersen, C., Scherh, W ., Nitsch, J ., Frech, M .M . and Kornhuber, H .H. (1986) The influence of concentration and relaxation on the EEG power spectra during a CNV Paradigm . Arch . Ital . Biol . 124, ?21 228 .