Topographic evoked potential mapping in obsessive-compulsive disorder: Evidence of frontal lobe dysfunction

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P.vrchiairr Research, 28,63-71

Elsevier

Topographic Evoked Potential Mapping in ObsessiveCompulsive Disorder : Evidence of Frontal Lobe Dysfunction Paul Malloy, Steven Rasmussen, William Braden, and Richard J . Haier Received .hate22 . 1988; revised version received September 30, 1988 ; accepted Nocernher 23, 1988 .

Abstract . Several lines of evidence suggest that frontal lobe dysfunction may underlie obsessive-compulsive disorder (OCD) . Eighteen patients with OCD were compared with I8 normals matched for age, gender . handedness . and education on a Go-NoGo task . Visual evoked potentials were measured during the task . Topographic evoked potential mapping revealed significantly smaller P300 magnitudes in orbital frontal areas in the OCD patients . Results are compared with those from studies using other methodologies, and etiological implications are discussed . Key

Words. Evoked potentials, obsessive-compulsive disorder, frontal lobe .

Several lines of evidence have implicated a neurological component in the pathogenesis of obsessive-compulsive disorder (OCD) . OCD patients have a high incidence of reported birth trauma and left-handedness, suggesting they may have atypical brain organization from a very early age (Floc-Henry et al ., 1979) . Electroencephalographic (EEG) abnormalities, including slow waves, spike discharges, and power spectrum lateralization differences, have been reported at rates ranging from Ito 64% in various OCD samples (Patella et al ., 1944 ; Rockwell and Simons, 1947 ; Epstein and Bailinc, 1971 ; Flor-Henry et al ., 1979 ; Insel et al ., 1983) . Frontal Lobe Dysfunction . 'f he frontal lobes have been specifically implicated in OCD . Gray (1982) has hypothesized that interactions between frontal and limbic /ones are important in obsessional and other anxiety disorders . Flor-Henry (1983) has suggested that the syndrome is secondary to dominant frontal dysfunction, with loss of normal inhibitory processes in that zone . 'I his disinhihition is said to account for "the fundamental aspect of obsessions : the inability to inhibit verbal ideational mental representations and their motor consequences" (Flor-Henry, 1983, p . 305) . On the basis of neurophysiological and psychosurgical data, Flor-Henry (1983)

Paul Mnlloy, Ph .D., is Assistant Professor, Steven Rasmus .scn, M .I) ., I, Assistant Professor: and William Braden, M .D ., is Clinical Assistant Professor, Butler Hospital and the Department of Psychiatry and Human Behavior, Brown University_ Richard 1 . Hater, Ph .D ., i .s Associate Professor of Psychiatry and Human Behavior, University o1 California, Irvine . (Reprint requests to Dr . P . Malloy, Boiler Hospital . 345 Blacksiunc Blvd ., Providence . RI 02906, USA .) 0165-17X1!89 ; $03 .50 a 1989

Elsevier Scientific Publishers Ireland

It If -

64 noted that "cingulate-orbital-frontal" inhibitory mechanisms seem to be disturbed in OCD . There is some empirical support for a frontal locus of dysfunction in OCD . Baxter et al . (1987) reported that OCD patients displayed abnormally high metabolic rates in left orbital frontal and bilateral caudate areas measured by positron emission tomography, compared to controls with other psychiatric disorders . Ncuropsychological studies of OCD patients have also found evidence of frontal lobe dysfunction, although results have been inconsistent (Flor-Henry et al ., 1979 ; Inset et al ., 1983 ; Behar et al ., 1984) . Evoked Potentials . The P300 component of the evoked potential (EP) is known to vary in amplitude with the information value of the eliciting stimulus, and is thought to reflect association cortex activity (Picton and Stuss, 1980) . A posterior P300 component having maximum amplitude in the centroparietal region can be evoked by a number of tasks requiring stimulus discrimination and by the presentation of unexpected stimuli to the passive subject (Ritter et al ., 1979) . It is possible, however, that P300 may reflect not only posterior sensory information processing, but also more anterior association cortex activity, if a task is chosen which demands frontal lobe functions . Go-NoGo tasks are one such task at which animals and humans with frontal lobe lesions are known to fail (Drewe, 1975 ; Rosenkilde, 1979 ; Foster, 1980 ; Malloy et al ., 1985) . In Go-NoGo paradigms the subject is required to make a response to the Go signal, and to withhold or inhibit response to the NoGo signal . Simson et al, (1977) have reported that P300 during a Go-NoGo paradigm was maximal in the midparietal area in normal subjects during Go trials (as in previous sensory discrimination studies), but was maximal in midfrontal areas during NoGo trials . This task appeared to offer several advantages for the present investigation because (1) it was possible to time-lock recordings of EPs to the imperative signals in the task ; (2) it was simple enough to be mastered by psychiatric patients with severe psychopathology and (3) it involved a frontal lobe function thought to be abnormal in OCD. It was predicted that in normals P300 would show the usual centroparietal maximum amplitudes during Go trials, but that there would be a frontal shift in P300 distribution when the inhibitory requirements of the NoGo trials were added . OCD patients were hypothesized to have frontal lobe dysfunction, which should result in differences in P300 amplitudes in this area during Go-NoGo .

Methods Subjects . Eighteen adult patients meeting DSM-111 criteria for OCD constituted the OCD group . Nine of the OCD subjects were taking a variety of prescribed medications at the time of the study, and nine were taking no medications . Eighteen normal volunteers were recruited from hospital staff and volunteer workers . The mean age of the OCD subjects was 34 (SD = 12.8), and the mean age of the controls was 28 (SD=8 .7), with no significant difference in age between the groups. On interview, the control subjects denied any history of neurological insult, psychiatric disorder, or substance abuse . None of the controls were taking any prescribed medication, and they denied consuming alcohol or other drugs within 48 hours of testing . The groups were matched for gender and handedness, with 8 males and 10 females, and 16 right-handed and 2 left-handed subjects in each group .

65 Procedure . Subjects were instructed to press a telegraph key when the word "GO" appeared in block letters 2 cm high on a cathode ray tube directly in front of them . They were instructed not to press when the word "STOP" appeared . Six practice trials were followed by 45 Go and 45 NoGo trials presented in a pseudorandom order . An Apple II+ computer controlled stimulus presentations and recorded correct or incorrect responses . "I he intertrial interval was a constant 7 sec . EPs were recorded from left hemisphere sites based on the 10-20 system of electrode placement. To ensure accurate measurement in frontal and parietal association areas of particular interest, four special electrode sites were added and designated FC, FTC, CP, and TCP (see Fig . I ) . Available equipment limited the total number of recording sites to 15, necessitating elimination of standard site 01 . The elect ro-oculogram (EOG) was recorded from two electrodes above and below the right eye, and averaged like a cortical potential .

Fig . 1 . Modified International 10-20 system of electrode placements

Recording began with the onset of the Go or NoGo signal and continued for 500 ms . To ensure that subjects were engaged in the cognitive task during recordings, EPs were averaged for correct trials only (i .e ., when the subject pressed to the Go signal and inhibited press to the NoGo signal) . Cortical potentials were amplified by a Grass model 12 polygraph and digitized every 4 ms with an 8-hit analog-to-digital converter. Peaks and valleys in the FP were identified by the computer . P100 amplitude was the maximum voltage occurring between 36 and 120 ms ; N 100 was the minimum voltage occurring between 100 and 160 ms ; P200 was the maximum voltage occurring between 160 and 250 ms ; N200 was the minimum voltage between 160 and 250 ms ; and P300 was the maximum voltage between 250 and 400 ms . Topographic mapping of mean P300 amplitude was accomplished using an adaptation of the techniques developed by Ruchsbaum et al_ ( 1992) . This essentially involved interpolating P300 amplitude values for each coordinate in a 40 X 40 pixel matrix forming a lateral brain map . Interpolated pixel values were computed by weighted averaging of the values of the four nearest electrode sites . Values for the Go and NoGo conditions were computed and displayed as color maps, with color indicating P300 amplitude at each pixel location . Color maps were then transformed into black and white maps suitable for publication by tracing the maps using a Summagraphics digitizing tablet and high-resolution bit-mapped graphics software . Finally, significance probability maps comparing the Go and NoGo conditions were calculated by entering paired t-test values for each electrode site into the mapping program . For ease of interpretation, the resulting significance probability map values were keyed to standard significance level cutoffs (i .e ., p < 0 .001, p < 0 .0 1, p < 0.05) .

66 Results Analysis of each EP component revealed no significant amplitude differences for N100, P100, N200, or P200 across conditions for either group . Subsequent analyses therefore emphasize the P300 differences that were observed . The magnitude of P300 measured at eye electrodes was small, and no significant differences were found across conditions, indicating that eyeblink artifact did not affect results . There were also no significant differences between males and females in P300 amplitude measured at any electrode site during any condition . P300 data for the normal subjects are displayed in 'fable I and Fig . 2 . It can be seen that during Go trials, the area of maximum activity as indexed by P300 amplitude occurred in the centroparietal area, as in previous stimulus discrimination studies, However, with the addition of inhibitory demands during NoGo trials, there was an anterior shift in P300 activity . When the two task conditions were compared by t tests, a statistically significant increase in P300 magnitude was revealed . This change was maximum in prefrontal areas (sites Fp, Fz, F3, and FC), less marked in sensorimotor areas (FTC, F7, CZ, C3 and CP), and essentially absent in posterior areas . This frontal shift in the topography of P300 magnitude is seen more readily in the significance probability map comparing Go and NoGo conditions (see Fig . 2, bottom) . the Go-NoGo paradigm thus appeared to evoke frontal lobe activity that could be detected by changes in P300 amplitude . P300 data for the OCD group are presented in Table I and Fig . 3 . Inspection of the data reveals that OCD patients displayed the usual posterior, centroparietal maximum in P300 amplitude during Go trials, and anterior increases in P300 during NoGo trials . The significance probability map reveals that significant increases were

Table 1 . Mean P300 magnitudes during Go and NoGo trials for normal and obsessive-compulsive subjects Normal Go

FP F7 FZ F3 FTC FC C3 CZ CP T3 T5 TCP PZ P3 OZ

Obsessive-compulsive NoGo

Go

NoGo

Mean

SD

Mean

SD

Mean

SD

Mean

SD

5 .2 4 .6 12 .2 12 .0 11 .0 15 .8 13 .6 17 .5 23 .4 6 .2 16 .9 13 .3 29 .2 20 .5 19 .9

17 .4 13 .3 14 .9 12.8 10 .0 10.6 10.3 13 .5 11 .5 8 .3 8 .9 10.5 13.7 10.8 7 .8

15 .3 12 .1 22 .4 21 .0 17 .8 24 .4 24 .9 29 .4 32 .2 10.8 17.5 19.9 33.0 25.2 20.7

16 .6 16 .6 18 .3 16 .0 13 .2 13 .8 14 .2 14 .7 13 .5 9 .3 11 .2 12 .9 12 .5 12 .4 11 .8

8.7 11 .4

13.2 23.5 12.6 11 .5 15.6 11 .6 11 .5 15.1 12.7 14.8 7.2 10.2 9.6 9.2 10.8

8.2 4 .1

13 .8 12 .1

14 .3 13 .8 9 .9 20 .7 17 .6 24 .3 27 .6 3 .5 10 .3 12 .8 25 .9 19.4 16 .3

12 .8 13 .3 11 .1 13 .8 11 .5 13 .5 11 .3 5 .6 6 .5 8 .3 8 .0 8 .9 6 .1

10.9 10 .7 11 .5 14 .8 13 .2 15 .6 22 .8 6 .1 10 .2 10 .7 26 .2 16 .2 18 .8



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smaller and topographically less extensive than in normal subjects (see Fig, 3, bottom) . Direct comparisons of P300 amplitudes for normal and OCD subjects during the NoGo condition are also illustrated in Fig . 4 . As the significance probability map illustrates, these differences indicate relative lack of activity in orbital frontal and possibly anterior temporal areas . A repeated measures analysis of variance (ANOVA) revealed significant Group (OCD-Normal) X Condition (Go-NoGo) interaction effects for the mean P300

magnitude at frontal sites Fp, F7, and FTC (F= 5 .45 ;

df=

1, 34 ; p < 0 .05) . This

interaction is illustrated in Fig . 5, which displays the mean magnitude of P300 at these three frontal sites for the two diagnostic groups during Go and NoGo conditions_ While normals displayed an increase in frontal activity during NoGo trials, the OCD subjects actually displayed a slight decrease at these sites . Because

Fig . 2 . Maps of P300 magnitudes in Fig . 3 . Maps of P300 magnitudes in normal subjects OCD subjects

P300 MEAN AMPLITUDE MAP NORMAL SUBJECTS 60 TRIALS

P300 MEAN AMPLITUDE MAP NORMAL SUBJECTS N060IRIRLS

SIGNIFICANCE PROBABILITY MAP NORMAL SUBJECTS GO VS NOGO TRIALS

P300 MEAN AMPLITUDE MAP DICE) SUBJECTS 60 TRIALS

P300 MEAN AMPLITUDE MAP DIED SUBJECTS NOGO TRIALS

SIGNIFICANCE PRODABILITY MAP LED SIID .I[CTS GO VS NUGU TRIALS

OCD = obsessive-compulsive disorder .

68 Fig . 4 . Significance probability map comparing normal and OCD subjects during NoGo condition

SIGNIFICANCE PRUUAMILILY MAP DCD V5 NURMAt SUUJECI`.i NUUD IRIAt5 OCD - obsessive-compulsive disorder .

the data were somewhat skewed (particularly at site F7), the analysis was repeated with the data log transformed . Results were essentially identical, with a significant Group X Condition interaction again revealed (F = 5 .46 ; df= I, 34 ; p < 0 .05) . Comparison of the medicated (n = 9) and nonmedicated (n = 9) OCD subjects revealed no significant differences during either the Go or NoGo conditions, suggesting drug effects did not account for the observed differences between the normal and OCI) groups . Discussion

"There has been considerable evidence linking the P300 to higher cognitive processing . The P300 is generated when a stimulus achieves significance either by its unexpected occurrence or by virtue of its assignment of signal value in behavioral tasks . P300 has been implicated in the cognitive processes involving orientation, response set for selective attention, uncertainty resolution, and decision confidence (Stuss and Picton, 1978 ; Picton and Stuss, 1980) . Abnormalities in the orientation response, selective attention, and ability to come to decisions have all been documented in OCD (Reed, 1985) . Given these facts, it is somewhat surprising that there has been so little attention paid to EPs in this disorder . Beech and coworkers hypothesized that obsessional patients would have increased EP amplitudes and shorter latencies, due to increased levels of arousal and strong defensive reactions to minimal stimulation . In two studies of visual EPs, they found that OCD patients did have reduced latencies of N220 and P300, but that amplitudes were lower than in normal controls (Cicsielski et al ., 1981 ; Beech et al ., 1983) . These data have recently been confirmed by Hollander and his colleagues (personal communication), who also found decreased peak latencies of N220 and P300 in 10 OCD patients who were compared to normals . To our knowledge, there has been no previous attempt to examine topographic abnormalities in the P300 component in OCD . Both raw data and topographic maps in the present study revealed patterns of P300 activity in OCD patients which were different from normals . Significantly lower amplitudes of P300 were found in orbital frontal areas during the NoGo trials of the Go-NoGo paradigm . These findings were consistent with the hypothesis that frontolimbic areas are dysfunctional in OCD (Gray, 1982 ; Flor-Henry, 1983) . On the

69 basis of observations of patients with frontal structural lesions, Eslinger and Damasio (1985) have noted that orbitomedial (OM) frontal areas not only connect directly with limbic structures, but also may provide a crucial route between dorsolateral frontal cortex and the limbic system . If these reciprocal interconnections are interrupted by lesions, the limbic system may have no way to activate frontal cortex, and frontal cortex will be unable to modulate limbic drives . Lesions in the orbitomedial division of the frontal lobes in animals cause difficulty inhibiting or unlearning previous response patterns when they are no longer appropriate (Miskin, 1964), and exaggerated emotional responses to previously nonthreatening cues (Butter et al ., 1979) . Similarly, OCD patients have great difficulty inhibiting rituals and obsessive thoughts, and develop progressive networks of "dangerous" situations which were formerly innocuous . A number of writers have recently noted some of the limitations of topographic mapping of brain electrical activity (see Kahn et al ., 1988, for review) . We endeavored to avoid some of these pitfalls by concentrating available electrodes over regions of interest, by measuring possible blink artifacts, and by using empirically verified methods of lateral projection of the maps . Raw group data were also presented for each electrode site, allowing better evaluation of the interpolated significance probability maps . We were forced by equipment limitations to measure only left hemisphere sites, so that results do not address any laterality effects which might exist . Further, activity of deep structures (such as basal ganglia and limbic areas which may be important in OCD) may be obscured or absent in surface measurements such as these . It will be recalled that Baxter et al . (1987) found evidence of both frontal and caudate changes in OCD patients . Further studies using the newer brain imaging technologies providing better resolution and measurement of the entire cerebrum may further elucidate these relationships . The Baxter et al . (1987) findings of frontal hypermetabolism using positron emission tomography may appear at first to be inconsistent with our findings of Fig . 5 . Mean P300 magnitudes of normal and OCD groups at selected frontal sites (Fp, F7, FTC) during Go and NoGo conditions 20

NORMAL w aD

CONDITION OCD = obsessive-compulsive disorder .

70 lowered frontal P300 magnitudes . However, the relationship between the two

methods of measurement may be complex . It is possible, for example, that orbital frontal areas of OCD patients could have high levels of glucose use, while being dysfunctional electrophysiologically and functionally . Less effective processing of information might be reflected in lower P300 values . In support of this interpretation, it is noteworthy that Hater et al . (1988) have reported that higher glucose metabolic rates measured by PET scan were associated with poorer performance on tests of abstract reasoning in normal subjects . These authors suggested higher metabolism may reflect lowered efficiency of cortical circuits . Frontal damage or dysfunction has been related to a number of psychiatric disorders in addition to OCD, particularly schizophrenia (I .evin, 1984) . This may he due to the prominent role of the frontal lobes in executive and self-regulatory behaviors (Stuss and Benson, 1986), which are disturbed in various ways in many psychiatric disorders . That is, frontal abnormalities may reflect the "final common pathway" for expression of abnormal behavior . Alternatively, the different disorders may result from dysfunction of different frontal subsystems . For example, recent work by Weinberger and his colleagues (Berman et al ., 1986 ; Weinberger et al ., 1986) has suggested that dorsolateral frontal zones are disturbed in schizophrenia, whereas orbital frontal areas have been implicated in OCD . In regard to evoked potentials, topographic P300 differences in schizophrenia have been found predominantly in posterior rather than frontal areas (Pritchard, 1986 ; Morihisa et al ., 1983 ; Faux et al ., 1988) . Further data using multiple measurement techniques (behavioral, elect rophysiological, structural, metabolic) and better understanding of the functional organization of the frontal lobes will he necessary before the relationships between frontal dysfunction and psychopathology can he elucidated definitively-

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