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negative symptoms in schizophrenia
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Visual Evoked Potential Correlates of Positive/Negative Symptoms in Schizophrenia Steven B. Schwarzkopf, J. Steven Lamberti, Maureen Jiminez, Catherine F. Kane, Michael Henricks, and Henry A. Nasrallah
Previous studies of schizophrenic patients have found evoked potential (EP) correlates of clinical symptomatology, including EP differences between subtypes of schizophrenia. In the current study, 14 medicated male schizophrenics underwent flash visual evoked potentials (VEP) and were clinically rated for positive and negative symptoms. We tested the hypothesis that positive symptoms would be associated with VEP latency reduction and negative symptoms with latency prolongation. Patients were divided into predominantly positive symptom and predominantly negative symptom groups using a combination of positive and negative symptom ratings. Patients with predominantly positive symptoms exhibited reduced latencies when compared with predominantly negative ~m~tom patients. Similarly, significant negative correlations between positive symptom ratings and P200 latency variables were found. Correlations between negative symptom measures and P200 latencies (in the opposite direction) were also noted, but were less significant. These relationships persisted when confounders were statistically controlled for. The results are consistent with previous findings of evoked potential correlates of clinical symptomatology, especially those finding EP latency correlates of psychosis severity and affective blunting. The findings are discussed in relationship to concepts relevant to psychosis, including arousal, sensory gating, and the dopamine hypothesis.
Introduction A number of studies have reported significant relationships between schizophrenic symptom patterns and EP parameters. Shagass (1980), in a review of findings, noted that schizophrenic patients who were chronic, "floridly psychotic," and less depressed, exhibited greater amplitudes and reduced wave shape variability in the first 100 msec after stimulus (visual and somatosensory modalities included) compared with other schizophrenic patients. This finding was recently replicated in a study dividing carefully diagnosed schizophrenic patients into psychotic versus nonpsychotic subgroups based on a self-administered personality inventory (Josiassen et al. 1986). Differences between schizophrenic subgroups have also been reported in a number of
From the Ohio State University College of Medicine, Columbus, Ohio (S.B.S., H.A.N.); and University of Rochester, Rochester, New York (J.S.L., M.J., C.F.K., M.H.) Address reprint requests to Dr. Steven B. Schwarzkopf, Ohio State University College of Medicine, 473 W. 12th AVE., Columbus, OH 43210-1228. Received August 27, 1988; revised May 7, 1989.
© 1990 Societyof BiologicalPsychiatry
0006-3223/90/$03.50
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studies using EP paradigms with stimuli of varying intensity. Using this type of EP paradigm, acute and chronic patients have been reported to differ on VEP measures (Landau et al. 1975). Connolly et al. (1983) also using visual stimuli of differing intensities, found topographical differences in the locatioa of abnormalities, depending on the patient's clinical symptoms. A left temporal a~normality was noted in "nuclear" schizophrenics and a left occipital deviation was noted in patients with hypomania and anxiety symptoms. Clinical correlates relevant to "positive" and "negative" psychotic symptoms have been observed in the NI00 and P200 EP latencies. Studies have found reduced latencies in schizophrenic patients with more "positive" symptoms (Saletu et al. 1973; Roth et al. 1980; Schlor et al. 1985) in college students with evidence of looseness of associations (Catts et al. 1986) and in controls with high ratings on psychoticism (Schlor et al. 1985). Saletu et al. (1973) also noted prolonged latencies in patients with "blunt affect," one of the primary negative symptoms. VEP latency differences have also been noted in schizophrenic patients with versus without a first degree family history of psychiatric illness (Romani et all. 1996): Based on these studies, we tested the hypothesis that patients with predominantly positive symptoms would have reduced VEP latencies compared with patients who have predominantly negative symptoms. Similarly, we tested for significant correlations between clinical symptom ratings and latency measures. VEP latencies (N140 and P200 wave) at fot~" intensities of light were measured as the variables of interest. VEPs and assessments for positive and negative symptoms were collected for 14 medicated male schizophrenic patients. Potential confounders, including neuroleptic dose, age, and chronicity, were examined and statistically controlled for.
Methods
Subjects Fourteen consecutively admitted, physically healthy, medicated, male schizophrenic or schizoaffective patients (by DSM III-R, structured clinical interview [SCID] [Spitzer et al. 1987]) consented to participate in the study. Patients were part of an ongoing study of neurophysiological correlates of psychotic symptoms and treatment response. The mean age for the sample was 28.1 years (SD 6.2), mean lifetime hospitalization was 22.5 months (SD 22.4), and patients were on an average neuroleptic dose of 1059.8 mg chlorpromazine equivalents (SD 690) (Baldessarini 1985). Demographic information is shown in Table 1. Means and SDS are shown for all patients and for patients divided by predominance of positive and negative symptomatology (defined using a median split on a combined positive and negative symptom score). Patients with predominantly positive symptoms did not differ significantly from patients with predominantly negative symptoms on age, chronicity, and neuroleptic dose.
Symptom Ratings Positive and negative symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen 1982). Ratings were completed by a researcher blind to evoked potential findings. Factor scores consistent with positive symptoms were computed from
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Table 1. Descriptive Statistics For All Patients and Patients Grouped by Symptoms (High POS-NEG, Low POS-NEG) Variable Age (in years) Chronicity (mo. hosp.)b Neuroleptic dose (CPZ equiv.y Proportion schizoaffective
All pts (N = 14) 28.07 (6.17) 22.46 (22.43) 1059.79 (690.70) 3/14
High POS-NEG" (N = 7) 27.57 (6.19) 16.71 (i4.03) 1052.57 (608.37) 2/7
Low POS-NEG a (N = 7) 28.57 (6.60) 29.17 (29.51 ) 1067.00 (814.5) 117
Mean SD. °High POS-NEG patients are those with positive-negtive symptom scores above the median, and Low POS-NEG patients have scores below the median score. High POS-NEG generally with predominantly positive symptoms, Low POS-NEG generally with predominantly negative symptoms. aChronicity in total months hospitalized. CChlorpromazine equivalents of neuroleptic medication.
the BPRS (factors: hostility, thought disorder, and activation), (Overall et al. 1967). The average of the three factor scores was used as the positive symptom score (POS SX). The average of the five global subscores of the SANS was used as the negative symptom score (NEG SX). Clinical variables for analysis included POS SX score, NEG SX score, and a contrast variable, POS-NEG, calculated by subtracting the NEG SX score from the POS SX score. The POS-NEG score is larger and positive if the patient has predominantly positive symptoms, and small or negative if negative symptoms predominate.
Testing Procedure A flash evoked potential (VEP) with varying stimulus intensity was chosen because of its previous use in differentiating subtypes of schizophrenic patients, recent focus on sensory gating in schizophrenia, and the potential for a more informative and powerful measure when using a within-subjects measure (i.e., change from one condition to another within the same subject). VEPs were recorded at CZ (monopolar recording, linked ear reference) to four intensities of light as detailed by Landau et al. (1975). Gold electrodes were used with skin impedance kept below l0 Kohm. The photostimulator was custom built to specifications of Landau et al. (1975), using a fluorescept screen (40 × 20 cm), with flash intensities of 3, 30, 80, and 240 foot iamberts measured at 50 cm from subject (distance at time of testing). Hash duration was 500 msec, interstimulus interval 988 msec, with intensities presented in a "pseudorandom" order (each intensity preceded each other intensity an equal number of times). A minimum of 50 nonartifacted trials were collected (EOG recorded with lateral and superior orbital electrodes). Electrooculograph (EOG) was monitored to rule out eye blink artifact using 100 IxV as the rejection criterion. Amplitude rejection criterion for CZ was also set at i00 ~V. Visual fixation on the center of the screen was the only task during testing. VEP latei~cies were measured using the following criteria: (1) P 100 as the maximal positivity from 60 msec to 140 msec, (2) Nl¢0 as Re maximal negativity from 80 msec to 180 msec, (3) P200 as the maximal positivity between 140 msec and 280 msec. NI40 and P200 peaks were easily identified for all patients. All recording involved online
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P2 A . . . . . . . . . . .
High
;
~
5'0
/
1(}0
Figure 1. Average flash VEPs at lowest and highest flash intensities for a single subject. P2 Low is the P200 latency at low intensity, and P2 A is the change in P200 latency between the low and high intensity condition (Low P2-High P2 latency in msec).
~i!ii
150 200 250 After Flash
300
Milliseconds
digitizing at a rate of 250 Hz (high and low pass filters set at 0.3 and 100 Hz, respectively) using Grass 1)511 amplifiers. After off-line averaging with elimination of trials with eye-blink artifact, the averaged wave form was plotted for each of the four intensities. The NI40 and P200 latencies were recorded by a researcher blind to clinical ratings of the patient. Interrater reliability for latencies was tested and found to be very high (r > 0.95). The latency change between the lowest intensity flash VEP and the highest intensity flash VEP was calculated (Figs. 1 and 2, P2 A). This variable indicates the within-subject change in latency from the low to high intensity flash condition (intensity l-intensity 2 latency). It was hoped that this measure might indicate both the baseline status (latency at low intensity) and the individuars response to increasing sensory input (latency at highest intensity). It was also hoped that this measure would control for interindividual variability at any particular flash intensity. Figure 1 shows two representative VEP wave forms. The lower wave form is averaged for the lowest flash intensity (30 foot lamberts) and the top wave form is averaged for the highest flash intensity (240 foot lamberts). Indicated in the figure are two variables of particular ic~terest, the P200 latency at the lowest flash intensity (P2 Low), and the P200 latency change from the lowest to the highest flash intensity (P2 A, P200 latency
P2 A
P Intensity
0
50
Figure 2. Average flash VEPs at lowest and highest flash intensities for a subject with very high ratings on positive symptoms. P2 Low is the P200 latency at low intensity, and P2 A is the change in P200 latency between the low and high intensity condition (Low P2High P2 latency in msec). Note the subject's much smaller P2 Low and I)2 A for thi~ sub ject compared with those in Figure 1.
IX~ !ii__\X 100 150 200 250 Milliseconds After Flash
300
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at lowest intensity-P200 latency at highest intensity) shown as the shaded area in the figure. This subject has a relatively prolonged P2 Low and a large positive P2 A. This pattern was characteristic of patients with predominantly negative symptoms in this study. Figure 2 shows the VEP wave forms from a patient with predominantly positive symptoms. The P2 Low for this subject and the P2 A score are smaller than those of the first subject. Although the majority of patients showed a "typical" pattern of reduced latency with increase in intensity, a number of high positive symptom patients had very small P2 Low values and a seemingly paradoxical increase in latency at the highest intensity. This pattern resulted m negative P2 A scores for these patients (4 of 7 in the high POS-NEG group, none of the 7 in the low POS-NEG group).
Data Analysis Analyses included initial testing of ci~nical and VEP variables for the assumption of normality of distribution using a standard statistical package (SAS, univariate procedure 1986). Patients were classified as either high POS-NEG or low POS-NEG based on a median split (upper 7 p~ients versus lower 7 patients on POS-NEG scores). Differences in group means for the latency measures were assessed using t-tests. In addition, Pearson's correlation coefficients between VEP latency measures and clinical rating scores were used to test for significance of association. One-tail testing was used because of the directional nature of the hypotheses. Significant correlations for the average clinical scores were followed up with examination of the individual subscales to further define which symptoms contributed most to the relationships. Correlations between possible confounders, including medication dosage, chronicity, and age, were calculated and tested for significant effects. The influence of potential confounders was also assessed using multiple regression and partial correlations, statistically controlling for the influence of each of the variables.
Results When patients were divided into those with highest versus lowest POS-NEG scores, no significant N140 latency differences were noted between the groups, although there was a consistent trend for the high POS-NEG patients to ha,,e shorter latencies. No significant correlations were noted between any of the NI40 latency values and symptom rating scales, though a strong trend was found for a correlation between POS SX and N I40 latency at the lowest intensity (negative correlation, p < 0.10). Table 2 shows the means and standard deviations of the P200 latencies at each of the four intensities (3, 40, 80, 240 foot lamberts), and for the P200 A. Mean values are shown for all patients as well as values for patients divided by their POS-NEG score, as in Table 1. The mean values show the high POS-NEG patients to have consistently reduced latencies compared with the low POS-NEG group, except at the very highest intensity, where the ~ u e s are virtually identical. These differences reached statistical significance for the latencies at the two lowest flash intensities and for the P200 A score. The mean P200 ~ score for high positive symptom patients was actually negative because of 4 patients who had larger latencies at intensi~" 4 than at intensity 1. The table shows that the mean P200 latency at intensity 1 for the high POS-NEG patients is less than the mean latency value at the highest intensity in the
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Table 2. P200 Latency Measures For All Patients and Patients Grouped by Symptoms (High POS-NEG, Low POS-NEG) Variable (msec) P200 Latency
All pts
High PGS-NEG ~
(N = 14)
(N = 7)
196.85 (28.47) 188.57 (27.48) 185.86 (20.71) 189.43 (20.49) 7.43 (28.15)
intensity 1
P200 Latency intensity 2
P200 Latency intensity 3 P200 Latency intensity 4
P200 Ad
Low POS-NEGe (N = 7)
178.29 (20.38) 173.71 (20.51) 181.14 (22.71) 189.71 (26.52) - 11.43 (19.92)
215.43 b (23. i4) 203.43 c (26.48) 188.57 (19.52) 189.14 (14.37) 26.2~ (22.13)
Mean SD. °High POS-NEG patientsare those with positive-negativesymptom scores above the median, and Low POS-NEG patients have scores below the median score. High POS-NEG patients have predominantly positive symptoms, Low POS-NEG have predominantly negative symptoms. bHigh POS-NEG patients significantly smaller than Low POS-NEG patients, p < 0.005, one-tailed t-test. thigh POS-NEG patients significantly smaller than Low POS-NEG patients, p < 0.05, one-tailed t-test. 'tp200 change score (P200 latency intensity l--P200 latency intensity 4)
low POS-NEG patients. This finding suggests a floor effect, with high POS-NEG patients being near their minimum latency even at the lowest flash intensity. The Pearson correlation coefficients are shown in Table 3 for the P200 latency variables versus the clinical symptom scores. Correlations were calculated between clinical ratings (POS SX, NEG SX, POS-NEG) and the P200 latencies (at each of the 4 intensities, 3, 30, 80, 240 foot lamberts) and the latency change score (P200 A). A number of significant negative correlations between POS SX and the P200 latency measures are shown (Table 3). These correlations were significant at the lowest intensity conditions (3 and 30 foot lamberts). The latency change variable, P200 A, showed even Stronger correlations than the individual latencies (p < 0.01). The NEG SX score (as me:,sured by the SANS) was not significantly correlated with the P200 latencies. There was, however, a significant positive correlation between NEG SX and the latency change variable, P200 A (p < 0.05). A number of the correlations between the symptom contrast variable, POS-NEG, and P200 latency measures were significant and negative. These correlations were slightly stronger but comparable with the POS SX correlations.
Table 3. Pearson Correlations Between P200 Latency Variables and Clinical Symptom Scores P200 Latencies by Intensity~
POS SX NEG SX POS-NEG
3
30
80
240
P200Ab
- 0.522 c 0.264 - 0.549 ~
- 0.577c 0.185 - 0.54Y
- 0.0t3 - 0.126 0.062
0.200 --0.267 0.305
- 0.674 c 0.462 ~ - 0.777 ~
alntensity in foot lamberts. bp200 latency change (low int. - high ;~nt.). Cp < 0.05,
dp <
0.01, ep < 0.001 (one-tailed).
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POS
SX
it
r=-.67
•
p < .01
ol
NEG
Figure 3. Scatter plots of the individual clinical rating scores versus the P200 A values (with-in subject P200 latencychange score from lowest to highest intensity flash, 1)2 Low-P2 High). Number 2 represents 2 subjects with values that are almost identical.
SX ,k
• •
r = +.46
p < .05
O" .
r = -.78
II
•
• • •
p < .001
.
POS-NEG 0 -2
i
-50
-25
P200 A
l
I
l
0
25
50
I
75
(milliseconds)
Figure 3 shows the raw data in scatterplot form for variable P200 A versus the three clinical symptom variables. The strong negative correlation between POS SX and P200 A is shown in the top plot. A very similar correlation between POS-NEG and 1)200 A is shown in the lower plot. The center plot shows the positive correlation between NEG SX and P200 A. The plots show that 4 patients with predominantly positive ~ymptoms had negative P200 A scores, which was due to their relatively brisk latencies at the lowest intensity and prolonged latencies at the highest intensity. This was most apparent for the patient with the highest positive symptom rating. Although NEG SX was not as strongly associated with latency values at POS SX or POS-NEG, examination of the individual SANS subscales showed that affective blunting was positively correlated with P2 Low, (r - +0.64, p < 0.01) and P200 A (r = +0.64, p < 0.01). Though not significant, there was also a positive association between the anhedonia-asociality score on the SANS and both the low intensity P200 latency and the P200 A (p < 0.10). Conversely, the SANS subscale, inattention, was nonsignificantly correlated with latency measures in the opposite direction compared with all other negative symptom scores (negative correlation with latency variables) and may explain the lack of stronger correlations for NEG SX (average SANS score). When patients were divided into those with moderate-to-severe affective blunting (N = 5) and those without affective blunting (N = 9), highly significant differences were noted for P200 latency at the lowest intensity and for P200 A (p < 0.01 for both, one-tailed t-test). Of the positive symptom factors of the BPRS, hostility and activation factors were most highly correlated with latency measures (r ffi -0.51 and r = -0.50, p < 0.05, respectively), with thought disorder being correlated less strongly (r = -0.39, p < 0.1). The individual SANS score and BPRS factor score correlations should be considered descriptive only, due to small numbers, discreteness of the measures, and less consistency with the normality assumption needed for correlational analysis.
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In an attempt to rule out confounding effects of neuroleptic medication, age, :and chronicity, correlations between these variables and P200 latencies were calculated. Chlorpromazine equivalents, age, and chronicity (as measured by total months hospitalized) were not significantly associated with the latency variables. A multiple regression approach, adding each of the confounders individually did not show any of the potential confounders to explain a significant portion of the latency variance. When all potential confounders were included in the model, symptom ratings continued to explain a significant portion of the variance in the model. Discussion The findings support the hypothesis that reduced VEP latencies are related to positive symptoms of schizophrenia (i.e., negatively correlated). This relationship is strongest at low intensity flash conditions and for the within-subject latency change score. Examination of individual factor scores of the BPRS showed consistent negative correlations with each positive symptom factor (thought disturbance, hostility, and activation). The data also support the hypothesis that prolonged VEP latencies are related to negative symptoms of schizophrenia (i~e., positively correlated), although the findings are less robust. When individual scale scores of the SANS were examined, significant associations were found between VEP latency variables (in the low intensity conditions) and the affective blunting and anhedonia-asociality ratings. There was an opposite correlation with the inattention rating. Supporting the relationship between affective blunting and prolonged latencies was the finding of significantly prolonged latencies in patients grouped by presence or absence of moderate-to-severe affective blunting. Although confounding cannot be ruled out, the latency values did not correlate significantly with medication dosage (daily chlorpromazine equivalents), age, or chronicity, nor did these variables account for the significant relationships when examined in a multiple regression model. The data are consistent with previous EP studies showing reduced EP latencies in patients with more positive symptoms (Saletu et al. 1973; Roth et al. 1980; SchIor et al. 1985) and prolonged latencies in patients with affective blunting (Saletu et al. 1973). Although little is known of the exact neuroanatomical source of the P200 wave, it, along with the rest of the "vertex potential," is effected by "the state of the subject, and by a wide variety of psychological variables related to cognitive processing (Goff et al. 1978). Goff et al. cite evidence that these wave forms likely arise from modality nonspecific brainstem and thalamic reticular projection systems. This makes the wave form seasitive to arousal level and ability to habituate to sensory stimuli (Buchsbaum 1977). An abnormally reduced P200 latency at low flash intensity and reduced change with increasing intensity, or a paradoxical increase in latency with increasing stimulus intensity, might represent increased arousal or a defect in neural inhibition, which has been postulated as a core feature of schizophrenic symptomatology and having EP correlates (Callaway 1979; Freedman et al. 1983). The data, therefore, might indicate that patients having the shortest latencies and highest positive symptom ratings have high baseline arousal and are least able to habituate to sensory stimuli. If true, we would then assume that patieats with prolonged latencies at intensity I and having the greatest latency change score would lower baseline arousal and be most able to habituate to !ow intensity sensory input. The data may be relevant to literature showing relationships between central dopamine (DA) activity and VEP latencies (Bodis-Wollner et al. 1982), and studies implicating central DA involvement in the production of positive symptoms of schizophrenia (Mackay and Crow
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1980; McKenna 1987; Meltzer 1987). There is evidence that some changes in the EP, especially latency changes, can be effected not only by psychological state, but by changes in central DA activity. Animal and human studies have shown reduction of visual evoked potential (VEP) latencies following central DA stimulation and latency prolongation after DA antagonists (Rey et al. 1980; Onofrj and Bodis-Wollner 1982). in addition, prolonged VEP latencies have been noted in Parkinson's disease (Bodis-Wollner et al. 1982), a DA deficiency state, with correction of the abnom~ality after successful DA precursor therapy. The same authors noted prolongation of VEP latencies after neuroleptic treatment in schizophrenic patients, as earlier noted by Salem (1977) and others. These studies consistently show a reduction of EP latencies after the administration of agents that increase central DA activity, and prolongation of EP latencies after DA blocking agents or under conditions of known DA hypofunction such as Parkinson's disease. Nonspecific effects on arousal and habituation cannot be ruled out in explaining these results. However, the results in Parkinson's patients are hard to explain on the basis of arousal alone. Although indirect, the data therefore might be considered supportive of DA involvement in positive symptoms of schizophrenia. The data also support the possibility of a relative decrease in arousal and possibly DA activity in patients with predominantly negative symptoms. This relationship seems to be most pronounced for two items from the negative symptom assessment scale---affective blunting and anhedonia-asociality. In the current sample, inattention was actually more related to positive than to negative symptoms and showed a relationship to latencies similar to the positive symptom ratings. The limitations of the study include the small sample size, presence of medication including the possibility of medication-induced negative symptoms, lack of I.Q. data on patients, heterogeneity of the group with regards to chronicity, and lack of control for nonspecific arousal. Although patients were closely matched on some of these factors, there was a trend for those with more positive symptoms to be less chronic. I~uture studies should involve larger numbers of medication-free patients with more similar course of illness. Although gender was not a confounder, future studies with female patients would be informative to explore whether or not these relationships are generalizable to female patients. In addition, simultaneous measures of central DA activity would be helpful in drawing stronger conclusions. These measures could include plasma or cerebrospinal fluid DA metabolites, or a more indirect measure such as eye blink rate. Lastly, it would be informative in future studies to test patients on both an EP paradigm and on a paradigm more specific to generalized arousal (startle/habituation paradigm) in order to assess the relationship between these measures and attempt to test for a specific neural inhibitory abnormality versus general arousal effects. Although the present evidence should be conside~d ~0reliminary in nature, it supports previous findings of relationships between psychotic symptomatology and EP parameters. It is unclear, however, whether or not this relationship is related to a specific abnormality in sensory processing, or merely differences in baseline arousal. If further studies show close correlations between VEP measures and central DA activity, the VEP might be useful as a noninvasive technique for describing the neurophysiological and central neurochemical status of patients.
References Andreasen NC (1982): Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry 39:784-788.
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Andreasen NC, Olsen S (1982): Negative v positive schizophrenia: Definition and validation. Arch Gen Psychiatry 39:789-794. Baldessarini ILl (1985): Chemotherapy in Psychiatry: Principles and Practice. Cambridge, Mass: Harvard University Press, pp 14-92. Bodis-Wollner I, Yahr MD, Mylin L, Thornton J (1982): Dopaminergic deficiency and delayed visual evoked potentials in humans. Ann Neurol 1.t :478-483. Buchsbaum MS (1977): The middle evoked response components and schizophrenia. Schizophr Bull 3:93-104. Callaway E (1979): Schizophrenia and evoked potentials. In Begleiter H (ed), Evoked Brain Potentials and Behavior, vol. 2. New York: Plenum Press, pp 419-435. Carts S V, Armstron MS, Ward PB, McConaghy (1986): Reduced P200 latency and allusive thinking: An auditory evoked potential index of a cognitive predisposition to schizophrenia? Int J Neurosci 30:173-179. Connolly JF, Gmzelier JH, Manchanda R, Hirsch SR (1983): Visual evoked potentials in schizophrenia: intensity effects and hemispheric a.~yw~e~y. Br J Psychiatry 142:152-155. Freedman R, Adler LE, Waldo MC, Pachtman E, Franks R (1983): Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: Comparison of medicated and drug-free patients. Biol Psychiatry 18:537-551. Goff WR, Allison T, Vanghan HG (1979): The functional neuroanatomy of event-related potentials. In Calloway E, Tueting P, Koslow SH (eds), Event-Related Potentials in Man. New York: Academic Press, pp 1-79. Josiassen RC, Shagass C, Roemer RA (1988): Somatosensory evoked potential correlates of schizophrenic subtypes identified by the Million Clinical Multiaxial Inventory. Psychiatry Res 23:209219. Landau SG, Buchsbaum MS, Carpenter W, Strauss J, Sacks M (1975): Schizophrenia and stimulus intensity control. Arch Gun Psychiatry 32:1239-1245. Mackay AVP, Crow TJ (1980): Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 137:379-386. McKenna PJ (1987): Pathology, phenomenology and the dopamine hypothesis of schizophrenia. Br J Psychiatry 151:288-301. Meltzer HY (1987): Biological studies in schizophrenia. Schizophr Bull 13:77-111. Onofrj M, Bodis-Wollner I (1982): Dopaminergic deficiency causes delayed visual evoked potential in rats. Ann Neurol 11:484-490. Overall JE, Gorham DR (1962): The brief psychiatric rating scale. Psychol Rep 10:779-812. Overall JE, Hollister LE, Pichot P (1967): Major psychiatric disorders: A four-dimensional model. Arch Gen Psychiatry 16:146-151. Rey AC, Buchsbaum MS, Post RM (1980): Apomorphine, haloperidol and the average evoked potentials in normal human volunteers. Commun Psychopharmacol 4:327-334. Romani A, Zerbi F, Mariotti G, Callieco R, Cosi V (1986): Computed tomography and pattern reversal visual evoked potentials in chronic schizophrenic patients. Acta Psychiatr Scand 73:566573. Roth WT, Horvath TB, Pfefferbaum A, Kopell BS (1980): Event-related potentials in schizophrenics. Electroenceph Clin Neurophys 48:127-139. Saletu B (1977): The evoked potential in pharmacopsychiatry. Neuropsychobiology 3:75-104. Saletu B, Saletu M, Itil TM (1973): The relationships between psychopathology and evoked responses before, during, and after psychotropic drug treatment. Biol Psychiatry 6:45-74. SAS Institute lnc (1985): SAS/STAT Guide for Personal Computers, ed 6. Cary, North Carolina: SAS !nstitute inc.
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Schlor KH, Moises HW, Haas S, Rieger H (1985): Schizophrenia, psychoticism, neuroleptics, and auditory evoked potentials. Pharmacopsychiatry 18:293-296. Shagass C (1980): Brain potential studies of psychopathology. Comp Psychiatry 21:483-491. Spitzer RL, Williams JBW, Gibbon M (1987): Structured Clinical Interview for DSM-HI-R (Patient Version SCID-P, 4-1-87). New York: Biometrics kesearch Department, New York State Psychiatric Institute.
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Visual Evoked Potential Correlates of Positive/Negative Symptoms in Schizophrenia Steven B. Schwarzkopf, J. Steven Lamberti, Maureen Jiminez, Catherine F. Kane, Michael Henricks, and Henry A. Nasrallah
Previous studies of schizophrenic patients have found evoked potential (EP) correlates of clinical symptomatology, including EP differences between subtypes of schizophrenia. In the current study, 14 medicated male schizophrenics underwent flash visual evoked potentials (VEP) and were clinically rated for positive and negative symptoms. We tested the hypothesis that positive symptoms would be associated with VEP latency reduction and negative symptoms with latency prolongation. Patients were divided into predominantly positive symptom and predominantly negative symptom groups using a combination of positive and negative symptom ratings. Patients with predominantly positive symptoms exhibited reduced latencies when compared with predominantly negative ~m~tom patients. Similarly, significant negative correlations between positive symptom ratings and P200 latency variables were found. Correlations between negative symptom measures and P200 latencies (in the opposite direction) were also noted, but were less significant. These relationships persisted when confounders were statistically controlled for. The results are consistent with previous findings of evoked potential correlates of clinical symptomatology, especially those finding EP latency correlates of psychosis severity and affective blunting. The findings are discussed in relationship to concepts relevant to psychosis, including arousal, sensory gating, and the dopamine hypothesis.
Introduction A number of studies have reported significant relationships between schizophrenic symptom patterns and EP parameters. Shagass (1980), in a review of findings, noted that schizophrenic patients who were chronic, "floridly psychotic," and less depressed, exhibited greater amplitudes and reduced wave shape variability in the first 100 msec after stimulus (visual and somatosensory modalities included) compared with other schizophrenic patients. This finding was recently replicated in a study dividing carefully diagnosed schizophrenic patients into psychotic versus nonpsychotic subgroups based on a self-administered personality inventory (Josiassen et al. 1986). Differences between schizophrenic subgroups have also been reported in a number of
From the Ohio State University College of Medicine, Columbus, Ohio (S.B.S., H.A.N.); and University of Rochester, Rochester, New York (J.S.L., M.J., C.F.K., M.H.) Address reprint requests to Dr. Steven B. Schwarzkopf, Ohio State University College of Medicine, 473 W. 12th AVE., Columbus, OH 43210-1228. Received August 27, 1988; revised May 7, 1989.
© 1990 Societyof BiologicalPsychiatry
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studies using EP paradigms with stimuli of varying intensity. Using this type of EP paradigm, acute and chronic patients have been reported to differ on VEP measures (Landau et al. 1975). Connolly et al. (1983) also using visual stimuli of differing intensities, found topographical differences in the locatioa of abnormalities, depending on the patient's clinical symptoms. A left temporal a~normality was noted in "nuclear" schizophrenics and a left occipital deviation was noted in patients with hypomania and anxiety symptoms. Clinical correlates relevant to "positive" and "negative" psychotic symptoms have been observed in the NI00 and P200 EP latencies. Studies have found reduced latencies in schizophrenic patients with more "positive" symptoms (Saletu et al. 1973; Roth et al. 1980; Schlor et al. 1985) in college students with evidence of looseness of associations (Catts et al. 1986) and in controls with high ratings on psychoticism (Schlor et al. 1985). Saletu et al. (1973) also noted prolonged latencies in patients with "blunt affect," one of the primary negative symptoms. VEP latency differences have also been noted in schizophrenic patients with versus without a first degree family history of psychiatric illness (Romani et all. 1996): Based on these studies, we tested the hypothesis that patients with predominantly positive symptoms would have reduced VEP latencies compared with patients who have predominantly negative symptoms. Similarly, we tested for significant correlations between clinical symptom ratings and latency measures. VEP latencies (N140 and P200 wave) at fot~" intensities of light were measured as the variables of interest. VEPs and assessments for positive and negative symptoms were collected for 14 medicated male schizophrenic patients. Potential confounders, including neuroleptic dose, age, and chronicity, were examined and statistically controlled for.
Methods
Subjects Fourteen consecutively admitted, physically healthy, medicated, male schizophrenic or schizoaffective patients (by DSM III-R, structured clinical interview [SCID] [Spitzer et al. 1987]) consented to participate in the study. Patients were part of an ongoing study of neurophysiological correlates of psychotic symptoms and treatment response. The mean age for the sample was 28.1 years (SD 6.2), mean lifetime hospitalization was 22.5 months (SD 22.4), and patients were on an average neuroleptic dose of 1059.8 mg chlorpromazine equivalents (SD 690) (Baldessarini 1985). Demographic information is shown in Table 1. Means and SDS are shown for all patients and for patients divided by predominance of positive and negative symptomatology (defined using a median split on a combined positive and negative symptom score). Patients with predominantly positive symptoms did not differ significantly from patients with predominantly negative symptoms on age, chronicity, and neuroleptic dose.
Symptom Ratings Positive and negative symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen 1982). Ratings were completed by a researcher blind to evoked potential findings. Factor scores consistent with positive symptoms were computed from
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Table 1. Descriptive Statistics For All Patients and Patients Grouped by Symptoms (High POS-NEG, Low POS-NEG) Variable Age (in years) Chronicity (mo. hosp.)b Neuroleptic dose (CPZ equiv.y Proportion schizoaffective
All pts (N = 14) 28.07 (6.17) 22.46 (22.43) 1059.79 (690.70) 3/14
High POS-NEG" (N = 7) 27.57 (6.19) 16.71 (i4.03) 1052.57 (608.37) 2/7
Low POS-NEG a (N = 7) 28.57 (6.60) 29.17 (29.51 ) 1067.00 (814.5) 117
Mean SD. °High POS-NEG patients are those with positive-negtive symptom scores above the median, and Low POS-NEG patients have scores below the median score. High POS-NEG generally with predominantly positive symptoms, Low POS-NEG generally with predominantly negative symptoms. aChronicity in total months hospitalized. CChlorpromazine equivalents of neuroleptic medication.
the BPRS (factors: hostility, thought disorder, and activation), (Overall et al. 1967). The average of the three factor scores was used as the positive symptom score (POS SX). The average of the five global subscores of the SANS was used as the negative symptom score (NEG SX). Clinical variables for analysis included POS SX score, NEG SX score, and a contrast variable, POS-NEG, calculated by subtracting the NEG SX score from the POS SX score. The POS-NEG score is larger and positive if the patient has predominantly positive symptoms, and small or negative if negative symptoms predominate.
Testing Procedure A flash evoked potential (VEP) with varying stimulus intensity was chosen because of its previous use in differentiating subtypes of schizophrenic patients, recent focus on sensory gating in schizophrenia, and the potential for a more informative and powerful measure when using a within-subjects measure (i.e., change from one condition to another within the same subject). VEPs were recorded at CZ (monopolar recording, linked ear reference) to four intensities of light as detailed by Landau et al. (1975). Gold electrodes were used with skin impedance kept below l0 Kohm. The photostimulator was custom built to specifications of Landau et al. (1975), using a fluorescept screen (40 × 20 cm), with flash intensities of 3, 30, 80, and 240 foot iamberts measured at 50 cm from subject (distance at time of testing). Hash duration was 500 msec, interstimulus interval 988 msec, with intensities presented in a "pseudorandom" order (each intensity preceded each other intensity an equal number of times). A minimum of 50 nonartifacted trials were collected (EOG recorded with lateral and superior orbital electrodes). Electrooculograph (EOG) was monitored to rule out eye blink artifact using 100 IxV as the rejection criterion. Amplitude rejection criterion for CZ was also set at i00 ~V. Visual fixation on the center of the screen was the only task during testing. VEP latei~cies were measured using the following criteria: (1) P 100 as the maximal positivity from 60 msec to 140 msec, (2) Nl¢0 as Re maximal negativity from 80 msec to 180 msec, (3) P200 as the maximal positivity between 140 msec and 280 msec. NI40 and P200 peaks were easily identified for all patients. All recording involved online
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P2 A . . . . . . . . . . .
High
;
~
5'0
/
1(}0
Figure 1. Average flash VEPs at lowest and highest flash intensities for a single subject. P2 Low is the P200 latency at low intensity, and P2 A is the change in P200 latency between the low and high intensity condition (Low P2-High P2 latency in msec).
~i!ii
150 200 250 After Flash
300
Milliseconds
digitizing at a rate of 250 Hz (high and low pass filters set at 0.3 and 100 Hz, respectively) using Grass 1)511 amplifiers. After off-line averaging with elimination of trials with eye-blink artifact, the averaged wave form was plotted for each of the four intensities. The NI40 and P200 latencies were recorded by a researcher blind to clinical ratings of the patient. Interrater reliability for latencies was tested and found to be very high (r > 0.95). The latency change between the lowest intensity flash VEP and the highest intensity flash VEP was calculated (Figs. 1 and 2, P2 A). This variable indicates the within-subject change in latency from the low to high intensity flash condition (intensity l-intensity 2 latency). It was hoped that this measure might indicate both the baseline status (latency at low intensity) and the individuars response to increasing sensory input (latency at highest intensity). It was also hoped that this measure would control for interindividual variability at any particular flash intensity. Figure 1 shows two representative VEP wave forms. The lower wave form is averaged for the lowest flash intensity (30 foot lamberts) and the top wave form is averaged for the highest flash intensity (240 foot lamberts). Indicated in the figure are two variables of particular ic~terest, the P200 latency at the lowest flash intensity (P2 Low), and the P200 latency change from the lowest to the highest flash intensity (P2 A, P200 latency
P2 A
P Intensity
0
50
Figure 2. Average flash VEPs at lowest and highest flash intensities for a subject with very high ratings on positive symptoms. P2 Low is the P200 latency at low intensity, and P2 A is the change in P200 latency between the low and high intensity condition (Low P2High P2 latency in msec). Note the subject's much smaller P2 Low and I)2 A for thi~ sub ject compared with those in Figure 1.
IX~ !ii__\X 100 150 200 250 Milliseconds After Flash
300
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at lowest intensity-P200 latency at highest intensity) shown as the shaded area in the figure. This subject has a relatively prolonged P2 Low and a large positive P2 A. This pattern was characteristic of patients with predominantly negative symptoms in this study. Figure 2 shows the VEP wave forms from a patient with predominantly positive symptoms. The P2 Low for this subject and the P2 A score are smaller than those of the first subject. Although the majority of patients showed a "typical" pattern of reduced latency with increase in intensity, a number of high positive symptom patients had very small P2 Low values and a seemingly paradoxical increase in latency at the highest intensity. This pattern resulted m negative P2 A scores for these patients (4 of 7 in the high POS-NEG group, none of the 7 in the low POS-NEG group).
Data Analysis Analyses included initial testing of ci~nical and VEP variables for the assumption of normality of distribution using a standard statistical package (SAS, univariate procedure 1986). Patients were classified as either high POS-NEG or low POS-NEG based on a median split (upper 7 p~ients versus lower 7 patients on POS-NEG scores). Differences in group means for the latency measures were assessed using t-tests. In addition, Pearson's correlation coefficients between VEP latency measures and clinical rating scores were used to test for significance of association. One-tail testing was used because of the directional nature of the hypotheses. Significant correlations for the average clinical scores were followed up with examination of the individual subscales to further define which symptoms contributed most to the relationships. Correlations between possible confounders, including medication dosage, chronicity, and age, were calculated and tested for significant effects. The influence of potential confounders was also assessed using multiple regression and partial correlations, statistically controlling for the influence of each of the variables.
Results When patients were divided into those with highest versus lowest POS-NEG scores, no significant N140 latency differences were noted between the groups, although there was a consistent trend for the high POS-NEG patients to ha,,e shorter latencies. No significant correlations were noted between any of the NI40 latency values and symptom rating scales, though a strong trend was found for a correlation between POS SX and N I40 latency at the lowest intensity (negative correlation, p < 0.10). Table 2 shows the means and standard deviations of the P200 latencies at each of the four intensities (3, 40, 80, 240 foot lamberts), and for the P200 A. Mean values are shown for all patients as well as values for patients divided by their POS-NEG score, as in Table 1. The mean values show the high POS-NEG patients to have consistently reduced latencies compared with the low POS-NEG group, except at the very highest intensity, where the ~ u e s are virtually identical. These differences reached statistical significance for the latencies at the two lowest flash intensities and for the P200 A score. The mean P200 ~ score for high positive symptom patients was actually negative because of 4 patients who had larger latencies at intensi~" 4 than at intensity 1. The table shows that the mean P200 latency at intensity 1 for the high POS-NEG patients is less than the mean latency value at the highest intensity in the
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Table 2. P200 Latency Measures For All Patients and Patients Grouped by Symptoms (High POS-NEG, Low POS-NEG) Variable (msec) P200 Latency
All pts
High PGS-NEG ~
(N = 14)
(N = 7)
196.85 (28.47) 188.57 (27.48) 185.86 (20.71) 189.43 (20.49) 7.43 (28.15)
intensity 1
P200 Latency intensity 2
P200 Latency intensity 3 P200 Latency intensity 4
P200 Ad
Low POS-NEGe (N = 7)
178.29 (20.38) 173.71 (20.51) 181.14 (22.71) 189.71 (26.52) - 11.43 (19.92)
215.43 b (23. i4) 203.43 c (26.48) 188.57 (19.52) 189.14 (14.37) 26.2~ (22.13)
Mean SD. °High POS-NEG patientsare those with positive-negativesymptom scores above the median, and Low POS-NEG patients have scores below the median score. High POS-NEG patients have predominantly positive symptoms, Low POS-NEG have predominantly negative symptoms. bHigh POS-NEG patients significantly smaller than Low POS-NEG patients, p < 0.005, one-tailed t-test. thigh POS-NEG patients significantly smaller than Low POS-NEG patients, p < 0.05, one-tailed t-test. 'tp200 change score (P200 latency intensity l--P200 latency intensity 4)
low POS-NEG patients. This finding suggests a floor effect, with high POS-NEG patients being near their minimum latency even at the lowest flash intensity. The Pearson correlation coefficients are shown in Table 3 for the P200 latency variables versus the clinical symptom scores. Correlations were calculated between clinical ratings (POS SX, NEG SX, POS-NEG) and the P200 latencies (at each of the 4 intensities, 3, 30, 80, 240 foot lamberts) and the latency change score (P200 A). A number of significant negative correlations between POS SX and the P200 latency measures are shown (Table 3). These correlations were significant at the lowest intensity conditions (3 and 30 foot lamberts). The latency change variable, P200 A, showed even Stronger correlations than the individual latencies (p < 0.01). The NEG SX score (as me:,sured by the SANS) was not significantly correlated with the P200 latencies. There was, however, a significant positive correlation between NEG SX and the latency change variable, P200 A (p < 0.05). A number of the correlations between the symptom contrast variable, POS-NEG, and P200 latency measures were significant and negative. These correlations were slightly stronger but comparable with the POS SX correlations.
Table 3. Pearson Correlations Between P200 Latency Variables and Clinical Symptom Scores P200 Latencies by Intensity~
POS SX NEG SX POS-NEG
3
30
80
240
P200Ab
- 0.522 c 0.264 - 0.549 ~
- 0.577c 0.185 - 0.54Y
- 0.0t3 - 0.126 0.062
0.200 --0.267 0.305
- 0.674 c 0.462 ~ - 0.777 ~
alntensity in foot lamberts. bp200 latency change (low int. - high ;~nt.). Cp < 0.05,
dp <
0.01, ep < 0.001 (one-tailed).
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POS
SX
it
r=-.67
•
p < .01
ol
NEG
Figure 3. Scatter plots of the individual clinical rating scores versus the P200 A values (with-in subject P200 latencychange score from lowest to highest intensity flash, 1)2 Low-P2 High). Number 2 represents 2 subjects with values that are almost identical.
SX ,k
• •
r = +.46
p < .05
O" .
r = -.78
II
•
• • •
p < .001
.
POS-NEG 0 -2
i
-50
-25
P200 A
l
I
l
0
25
50
I
75
(milliseconds)
Figure 3 shows the raw data in scatterplot form for variable P200 A versus the three clinical symptom variables. The strong negative correlation between POS SX and P200 A is shown in the top plot. A very similar correlation between POS-NEG and 1)200 A is shown in the lower plot. The center plot shows the positive correlation between NEG SX and P200 A. The plots show that 4 patients with predominantly positive ~ymptoms had negative P200 A scores, which was due to their relatively brisk latencies at the lowest intensity and prolonged latencies at the highest intensity. This was most apparent for the patient with the highest positive symptom rating. Although NEG SX was not as strongly associated with latency values at POS SX or POS-NEG, examination of the individual SANS subscales showed that affective blunting was positively correlated with P2 Low, (r - +0.64, p < 0.01) and P200 A (r = +0.64, p < 0.01). Though not significant, there was also a positive association between the anhedonia-asociality score on the SANS and both the low intensity P200 latency and the P200 A (p < 0.10). Conversely, the SANS subscale, inattention, was nonsignificantly correlated with latency measures in the opposite direction compared with all other negative symptom scores (negative correlation with latency variables) and may explain the lack of stronger correlations for NEG SX (average SANS score). When patients were divided into those with moderate-to-severe affective blunting (N = 5) and those without affective blunting (N = 9), highly significant differences were noted for P200 latency at the lowest intensity and for P200 A (p < 0.01 for both, one-tailed t-test). Of the positive symptom factors of the BPRS, hostility and activation factors were most highly correlated with latency measures (r ffi -0.51 and r = -0.50, p < 0.05, respectively), with thought disorder being correlated less strongly (r = -0.39, p < 0.1). The individual SANS score and BPRS factor score correlations should be considered descriptive only, due to small numbers, discreteness of the measures, and less consistency with the normality assumption needed for correlational analysis.
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In an attempt to rule out confounding effects of neuroleptic medication, age, :and chronicity, correlations between these variables and P200 latencies were calculated. Chlorpromazine equivalents, age, and chronicity (as measured by total months hospitalized) were not significantly associated with the latency variables. A multiple regression approach, adding each of the confounders individually did not show any of the potential confounders to explain a significant portion of the latency variance. When all potential confounders were included in the model, symptom ratings continued to explain a significant portion of the variance in the model. Discussion The findings support the hypothesis that reduced VEP latencies are related to positive symptoms of schizophrenia (i.e., negatively correlated). This relationship is strongest at low intensity flash conditions and for the within-subject latency change score. Examination of individual factor scores of the BPRS showed consistent negative correlations with each positive symptom factor (thought disturbance, hostility, and activation). The data also support the hypothesis that prolonged VEP latencies are related to negative symptoms of schizophrenia (i~e., positively correlated), although the findings are less robust. When individual scale scores of the SANS were examined, significant associations were found between VEP latency variables (in the low intensity conditions) and the affective blunting and anhedonia-asociality ratings. There was an opposite correlation with the inattention rating. Supporting the relationship between affective blunting and prolonged latencies was the finding of significantly prolonged latencies in patients grouped by presence or absence of moderate-to-severe affective blunting. Although confounding cannot be ruled out, the latency values did not correlate significantly with medication dosage (daily chlorpromazine equivalents), age, or chronicity, nor did these variables account for the significant relationships when examined in a multiple regression model. The data are consistent with previous EP studies showing reduced EP latencies in patients with more positive symptoms (Saletu et al. 1973; Roth et al. 1980; SchIor et al. 1985) and prolonged latencies in patients with affective blunting (Saletu et al. 1973). Although little is known of the exact neuroanatomical source of the P200 wave, it, along with the rest of the "vertex potential," is effected by "the state of the subject, and by a wide variety of psychological variables related to cognitive processing (Goff et al. 1978). Goff et al. cite evidence that these wave forms likely arise from modality nonspecific brainstem and thalamic reticular projection systems. This makes the wave form seasitive to arousal level and ability to habituate to sensory stimuli (Buchsbaum 1977). An abnormally reduced P200 latency at low flash intensity and reduced change with increasing intensity, or a paradoxical increase in latency with increasing stimulus intensity, might represent increased arousal or a defect in neural inhibition, which has been postulated as a core feature of schizophrenic symptomatology and having EP correlates (Callaway 1979; Freedman et al. 1983). The data, therefore, might indicate that patients having the shortest latencies and highest positive symptom ratings have high baseline arousal and are least able to habituate to sensory stimuli. If true, we would then assume that patieats with prolonged latencies at intensity I and having the greatest latency change score would lower baseline arousal and be most able to habituate to !ow intensity sensory input. The data may be relevant to literature showing relationships between central dopamine (DA) activity and VEP latencies (Bodis-Wollner et al. 1982), and studies implicating central DA involvement in the production of positive symptoms of schizophrenia (Mackay and Crow
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1980; McKenna 1987; Meltzer 1987). There is evidence that some changes in the EP, especially latency changes, can be effected not only by psychological state, but by changes in central DA activity. Animal and human studies have shown reduction of visual evoked potential (VEP) latencies following central DA stimulation and latency prolongation after DA antagonists (Rey et al. 1980; Onofrj and Bodis-Wollner 1982). in addition, prolonged VEP latencies have been noted in Parkinson's disease (Bodis-Wollner et al. 1982), a DA deficiency state, with correction of the abnom~ality after successful DA precursor therapy. The same authors noted prolongation of VEP latencies after neuroleptic treatment in schizophrenic patients, as earlier noted by Salem (1977) and others. These studies consistently show a reduction of EP latencies after the administration of agents that increase central DA activity, and prolongation of EP latencies after DA blocking agents or under conditions of known DA hypofunction such as Parkinson's disease. Nonspecific effects on arousal and habituation cannot be ruled out in explaining these results. However, the results in Parkinson's patients are hard to explain on the basis of arousal alone. Although indirect, the data therefore might be considered supportive of DA involvement in positive symptoms of schizophrenia. The data also support the possibility of a relative decrease in arousal and possibly DA activity in patients with predominantly negative symptoms. This relationship seems to be most pronounced for two items from the negative symptom assessment scale---affective blunting and anhedonia-asociality. In the current sample, inattention was actually more related to positive than to negative symptoms and showed a relationship to latencies similar to the positive symptom ratings. The limitations of the study include the small sample size, presence of medication including the possibility of medication-induced negative symptoms, lack of I.Q. data on patients, heterogeneity of the group with regards to chronicity, and lack of control for nonspecific arousal. Although patients were closely matched on some of these factors, there was a trend for those with more positive symptoms to be less chronic. I~uture studies should involve larger numbers of medication-free patients with more similar course of illness. Although gender was not a confounder, future studies with female patients would be informative to explore whether or not these relationships are generalizable to female patients. In addition, simultaneous measures of central DA activity would be helpful in drawing stronger conclusions. These measures could include plasma or cerebrospinal fluid DA metabolites, or a more indirect measure such as eye blink rate. Lastly, it would be informative in future studies to test patients on both an EP paradigm and on a paradigm more specific to generalized arousal (startle/habituation paradigm) in order to assess the relationship between these measures and attempt to test for a specific neural inhibitory abnormality versus general arousal effects. Although the present evidence should be conside~d ~0reliminary in nature, it supports previous findings of relationships between psychotic symptomatology and EP parameters. It is unclear, however, whether or not this relationship is related to a specific abnormality in sensory processing, or merely differences in baseline arousal. If further studies show close correlations between VEP measures and central DA activity, the VEP might be useful as a noninvasive technique for describing the neurophysiological and central neurochemical status of patients.
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Schlor KH, Moises HW, Haas S, Rieger H (1985): Schizophrenia, psychoticism, neuroleptics, and auditory evoked potentials. Pharmacopsychiatry 18:293-296. Shagass C (1980): Brain potential studies of psychopathology. Comp Psychiatry 21:483-491. Spitzer RL, Williams JBW, Gibbon M (1987): Structured Clinical Interview for DSM-HI-R (Patient Version SCID-P, 4-1-87). New York: Biometrics kesearch Department, New York State Psychiatric Institute.