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Neuropsychological deficit and hypothetical risk for schizophrenia
636
BIOL PSYCHIATRY 1995:37:593-683
ceived one dose of MK801 (0.05, 0.1 or 0.5 mg/kg) and saline in a counterbalanced design (l week between tests). Thirty minutes after injection, animals were exposed to 5 minutes background noise (70 dB) followed by 5 types of startle stimuli (total of 111 trials): startle pulse alone (PA, 116 dB, 30 msec duration), and PA preceded by inhibitory prepulses (75, 80, or 85 dB, 30 msec duration), or by a facilitatory prepulse (73 dB, 10 msec duration). Baseline startle, percent inhibition/facilitation, and within session habituation were calculated. Complete disruption of PPI for all inhibitory trials occurred at the two higher doses of MK-801. Baseline amplitude and PPF were enhanced by low-dnse MK-801 but reduced by higher doses, and habituation of ASR was impaired by the higher doses. These findings further support the involvement of PCP or NMDA receptors in the modulation of sensory gating and suggest that unique sensory gating abnormalities result from NMDA antagonists and DA agonists. Similar patterns, if present in subgroups of schizophrenia patients, would provide indirect evidence for DA hyperactivity vs. hypoglutamatergia. Such differentiation could further our understanding of the pathophysiology and treatment resl:xmse of schizophrenic patients. (Supported by MH00859.)
153. AUDITORY ERPs IN SCHIZOPHRENIA: DIAGNOSTIC AND SYMPTOM CORRELATES S.B. Schwarzkopf, G.A. Light, J.S. Lamberti, & S.M. Silverstein University o f Rochester, Departments o f Psychiatry and Psychology, Rochester, NY 14642 Although physiologic abnormalities are well documented in schizophrenic patients, further study is needed to determine which abnormalities represent vulnerability markers vs. state-related phenomena. Mid- and long-latency cortical evoked response potentials (ERPs) are altered in schizophrenic patients, with conflicting findings regarding their state/trait characteristics. In this study, mid- and long-latency ERPs were measured in a paired click paradigm to assess relationships between ERP measures and both diagnostic category and acute symptomatology. Twenty two controls (n = 13/9 males/females) with no personal history of psychiatric illness or family history of schizophrenia and twenty two DSM-III-R schizophrenic patients (n = 13/9 males/females) underwent auditory ERP testing in a conditioning/testing paradigm as previously described. Amplitudes and latencies were calculated for waveforms occurring at approximately 50, 100, and 160 msec poststinmlus (P50, N1, and P2 waveforms respectively). Patients were rated on the PANNS scale for [x)sitive, negative, and general symptomatology (interrater reliability ICC > 0.75). Multivariate ANOVAs were performed for the amplitude and latency measures to assess diagnosis and gender effects. Spearman correlations were used to assess relationships between clinical symptomatology and amplitudes and latencies. Patients exhibited reduced N1 and P2, but similar P50 amplitudes, compared to controls (group x peak type interaction, p < 0.005). Latencies were reduced for the NI and P2 but not P50 waveforms in female patients only (group x peak type x gender interaction, p < 0.04). Lower P50 amplitudes predicted greater positive symptoms (p < 0.01, no gender difference) and less negative symptomatology (p < 0.05) for male and female patients. Findings are consistent with previous relx)rts indicating relatively normal early vs. late ERP amplitudes in schizophrenic patients; however, variability in the relatively "normal" P50 amplitude was highly predictive of specific clinical symptomatology. Findings suggest that P50 amplitude may be highly sensitive to alterations of the neural substrates underlying positive and negative schizophrenic symptoms. (Supported by MH00859.)
FRIDAY,, MAY 19
154. NEUROPSYCHOLOGICAL DEFICIT AND HYPOTHETICAL RISK FOR SCHIZOPHRENIA S.A. Bums, S.E. Miller, C.C. Evans, & L.S. Miller Department o f Psychology, The University o f Georgia, Athens, G A 30602-3013 Replicable findings of neuropsychological deficits, including abstraction, attention, memory, language, and motor impairments, have been found in a significant subset of schizophrenic patients. Research methods have also been utilized to identify persons predisposed or vulnerable to develop schizophrenia. To date, only limited attempts at identifying similar deficits have been reported in populations hypothetically at-risk for schizophrenia. We identified a smaller group of these subjects from self-report data collected via large group testing on over 1500 young adults using the Chapman Scales of Psychosis-Proneness: Magical Ideation, Perceptual Aberration, Physical Anhedonia, Social Anhedonia, and Impulsivity. Individuals identified as at increased risk for schizophrenia on the basis of these scales were administered a comprehensive neuropsychological battery (n = 49; 33 f, 16 m) and compared to a well-matched control group (n =28; 16 f, 12 m). There were no differences in age, race, or sex between the two groups. Deficits in the at-risk group as compared to controls included a substantial pattern of deficits in gross motor speed (Grooved Pegboard p < 0.01) and fine motor control (Finger Tapping p < 0.03), set-shifting (WCS-categories p < 0. 01), perseveration to stimuli (WCSperseverations p < 0.01 ) and verbal proficiency (WAIS-R Vocabulary p < 0.02). No deficits in visual and verbal memory, visuospatial tasks, or attentional measures were indicated for the at-risk group as compared to controls. Findings supported and extended previous research investigating discrete neuropsychological deficits in schizophrenics and at-risk individuals. Results are discussed in relation to possible neurodevelopmental mechanisms involved in the manifestation of schizophrenia.
155. THE ANTERIOR CINGULATE GLUCOSE METABOLIC RATE IN SCHIZOPHRENIA
M.M. Haznedar, M.S. Buchsbaum, E.A. Hazlett, L.Shihabuddin, M. Metzger, & B. Siegel Mount Sinai Medical Center, N e w York NY, 10029 Previous brain imaging studies with both positron emission tomography (PET) and cerebral blood flow have demonstrated a reduction in frontal activity in schizophrenic patients but have not differentiated among frontal regions. Postmortem studies have indicated neuroanatomical changes in the cingulate gyrus of schizophrenic patients. PET with fluorodeoxyglucose (FDG) were used to study the metabolic rate of the cingulate gyrus in a completely new cohort of 19 schizophrenic patients (mean age = 37.7, SD = 14.7) and 25 normal controls (mean age = 36.5, SD = 13.2). Subjects were scanned with our new high resolution (4.2-4.5 mm FWHM) scanner. Schizophrenia patients were off medication at least 2 weeks prior to the PET scanning. They met the DSM-III-R criteria for schizophrenia and were assessed by the Brief Psychiatric Rating Scale (BPRS), on the day of the scan. During the FDG uptake period, subjects performed a modified version of the California Verbal Learning Task (CVLT). We developed a stereotaxic template from the magnetic resonance imaging (MRI) scans of 16 subjects to examine better the anterior aspect of the cingulate cortex. Glucose metabolic rates (GMR) were determined using this template. Repeated measures ANOVA was used to analyze five different regions at three different levels of the cingulate cortex. GMR was significantly lower in the cingulate of the patients (p < 0.03,f = 3.01, df = 3.53). Exploratory correlation analysis showed negative correlations between the superior frontal gyms metabolic rate and the positive symptom subscale of the BPRS (p < 0.05, r= ~).51 ) and also negative
BIOL PSYCHIATRY 1995:37:593-683
ceived one dose of MK801 (0.05, 0.1 or 0.5 mg/kg) and saline in a counterbalanced design (l week between tests). Thirty minutes after injection, animals were exposed to 5 minutes background noise (70 dB) followed by 5 types of startle stimuli (total of 111 trials): startle pulse alone (PA, 116 dB, 30 msec duration), and PA preceded by inhibitory prepulses (75, 80, or 85 dB, 30 msec duration), or by a facilitatory prepulse (73 dB, 10 msec duration). Baseline startle, percent inhibition/facilitation, and within session habituation were calculated. Complete disruption of PPI for all inhibitory trials occurred at the two higher doses of MK-801. Baseline amplitude and PPF were enhanced by low-dnse MK-801 but reduced by higher doses, and habituation of ASR was impaired by the higher doses. These findings further support the involvement of PCP or NMDA receptors in the modulation of sensory gating and suggest that unique sensory gating abnormalities result from NMDA antagonists and DA agonists. Similar patterns, if present in subgroups of schizophrenia patients, would provide indirect evidence for DA hyperactivity vs. hypoglutamatergia. Such differentiation could further our understanding of the pathophysiology and treatment resl:xmse of schizophrenic patients. (Supported by MH00859.)
153. AUDITORY ERPs IN SCHIZOPHRENIA: DIAGNOSTIC AND SYMPTOM CORRELATES S.B. Schwarzkopf, G.A. Light, J.S. Lamberti, & S.M. Silverstein University o f Rochester, Departments o f Psychiatry and Psychology, Rochester, NY 14642 Although physiologic abnormalities are well documented in schizophrenic patients, further study is needed to determine which abnormalities represent vulnerability markers vs. state-related phenomena. Mid- and long-latency cortical evoked response potentials (ERPs) are altered in schizophrenic patients, with conflicting findings regarding their state/trait characteristics. In this study, mid- and long-latency ERPs were measured in a paired click paradigm to assess relationships between ERP measures and both diagnostic category and acute symptomatology. Twenty two controls (n = 13/9 males/females) with no personal history of psychiatric illness or family history of schizophrenia and twenty two DSM-III-R schizophrenic patients (n = 13/9 males/females) underwent auditory ERP testing in a conditioning/testing paradigm as previously described. Amplitudes and latencies were calculated for waveforms occurring at approximately 50, 100, and 160 msec poststinmlus (P50, N1, and P2 waveforms respectively). Patients were rated on the PANNS scale for [x)sitive, negative, and general symptomatology (interrater reliability ICC > 0.75). Multivariate ANOVAs were performed for the amplitude and latency measures to assess diagnosis and gender effects. Spearman correlations were used to assess relationships between clinical symptomatology and amplitudes and latencies. Patients exhibited reduced N1 and P2, but similar P50 amplitudes, compared to controls (group x peak type interaction, p < 0.005). Latencies were reduced for the NI and P2 but not P50 waveforms in female patients only (group x peak type x gender interaction, p < 0.04). Lower P50 amplitudes predicted greater positive symptoms (p < 0.01, no gender difference) and less negative symptomatology (p < 0.05) for male and female patients. Findings are consistent with previous relx)rts indicating relatively normal early vs. late ERP amplitudes in schizophrenic patients; however, variability in the relatively "normal" P50 amplitude was highly predictive of specific clinical symptomatology. Findings suggest that P50 amplitude may be highly sensitive to alterations of the neural substrates underlying positive and negative schizophrenic symptoms. (Supported by MH00859.)
FRIDAY,, MAY 19
154. NEUROPSYCHOLOGICAL DEFICIT AND HYPOTHETICAL RISK FOR SCHIZOPHRENIA S.A. Bums, S.E. Miller, C.C. Evans, & L.S. Miller Department o f Psychology, The University o f Georgia, Athens, G A 30602-3013 Replicable findings of neuropsychological deficits, including abstraction, attention, memory, language, and motor impairments, have been found in a significant subset of schizophrenic patients. Research methods have also been utilized to identify persons predisposed or vulnerable to develop schizophrenia. To date, only limited attempts at identifying similar deficits have been reported in populations hypothetically at-risk for schizophrenia. We identified a smaller group of these subjects from self-report data collected via large group testing on over 1500 young adults using the Chapman Scales of Psychosis-Proneness: Magical Ideation, Perceptual Aberration, Physical Anhedonia, Social Anhedonia, and Impulsivity. Individuals identified as at increased risk for schizophrenia on the basis of these scales were administered a comprehensive neuropsychological battery (n = 49; 33 f, 16 m) and compared to a well-matched control group (n =28; 16 f, 12 m). There were no differences in age, race, or sex between the two groups. Deficits in the at-risk group as compared to controls included a substantial pattern of deficits in gross motor speed (Grooved Pegboard p < 0.01) and fine motor control (Finger Tapping p < 0.03), set-shifting (WCS-categories p < 0. 01), perseveration to stimuli (WCSperseverations p < 0.01 ) and verbal proficiency (WAIS-R Vocabulary p < 0.02). No deficits in visual and verbal memory, visuospatial tasks, or attentional measures were indicated for the at-risk group as compared to controls. Findings supported and extended previous research investigating discrete neuropsychological deficits in schizophrenics and at-risk individuals. Results are discussed in relation to possible neurodevelopmental mechanisms involved in the manifestation of schizophrenia.
155. THE ANTERIOR CINGULATE GLUCOSE METABOLIC RATE IN SCHIZOPHRENIA
M.M. Haznedar, M.S. Buchsbaum, E.A. Hazlett, L.Shihabuddin, M. Metzger, & B. Siegel Mount Sinai Medical Center, N e w York NY, 10029 Previous brain imaging studies with both positron emission tomography (PET) and cerebral blood flow have demonstrated a reduction in frontal activity in schizophrenic patients but have not differentiated among frontal regions. Postmortem studies have indicated neuroanatomical changes in the cingulate gyrus of schizophrenic patients. PET with fluorodeoxyglucose (FDG) were used to study the metabolic rate of the cingulate gyrus in a completely new cohort of 19 schizophrenic patients (mean age = 37.7, SD = 14.7) and 25 normal controls (mean age = 36.5, SD = 13.2). Subjects were scanned with our new high resolution (4.2-4.5 mm FWHM) scanner. Schizophrenia patients were off medication at least 2 weeks prior to the PET scanning. They met the DSM-III-R criteria for schizophrenia and were assessed by the Brief Psychiatric Rating Scale (BPRS), on the day of the scan. During the FDG uptake period, subjects performed a modified version of the California Verbal Learning Task (CVLT). We developed a stereotaxic template from the magnetic resonance imaging (MRI) scans of 16 subjects to examine better the anterior aspect of the cingulate cortex. Glucose metabolic rates (GMR) were determined using this template. Repeated measures ANOVA was used to analyze five different regions at three different levels of the cingulate cortex. GMR was significantly lower in the cingulate of the patients (p < 0.03,f = 3.01, df = 3.53). Exploratory correlation analysis showed negative correlations between the superior frontal gyms metabolic rate and the positive symptom subscale of the BPRS (p < 0.05, r= ~).51 ) and also negative