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Does semantic “hyperpriming” correlate with impaired sensory gating in schizophrenia?
ABSTRACTS
Society of Biological Psychiatry 1994 Annual Meeting THURSDAY, MAY 19 I. VOLUNTARY AND INVOLUNTARY ATrENTIONAL DEFICITS IN.SCHIZOPHRENIA
D:L. Braff, D.L. Filion, N.R. Swerdlow, K.S. Cadenhead, & M.A. Geyer Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804 Numerous studies have been conducted in an attempt to identify whether the attentional deficits of schizophrenic patients are voluntary (a result of poor effort) or involuntary (a result of impaired, automatic processing). One paradigm that was introduced as a measure of involuntary information processing is the prepulse inhibition (PPl) of the startle response. A strong stimulus normally elicits a startle response. The introduction of a weak prepuise i 00 msec before the startle-eliciting stimulus causes a diminution of the startle response called the prepulse inhibition (PPl) effect. PPl is seen in infants and all mammals, supporting the view of PPl as a measure of volition-free automatic, involuntary processing. Schizophrenic patients exhibit deficient gating or PPl, supporting the view of schizophrenia as being characterized by deficient automatic processing of information. Recent studies have led investigators to re-think the traditional interpretation of PP! deficits in the group of schizophrenias. Data will be presented that I) delineate the subcorticai neural circuitry that modulates PPI; 2) clarify that PPi deficits occur in "boundary", non-psychotic schizophrenia spectrum patients (eg, schizotypal patients); and 3) support the use of new paradigms where attention is directed to the prepulse, resulting in increased PPi. in over 50 normal controls and schizophrenic patients, a new paradigm will be described that allows us to separate voluntary and involuntary attentional deficits in a single test session. The neurobiological substrate of schizophrenia and information processing will be reviewed in light of these studies.
2. IMPAIREDCOGNITIVE PROCESSING WITHIN 10 AUDITORY CORTEX IN SCHIZOPHRENIA
D.C. Javitt!'3, A.M. Shelley 1, S. Grochowski i, & W. Ritter2 Departments of Psychiatry ! and Neuroscience 2, Albert Einstein College of Medicine/Bronx Psychiatric Center 3, Bronx, NY 10461 © 1994Societyof Biological Psychiatry
Cognitive dysfunction represents a core feature of the schizophrenic syndrome and a primary cause of chronic disability. Deficits in cognitive information processing have been documented most extensively on tests that require involvement of association cortices within frontal, mesial temporal and temporoparietal brain regions. By contrast, information processing at the level of sensory cortex has been investigated to a limited degree, in the present study, cognitive event-related potentials (ERP) were utilized to investigate auditory information processing in schizophrenia at the level of primary auditory cortex. Mismatch negativity (MMN) is a short-duration cognitive ERP component that reflects detec. lion of stimulus deviance by neural structures within primary auditory cortex, in an auditory oddball paradigm, MMN precedes P300 by approximately 200 msec and indexes a prior stage of auditory information processing. In the present study, MMN generation was investigated in a group of medicated (n-20) and unmedicated (n-11) chronic schizophrenic subjects relative to age- and IQ matched normal volunteers (n-! i). MMN amplitude was decreased in unmedicated, as well as medicated, schizophrenic subjects relative to controls. Moreover, across groups, the deficit in MMN generation correlated significantly with the deficit in P3, suggesting that neurophysiological deficits in schizophrenia are present even at the level of primary cortex, in monkeys, deficits in MMN generation similar to those observed in schizophrenia may be induced by focal, intracortical infusion of competitive and non-competitive NMDA receptor antagonists, suggesting that NMDA receptor dysfunction or dysregulation may contribute significantly to the information processing deficits associated with schizophrenia.
3. DOES SEMANTIC "HYPERPRIMING" CORRELATE WITH IMPAIRED SENSORY GATING IN SCHIZOPHRENIA? S. Vinogradov !'2, S. Solomon l, B.A. Ober3.4, C. Biggins t,2, G.K. Shenaut3.4, & G. Fein t,2 IUniversity of California, San Francisco, San Francisco, CA 94143; 2Department of Veterans Affairs Medical Center, San Francisco, CA 94121; 3University of California, Davis, Davis, CA 95616; 4Department of Veterans Affairs Medical Center, Martinez, CA 94550 A number of investigators have suggested that schizophrenia may be characterized by a defect in inhibitory pathways which allows for faster or "'stronger" automatic information processing as compared to normals, and that this might account for the clinical findings of cognitive fragmentation seen in schizophrenic patients (e.g., the models of Frith, 1979; Cal0006-3223/94/$07.00
6 !6
BIOL PSYCHIATRY 1994;35:615-747
loway and Naghdi, 1982; Freedman et al., 1992; Braff et al., 1992). Semantic priming effects-- one of the most widely studied phenomena in cognitive psychology--- are experimental findings which relate to the simple discovery that subjects respond faster to a word (such as mouse) when it follows a related word (such as cat) than when it follows an unrelated word. The study of semantic priming effects provides a useful experimental tool for uncovering structural and processing characteristics of the semantic memory system, including basic information processing mechanisms such as spreading activation and attentional operations. We have studied a preliminary series of schizophrenic subjects who have undergone both a semantic priming experiment which examined mainly automatic information processing (spread of activation in the semantic memory network) and an auditory-evoked potential measure of sensory gating, the PS0 conditioning-testing (C/T) ratio, which examines automatic processing of auditory information. In our initial sample of subjects (n-7), we find a strong positive correlation between the PS0 C/T ratio and ~emantic priming effects obtained on the "automatic" semantic information processing task. Subjects who show greater-than-normal semantic priming effects ('hyperpriming") also show a failure to gate or inhibit their PS0 response to the testing stimulus. This finding may imply that a similar defect in inhibitory pathways underlies both impaired sensory gating and greater-than-normal automatic information processing or spread of activation in the semantic memory network of some schizophrenic subjects.
4. SENSORIMOTOR GATING OF THE HUMAN STARTLE REFLEX: GENDER AND LATERALITY N.R. Swerdiow, P.L. Hartman, & P.P. Auerbach Department of Psychiatry, UCSD School of Medicine, La Jolla,
THURSDAY, MAY 19
Previous work (Erwin et al. Biological Psychiatry, 1991) has suggested that there is a modest positive correlation between clinical symptomatology and recovery cycle abnormalities of the Pl component of midlatency auditory evoked potential in schizophrenia. However, this finding was not replicated in a more recent study (Erwin et al. Schizophrenia Research, in press). To further examine the relationship between these measures, midlatency auditory evoked potentials were recorded from 47 patients with schizophrenia in response to binaural clicks presented at three stimulus rates: I/sec, 5/sec and 10/sec. After computation of a recovery cycle measure (10/sec divided by l/sec Pl amplitudes) patients were divided into high abnormality (> 50% recovery) and low abnormality groups. Twelve patients from each of these groups who were matched on sex, age and race, and balanced for diagnostic subtype and medication status were then selected for use in the analysis of clinical measures. Summary measures obtained from the Brief Psychiatric Rating Scale (BPRS) reflecting symptoms specific to schizophrenia and nonspecific symptoms were used as dependent measures in a mixed model analysis of variance in which low and high Pl abnormality groups were contrasted. A significant Group x BPRS measure interaction (F-4.52, p <.05) was obtained. The low Pl recovery cycle abnormality group had greater BPRS scores for symptoms specific to schizophrenia than did the high abnormality group. These findings suggest that Pl abnormalities in schizophrenia as assessed by this protocol may in part reflect compensatory mechanisms rather than inherent neurobiological abnormalities.
6. NEUROPSYCHOLOGICAL FUNCTION AND NOVEL P300 IN SCHIZOPHRENICS
C A 92093-0804
The acoustic startle reflex is normally inhibited when the startling stimulus is preceded by a weak prepulse. In a recent report (Swerdlow et al. Biol Psychiat 34: 253-260,1993), we observed striking gender differences in this "prepulse inhibition" (PPI) of the startle reflex. Specifically, the startle reflex in males was significantly more inhibited by weak prepulses than was the startle reflex in female control subjects. A retrospective analysis of data from our previously published studies in psychiatric patients and normal controls supported this observation, in order to assess potential hormonal substrates for the observed gender differences in PPI, we measured eyeblink startle and PPi in female controls during different portions of the menstrual cycle. Subjects were selected using established criteria to exclude individuals with psychiatric disorders, substance abuse, serious neurologic or medical illness or pregnancy; subjects were also excluded for use of oral contraceptives or if they noted menstrual cycle instability. PPl was then compared using menstrual phase (follicular vs. luteal) as the betweensubject variable. Because of observations of gender differences in hemispheric laterality and our own data suggesting limbic cortical modulation of PPl, we also examined laterality differences in PPl in male and female control subjects. PPl in these individuals was assessed using EMG measures of right and left orbicularis oculi, in total, these data address the neural and hormonal substrates of gender differences in sensorimotor gating.
5. PI RECOVERY CYCLE ABNORMALITIES AND CLINICAL PHENOMENOLOGY IN SCHIZOPHRENIA R.J. Erwin, R.C. Gur, & R.E. Gur Dept. of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104
E. L. Merrin !,2, T.C. Floyd !, & R. F. Deicken 1,2 tPsychiatry Service, San Francisco DVA Medical Center, 2Depm~ment of Psychiatry, University of California at San Francisco The relationship between neuropsychological performance and P300 responses to novel auditory stimuli were studied in 14 DSM-liI-R male schizophrenics (predominantly medicated) and 14 male hospital employees without histories of major psychiatric disorders. Subjects were in. structed to respond with a finger lift to infrequently occurring (probability - . 15) 2000 Hz target tones while ignoring frequent 1000 Hz background tones and infrequently occurring (p=. 15) novel auditory stimuli. EEG recordings from 16 electrode sites were transformed to source derivation and ERP component latencies identified from peaks in Global Field Power (GFP). During a separate session all subjects were administered a battery of tests including the Wisconsin Card Sort (WCS) and parts of the Wechsler Memory Scale-Revised. in both groups, a higher rate of perseverative errors on the WCS was associated with decreases in P300 amplitude, particularly after novel stimuli. However, this effect was localized differently in the two groups, primarily right central/parietal in sch.;zophrenics (p-.007) but bilateral frontal and inferior frontal in normal controis (p-.007). Higher perseverative error scores also predicted slower P300 latencies in the novel condition (p-.023). There were additional correlations between left-sided P300 amplitude and verbal memory performance in schizophrenics only (p-.002). None of these effects were present for a standard oddball paradigm administered during the same session. Correlations between negative symptoms and both P300 amplitude/GFP and WCS performance were also observed. The results suggested complex relationships between functioning of the prefrontal cortex, cognition, and generation of P300 responses to novel stimuli in schizophrenics.
Society of Biological Psychiatry 1994 Annual Meeting THURSDAY, MAY 19 I. VOLUNTARY AND INVOLUNTARY ATrENTIONAL DEFICITS IN.SCHIZOPHRENIA
D:L. Braff, D.L. Filion, N.R. Swerdlow, K.S. Cadenhead, & M.A. Geyer Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804 Numerous studies have been conducted in an attempt to identify whether the attentional deficits of schizophrenic patients are voluntary (a result of poor effort) or involuntary (a result of impaired, automatic processing). One paradigm that was introduced as a measure of involuntary information processing is the prepulse inhibition (PPl) of the startle response. A strong stimulus normally elicits a startle response. The introduction of a weak prepuise i 00 msec before the startle-eliciting stimulus causes a diminution of the startle response called the prepulse inhibition (PPl) effect. PPl is seen in infants and all mammals, supporting the view of PPl as a measure of volition-free automatic, involuntary processing. Schizophrenic patients exhibit deficient gating or PPl, supporting the view of schizophrenia as being characterized by deficient automatic processing of information. Recent studies have led investigators to re-think the traditional interpretation of PP! deficits in the group of schizophrenias. Data will be presented that I) delineate the subcorticai neural circuitry that modulates PPI; 2) clarify that PPi deficits occur in "boundary", non-psychotic schizophrenia spectrum patients (eg, schizotypal patients); and 3) support the use of new paradigms where attention is directed to the prepulse, resulting in increased PPi. in over 50 normal controls and schizophrenic patients, a new paradigm will be described that allows us to separate voluntary and involuntary attentional deficits in a single test session. The neurobiological substrate of schizophrenia and information processing will be reviewed in light of these studies.
2. IMPAIREDCOGNITIVE PROCESSING WITHIN 10 AUDITORY CORTEX IN SCHIZOPHRENIA
D.C. Javitt!'3, A.M. Shelley 1, S. Grochowski i, & W. Ritter2 Departments of Psychiatry ! and Neuroscience 2, Albert Einstein College of Medicine/Bronx Psychiatric Center 3, Bronx, NY 10461 © 1994Societyof Biological Psychiatry
Cognitive dysfunction represents a core feature of the schizophrenic syndrome and a primary cause of chronic disability. Deficits in cognitive information processing have been documented most extensively on tests that require involvement of association cortices within frontal, mesial temporal and temporoparietal brain regions. By contrast, information processing at the level of sensory cortex has been investigated to a limited degree, in the present study, cognitive event-related potentials (ERP) were utilized to investigate auditory information processing in schizophrenia at the level of primary auditory cortex. Mismatch negativity (MMN) is a short-duration cognitive ERP component that reflects detec. lion of stimulus deviance by neural structures within primary auditory cortex, in an auditory oddball paradigm, MMN precedes P300 by approximately 200 msec and indexes a prior stage of auditory information processing. In the present study, MMN generation was investigated in a group of medicated (n-20) and unmedicated (n-11) chronic schizophrenic subjects relative to age- and IQ matched normal volunteers (n-! i). MMN amplitude was decreased in unmedicated, as well as medicated, schizophrenic subjects relative to controls. Moreover, across groups, the deficit in MMN generation correlated significantly with the deficit in P3, suggesting that neurophysiological deficits in schizophrenia are present even at the level of primary cortex, in monkeys, deficits in MMN generation similar to those observed in schizophrenia may be induced by focal, intracortical infusion of competitive and non-competitive NMDA receptor antagonists, suggesting that NMDA receptor dysfunction or dysregulation may contribute significantly to the information processing deficits associated with schizophrenia.
3. DOES SEMANTIC "HYPERPRIMING" CORRELATE WITH IMPAIRED SENSORY GATING IN SCHIZOPHRENIA? S. Vinogradov !'2, S. Solomon l, B.A. Ober3.4, C. Biggins t,2, G.K. Shenaut3.4, & G. Fein t,2 IUniversity of California, San Francisco, San Francisco, CA 94143; 2Department of Veterans Affairs Medical Center, San Francisco, CA 94121; 3University of California, Davis, Davis, CA 95616; 4Department of Veterans Affairs Medical Center, Martinez, CA 94550 A number of investigators have suggested that schizophrenia may be characterized by a defect in inhibitory pathways which allows for faster or "'stronger" automatic information processing as compared to normals, and that this might account for the clinical findings of cognitive fragmentation seen in schizophrenic patients (e.g., the models of Frith, 1979; Cal0006-3223/94/$07.00
6 !6
BIOL PSYCHIATRY 1994;35:615-747
loway and Naghdi, 1982; Freedman et al., 1992; Braff et al., 1992). Semantic priming effects-- one of the most widely studied phenomena in cognitive psychology--- are experimental findings which relate to the simple discovery that subjects respond faster to a word (such as mouse) when it follows a related word (such as cat) than when it follows an unrelated word. The study of semantic priming effects provides a useful experimental tool for uncovering structural and processing characteristics of the semantic memory system, including basic information processing mechanisms such as spreading activation and attentional operations. We have studied a preliminary series of schizophrenic subjects who have undergone both a semantic priming experiment which examined mainly automatic information processing (spread of activation in the semantic memory network) and an auditory-evoked potential measure of sensory gating, the PS0 conditioning-testing (C/T) ratio, which examines automatic processing of auditory information. In our initial sample of subjects (n-7), we find a strong positive correlation between the PS0 C/T ratio and ~emantic priming effects obtained on the "automatic" semantic information processing task. Subjects who show greater-than-normal semantic priming effects ('hyperpriming") also show a failure to gate or inhibit their PS0 response to the testing stimulus. This finding may imply that a similar defect in inhibitory pathways underlies both impaired sensory gating and greater-than-normal automatic information processing or spread of activation in the semantic memory network of some schizophrenic subjects.
4. SENSORIMOTOR GATING OF THE HUMAN STARTLE REFLEX: GENDER AND LATERALITY N.R. Swerdiow, P.L. Hartman, & P.P. Auerbach Department of Psychiatry, UCSD School of Medicine, La Jolla,
THURSDAY, MAY 19
Previous work (Erwin et al. Biological Psychiatry, 1991) has suggested that there is a modest positive correlation between clinical symptomatology and recovery cycle abnormalities of the Pl component of midlatency auditory evoked potential in schizophrenia. However, this finding was not replicated in a more recent study (Erwin et al. Schizophrenia Research, in press). To further examine the relationship between these measures, midlatency auditory evoked potentials were recorded from 47 patients with schizophrenia in response to binaural clicks presented at three stimulus rates: I/sec, 5/sec and 10/sec. After computation of a recovery cycle measure (10/sec divided by l/sec Pl amplitudes) patients were divided into high abnormality (> 50% recovery) and low abnormality groups. Twelve patients from each of these groups who were matched on sex, age and race, and balanced for diagnostic subtype and medication status were then selected for use in the analysis of clinical measures. Summary measures obtained from the Brief Psychiatric Rating Scale (BPRS) reflecting symptoms specific to schizophrenia and nonspecific symptoms were used as dependent measures in a mixed model analysis of variance in which low and high Pl abnormality groups were contrasted. A significant Group x BPRS measure interaction (F-4.52, p <.05) was obtained. The low Pl recovery cycle abnormality group had greater BPRS scores for symptoms specific to schizophrenia than did the high abnormality group. These findings suggest that Pl abnormalities in schizophrenia as assessed by this protocol may in part reflect compensatory mechanisms rather than inherent neurobiological abnormalities.
6. NEUROPSYCHOLOGICAL FUNCTION AND NOVEL P300 IN SCHIZOPHRENICS
C A 92093-0804
The acoustic startle reflex is normally inhibited when the startling stimulus is preceded by a weak prepulse. In a recent report (Swerdlow et al. Biol Psychiat 34: 253-260,1993), we observed striking gender differences in this "prepulse inhibition" (PPI) of the startle reflex. Specifically, the startle reflex in males was significantly more inhibited by weak prepulses than was the startle reflex in female control subjects. A retrospective analysis of data from our previously published studies in psychiatric patients and normal controls supported this observation, in order to assess potential hormonal substrates for the observed gender differences in PPI, we measured eyeblink startle and PPi in female controls during different portions of the menstrual cycle. Subjects were selected using established criteria to exclude individuals with psychiatric disorders, substance abuse, serious neurologic or medical illness or pregnancy; subjects were also excluded for use of oral contraceptives or if they noted menstrual cycle instability. PPl was then compared using menstrual phase (follicular vs. luteal) as the betweensubject variable. Because of observations of gender differences in hemispheric laterality and our own data suggesting limbic cortical modulation of PPl, we also examined laterality differences in PPl in male and female control subjects. PPl in these individuals was assessed using EMG measures of right and left orbicularis oculi, in total, these data address the neural and hormonal substrates of gender differences in sensorimotor gating.
5. PI RECOVERY CYCLE ABNORMALITIES AND CLINICAL PHENOMENOLOGY IN SCHIZOPHRENIA R.J. Erwin, R.C. Gur, & R.E. Gur Dept. of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104
E. L. Merrin !,2, T.C. Floyd !, & R. F. Deicken 1,2 tPsychiatry Service, San Francisco DVA Medical Center, 2Depm~ment of Psychiatry, University of California at San Francisco The relationship between neuropsychological performance and P300 responses to novel auditory stimuli were studied in 14 DSM-liI-R male schizophrenics (predominantly medicated) and 14 male hospital employees without histories of major psychiatric disorders. Subjects were in. structed to respond with a finger lift to infrequently occurring (probability - . 15) 2000 Hz target tones while ignoring frequent 1000 Hz background tones and infrequently occurring (p=. 15) novel auditory stimuli. EEG recordings from 16 electrode sites were transformed to source derivation and ERP component latencies identified from peaks in Global Field Power (GFP). During a separate session all subjects were administered a battery of tests including the Wisconsin Card Sort (WCS) and parts of the Wechsler Memory Scale-Revised. in both groups, a higher rate of perseverative errors on the WCS was associated with decreases in P300 amplitude, particularly after novel stimuli. However, this effect was localized differently in the two groups, primarily right central/parietal in sch.;zophrenics (p-.007) but bilateral frontal and inferior frontal in normal controis (p-.007). Higher perseverative error scores also predicted slower P300 latencies in the novel condition (p-.023). There were additional correlations between left-sided P300 amplitude and verbal memory performance in schizophrenics only (p-.002). None of these effects were present for a standard oddball paradigm administered during the same session. Correlations between negative symptoms and both P300 amplitude/GFP and WCS performance were also observed. The results suggested complex relationships between functioning of the prefrontal cortex, cognition, and generation of P300 responses to novel stimuli in schizophrenics.