Processing of word-level and paragraph-level information in schizotypy

256 Because of the wide range of conduction velocities in long corticocortical axons, excitatory signals produced by a phasic stimulus are likely to undergo temporal dispersion. This will reduce the degree of summation at the postsynaptic sites to exceed firing threshold. According to the hypothesis adopted here, temporal dispersion will be greater in schizophrenia than in normals, and therefore the rebound inhibtion will be less than normal. As a result the suppression of the P50 to the second of two closely spaced stimuli will be less than normal. The difference between the potential produced by a standard stimulus and a deviant one will be less than normal. For unattended stimuli this process leads to reduced MMN in schizophrenia. For attended ones (which involve much more complex pathways than the MMN) it accounts for the reduction in amplitude and prolongation of latency of the P300.

HEART RATE VARIABILITY IN MEDICATIONFREE PATIENTS WITH SCHIZOPHRENIA MAY PROVIDE CLUES TOWARDS UNDERSTANDING LIMBIC DYSREGULATION IN PSYCHOSIS L. R. Mujica-Parodi,* V. Yeregani, D. M a l a s p i n a

Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA Objective: We aimed to investigate whether sympathetic and/or parasympathetic autoregulatory mechanisms are impaired in schizophrenia. Heart-rate-variability reflects functioning of the autonomic nervous system and regulation by the neural limbic system, abnormalities of which have both figured prominently in some etiological models of psychosis. Method: After obtaining 24-hour electrocardiogram (ECG) measurements on 9 medication-free schizophrenia patients and 24 matched healthy controls, we performed spectral and nonlinear complexity ("chaos") heart-rate-variability analyses of this data. Results: (1) Patients showed impaired c~diac autonomic regulation at both the global and acute levels, as evidenced by spectral and nonlinear complexity analysis. (2) Spectral analysis suggests this impairment is particularly of the sympathetic but also the parasympathetic nervous system. (3) Analysis of sleep/wake cycles demonstrates patients' primary deficit to be one of arousal inhibition, causing hyper-arousal. Conclusions: Group differences are not explained by age, sex, medication, physical health, or posture, and are likely attributable to patients' mental disorder. These results support the hypothesis of a central neural deficit of limbic dysregulation in schizophrenia, particularly inhibitory mechanisms.

THE RECOGNITION POTENTIAL IN THE STUDY OF FORMAL THOUGHT DISORDER AND ABNORMAL SEMANTIC PROCESSING IN SCHIZOPHRENIA E M u n o z , * M. M a r t i n - L o e c h e s , V. Molina, J. A. Hinojosa, R Casado, A. Iglesias

Cognitive Neuroscience Unit, UCM-ISCII1 CentreJbr Human Evolution and Behavioul; Madrid, Spain Formal thought disorder (FTD) is highly related to language and appears to be the result of an improper management of semantic processes, like abnormal lexical access to the nodes that encode semantic attributes. Recognition Potential (RP) is an electrical brain response that seems to reflect higher-order semantic or conceptual word processing, therefore it could be used as a tool in the evaluation of the outlined abnormalities in the semantic system of schizo-

16. Electrophysiology phrenics. Thirteen paranoid inpatients with first episode and 15 normal subjects were studied. The SAPS (fourth subscale) was used for the assessment of FTD. During the EEG recordings a rapid stream stimulation procedure (SOA of 250 ms) was used that displayed animal names (targets), no-animals words, pseudowords, strings of random letters, control and background stimuli. A total of 8 sequences, each containing five of each type of stimulus, were presented to the subjects. EEG data were recorded by means of 60 electrodes re-referenced to an average-reference. Patients were pooled into two groups according to FTD severity. An RP wave was obtained for controis and low FTD patients, but not for high FTD patients. RP latency was different between controls (260 ms) and low FTD patients (364 ms) (U=4; p<.0001), but not its amplitude (U=33; p>.l). The main finding is that RP disappears or is neglected in schizophrenic patients with higher FTD scores. This absence of RP in the high FFD patients could be due to one of three alternative explanations. First, these patients might show RP waves but in variable time latencies. This possibility was discarded after visual inspection of individual data. A second possibility might be that high FTD patients activate a superior number of nodes when a word is presented, engendering the cancellation of multiple electrical fields coming from a large cortical surface. A third explanation could be a lack of synchronic neuronal activations involved in RP generation due to an abnormal neuromodulation, or to a structural deterioration in basal temporal and related areas. RP amplitude could therefore reflect relevant mechanisms that are failing in schizophrenics with FTD.

PROCESSING OF WORD-LEVEL AND PARAGRAPH-LEVEL INFORMATION IN SCHIZOTYPY M. A. Niznikiewicz,* S. D. Hun, R G. Nestor, C. D o d d , M. E. Shenton, R. W. M c C a r l e y

Psychiatly, Boston VA Healthcare System, Brockton, MA, USA N400 is sensitive to immediate contextual evaluation of words in sentences ( Berkum et al., 1999). In this study, we tested if semantically related words that carry information contradictory to the prior context will evoke the standard N400 or if semantic relatedness will supersede discourse-level processes and result in the absence of the N400 in normal and schizotypa! personality disorder persons. We measured the N400 at the point of delivery of crucial target word, and at the end of the sentence, where most studies examined processes of context integration in schizophrenia and SPD. Twelve normal adults (NC) (25-45 years old) and twelve male SPD subjects judged if two sentences presented together made sense. The two-sentence paragraphs were either: congruent (Jane made a short speech. The speech was informative and thoughtful); incongruent (Bob bought a new car. The car was old and rusty); or sentence-incongruent (Jack cooked a light supper The supper was thorny and spicy (control condition). EEG was recorded to the critical words (e.g., informative, old, thorny), and the sentence final words (thoughtful, rusty, spicy). In NCs, the N400 to unrelated-non-contradictory words was more negative relative to related- contradictory words (p <.02) and did not differ from the N400 to a standard incongruent sentence word (p <.7). In contrast, the N400 recorded to final words in paragraphs which included unrelated-non- contradictory words was less negative than in those which included related, contradictory words (p < .01). In SPD, there was no difference in the N400 to unrelated non-contradictory and related but contradictory words. In both conditions a small N400 was present. For the sentence final words, there was a trend towards a more negative N400 to words included in paragraphs that contained contradictory relative to those that included non-con-

International Congress on Schizophrenia Research 2003

16. Electrophysiology

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tradictory information. At the word sentence final positions, the results conformed to those published on sentence context processing in SPD, i.e., more negative N400 was found in SPD to words in congruent paragraphs. Together, these results suggest temporal binding of semantically related words that may impact processing of incoming context; Different decay functions exist for the temporal binding in the normal and SPD individuals. Paragraph-level integrational processes supersede word-level effects at sentence boundaries. These processes of final context integration are abnormal in SPD.

DOPAMINE-GLUTAMATE INTERACTIONS IN THE PREFRONTAL CORTEX: D1 GATING OF INFORMATION PROCESSING R O ' D o n n e l l , * K. Y. T s e n g

Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, NY, USA Dopamine (DA) has several impoitant actions in the prefrontal cortex (PFC), and this transmitter is an important component in antipsychotic drug actions. Current tines of work on the elusive mechanisms of DA action focus on its ability to enhance or dampen responses to glutamatergic afferents. Although the interactions between these transmitters can be best studied in vitro, one critical element absent in those preparations is the bistable membrane potential pyramidal cells exhibit in vivo. We explored the interactions between D1 and D2 DA receptors and NMDA and AMPA glutamate receptors on their effects on cell excitability using whole-cell recordings from rat medial PFC pyramidal neurons. As reported previously (Wang & O'Donnell, Cer. Cor. 2001), we found a dose-dependent Dl-mediated enhancement of NMDA responses (n=10). The D1 agonist SKF38393 failed to augment AMPA responses, whereas the D2 agonist quinpirole reduced the excitability increase elicited by either AMPA (n=7) or NMDA (n=8). These data suggest that D 1 dopamine receptors may enhance cell excitability by an interaction with NMDA receptors. We also tested whether D 1 agonists combined with NMDA administration would enable the appearance of spontaneous up states in PFC slices. Administration of SKF38393 (2 uM) did not result in changes in spontaneous activity, even in the presence of cell depolarization (n=5). NMDA (8 uM) depolarized the neurons and in 10/11 cells resulted in continuous spontaneous firing (without plateau depolarizations). Combining SKF and NMDA resulted in periodic depolarizations resembling the in vivo up states in 9/10 cells tested. These were 400-1,000 ms in duration and occurred at near I Hz. Prior administration of the D1 antagonist SCH23390 prevented the appearance of these spontaneous depolarizations (n=5). These results indicate that D 1 DA receptors interaction with NMDA receptors may be an important component in determining active periods in PFC pyramidal neurons. Thus, D1 contribution to working memory and overall PFC function may involve an ability to sustain NMDAdependent UP states in the appropriate ensembles of neurons. Supported by MH57683, MH60I 31 and a NARSAD Independent Investigator Award (RO'D).

MODULATING SENSORY GATING IN HEALTHY VOLUNTEERS: THE EFFECTS OF DESIPRAMINE AND HALOPERIDOL B. Oranje,* R. S. Kahn, M. N. Verbaten Psychiatry, UMC Utrecht, Utrecht, Netherlands" In schizophrenia both an involvement of a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity have

been suggested. In addition, patients suffering from schizophrenia show reduced sensorimotor gating and reduced habituation. If there is a causal relationship between these neurotransmitters and these processes, then either a reduction in dopaminergic activity or an enhanced noradrenergic activity in healthy volunteers would result in reduced scnsorimotor gating and reduced habituation. A group of 12 healthy male volunteers was tested four times in a PPI paradigm 2.5 hours following administration of placebo/placebo, placebo/desipramine (50 mg), placebo/haloperidol (2mg) and desipramine(50 mg)/haloperidol(2 mg). A significant reduction of percentage PPI was found in 'all active drug conditions compared to the placebo/placebo condition, while no drug effects on habituation were found. Furthermore, a significant increase in heart rate was found in both desipramine conditions, from 120 minutes following oral intake onwards. Since both desipramine and haloperidol reduced PPI, this suggests that both an enhanced noradrenergic activity and a reduced dopaminergic activity leads to a reduction in sensorimotor gating. This in turn may indicate that a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity is involved in schizophrenia. Furthermore, the combination of haloperidol and desipramine did not have a synergistic effect on PPI, which indicates an interaction between the compounds. The site for this interaction is most likely located in the prefrontal cortex, since evidence is accumulating that extracellular dopamine concentration is regulated by noradrenergic terminals, particularly in that area of the brain. Since no effects on habituation were found, this suggests that neither an enhanced noradrenergic nor a decreased dopaminergic activity is involved in this process.

SENSORY GATING IN SCHIZOPHRENIA: CLINICAL, P50, AND PPI MEASURES J. Patterson,* Y. Jin, R Kang, R J. B r a h m a n , J. Bunney, S. Potkin, C. S a n d m a n , W. E. B u n n e y

Department of Psychiatry, University of California, Irvine, Irvine, CA, USA Deficits in perception and attention may underlie some of the symptoms of schizophrenia. An hypothesis proposed to account for these deficits is that schizophrenics cannot inhibit or gate sensory input, leading to an overload of sensory information reaching consciousness.In normal controls, but not in many schizophrenics, the P50 evoked brain response to the second of two paired clicks ($2) is typically gated or inhibited, compared with the response to the first(S 1), supporting hypotheses of a defect in inhibitory neuronal pathways in schizophrenia. Similarly, schizophrenics often show impaired inhibition of the acoustic startle response when it is preceded by a weaker auditory stimulus (prepulse inhibition or PPI). Schizophrenics also report perceptual abnormalities which could be consistent sensory gating deficit. We have developed the Structured Interview for the Assessment of Perceptual Anomalies (SIAPA) to clinically record anomalies reflecting sensory inundation. No previous studies have assessed sensory gating as measured by P50 and PPI and clinical reports of external sensory gating simultaneously and in the same subjects. Previous work suggests that clinical reports of perceptual anomalies may not always predict deficits in P50 suppression, and P50 suppression and PPI may not correlate. In this research, the meaning and significance of a sensory gating construct in schizophrenia was evaluated by comparing P50 and PPI data from 13 schizophrenic subjects who reported poor clinical gating (increased incidence of perceptual anomalies on the SIAPA, 13 schizophrenic

International Congress on Schizophrenia Research 2003