Automatic sensory information processing abnormalities across the illness course of schizophrenia.

BACKGROUND: Deficits in automatic sensory discrimination, as indexed by a reduction in the mismatch negativity (MMN) and P3a event-related potential amplitudes, are well documented in chronic schizophrenia. However, MMN and P3a have not been sufficiently studied early in the course of psychotic illness. The present study aimed to investigate MMN, P3a and reorienting negativity (RON) across the course of schizophrenia. METHOD: MMN, P3a, and RON were assessed in 118 subjects across four groups: (1) individuals at risk for psychosis (n=26); (2) recent-onset patients (n=31); (3) chronic patients (n=33); and (4) normal controls (n=28) using a duration-deviant auditory oddball paradigm. RESULTS: Frontocentral deficits in MMN and P3a were present in all patient groups. The at-risk group's MMN and P3a amplitudes were intermediate to those of the control and recent-onset groups. The recent-onset and chronic patients, but not the at-risk subjects, showed significant RON amplitude reductions, relative to the control group. Associations between MMN, P3a, RON and psychosocial functioning were present in the chronic patients. In the at-risk subjects, P3a and RON deficits were significantly associated with higher levels of negative symptoms. CONCLUSIONS: Abnormalities in the automatic processes of sensory discrimination, orienting and reorienting of attention are evident in the early phases of schizophrenia and raise the possibility of progressive worsening across stages of the illness. The finding that MMN and P3a, but not RON, were reduced before psychosis onset supports the continued examination of these components as potential early biomarkers of schizophrenia.

Deviation from expected cognitive ability is a core cognitive feature of schizophrenia related to neurophysiologic, clinical and psychosocial functioning.

Cognitive functioning in schizophrenia is characterized by a generalized impairment in current cognitive ability based on traditional population-based norms. However, these norms assume a normal cognitive trajectory and do not directly account for illness-related declines from expected cognitive potential. Indeed, schizophrenia patients exhibit even greater deviation between their observed and expected cognitive functioning based on expanded norms that leverage premorbid variables resistant to illness-related features. The current study further quantified the extent to which illness-related features account for this deviation from expectation and assessed its relationship to neurophysiologic (mismatch negativity, P3a, theta oscillations), clinical, and psychosocial functioning in schizophrenia patients. Expected cognitive ability (PENN-CNB global cognition) in patients (n = 684) was calculated using healthy comparison subject (n = 660) weighted regression based on premorbid variables resistant to illness-related decline (demographics, single-word reading, parental education). The magnitude of any deviation between current (observed) and regression-predicted (expected) cognitive ability was calculated. Results indicated that 24% (n = 164) of the total patient population exhibited significant (≥-1.96 SD) deviation between observed and expected global cognitive ability. Interestingly, 20% of the total patient population (n = 136) had "normal" range cognitive performance when using traditional population-based norms, but also had significant deviation from expected cognitive ability. The magnitude of this deviation was associated with more severe neurophysiologic abnormalities, longer illness duration, higher levels of negative symptoms, and worse psychosocial functioning. Assessment of cognitive deviation is thus a complementary metric for characterizing the severity of illness-related cognitive declines in patients, while also reflecting the expression and severity of key endophenotypes of schizophrenia.

Decomposing the constituent oscillatory dynamics underlying mismatch negativity generation in schizophrenia: Distinct relationships to clinical and cognitive functioning.

Abnormalities in early auditory information processing (EAIP) contribute to higher-order deficits in cognition and psychosocial functioning in schizophrenia. A passive auditory oddball paradigm is commonly used to evoke event-related potential (ERP) measures of EAIP reflecting auditory sensory registration and deviance detection, including mismatch negativity (MMN) and P3a responses. MMN and P3a have been extensively studied in healthy subjects and neuropsychiatric patient populations and are increasingly used as translational biomarkers in the development of novel therapeutics. Despite widespread use, relatively few studies have examined the constituent oscillatory elements and the extent to which sensory registration and deviance detection represent distinct or intercorrelated processes. This study aimed to determine the factor structure and clinical correlates of these oscillatory measures in schizophrenia patients (n = 706) and healthy comparison subjects (n = 615) who underwent clinical, cognitive, and functional characterization and EEG testing via their participation in the Consortium of Genomics in Schizophrenia (COGS-2) study. Results revealed significant deficits in theta-band (4-7 Hz) evoked power and phase locking in patients. Exploratory factor analyses of both ERP and oscillatory measures revealed two dissociable factors reflecting sensory registration and deviance detection. While each factor shared a significant correlation with social cognition, the deviance detection factor had a unique relationship to multiple cognitive and clinical domains. Results support the continued advancement of functionally relevant oscillatory measures underlying EAIP in the development of precognitive therapeutics.

Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully assessed drug effects on sensorimotor gating in SD versus W strains, across rat suppliers (H vs BK). Significantly greater SDH than WH apomorphine sensitivity in PPI measures was observed in both adult and 18 d pups, confirming that these strain differences are both robust and innate. These strain differences in apomorphine sensitivity were not found in adult BK rats. Supplier differences in sensitivity (SDH > SDBK) were also evident in the PPI-disruptive effects of D1 but not D2-family agonists; PPI was clearly disrupted by quinpirole in both SDH and SDBK rats. These findings demonstrate robust, innate, neurochemically specific, and apparently heritable phenotypic differences in an animal model of sensorimotor gating deficits in human neuropsychiatric disorders.

Methylphenidate-induced information processing dysfunction in nonschizophrenic patients.

To examine the relationship of aminergic overactivity to information processing, we gave methylphenidate hydrochloride, oxazepam, or placebo to 12 nonpsychotic patients in one-week blocks in a double-blind, randomized design. Methylphenidate induced a pattern of information processing dysfunction similar to that seen in schizophrenic patients, strengthening the linkage of the schizophrenia-information processing dysfunction-aminergic overactivity relationship. Further, the time course of the observed deficits in both schizophrenic and methylphenidate-induced states is strikingly compatible with the temporal mapping pattern of monoaminergic neuronal systems. More research is needed to identify definitively the aminergic influences on attentional functioning. A psychophysical task-pharmacologic probe strategy should prove useful.

Early information processing deficit in schizophrenia. New findings using schizophrenic subgroups and manic control subjects.

In recent years, the idea that schizophrenia involves a primary disturbance of the higher cognitive (ie, cortical) thinking processes has been challenged by investigators who have shown that there may be a primary disturbance in schizophrenia in the early stages of information processing that occurs during the first few hundred milliseconds after the stimulus reaches the sense organs. Among the hypothesized early information processing deficits are deficiencies in iconic storage (a brief peripheral memory store) and slowness of processing from iconic storage to a more permanent memory system. Three experiments were conducted using tachistoscopically presented stimuli in order to evaluate these two stages of information processing (iconic storage and speed of processing) in schizophrenic and control subjects. Results converged in supporting the hypothesis, that independent of iconic storage and sensory registration, slow information processing is a relatively stable deficit of schizophrenic patients with a poor prognosis. The schizophrenic patients with a good prognosis had a similar deficit, which was reversible. Results are discussed as they relate to the early information processing deficit theories of schizophrenia.

Sensorimotor gating and schizophrenia. Human and animal model studies.

Human and animal model studies of sensorimotor gating allow us to understand the functional significance of attentional abnormalities and monoaminergic alterations in patients with schizophrenic disorders. Clinically, schizophrenic patients report oversensitivity to sensory stimulation that theoretically correlates with stimulus overload and leads to cognitive fragmentation. Paradigms using cortical event-related potentials and the prepulse inhibition of startle responses show that schizophrenic patients also have impaired central nervous system inhibition (sensorimotor gating). Animal model studies demonstrate that increased systemic aminergic activity and increased nucleus accumbens dopamine tone causes sensorimotor gating failure, similar to that seen in schizophrenic patients. The time course of the observed schizophrenic and animal model deficits is compatible with the "temporal map" of monoaminergic neuron functions (le, several hundred milliseconds). Studies of sensorimotor gating allow investigators to comment on the spatial and temporal mapping of neurons, trait and state deficits, and vulnerability factors in the schizophrenic spectrum of disorders. By translating attentional theories into testable hypotheses, the neurobiology of schizophrenic disorders becomes clearer.

Gating and habituation of the startle reflex in schizophrenic patients.

Schizophrenic patients exhibit impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have well-described neurobiologic bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize patients with schizophrenic spectrum disorders. In this context, the startle response is particularly interesting, because it is a cross-species response to strong stimuli that is plastic or alterable using experimental and neurobiologic manipulations. Thirty-nine medicated schizophrenic patients and 37 normal control subjects were studied in a new electromyography based startle response paradigm in which both prepulse inhibition (an operational measure of sensorimotor gating) and habituation (the normal decrease in response magnitude to repeated stimuli over time) can be separated and assessed in one test session. The results indicate that schizophrenic patients have extensive deficits in both intramodal and cross-modal sensorimotor gating and a trend to show acoustic startle habituation deficits. The deficit in prepulse inhibition of startle amplitude exhibited by schizophrenic patients was evident when an acoustic prepulse stimulus preceded either an acoustic or a tactile startle stimulus. No deficit was observed in the prepulse-induced facilitation of startle latencies, indicating that the failure of gating was not due to a failure of stimulus detection. These findings suggest centrally mediated deficits in sensorimotor gating in schizophrenic patients.

Sensorimotor gating and thought disturbance measured in close temporal proximity in schizophrenic patients.

BACKGROUND: Sensorimotor gating abnormalities have been previously correlated with thought disturbance in schizophrenic patients. These correlative studies have led to the hypothesis that sensorimotor gating abnormalities may underlie thought disturbance. Several authors have cautioned, however, that this and similar hypotheses are supported by data recorded at different times or during resting states" and therefore incorrectly assume that the observed association represents a concurrent relationship. To address this issue, sensorimotor gating and thought disturbance were measured in close temporal proximity, thus strengthening the evidence for the association of these 2 abnormalities in schizophrenic patients. METHODS: Twenty-one schizophrenic men were assessed on measures of sensorimotor gating and thought disturbance. Sensorimotor gating was examined operationally via the use of prepulse inhibition. Thought disturbance was assessed via the Rorschach test measures of perceptual inaccuracy, disordered cognition, and the expression of normally repressed contents. Symptom rating scales (the Scale for the Assessment of Positive Symptoms and the alogia subscale of the Scale for the Assessment of Negative Symptoms) were also used. RESULTS: Deficient prepulse inhibition correlated significantly with 2 of the 3 Rorschach-derived thought disturbance measures. Prepulse inhibition was not correlated significantly with symptom rating scales. The Rorschach measure of impaired perceptual accuracy independently accounted for 60% of the variance in prepulse inhibition measures and contributed 35% of the unique variance beyond the effect attributable to the Scale for the Assessment of Positive Symptoms. CONCLUSIONS: Assessment of information processing and thought disturbance measures in close temporal proximity resulted in strong evidence that gating deficits correlate highly with measures of perceptual and reasoning disturbances. This relationship may form an important basis for the cognitive dysfunction observed among schizophrenic patients.

Very short-term memory dysfunction in schizophrenia. Defective short time constant information processing in schizophrenia.

Disordered, very short-term memory (VSTM) has been hypothesized as the fundamental cognitive deficit in schizophrenia. We describe a method that measures VSTM using self-stimulated auditory average evoked potentials. This paradigm allows the VSTM hyothesis to be tested relatively free of superficial attentional and motivational artifacts. The experimental results are consistent with a VSTM dysfunction in schizophrenia. Very short-term memory dysfunction is discussed in light of recent blink reflex evidence that there is a short time constant information processing system with a time base similar to VSTM (ie, 1 to 1,000 msec). This leads to new testable hypotheses about information processing and VSTM in schizophrenia. It also lays the basis for interpreting this phenomenon as a pathologic exaggeration of an adaptive neurophysiologic mechanism.

The therapeutic community as a research ward: myths and facts.

The clinical research ward run as a therapeutic community has been criticized as inefficient and scientifically unsound. This article discusses the therapeutic community as a research ward and identifies certain misconceptions which underlie many criticisms. The following myths are discussed and refuted: (1) There is an insurmountable community-research chasm. (2) The therapeutic community induces stress that interferes with research. (3) Patient passivity is engendered by research and this is destructive to the therapeutic community. (4) Symptoms are exacerbated by a research ward that is disruptive to the community. (5) Normal research subjects cannot live in a therapeutic community without pathologic psychic changes. These inaccurate myths are seen as a reflection of attempts to oversimplify very complex clinical and research issues. The use of mythology to simplify experiments, to artificially "clarify" complex issues, or to "protect" patients is seen as a disservice. The therapeutic community and research are syntonic when both receive appropriate support.

Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients.

Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency (rs = .991) and D2-receptor affinity (rs = .893). Antipsychotics that restore PPI in apomorphine-treated rats include "typical" antipsychotics and the "atypical" antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.

Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex in schizophrenia.

Neuropathologic and brain imaging studies have produced evidence of brain abnormalities in schizophrenic patients, often within the cerebrum's limbic lobe, and, less frequently, within basal ganglia. In the present study we used magnetic resonance imaging morphometric techniques to estimate volumes of specific cerebral structures in schizophrenic patients and age- and sex-matched normal controls. Estimates of the volume of mesial temporal lobe structures were reduced and estimates of the volume of the lenticular nucleus were increased in the schizophrenic patients. There was also evidence of reduced cranial volume in some schizophrenics. The magnitude of the lenticular abnormality, but not the temporal lobe abnormality, was associated with age at first psychiatric contact; earlier onset was associated with larger lenticular nuclei. The possible relevance of these results to neurodevelopmental hypotheses about the pathogenesis of schizophrenia is discussed.

The generalized pattern of neuropsychological deficits in outpatients with chronic schizophrenia with heterogeneous Wisconsin Card Sorting Test results.

Forty schizophrenic outpatients and 40 normal subjects were assessed using extensive clinical (eg, Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms) and neuropsychological (extended Halstead-Reitan Battery) measures. The schizophrenic patients had multiple neuropsychological deficits on tests of complex conceptual reasoning, psychomotor speed, new learning and incidental memory, and both motor and sensory-perceptual abilities. Neuropsychological impairment correlated more strongly with negative than positive symptoms. Overall, the schizophrenic outpatients showed relatively modest increases in the number of perseverative responses on the Wisconsin Card Sorting Test of abstraction flexibility. A subgroup of these schizophrenic patients seemed to be particularly impaired on the Wisconsin Card Sorting Test. This pattern of results, in conjunction with previous studies, supports the idea that, while some schizophrenic patients may have fixed, frontally based dysfunctions, these dysfunctions may be most prominent, and even fixed, in deteriorated, kraepelinian patients. These data provide evidence for diffuse and far-reaching deficits in a majority of outpatients with chronic schizophrenia.

Increased distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence.

The inability of schizophrenics to filter irrelevant information has often been implicated in the psychopathology of schizophrenia. Despite numerous attempts at characterizing the behavior of schizophrenics in the presence of distractors, evidence of increased distractibility has been equivocal due to the difficulty of assessing simultaneously the behavioral and neurophysiological effects of distracting stimuli. We report the results of an experiment in which event-related potential and performance measures were used to assess distractibility during reaction time tasks under different distracting conditions. The results supported the view of an increased distractibility in schizophrenic patients. Event-related potential data suggested that in schizophrenic patients, a reduced amount of processing resources is allocated to process external stimuli and attention is abnormally apportioned to task-irrelevant vs task-relevant stimuli.

Do self-reports of perceptual anomalies reflect gating deficits in schizophrenia patients?

Jin and colleagues presented an innovative study examining P50 suppression and patients' self-reported perceptual anomalies as two related operational measures of sensory gating deficits in schizophrenia patients. They found that those schizophrenia patients who endorsed experiences of sensory inundation had normal levels of P50 suppression, whereas patients who tended to endorse fewer complaints of perceptual anomalies had P50 suppression deficits. Jin et al's finding challenges the common belief that P50 suppression deficits are associated with cognitive and sensory anomalies reflecting poor gating in schizophrenia patients. This article comments on how the dissociation between phenomenological experiences of gating disturbances and P50 suppression might be explained by the limits of self-report in schizophrenia patients who have deficient insight and self-awareness. We hypothesize that the self-reported inability to screen out irrelevant stimuli reflects a voluntary, controlled process that is different from the involuntary, automatic process measured by P50 suppression.

Acute and chronic LSD effects on rat startle: data supporting an LSD--rat model of schizophrenia.

Animal models of human schizophrenia using LSD and related hallucinogens have been challenged on several grounds. One compelling argument against the LSD model is that while schizophrenia can be chronically debilitating, animal and human effects of LSD exhibit behavioral tolerance following chronic administration. The present study tested the effects of acute and chronic LSD on measures of rat startle, a widely used behavioral measure of reactivity and habituation. The results suggest that behavioral tolerance after chronic LSD administration is incomplete, with tolerance exhibited to the acute impairment of habituation but potentiation of startle magnitude on both the first response and the first block of 30 trials. These results are interpreted as supporting the viability of LSD as a model for one or more of the group of schizophrenias.

The "incredible shrinking" P50 event-related potential.

The P50 component of the auditory evoked response has been utilized in studies of sensory gating in schizophrenia for over 15 years. As P50 gating studies have had a greater impact in neuroscience research, investigators have refined several key variables (e.g., filtering) to enhance signal-to-noise ratios. A comprehensive review of P50 reports suggests P50 amplitude has been steadily decreasing over the years. Certain methodological "advances" are suggested as key reasons for this apparent reduction in P50 amplitude. Gating studies continue to yield interesting findings in neuropsychiatric research, especially when ratio vs. absolute difference scores are used.

Translating the basic and clinical cognitive neuroscience of schizophrenia to drug development and clinical trials of antipsychotic medications.

Neurocognitive deficits have become increasingly important defining features of schizophrenia and its treatment. Multiple domains of neurocognitive functions are impaired in schizophrenia patients, and these impairments are considered to be core features of the disorder. Many recent reports support the importance of the relationship of these neurocognitive deficits to measures of "functional outcome" such as social skills acquisition, social problem solving, and community outcome. Neurocognitive deficits appear to be improved with newer (atypical) antipsychotic medications across a broad range of domains in schizophrenia patients. Together with clinical neuroscience advances, basic research in cognitive neuroscience ranging from animal models of gating functions to early gene expression induced by antipsychotic medications has illuminated the specific neural basis of neurocognitive deficits in schizophrenia and the neurobiology of antipsychotic actions. These translational basic and clinical studies provide powerful screening tools and strategies for drug development and the subsequent assessment of the clinical efficacy of new antipsychotic medications. These interlocking clinical and basic research findings have substantial implications for improving both drug development and improving clinical trials methodology for antipsychotic medications. Thus, there is an informed translation and cross-fertilization between basic and clinical research focused on the development and assessment of putative new antipsychotic compounds.