Biomedical subjects

D L Braff

Publications and source records attributed to D L Braff.

At least 19 recordsLinked to original sources

PubMed1992

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.

Acoustic Stimulation↗

PubMed1992

Wisconsin Card Sorting Test deficits in chronic paranoid schizophrenia. Evidence for a relatively discrete subgroup?

Some, although not all, researchers have reported dramatically increased numbers of perseverative responses on the Wisconsin Card Sorting Test (WCST) in schizophrenic patients compared to normal comparison subjects. The current study was designed to further explore the nature of possible WCST deficits in a group of paranoid schizophrenic patients compared to normal and psychiatric comparison subjects. In the current study, schizophrenic patients had significantly greater numbers of perserverative responses on the WCST than the comparison groups. The sample of patients with schizophrenia appeared to be characterized by a non-Gaussian distribution of perseverative responses on the WCST. WCST-impaired and WCST-nonimpaired schizophrenic subgroups were compared on cognitive and symptom measures, and increased perseverative responding was associated with negative symptoms, slowed reaction time, and more hospitalizations. While additional research is necessary to further investigate hypotheses of frontal versus generalized brain dysfunction in schizophrenic patients, WCST impairment seems to be present in a clinically meaningful subgroup of paranoid schizophrenic patients.

Adult↗

PubMed1992

Reply to cognitive therapy and schizophrenia.

These interesting articles on cognitive deficits and rehabilitation in schizophrenic patients stimulate many questions, two of which are discussed in this reply. First, it seems likely that skepticism regarding the utilization and efficacy of cognitive rehabilitation strategies is born of despair that these treatments will ever be funded and delivered. This unfortunate state of affairs can only be corrected by effective social and political lobbying for adequate funding for mental health care. Second, the traditional tension between allocation and stage models of attention/information-processing deficits in schizophrenic patients may now be resolved by emerging theories that creatively integrate elements of stage and allocation theories. As we test these integrated theories, old "distinctions" seem to disappear and a clearer picture of information-processing dysfunctions in schizophrenic patients is emerging.

Brain Injuries↗

PubMed1992

Negative symptomatology in schizophrenic outpatients.

This study examines the prevalence of negative symptoms, and assesses the convergence of negative and depressive symptoms in 60 chronically ill schizophrenic outpatients. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms and the negative symptom cluster of the Brief Psychiatric Rating Scale (BPRS). Depressive symptoms were assessed with the depression subscale of the Brief Symptom Inventory and the depressive symptom cluster of the BPRS. A majority of patients in this group of relatively stable, schizophrenic outpatients demonstrated mild to moderate degrees of both negative and depressive symptoms. Correlations were not significant between negative symptom and depressive symptom measures, which suggests that the symptom constructs are relatively independent. Comparisons between a subgroup with prominent negative symptoms (N = 18) and a subgroup with minimal negative symptoms (N = 32) also revealed no significant group differences in variables that characterize clinical course (i.e., age of onset and frequency and duration of hospitalization) or in the severity of depressive symptoms. This lack of any significant differences on the clinical course variables may be partially explained by the heterogeneity of negative symptoms. The constellation of negative symptoms may differ not only in etiology but also in their temporal relationships to other aspects of the patient's clinical course. Longitudinal studies will be needed to track the long-term outcome of negative and depressive symptoms.

Adolescent↗

PubMed1992

Sensory gating deficits in schizophrenia: new results.

OBJECTIVE: It has been widely hypothesized that sensory gating failures and sensory overload occur in schizophrenic patients compared to normal subjects. The authors of this study sought to confirm and extend results of earlier studies that showed specific sensory gating deficits in schizophrenic patients. METHOD: Age- and sex-matched schizophrenic patients (N = 20) and normal subjects (N = 20) were tested using electrophysiologically recorded P50 event-related potentials to assess the overall competence of the subjects' central sensory inhibitory capacity by measuring sensory filtering or gating. P50 area responses to two 75-dB (conditioning and test) click stimuli of 0.04-msec duration, averaged over 60 trials, were recorded for each subject. Normally, the first (conditioning) click stimulus induces gating mechanisms that result in diminished or gated P50 event-related potentials in response to the second click stimulus. RESULTS: The schizophrenic subjects manifested a significant sensory gating deficit at frontal, central, and parietal electrode placement sites, with a nonsignificant tendency for the deficit to be most prominent in the frontal areas of the brain. CONCLUSIONS: These data reflect a regionally diffuse loss of normal sensory gating in schizophrenic patients.

Acoustic Stimulation↗

PubMed1991

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.

Adolescent↗

PubMed1991

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.

Adult↗

PubMed1991

Delusions: a review and integration.

Delusions are often prominent symptoms in schizophrenia and other psychiatric and neurologic disorders. Despite the central descriptive importance of delusions, there is a paucity of comprehensive reviews, theoretical formulations, and empirical evaluations in this area. Research and theoretical work pertinent to delusions are reviewed with particular emphasis on current findings in the neurobiological, cognitive, and information-processing literature. Research on delusional thought seen in various psychiatric disorders is reviewed and integrated with critical aspects of schizophrenia research. Consideration of three factors may help in understanding delusional thought processes. These factors are state-trait variables, perseverative thought, and cognitive functional integrity.

Delusions↗

PubMed1991

Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat.

Previous work suggests that the dopamine agonist apomorphine decreases prepulse inhibition (PPI) of the acoustic startle response in rats. To better understand the dopamine substrates of this apomorphine response, we investigated the effects of four pharmacologically distinct dopamine antagonists on the apomorphine-induced loss of PPI. Apomorphine (0.5 mg/kg s.c.) markedly decreased PPI for all prepulse intervals tested. This effect of apomorphine on PPI was reversed by pretreatments with the D2 antagonists spiperone and raclopride but not by pretreatment with the D1 antagonist SCH 23390. The atypical antipsychotic clozapine exhibited an "inverted-U" shaped dose-response curve, reversing the apomorphine-induced loss of PPI at low doses but not at high doses. High doses of both SCH 23390 and clozapine decreased PPI independent of apomorphine treatment. The effects of apomorphine on baseline startle amplitude were also differentially modified by these drugs: apomorphine potentiated startle amplitude in spiperone- and raclopride-pretreated animals, but apomorphine decreased startle amplitude in animals pretreated with SCH 23390 or high doses of clozapine. Prepulse inhibition has been shown to be markedly impaired in humans with schizophrenia. Since our present findings suggest that the activation of D2 dopamine receptors is responsible for the loss of PPI in rats, overactivity of D2 dopamine receptors might also be a substrate for PPI deficits in schizophrenia.

Analysis of Variance↗

PubMed1990

GABAergic projection from nucleus accumbens to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats.

Previous studies have demonstrated that increased mesolimbic dopamine (DA) activity disrupts sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. Other behavioral changes following mesolimbic DA activation are mediated through GABAergic efferent projections from the nucleus accumbens (NAC) to the ventral pallidum (VP). In this experiment, we examined whether PPI deficits in rats following mesolimbic DA activation are mediated through these same GABAergic substrates. PPI was significantly disrupted in rats following infusion of DA (40 micrograms) into the NAC, and this effect was reversed by infusion of a low dose (10 ng) of the GABA agonist muscimol into the VP. In a second experiment, we tested the hypothesis and the loss of PPI following intra-NAC DA infusion results from a disruption of GABAergic activity within the VP. Consistent with this hypothesis, infusion of the GABA antagonist picrotoxin (0-0.2 micrograms) into the VP caused a significant loss of PPI. These findings strongly suggest that the accumbens-ventral pallidal GABAergic circuitry is a substrate for the decrease in sensorimotor gating induced by mesolimbic DA overactivity.

Acoustic Stimulation↗

PubMed1990

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.

Adolescent↗

PubMed1990

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.

Animals↗

PubMed1990

Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens.

Previous studies have demonstrated that several dopamine agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. Schizophrenic patients also exhibit deficits in PPI when the prepulse precedes the startle stimulus by less than 500 ms. In experiment 1, dopamine (0-40 micrograms) infused directly into the nucleus accumbens in rats caused a dose-dependent decrease in PPI at prepulse intervals shorter than 500 ms. In experiment 2, this effect of accumbens dopamine infusion on sensorimotor gating was found to vary with changes in prepulse intensity. These findings strongly suggest that increased mesolimbic dopamine activity is one substrate of the sensorimotor gating deficits in rats that are caused by treatment with dopamine agonists; similar substrates might mediate deficits in PPI exhibited by schizophrenic patients.

Animals↗

PubMed1990

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine.

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats.

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.

Acoustic Stimulation↗

PubMed1990

Startle response models of sensorimotor gating and habituation deficits in schizophrenia.

Studies of prepulse inhibition and habituation of startle responses elicited by intense stimuli provide some unusual opportunities for cross-species explorations of attentional deficits characteristic of schizophrenic patients. Schizophrenic patients exhibit deficits in both the prepulse inhibition of startle and the habituation of startle. The behavioral plasticity of startle responses and the comparability of the test paradigms used in rats and humans greatly facilitates the development of animal models of specifiable behavioral abnormalities in schizophrenic patients. This review describes two such examples of parallel animal and human models, one involving sensorimotor gating and the other examining behavioral habituation. Evidence is presented supporting the involvement of mesolimbic dopaminergic systems in the modulation of prepulse inhibition or sensorimotor gating and the importance of central serotonergic systems in the habituation of startle.

Animals↗

PubMed1990

Physiological evidence of exaggerated startle response in a subgroup of Vietnam veterans with combat-related PTSD.

One of the diagnostic criteria for posttraumatic stress disorder (PTSD) is an exaggerated startle response; however, this phenomenon has not been verified empirically. The authors compared 20 Vietnam combat veterans with PTSD and 18 combat veterans without PTSD on the eyeblink reflex electromyographic response of the startle reaction. Subjects in both groups who failed to show an eyeblink response to the startle stimuli were eliminated from further analyses. Among the remaining subjects, the 13 with PTSD had a significantly greater startle response amplitude than the 12 control subjects at intermediate intensities of acoustic stimuli. The relationship between startle responsivity and both negative and positive symptoms was also investigated.

Acoustic Stimulation↗

PubMed1990

A D2 dopamine receptor agonist disrupts sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia.

Prepulse inhibition of acoustic startle is deficient in schizophrenic patients and in animals injected with either direct or indirect dopamine (DA) agonists. The present experiments confirmed the hypothesis that the dopaminergic blockade of prepulse inhibition is attributable to the activation of D2 DA receptors. After systemic administrations of the D1 agonist SK&F 38393, the D2 agonist quinpirole, or a combination of the two, rats were tested for prepulse inhibition of the startle response by presenting acoustic stimuli or acoustic stimuli preceded by weak prepulses that inhibit startle. Although the D1 agonist SK&F 38393 had no effect on prepulse inhibition [0.3 to 30.0 mg/kg (1.03 to 102.82 mumols/kg)], the D agonist, quinpirole, blocked prepulse inhibition at doses of 0.3 mg/kg (1.17 mumols/kg) and 0.9 mg/kg (3.51 mumols/kg). Lower doses of quinpirole, 0.03 mg/kg (0.12 mumols/kg) and 0.1 mg/kg (0.39 mumols/kg), were ineffective. When an ineffective dose of quinpirole (0.1 mg/kg) was coadministered with 10.0 mg/kg SKF 38393, prepulse inhibition was reduced relative to saline controls. This reduction of prepulse inhibition is consistent with the synergistic effect of D1 and D2 DA receptor stimulation noted in studies of dopaminergic influences on stereotyped behavior in rats. These findings confirm that a disruption of sensorimotor gating results from D2 dopaminergic stimulation in the rat and extend the applicability of this animal model for the similar behavioral deficits exhibited by schizophrenic patients.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗