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D L Braff

Publications and source records attributed to D L Braff.

At least 37 records · Page 2Linked to original sources
PubMed2000

Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits.

OBJECTIVE: Patients with schizophrenia spectrum disorders have been shown to have deficits in sensorimotor gating as assessed by prepulse inhibition of the startle response. The authors hypothesized that nonschizophrenic relatives of patients with schizophrenia would also have prepulse inhibition deficits, thereby reflecting a genetically transmitted susceptibility to sensorimotor gating deficits. METHOD: Twenty-five comparison subjects, 23 patients with schizophrenia, 34 relatives of the schizophrenic patients, and 11 subjects with schizotypal personality disorder were assessed in an acoustic startle paradigm. The eye-blink component of the startle response was assessed bilaterally by using electromyographic recordings of orbicularis oculi. RESULTS: The patients with schizophrenia, their relatives, and subjects with schizotypal personality disorder all had reduced prepulse inhibition relative to comparison subjects, and these deficits were more evident in measures of right eye-blink prepulse inhibition. Comparison subjects demonstrated greater right versus left eye-blink prepulse inhibition, whereas the probands, their relatives, and subjects with schizotypal personality disorder showed less asymmetry of prepulse inhibition. CONCLUSIONS: These data suggest a genetically transmitted deficit in prepulse inhibition (sensorimotor gating) in patients with schizophrenia spectrum disorders, including subjects with schizotypal personality disorder and relatives of patients with schizophrenia.

Acoustic Stimulation↗
PubMed2000

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications.

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.

Acoustic Stimulation↗
PubMed1999

Amphetamine disrupts P50 suppression in normal subjects.

BACKGROUND: P50 suppression is viewed as an operational measure of sensory "gating" that is reduced in patients with schizophrenia and their family members. Previous reports have demonstrated that neural gating is regulated by monoaminergic tone in rodent models of P50 suppression. METHODS: In this study, 11 healthy subjects participated in P50 event-related potential recordings at baseline and after either oral administration of dextroamphetamine (.3 mg/kg) or placebo, to determine if the administration of a monoaminergic agonist produces P50 suppression deficits similar to those observed in patients with schizophrenia. RESULTS: As hypothesized, amphetamine disrupted the suppression of the P50 event-related potential. There was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t10 = 3.15, p < .01, mean difference = -44.1%, d = -2.5) relative to the baseline P50 condition. A comparison of P50 suppression in the placebo and amphetamine conditions (both after a baseline recording session) revealed a significant amphetamine-induced disruption of P50 suppression (t6 = 3.71, p < .01, mean difference = -54.4%, d = -3.14). CONCLUSIONS: The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. The findings are consistent with several careful examinations of suppression deficits in rodent models that have identified the monoaminergic regulation of P50 suppression. These data indicate that amphetamine induces a disruption of P50 suppression in normal subjects.

Adrenergic Agents↗
PubMed1999

The nonlinear, complex sequential organization of behavior in schizophrenic patients: neurocognitive strategies and clinical correlations.

BACKGROUND: Thought disorder is a hallmark of schizophrenia and can be inferred from disorganized behavior. Measures of the sequential organization of behavior are important because they reflect the cognitive processes of the selection and sequencing of behavioral elements, which generate observable and analyzable behavioral patterns. In this context, sequences of choices generated by schizophrenic patients in a two-choice guessing task fluctuate significantly, which reflects an "oscillating dysregulation" between highly predictable and highly unpredictable subsequences within a single test session. In this study, we aimed to clarify the significance of dysregulation by seeing whether demographic, clinical, neuropsychological, and psychological measures predict the degree of dysregulation observed on this two-choice task. METHODS: Thirty schizophrenic patients repeatedly performed a LEFT or RIGHT key press that was followed by a stimulus, which occurred randomly on the left or right side of the computer screen. Thus, the stimulus location had nothing to do with the key press behavior. The range of key press sequence predictabilities as measured by the dynamical entropy was used to quantify the dysregulation of response sequences and reflects the range of fixity and randomness of the responses. A factor analysis was performed and step-wise multiple regression analyses were used to relate the factor scores to demographic, clinical, symptomatic, Wisconsin Card Sorting Test (WCST), and Rorschach variables. RESULTS: The LEFT/RIGHT key press sequences were determined by three factors: 1) the degree of win-stay/lose-shift strategy; 2) the degree of contextual influence on the current choice; and 3) the degree of dysregulation on the choice task. Demographic and clinical variables did not predict any of the three response patterns on the choice task. In contrast, the WCST and Rorschach test predicted performance on various factors of choice task response patterns. CONCLUSIONS: Schizophrenic patients employ several rules, i.e., "win-stay/lose-shift" and "decide according to the previous choice," that fluctuate significantly when generating sequences on this task, confirming that a basic behavioral dysregulation occurs in a single schizophrenic subject across a single test session. The organization or the "temporal architecture" of the behavioral sequences is not related to symptoms per se, but is related to deficits in executive functioning, problem solving, and perceptual organizational abilities.

Adult↗
PubMed1999

Cross-species studies of sensorimotor gating of the startle reflex.

Sensorimotor gating of the startle reflex can be assessed across species, using similar stimuli to elicit comparable response characteristics. As measured by prepulse inhibition (PPI), gating is reduced in patients with some neuropsychiatric disorders, and in rats after manipulations of limbic cortex, striatum, pallidum, or pontine tegmentum. This limbic "CSPP" circuitry can be studied in rats to reveal the neurochemical and neuroanatomical substrates regulating PPI at a high level of resolution. This detailed circuit information is used as a "blueprint" to identify substrates that may lead to PPI deficits in psychiatric-disordered humans. Some human disorders with identifiable, localized lesions in CSPP circuitry, for example, Huntington's disease, provide direct validation for this cross-species model. Studies have begun to assess the pharmacological homology of PPI across species, as an initial step towards translating detailed neural circuit information from rats to humans. These initial studies suggest the possibility that the effects of dopaminergic (DAergic) drugs on PPI (reducing PPI) may be homologous across species; nicotinic drugs may also produce similar effects on PPI across species (increasing PPI). By contrast, the effects of glutamatergic and serotonergic drugs may exhibit disparate effects on PPI across species. The use of DAergic agonists in human studies is complicated by their significant side effects, but new studies demonstrate that several "human friendly" direct DA agonists disrupt PPI in rats and are thus good candidates for further studies of the cross-species homology of the DAergic regulation of PPI. In this manner, PPI can be used to probe the sensitivity of DAergic systems, and perhaps other CSPP elements, across normal and neuropsychiatric-disordered populations.

Animals↗
PubMed1999

Cognitive functions in schizotypal personality disorder.

OBJECTIVE: Schizophrenia spectrum subjects have cognitive deficits in a variety of domains. Schizotypal personality disordered (SPD) subjects do not have many of the confounds seen in schizophrenic patients, but may have the same pattern of cognitive deficits in attention and executive functioning. HYPOTHESIS: We hypothesized that SPD subjects would have impairments on measures of attention, abstract reasoning, cognitive inhibition, working memory and verbal recognition memory when compared to normal subjects, and that these deficits would be intermediate to those observed in schizophrenic patients. METHOD: SPD subjects (N=20) were compared to age-, gender- and education-matched schizophrenic patients (N=20) and normal comparison subjects (N=20) on a battery of cognitive measures. RESULTS: The data were analyzed using standard statistical methods, including effect sizes. Using a conservative alpha level of 0.01, schizophrenic patients had deficits on many of these measures compared to normal subjects. Although the SPD subjects did not significantly differ from normal comparison subjects at the p < 0.01 level, there were trends (p < 0.019-0.028) toward impairment on measures of working memory and general intellectual functioning. On further effect size analyses, SPD subjects performed intermediate to normals and schizophrenic patients on measures of attention, abstract reasoning, cognitive inhibition, verbal working memory, recognition memory, and general intellectual functioning, with moderate to large effect sizes separating groups. CONCLUSIONS: These results suggest that SPD subjects have possible widespread cognitive deficits that are of lesser magnitude than those observed in schizophrenic patients.

Cognition↗
PubMed1999

Prepulse inhibition and habituation of the startle response are stable neurobiological measures in a normal male population.

Prepulse inhibition (PPI) and habituation of the startle response are operational measures of sensorimotor gating and information processing. Changes in the normal inhibition and habituation of the startle response may provide trait markers for illnesses such as schizophrenia that have altered neurotransmitter control of the neural circuitry that modulates these measures. The stability of PPI and habituation was assessed in 10 normal male subjects. Prepulse inhibition was found to be most stable in the more intense prepulse conditions, and habituation was most stable in the early portion of the test session. These data support the hypothesis that PPI and habituation are relatively stable neurobiological markers.

Acoustic Stimulation↗
PubMed1999

Long-range correlations in choice sequences of schizophrenic patients.

Schizophrenic patients significantly greater than normals exhibit long-range correlations in sequences of choices in a simple binary choice task. Moreover, schizophrenic patients also are significantly less influenced by external stimuli than are normal comparison subjects. These effects are not significantly correlated with each other, suggesting that they do not result from a uniform attentional deficit nor are they due to simple perseverative responding or any other uniform process. The interdependence of responses over many trials suggests that the response history of many previous behavioral responses contributes significantly to the temporal architecture of schizophrenic patients. In agreement with others (Lyon et al., 1994), we find that similar organizational principles apply to physical, economical, or biological systems and seem to play an important role in human psychopathology.

Adult↗
PubMed1999

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.

Acoustic Stimulation↗
PubMed1999

Sex differences in sensorimotor gating of the human startle reflex: all smoke?

RATIONALE: A recent report described sex differences in the effects of nicotine use and withdrawal on prepulse inhibition of acoustic startle (PPI), but no sex differences in PPI in non-smokers. OBJECTIVE: To determine whether previously reported male>female acoustic PPI reflect sex differences in smoking effects on PPI, rather than simple sex differences in the regulation of PPI. A retrospective analyses of >600 carefully screened normals tested over the past 12 years was completed. RESULTS: Male>female acoustic PPI was detected in analyses that included: 1) all subjects; or 2) self-declared non-smokers. CONCLUSIONS: Sex differences in PPI cannot be accounted for by smoking history, because they are present across a large sample of non-smoking normal controls.

Acoustic Stimulation↗
PubMed1999

Human and animal studies of schizophrenia-related gating deficits.

Prepulse Inhibition (PPI) of the startle response and the P50 auditory-evoked potential suppression are used to assess impairments in the regulation of the neural substrates and to determine the clinical significance of inhibitory deficits in schizophrenia. The study of gating deficits in schizophrenia and in related animal model studies have already advanced our understanding of the neural substrates of information processing abnormalities in patients with schizophrenia. Individuals with schizotypal personality disorder as well as clinically unaffected family members of patients with schizophrenia show PPI and P50 suppression deficits. These "schizophrenic spectrum" populations are not grossly psychotic, nor are they receiving antipsychotic medications. Therefore, the gating deficits are presumed to reflect core (eg, intermediate phenotypic) schizophrenia-linked information processing abnormalities. Several studies have reported that gating deficits are associated with clinical ratings of psychiatric symptoms, thought disorder, and neuropsychologic deficits in patients with schizophrenia. In addition, recent human pharmacologic studies have indicated that gating deficits can be reversed by rationally-selected compounds. Animal model studies have generally shown convergence with the human studies and may lead to improved identification of efficacious new antipsychotic medications for patients with schizophrenia.

Animals↗
PubMed1999

Is there a critical developmental 'window' for isolation rearing-induced changes in prepulse inhibition of the acoustic startle response?

In a previous study, rats reared in isolation from weaning exhibited normal prepulse inhibition (PPI) before puberty, whilst after puberty (6-8 weeks post weaning) isolation reared rats exhibited deficits in PPI. The developmental timing of the onset of this isolation effect appears to be critical because similar isolation of adult rats has no effect on PPI. The present study examined the time and duration of the period or 'window' of isolation necessary to induce these behavioral changes. Male Sprague-Dawley rats were isolated for either only the first 2 weeks from weaning, only the first 4 weeks from weaning, only weeks 3 and 4, or continuously from weaning (ISO group), and compared with rats reared in normal social conditions (SOC group). Eight weeks after weaning, we compared acoustic and airpuff startle reactivity, acoustic and light PPI, and acoustic and airpuff startle habituation across the groups. There were no significant changes in any of the measures in the groups exposed to 2- or 4-week periods of isolation. In the ISO and SOC groups, acoustic or airpuff startle reactivity was similar, while acoustic PPI was reduced significantly in the ISO group. Airpuff startle habituation was increased significantly in the ISO group compared to SOC controls and there was a similar trend with acoustic startle habituation. These results indicate that only animals isolated for more than 4 weeks after weaning display deficits in PPI, and provide evidence that there is no critical pre-pubertal developmental window for inducing PPI deficits, rather, continuous post-weaning isolation is needed to induce the PPI deficit effect.

Age Factors↗
PubMed1999

Symptom correlates of prepulse inhibition deficits in male schizophrenic patients.

OBJECTIVE: Information processing, inhibitory, and gating deficits in human and animal model studies of schizophrenia are demonstrated by using prepulse inhibition of the startle reflex. Prepulse inhibition deficits in schizophrenic patients correlate with core cognitive symptoms, such as thought disorder and distractibility, but their relationship to positive and negative symptoms of schizophrenia is less clear. METHOD: Fifty-one male schizophrenic patients and 26 male normal comparison subjects were tested for prepulse inhibition of the eyeblink component of the startle reflex measured by electromyogram recording. Startling stimuli (118 dB) were presented alone (pulse only) or were preceded 60 msec by discrete prepulse stimuli of 2, 4, 8, or 16 dB above the background 70-dB noise level. In addition, patients were assessed for demographic variables, generalized symptoms (Brief Psychiatric Rating Scale), and positive and negative symptoms. RESULTS: Schizophrenic and comparison groups differed significantly in the amount of prepulse inhibition produced by the 16-dB prepulse, with schizophrenic patients showing the expected deficient prepulse inhibition. Latency of the eyeblink response was generally slower for the schizophrenic patients, but the prepulse-induced latency facilitation for schizophrenic patients and comparison subjects did not differ significantly. The pattern of prepulse inhibition deficits in schizophrenic patients remained, with age and education controlled, in an analysis of covariance and subgroup matching. Deficient prepulse inhibition correlated with both positive and negative symptoms of schizophrenia. CONCLUSIONS: Under these experimental conditions, schizophrenia-linked deficits in prepulse inhibition detected with a relatively strong prepulse are correlated with both positive and negative symptoms of schizophrenia. The level of correlation, while significant in this cohort, is not as robust as that in previous reports linking prepulse inhibition deficits with other measures, such as thought disorder. Future work should probably focus on the relationship of prepulse inhibition deficits to measures such as thought disorder rather than positive and negative symptoms.

Acoustic Stimulation↗
PubMed1998

A multimethod approach to assessing perseverations in schizophrenia patients.

Perseverations have been associated with frontal lobe impairment and are often observed among schizophrenia patients. We assessed perseverations in schizophrenia patients (N = 71) using the Wisconsin Card Sorting Test (WCST) and a new Rorschach perseveration scale which yields three perseveration scores. We also compared the results of the schizophrenia patients with those of a normal comparison group (N = 71). We found that schizophrenia patients demonstrated a high number of perseverations on both the WCST and the Rorschach perseveration scale when compared to the normal comparison subjects. Among schizophrenia patients, WCST perseverative responses were significantly correlated with Rorschach-derived stuck-in-set perseverations, WAIS-R Vocabulary scores and negative symptom ratings. No significant differences in any of the measures of perseveration were found to be associated with diagnostic subtype. Finally, WCST and Rorschach measures for the schizophrenia and normal comparison participants were entered into a logistic regression. The WCST total errors and the three Rorschach perseveration measures resulted in the correct classification of 89.4% of the total cases, with a sensitivity of 91%, specificity of 91% and positive predictive power of 87.8%. These data provide evidence that perseverative behavior is widely observed in schizophrenia patients using a variety of instruments. The authors discuss the benefit of using multiple measures of perseveration in schizophrenia research.

Adult↗
PubMed1998

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.

Evoked Potentials, Auditory↗
PubMed1998

Reversal of isolation rearing-induced deficits in prepulse inhibition by Seroquel and olanzapine.

BACKGROUND: Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. Deficits in PPI produced by isolation rearing can be reversed by antipsychotics. METHODS: We evaluated the ability of Seroquel and olanzapine to reverse the isolation-induced disruption of PPI. Rats housed for 8 weeks singly or in groups of 3 were tested every 2 weeks after either Seroquel (0, 5.0 mg/kg) or olanzapine (0, 2.5, 5.0 mg/kg). Startle was elicited by 120-dB pulses presented either with or without prepulses (3, 6, or 12 dB above a 65-dB background). RESULTS: Isolation rearing repeatedly disrupted PPI and sometimes increased startle reactivity. Seroquel reversed these deficits without affecting PPI in socially reared controls. Olanzapine (2.5 mg/kg) reversed the isolation rearing-induced PPI deficit and tended to increase basal PPI levels. Both antipsychotics antagonized the isolation rearing-induced increase in startle reactivity. CONCLUSIONS: Isolation rearing produces deficits in sensorimotor gating in rats that are reversible by atypical antipsychotics, and may therefore aid in identifying new treatments for schizophrenia.

Acoustic Stimulation↗