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Biomedical subjects

David L Braff

Publications and source records attributed to David L Braff.

34 records · Page 2Linked to original sources
PubMed2005

Stability of mismatch negativity deficits and their relationship to functional impairments in chronic schizophrenia.

OBJECTIVE: Because previous studies have demonstrated that patients with chronic schizophrenia have deficits in mismatch negativity associated with poor everyday functioning, the authors investigated the longitudinal stability of mismatch negativity deficits and their longitudinal relationship to poor functional status. METHOD: Ten patients with chronic schizophrenia underwent testing twice over a 1-2-year period. Tests used included mismatch negativity, the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, and the Global Assessment of Functioning Scale. Patients' test results from both sessions were compared with results for 10 age-matched normal subjects. RESULTS: Patients with schizophrenia had mismatch negativity deficits with large effect sizes that were reliable over time. Mismatch negativity deficits were also significantly associated with poor functional status at both the first and second session. CONCLUSIONS: Mismatch negativity deficits and their relationship to poor functional status are stable over time in patients with chronic schizophrenia, suggesting that mismatch negativity may be useful for assessing medication response and other factors in longitudinal studies. Future studies will clarify the emergence, progression, and treatment effects of mismatch negativity deficits in patients with schizophrenia.

Acoustic Stimulation↗
PubMed2005

The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia.

Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.

Animals↗
PubMed2004

Preattentional and attentional cognitive deficits as targets for treating schizophrenia.

BACKGROUND AND RATIONALE: Pharmacotherapy of schizophrenia has traditionally targeted positive psychotic symptoms. An emerging view is that developing medications that improve cognition in schizophrenia patients is a major step forward in achieving better functional outcome. The cognitive deficits that are often observed in schizophrenia can be assessed using (1) neuropsychological tests; and (2) neurophysiological tests, the topic of this article. These neurophysiological measures cover a spectrum from automatic preattentional to attention-dependent processes. OBJECTIVES: This article focuses on cognitive deficits that appear to be promising targets for a new "third generation" of medications that may be used to treat schizophrenia and other patients with specific deficits in cognition and functioning. We discuss the possible use of the following six measures of preattentional and attention-dependent cognitive deficits: mismatch negativity, P50 event-related potential suppression, prepulse inhibition of the startle response, P300 event-related potential, continuous performance task performance, and oculomotor antisaccade performance. CONCLUSIONS: The use of preattentional and attention-dependent measures offer unique opportunities to improve our armamentarium of pharmacologic strategies for the treatment of cognitive deficits in schizophrenia patients. This review illustrates the usefulness of these measures as targets for existing and new antipsychotic medications that will potentially (1) characterize the cognitive deficits that occur in schizophrenia patients and (2) assess medication-related improvement on these measures and the potential associated improvement in functional outcome.

Animals↗
PubMed2004

Sensitization and habituation of the acoustic startle reflex in patients with schizophrenia.

Assessments of prepulse inhibition and habituation of the acoustic startle response have proved to be valuable tools for assessing deficits of sensorimotor gating and information processing in schizophrenia patients. Recent studies, however, have reported inconsistent results regarding startle habituation deficits in schizophrenia using block-to-block analyses. Some of these inconsistencies may be due to abnormal initial sensitization effects to startle-eliciting stimuli. In a longitudinal study during the course of an acute psychotic episode, 34 medicated inpatients were examined with regard to sensitization and habituation effects in a trial-by-trial analysis and compared with 18 normal control subjects. On two examinations--10 days after admission and after psychopathological improvement 2-3 weeks later--schizophrenia patients exhibited an exaggerated magnitude increment across the first few startle-eliciting stimuli and habituation deficits that were evident when the effect of sensitization was removed from analysis. In the present study, both increased sensitization and reduced habituation appeared to be trait markers of schizophrenic psychoses. The enhanced sensitization effect--presumably due to an abnormal arousal modulation--reflects abnormal stimulus processing in schizophrenia, i.e. the diminished ability to learn the irrelevance of simple identical stimuli. In addition, the present data have important implications for designing startle studies to assess sensitization, habituation and prepulse inhibition in one session.

Adult↗
PubMed2003

Visual masking as a probe for abnormal gamma range activity in schizophrenia.

BACKGROUND: Visual masking procedures assess very early stages of visual perception. Patients with schizophrenia consistently show deficits on visual masking tasks, and these deficits likely reflect vulnerability to schizophrenia. We conducted two experiments to determine whether visual masking procedures can reveal underlying abnormalities in gamma range oscillations in schizophrenia. METHODS: In the first experiment, we conducted nonlinear modeling of visual masking performance data from 89 male schizophrenic patients and 20 male comparison subjects. In the second experiment, electrophysiological recordings of event-related gamma activity were taken during a visual masking task in a subset of eight patients and seven control subjects. RESULTS: In the first experiment, nonlinear modeling of the performance data revealed evidence of oscillations in the gamma range (30 and 35 Hz) for the comparison group but not patients. In the second experiment, the comparison group, but not the patients, showed a burst of gamma range activity 200-400 msec following target presentation. The difference between patients and comparison subjects in this time period was significant (p <.05). CONCLUSIONS: Visual masking procedures can serve as a probe for underlying gamma range activity, which appears to be aberrant in schizophrenia. Perceptual problems in schizophrenia may, at least in part, be due to a failure to establish and/or maintain gamma range oscillations.

Case-Control Studies↗
PubMed2003

Chaos and schizophrenia: does the method fit the madness?

Over the past 30 years, investigators have used nonlinear and so-called chaos theory-based techniques to examine a wide range of phenomena ranging from electroencephalogram and cardiac rate and rhythm analyses to stock market and weather predictions. Psychiatric neuroscientists are now beginning to apply nonlinear methods to mental disorders such as schizophrenia. These applications are relevant from the level of complex genetic architecture and calcium channel dynamics to the symptomatic, behavioral, and functional outcome of schizophrenia. The key point of this surge of interest is distinguishing complex, nonlinear but lawfully mediated systems from truly random systems. The application of these methods to studies in schizophrenia has yielded findings that are consistent with the general hypothesis that an altered sequential or temporal architecture is a key feature of this disorder. Specifically, we propose that the temporal architecture of schizophrenia is characterized by bursts of complex, nonlinear phenomena alternating with truly random events. Analyzing these patterns of molecular (e.g., calcium channel activity) to molar (e.g., symptom level) phenomena via nonlinear systems methods can provide new approaches to understanding complex temporal and sequential shifts in neural substrate activity, pathophysiology, and the course and treatment and outcome of schizophrenia.

Calcium Channels↗
PubMed2003

The relationship of age to prepulse inhibition and habituation of the acoustic startle response.

Prepulse inhibition (PPI) of the startle response reflects an early stage of information processing that is abnormal in schizophrenia and certain other specific neuropsychiatric disorders that are distinguished by the inability to inhibit redundant or relatively irrelevant sensory, cognitive, or motor information. The goal of the present study was to characterize the effect of normal aging on PPI and habituation of the startle response and to examine the hypothesis that normal aging is characterized by a global decline in inhibitory function. Ninety-seven non-psychiatric controls (age range 18-88) were tested for startle eyeblink response using electromyogram (EMG) recording. Startle magnitude decreased and startle latency increased with aging. PPI demonstrated an inverted U-shaped function with age (greatest PPI at intermediate ages) while there was no significant effect of age on startle habituation. The results do not support the theory that aging is associated with a general decline in inhibitory function and contrast with previous studies that have compared only extreme age groups and have found no effects of age on PPI.

Acoustic Stimulation↗
PubMed2002

Schizophrenia subjects show intact success-related neural activation but impaired uncertainty processing during decision-making.

Decision-making is a complex process that is important for everyday life. This study examined the effect of the degree of success, and outcome uncertainty, on decision-making and associated neural substrate activation in schizophrenia subjects (SZS) and normal comparison subjects (NCS). A total of 15 subjects with a diagnosis of schizophrenia and 15 age- and education-matched NCS participated in this study. These subjects completed the two-choice prediction task during functional magnetic resonance imaging. Decision-making characteristics and activation of neural substrates were obtained at 20, 50, or 80% error rate. Success and uncertainty influenced the behavioral characteristics on the two-choice prediction task, and the task-related activation in SZS and NCS. Neither success nor uncertainty differentially affected the behavioral characteristics of SZS relative to NCS during the two-choice prediction task. Nonetheless, there was a significant interaction between group and error rate in bilateral parietal cortex. The activation in NCS was the highest when the outcome was most uncertain. In contrast, task-related activation in SZS was not modulated by the degree of uncertainty. Thus, SZS failed to utilize the parietal cortex to process decision-making situations with highly uncertain outcomes.

Adult↗
PubMed2002

Parietal dysfunction is associated with increased outcome-related decision-making in schizophrenia patients.

BACKGROUND: Decision-making is a complex process and depends on a network of fronto-parietal and cingulate areas. Decision-making dysfunctions in schizophrenia patients are characterized by an alternation between stereotypic and unpredictable responses. This study tested the hypothesis that schizophrenia patients show less decision-making-related activation in the prefrontal and parietal cortex. METHODS: Fifteen schizophrenia patients were matched with fifteen normal comparison subjects. During functional magnetic resonance imaging (fMRI) scanning, subjects were tested on the two-choice prediction task (predicting the location of a randomly presented stimulus) and the two-choice response task (responding according to the location of the stimulus). RESULTS: Schizophrenia patients relative to comparison subjects generated more outcome-dependent responses. Schizophrenia patients and normal comparison subjects showed decision-making-related activation in right prefrontal cortex, insula, anterior cingulate, and bilateral precuneus. Schizophrenia patients showed less activation in inferior, medial prefrontal, and right superior temporal cortex and more activation in the postcentral and inferior parietal cortex. Decision-making-related activation in both right prefrontal and bilateral parietal cortex was higher in medicated compared to unmedicated schizophrenia patients. CONCLUSIONS: These results support the hypothesis that the interaction between prefrontal and parietal cortex during decision-making by schizophrenia patients is dysregulated, which results in an increased outcome-dependent response selection.

Adult↗
PubMed2002

Endophenotyping schizotypy: a prelude to genetic studies within the schizophrenia spectrum.

Schizophrenia is a complex genetic disease with a prevalence rate of 1% in the general population. Schizotypal personality disorder (SPD) occurs in up to 3% of the population, and these subjects are phenomenologically and perhaps genotypically related to schizophrenia. The diagnosis of SPD was empirically derived based on the symptoms of individuals with a genetic relationship to schizophrenia patients and SPD may be a more common phenotypic expression of a schizophrenia-related diathesis than is schizophrenia itself. Family-genetic studies have determined that (1) relatives of schizophrenic patients have an increased risk of SPD and (2) relatives of SPD subjects have increased the rates of both schizophrenia and SPD. Because SPD subjects do not typically have the confounding effects of a chronic illness, long-term hospitalization or chronic neuroleptic treatment, they are ideal for the study of the proposed trait-related vulnerability markers in schizophrenia spectrum individuals. The study of vulnerability markers in SPD subjects has become increasingly important because it provides a means of assessing phenotypic traits that may not be evident clinically. By combining multiple inhibitory/gating information processing measures, it may be possible to identify a subgroup of SPD subjects with multiple inhibitory deficits who are phenotypically most similar to patients with schizophrenia. Composite phenotypes can also be developed, which increase the probability of identifying the complex genetic architecture of schizophrenia spectrum disorders, which interact with nongenetic protective and exacerbating factors.

Chromosomes, Human, Pair 22↗
PubMed2002

Neural correlates of refixation saccades and antisaccades in normal and schizophrenia subjects.

BACKGROUND: Schizophrenia subjects demonstrate difficulties on tasks requiring saccadic inhibition, despite normal refixation saccade performance. Saccadic inhibition is ostensibly mediated via prefrontal cortex and associated cortical/subcortical circuitry. The current study tests hypotheses about the neural substrates of normal and abnormal saccadic performance among subjects with schizophrenia. METHODS: Using functional magnetic resonance imaging, blood oxygenation level-dependent (BOLD) data were recorded while 13 normal and 14 schizophrenia subjects were engaged in refixation and antisaccade tasks. RESULTS: Schizophrenia subjects did not demonstrate the increased prefrontal cortex BOLD contrast during antisaccade performance that was apparent in the normal subjects. Schizophrenia subjects did, however, demonstrate normal BOLD contrast associated with refixation saccade performance in the frontal and supplementary eye fields, and posterior parietal cortex. CONCLUSIONS: Results from the current study support hypotheses of dysfunctional prefrontal cortex circuitry among schizophrenia subjects. Furthermore, this abnormality existed despite normal BOLD contrast observed during refixation saccade generation in the schizophrenia group.

Adult↗
PubMed2002

Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects.

Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions. Studies of drug craving, reward association, and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence. Here, a functional magnetic resonance imaging (fMRI) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas. This investigation tested the behavioral hypothesis that methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection. It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex. Ten methamphetamine-dependent subjects were compared with ten age- and education-matched controls performing a two-choice prediction task and a two-choice response task during a fMRI session. Response bias, latency, and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained. First, methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects. Second, methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex (BA 9) and failed to activate ventromedial cortex (BA 10,11) during the two-choice prediction task compared with the two-choice response task. These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction.

Adult↗
PubMed2002

Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype?

OBJECTIVE: Subjects with schizotypal personality disorder demonstrate deficits in inhibition when assessed on prepulse inhibition, P50 suppression, and antisaccade paradigms. This study determined if distinct subgroups of subjects with schizotypal personality disorder could be identified on the basis of performance on these measures and whether endophenotypes could be defined for future genetic study by using measures of inhibitory function. METHOD: Prepulse inhibition, P50 suppression, and antisaccade paradigms were assessed in 21 subjects with schizotypal personality disorder. RESULTS: Seven subjects with schizotypal personality disorder had deficits on each paradigm; seven had no deficits on any paradigm. P50 and antisaccade deficits were present in five of the same subjects and significantly correlated. CONCLUSIONS: These results suggest that P50 and antisaccade performance reflects a common endophenotype and that prepulse inhibition identifies a separate endophenotype reflecting different neurobiological substrate(s) in subjects with schizotypal personality disorder. This pattern may generalize to schizophrenia spectrum disorder patients.

Acoustic Stimulation↗
PubMed2002

Information processing deficits in acutely psychotic schizophrenia patients medicated and unmedicated at the time of admission.

OBJECTIVE: In patients with schizophrenia, information processing deficits, such as those reported in studies that measured prepulse inhibition of the human startle response and habituation of startle magnitude, may be improved with atypical antipsychotic treatment. However, it remains unclear whether antipsychotic medication is directly responsible for the improvement or whether differences in prepulse inhibition reflect other factors, such as acuity status. The present study investigated the effects of antipsychotics on prepulse inhibition and startle habituation in acutely hospitalized patients with schizophrenia. METHOD: Forty-one acutely psychotic schizophrenia patients (21 who were unmedicated at the time of admission and 20 who had been receiving antipsychotic treatment) were tested within 72 hours of hospital admission. Thirteen healthy subjects were also studied for comparative purposes. Primary dependent measures were startle responsivity, reactivity, prepulse inhibition, and startle habituation. RESULTS: Schizophrenia patients, whether medicated or unmedicated at admission, showed prepulse inhibition deficits compared with healthy subjects and did not statistically differ from each other in startle magnitude, prepulse inhibition, or habituation. There was a higher number of startle "nonresponders" among those who had been receiving medication versus those unmedicated at the time of admission. CONCLUSIONS: The present findings suggest that antipsychotic effects on prepulse inhibition may not be evident at a time when schizophrenia patients are acutely symptomatic. These results suggest that the neurobiological substrate underlying prepulse inhibition deficits may be dysregulated during acute psychotic states while the patients are in early phases of medication treatment.

Acoustic Stimulation↗