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Robert M Bilder

Publications and source records attributed to Robert M Bilder.

At least 37 records · Page 2Linked to original sources
PubMed2004

The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes.

Diverse phenotypic associations with the catechol-O-methyltransferase (COMT) Val158Met polymorphism have been reported. We suggest that some of the complex effects of this polymorphism be understood from the perspective of the tonic-phasic dopamine (DA) hypothesis. We hypothesize that the COMT Met allele (associated with low enzyme activity) results in increased levels of tonic DA and reciprocal reductions in phasic DA in subcortical regions and increased D1 transmission cortically. This pattern of effects is hypothesized to yield increased stability but decreased flexibility of neural network activation states that underlie important aspects of working memory and executive functions; these effects may be beneficial or detrimental depending on the phenotype, a range of endogenous factors, and environmental exigencies. The literature on phenotypic associations of the COMT Val158Met polymorphism is reviewed, highlighting areas where this hypothesis may have explanatory value, and pointing to possible directions for refinement of relevant phenotypes and experimental evaluation of this hypothesis.

Animals↗
PubMed2004

Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility.

OBJECTIVE: The catechol O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and behavioral phenotypes in schizophrenia. Whether COMT genotype is beneficial may depend on phenotype definition. The authors examined the effects of COMT genotype on a task that distinguishes imitation from reversal learning. They hypothesized that the Val and Met alleles would be associated with deficits in imitation learning and reversal learning, respectively. METHOD: Twenty-six patients with schizophrenia and schizoaffective disorder completed a task requiring alternation between imitation and reversal rules. RESULTS: Met homozygotes showed better acquisition of the imitation rule but greater deficit shifting from imitation to reversal. Val homozygotes had poorer imitation performance and slower reaction times. CONCLUSIONS: The Met allele, by increasing tonic dopamine, may promote cognitive stability but limit cognitive flexibility.

Adult↗
PubMed2004

Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: Follow-up studies have found that a substantial number of patients with schizophrenia achieve full recovery (i.e., sustained improvement in both symptoms and social/vocational functioning) when examined decades after an index admission. This study addressed recovery during the crucial early course of the illness. METHOD: Subjects in their first episode of schizophrenia or schizoaffective disorder (N=118) were assessed at baseline and then treated according to a medication algorithm. Full recovery required concurrent remission of positive and negative symptoms and adequate social/vocational functioning (fulfillment of age-appropriate role expectations, performance of daily living tasks without supervision, and engagement in social interactions). RESULTS: After 5 years, 47.2% (95% CI=36.0%-58.4%) of the subjects achieved symptom remission, and 25.5% (95% CI=16.1%-34.7%) had adequate social functioning for 2 years or more. Only 13.7% (95% CI=6.4%-20.9%) of subjects met full recovery criteria for 2 years or longer. Better cognitive functioning at stabilization was associated with full recovery, adequate social/vocational functioning, and symptom remission. Shorter duration of psychosis before study entry predicted both full recovery and symptom remission. More cerebral asymmetry was associated with full recovery and adequate social/vocational functioning; a schizoaffective diagnosis predicted symptom remission. CONCLUSIONS: Although some patients with first-episode schizophrenia can achieve sustained symptomatic and functional recovery, the overall rate of recovery during the early years of the illness is low.

Activities of Daily Living↗
PubMed2003

Sex differences in frontal lobe white matter microstructure: a DTI study.

There is evidence that the brains of men and women are structurally different, but there are few data regarding possible sex differences in white matter microstructure. Using diffusion tensor imaging we assessed fractional anisotropy (FA) in the frontal lobe white matter on contiguous 5 mm slices in nine healthy male and 11 healthy female adults. Overall, women had higher FA in the left frontal lobe compared to men and a leftward asymmetry of FA in contrast to men, who showed no hemispheric asymmetry. Among women, greater leftward asymmetry of frontal lobe FA correlated significantly with better verbal comprehension and memory functioning. Our findings may be indicative of increased directional coherence and/or density of left hemisphere white matter fibers and a leftward asymmetry of this structural integrity among women compared to men.

Adult↗
PubMed2003

Functional magnetic resonance imaging of source versus item memory.

Both the frontal lobes and the medial temporal lobe (particularly the hippocampus) have been implicated in encoding and retrieval of episodic memory information. We report an experiment that manipulates whether source information, item information, or both are required at retrieval. Two sources were used in a factorial design in which the main effect of source and item retrieval, along with their interaction, could be measured by fMRI activations. When source information was required at retrieval the left frontal lobe showed significant activation but not when item retrieval was required. Hippocampal activation showed no difference between source and item retrieval. This pattern of results supports a model proposing a larger role for the frontal lobes in encoding and retrieval of source information.

Acoustic Stimulation↗
PubMed2003

Reversed cerebellar asymmetry in men with first-episode schizophrenia.

BACKGROUND: Abnormalities in cerebellar structure and function have been implicated in the pathophysiology of schizophrenia. In this study, we investigated whether patients experiencing first-episode schizophrenia differed from healthy comparison subjects in regional cerebellar volumes or cerebellar asymmetry. METHODS: Volumes of four cerebellar regions (right, left; anterior, posterior) were measured from contiguous coronal magnetic resonance (MR) images in 69 (37 men, 32 women) patients experiencing first-episode schizophrenia and in 49 (27 men, 22 women) healthy comparison subjects. Patients were rated on the Scale for the Assessment of Negative Symptoms and the Schedule for Affective Disorders and Schizophrenia-Psychosis/Disorganization before the initiation of antipsychotic medication and at the time of the MR imaging exam. RESULTS: Patients and healthy comparison subjects did not differ in regional cerebellar volumes, but male patients demonstrated significantly reversed anterior and posterior asymmetry compared with healthy male subjects. Among male patients, greater reversals in a composite measure of cerebellar asymmetry (i.e., torque) correlated significantly with increased negative symptoms before the initiation of antipsychotic medication. CONCLUSIONS: These findings implicate an aberrant neurodevelopmental process involving the metencephalon in the pathophysiology of schizophrenia and are consistent with prior studies implicating abnormal asymmetry in schizophrenia at the neocortical level.

Adult↗
PubMed2003

Impairments in perceptual competency and maintenance on a visual delayed match-to-sample test in first-episode schizophrenia.

BACKGROUND: Deficits in working memory (WM) have been reported in patients with schizophrenia, but WM is a complex construct dependent on several subprocesses, including input representation (perceptual competency) and holding stimuli on-line (maintenance). A visual delayed match-to-sample task (DMST) was developed to isolate perceptual competency from maintenance during delays. It was hypothesized that patients in the first episode of schizophrenia would exhibit dissociable deficits in both WM domains. METHODS: Performance on the DMST was assessed in 57 patients in the first episode of schizophrenia or schizoaffective disorder and 22 healthy comparison subjects. In phase 1 of the DMST, a complex visual stimulus (target) was followed immediately by a forced choice between 2 test stimuli, and item difficulty (differences between the test stimuli) was titrated until each subject achieved a consistent accuracy (80%-90%) in this no-delay condition. In phase 2, a delay of 4 or 8 seconds with a mask of randomly illuminated pixels was introduced between target and test stimuli; test stimuli were fixed in difficulty level based on phase 1 titration. Main outcome measures were mean item difficulty attained in the no-delay condition and mean accuracy in matching after delay. RESULTS: Compared with controls, patients attained a lower level of difficulty in the no-delay condition (P =.001) and significantly lower accuracy with delay (P =.002). CONCLUSIONS: Deficits in both domains of WM suggest abnormality in the posterior and prefrontal cortexes. These deficits can be observed in a task involving complex visual pattern stimuli using only a brief delay and are present even in unmedicated patients in the first episode of illness.

Adult↗
PubMed2003

Adolescent immaturity in attention-related brain engagement to emotional facial expressions.

Selective attention, particularly during the processing of emotionally evocative events, is a crucial component of adolescent development. We used functional magnetic resonance imagining (fMRI) with adolescents and adults to examine developmental differences in activation in a paradigm that involved selective attention during the viewing of emotionally engaging face stimuli. We evaluated developmental differences in neural activation for three comparisons: (1) directing attention to subjective responses to fearful facial expressions relative to directing attention to a nonemotional aspect (nose width) of fearful faces, (2) viewing fearful relative to neutral faces while attending to a nonemotional aspect of the face, and (3) viewing fearful relative to neutral faces while attention was unconstrained (passive viewing). The comparison of activation across attention tasks revealed greater activation in the orbital frontal cortex in adults than in adolescents. Conversely, when subjects attended to a nonemotional feature, fearful relative to neutral faces influenced activation in the anterior cingulate more in adolescents than in adults. When attention was unconstrained, adolescents relative to adults showed greater activation in the anterior cingulate, bilateral orbitofrontal cortex, and right amygdala in response to the fearful relative to neutral faces. These findings suggest that adults show greater modulation of activity in relevant brain structures based on attentional demands, whereas adolescents exhibit greater modulation based on emotional content.

Adolescent↗
PubMed2003

Category fluency in first-episode schizophrenia.

Animal word list generation (ANWLG) was administered to 47 first-episode schizophrenia (FES) participants and 31 controls. Fifty-nine left temporal lobe epilepsy (LTLE) participants were included as a comparison group with known temporal lobe damage and expected semantic deficits. Semantic knowledge was assessed with the Association Index (AI), a measure of the semantic relatedness of all consecutive ANWLG responses. Neuropsychological tests of language and executive functioning were also administered. Results showed that both FES and LTLE groups generated fewer ANWLG responses than controls, but only the LTLE participants obtained a lower AI relative to controls. FES participants did not differ from controls on the AI. FES and LTLE groups produced fewer semantic subcategories (clusters), however, only the LTLE group produced fewer words per subcategory compared to controls (cluster size). FES participants produced a higher rate of perseverative responses compared to the other groups. Finally, correlation analyses showed that for FES participants both executive and language tests significantly correlated with ANWLG total responses, while the correlation between ANWLG and only 1 language test was significant for LTLE participants. Taken together, the results suggest that reduced ANWLG output in FES participants may be best conceptualized as a deficit in the executive component of word list generation (i.e., semantic search/access, response monitoring) or global cognitive impairment.

Adolescent↗
PubMed2003

Neurocognitive assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project schizophrenia trial: development, methodology, and rationale.

Patients with schizophrenia are severely impaired in crucial aspects of neurocognitive function. This impairment is the strongest clinical correlate of poor long-term outcome and adaptive dysfunction. Reports of neurocognitive enhancement with second generation antipsychotic medications have thus offered promise for improvement in the long-term outcome of patients with schizophrenia. However, the majority of these studies have had serious weaknesses in methodology, such as open-label design, small samples, or inappropriate dosing of medications. More recent studies have addressed these methodological issues but have been of short duration and have largely been sponsored by pharmaceutical companies. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project is a unique opportunity to address the comparative neurocognitive effectiveness of available antipsychotic medications. This article describes the neurocognitive methods used in the schizophrenia trial of the CATIE project, including the selection and training of neurocognitive raters, patient inclusion criteria for assessment, rationale for the choice of neurocognitive instruments, and methodology for each neurocognitive test.

Antipsychotic Agents↗
PubMed2003

Lack of normal association between cerebellar volume and neuropsychological functions in first-episode schizophrenia.

OBJECTIVE: Functional neuroimaging studies have identified a role for the cerebellum in the neuropsychology of schizophrenia. Few studies, however, have examined the relationship between cerebellar size and neuropsychological functioning in schizophrenia. The authors' goal was to examine this relationship in patients and healthy comparison subjects. METHOD: Total cerebellar volume was computed from magnetic resonance images in 48 male and 33 female patients experiencing a first episode of schizophrenia and in 14 male and nine female healthy comparison subjects. Patients and comparison subjects completed a comprehensive neuropsychological assessment encompassing six domains of functioning: executive, motor, language, visuospatial, memory, and attention. A global domain of functioning was computed as the mean of these six domains. RESULTS: Larger cerebellar volume correlated significantly with better global functioning in healthy subjects but not among patients with schizophrenia; this relationship was significantly stronger in healthy subjects than in patients. Additional analyses revealed significant associations between cerebellar volume and visuospatial, executive, and memory functions in healthy volunteers but not among patients. CONCLUSIONS: The cerebellum plays a role in higher cognitive functions in healthy individuals, and normal associations between cerebellar size and function are absent in patients experiencing a first episode of schizophrenia. These findings are consistent with neurobiological models implicating the cerebellum in the pathogenesis of schizophrenia.

Adult↗
PubMed2003

Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia.

OBJECTIVE: The authors investigated volumetric alterations of the anterior hippocampal formation in patients experiencing a first episode of schizophrenia relative to healthy comparison subjects. METHOD: From contiguous 1.5-mm coronal magnetic resonance images, the hippocampal formation was divided into posterior and anterior segments, and the anterior hippocampal formation was separated from the amygdala. Volumes of the posterior and anterior hippocampal formation and amygdala were computed in 46 (31 male and 15 female) patients experiencing a first episode of schizophrenia and in 34 (21 male and 13 female) healthy comparison subjects. Twenty-four patients were antipsychotic naive at the time of the scan. RESULTS: Patients had significantly reduced total (right plus left) anterior hippocampal formation volume relative to healthy comparison subjects but did not differ in volumes of either the posterior hippocampal formation or amygdala. Similar findings were obtained when analyses were restricted to the antipsychotic-naive subgroup of patients. CONCLUSIONS: These findings suggest that volumetric abnormalities of the hippocampus-amygdala complex may be specific to the anterior hippocampal formation in patients experiencing a first episode of schizophrenia and are consistent with hypotheses regarding abnormal frontolimbic connectivity playing a role in the pathophysiology of the disorder.

Acute Disease↗
PubMed2002

Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia.

BACKGROUND: Neurocognitive deficits are recognized as a cardinal feature of schizophrenia, but the determinants of these deficits remain unknown. Recent reports have suggested that a functional polymorphism, Val(158)Met in exon III of the catechol-O-methyltransferase gene, shares approximately 4% variance with performance on the Wisconsin Card Sorting Test. These findings led to suggestions that the catechol-O-methyltransferase polymorphism may exert its effects by modulating prefrontal dopamine function, but few other neurocognitive measures have been examined, leaving open questions about phenotypic specificity. METHODS: We examined the effects of the catechol-O-methyltransferase Val(158)Met polymorphism in 58 individuals with chronic schizophrenia who completed a battery of 15 neurocognitive tests, which were reduced to four reliable neurocognitive domain scores. We examined the effects of genotype on these four domains and on global neurocognitive ability. RESULTS: The Met allele was associated with better performance in the Processing Speed and Attention domain, but not with other domain scores measuring executive and visuoperceptual functions, declarative verbal learning and memory, simple motor ability, or global neurocognitive function. Genotype shared approximately 11% of variance with Processing Speed and Attention scores, and approximately 2% of variance with Wisconsin Card Sorting Test scores. CONCLUSIONS: The findings provide independent support for the hypothesis that the catechol-O-methyltransferase Val(158)Met polymorphism influences neurocognitive function in schizophrenia, and suggest that the functional effects may be expressed on measures of Processing Speed and Attention. This information may prompt reconsideration of the "prefrontal dopamine" hypothesis and invites examination of a broader range of effects in efforts to refine the neurocognitive phenotype that is most relevant to variation in catechol-O-methyltransferase expression.

Adult↗
PubMed2002

Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder.

BACKGROUND: Enhancing medication adherence early in the course of schizophrenia and schizoaffective disorder may substantially improve long-term course. Although extensively studied in multi-episode patients, little data exist on medication adherence by first-episode patients. METHOD: Medication adherence was assessed during the first year of treatment and following recovery from the first relapse in patients treated by a standardized medication algorithm. RESULTS: During the first year of treatment, patients with poorer premorbid cognitive functioning were more likely to stop antipsychotics (t=-2.54, df=75, p=0.01). Parkinsonian side effects increased the likelihood (hazard ratio=41.22; 95% CI=2.30, 737.89; p=0.01), and better executive function decreased the likelihood (hazard ratio=0.40; 95% CI=0.18, 0.88; p=0.02) that patients discontinued maintenance medication after a first relapse. CONCLUSION: Interventions to ameliorate cognitive deficits and Parkinsonian side effects may enhance treatment adherence.

Adult↗
PubMed2002

No evidence for phenotypic variation between probands in case-control versus family-based association studies of schizophrenia.

Traditional case-control genetic association studies utilizing unrelated probands are often used interchangeably with family-based designs to detect genes for complex psychiatric disorders. This strategy may be limited, however, if significant phenotypic variation exists between probands enrolled in these two types of studies. The present study compared 37 probands enrolled in a case-control study of schizophrenia with 37 age-, sex-, and ethnically matched probands enrolled in a family-based study of schizophrenia. Age of onset of illness was compared as well as performance on a battery of cognitive tests assessing attention, working memory, executive function, and verbal memory. Results revealed no significant differences in age of onset between the two groups or on any measure of cognitive performance. These data do not support reports of significant phenotypic variation between probands in case-control and family-based studies, and suggest that studies utilizing family-based approaches may be used to replicate reports of association made with case-control designs in schizophrenia.

Adult↗
PubMed2002

Frontal white matter microstructure, aggression, and impulsivity in men with schizophrenia: a preliminary study.

BACKGROUND: Aggression and impulsivity may involve altered frontal white matter. METHODS: Axial diffusion tensor images were acquired in 14 men with schizophrenia using a pulsed gradient, double spin echo, echo planar imaging method. White matter microstructural measures (fractional anisotropy and trace) were calculated from these data. Regions of interest were placed in frontal white matter on four slices. Impulsivity was measured using the Motor Impulsiveness factor of the Barratt Impulsiveness Scale. Aggressiveness was measured using the Assaultiveness scale of the Buss Durkee Hostility Inventory and the Aggression scale of the Life History of Aggression. RESULTS: Lower fractional anisotropy in right inferior frontal white matter was associated with higher motor impulsiveness. Higher trace in these regions was associated with aggressiveness. CONCLUSIONS: Inferior frontal white matter microstructure was associated with impulsivity and aggression in men with schizophrenia. These results implicate frontal lobe dysfunction in aggression and certain aspects of impulsivity.

Adult↗
PubMed2002

The effects of second-generation antipsychotics on cognitive functioning and psychosocial outcome in schizophrenia.

Neuropsychological deficits seem to be a major predictor of psychosocial outcome in patients with schizophrenia. Second-generation antipsychotics have shown greater promise in treating neuropsychological deficits than conventional antipsychotic drugs. This article summarizes the effect of newer antipsychotics on cognitive functioning and the implications for functional outcome. In this context it also addresses several methodological and conceptional issues that limited the comparison of these studies.

Antipsychotic Agents↗