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Biomedical subjects

R M Bilder

Publications and source records attributed to R M Bilder.

At least 19 recordsLinked to original sources
PubMed2005

Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation.

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

Adult↗
PubMed2001

Working memory deficits in schizophrenia are not necessarily specific or associated with MRI-based estimates of area 46 volumes.

Despite substantial evidence that the prefrontal cortex does not function normally in patients diagnosed with schizophrenia, evidence for prefrontal structural abnormalities, as measured by magnetic resonance imaging (MRI), has been inconsistent. Additionally, evidence for relationships between prefrontal structural and functional measures has been limited. The inconsistencies in the MRI literature are, at least in part, due to a lack of standard and specific measurement protocols that allow delineation of functionally distinct cortical regions. In this study, reliable methods for measuring an estimate of area 46 (estimate referred to as area 46(e)), as defined by 'Cereb. Cortex 5 (1995) 323', were developed and used to examine relationships between area 46(e) volumes, working memory, and symptom severity in 23 male patients and 23 healthy male comparison subjects. Patients performed more poorly than healthy reference subjects on all cognitive measures including measures of spatial and non-spatial working memory, but showed no significant corresponding deficits in area 46(e) volumes or whole brain volumes. Moreover, there were no significant relationships between symptom severity and area 46(e) volumes. These findings suggest that the prefrontal functional abnormalities observed in schizophrenia may occur in the absence of prefrontal volume deficits, and may instead involve more widespread brain systems or prefrontal connections with other brain regions.

Adult↗
PubMed2001

Methods for developmental studies of fear conditioning circuitry.

Psychophysiologic studies use air puff as an aversive stimulus to document abnormal fear conditioning in children of parents with anxiety disorders. This study used functional magnetic resonance imaging (fMRI) to examine changes in amygdala activity during air-puff conditioning among adults. Blood oxygen level-dependent (BOLD) signal was monitored in seven adults during 16 alternating presentations of two different colored lights (CS+ vs. CS-), one of which was consistently paired with an aversive air puff. A region-of-interest analysis demonstrated differential change in BOLD signal in the right but not left amygdala across CS+ versus CS- viewing. The amygdala is engaged by pairing of a light with an air puff. Given that prior studies relate air-puff conditioning to risk for anxiety in children, these methods may provide an avenue for directly studying the developmental neurobiology of fear conditioning.

Adult↗
PubMed2001

The timing of neurodevelopmental abnormality in schizophrenia: an integrative review of the neuroimaging literature.

In this paper we will review recent neuroimaging research in schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and the timing of the neuroanatomic abnormalities underlying the disorder. Specifically, enlargement of cerebrospinal fluid spaces, deficits in cortical gray matter, and reduced volume of mesiotemporal structures have all been reported in patients in the first episode of schizophrenia, their first-degree relatives, and individuals with schizotypal personality disorder, supporting the possibility that these abnormalities reflect a genetically mediated neurodevelopmental disorder. These findings from the empirical literature will be synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. We believe that the evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, in order to more definitively determine the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and ultimately the prevention of schizophrenia.

Journal Article↗
PubMed2001

Cortical brain regions engaged by masked emotional faces in adolescents and adults: an fMRI study.

Face-emotion processing has shown signs of developmental change during adolescence. Functional magnetic resonance imaging (fMRI) was used on 10 adolescents and 10 adults to contrast brain regions engaged by a masked emotional-face task (viewing a fixation cross and a series of masked happy and masked fearful faces), while blood oxygen level dependent signal was monitored by a 1.5-T MRI scanner. Brain regions differentially engaged in the 2 age groups were mapped by using statistical parametric mapping. Summed across groups, the contrast of masked face versus fixation-cross viewing generated activations in occipital-temporal regions previously activated in passive face-viewing tasks. Adolescents showed higher maxima for activations in posterior association cortex for 3 of the 4 statistical contrasts. Adolescents and adults differed in the degree to which posterior hemisphere brain areas were engaged by viewing masked facial displays of emotion.

Adolescent↗
PubMed2001

Neurodevelopmental models of schizophrenia: pathophysiologic synthesis and directions for intervention research.

This paper examines contemporary models of the pathophysiology of schizophrenia from a neurodevelopmental perspective. Specifically, this article reviews recent research in the neuropathology, neuroimaging, and developmental psychopathology of schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and timing of both the neuroanatomic abnormalities underlying the disorder and their behavioral manifestations. Findings from the empirical literature are synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. The evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, to determine more definitively the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and, ultimately, prevention of schizophrenia.

Adolescent↗
PubMed2000

Reduced anterior cingulate gyrus volume correlates with executive dysfunction in men with first-episode schizophrenia.

Although frontal lobe structural and functional abnormalities have been identified in schizophrenia, their relationship remains elusive. Because the frontal lobes are both structurally and functionally heterogeneous, it is possible that some measures of frontal lobe structure may not have accurately identified relevant frontal lobe subregions. The authors hypothesized that the volumes of two dorsal, 'archicortical' subregions (i.e. superior frontal gyrus and anterior cingulate gyrus), but not a ventral, 'paleocortical' subregion (i.e. orbital frontal region) would be significantly and selectively correlated with executive and motor dysfunction in patients with schizophrenia as previously reported for the anterior hippocampal region. Volumes of these frontal lobe subregions were measured from magnetic resonance images based on sulcal anatomy in 20 men and 15 women with first-episode schizophrenia. All patients completed a comprehensive neuropsychological test battery while clinically stabilized that encompassed six domains of functioning: attention, executive, motor, visuospatial, memory and language. Findings indicated that reduced anterior cingulate gyrus volume was significantly correlated with worse executive functioning in men; among women, there were no significant correlations. Among men, anterior cingulate gyrus volume was significantly more strongly correlated with executive functioning than with attention, visuospatial, memory, language and general intellectual functioning. Neither executive nor motor functioning was significantly more strongly correlated with the dorsal 'archicortical' volumes than with orbital frontal volume. These findings suggest a link between executive deficits and dysfunction of the dorsal 'archicortical' system and implicate sex differences in their relationship in first-episode schizophrenia.

Adult↗
PubMed2000

Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates.

OBJECTIVE: Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited. METHOD: Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored. RESULTS: Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome. CONCLUSIONS: The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.

Adult↗
PubMed2000

Dual cytoarchitectonic trends: an evolutionary model of frontal lobe functioning and its application to psychopathology.

OBJECTIVE: To introduce and discuss an evolutionary model of frontal lobe functioning (the dual cytoarchitectonic trends theory [DTT]) and its application to understanding the neurobiology of schizophrenia and anxiety disorders. METHOD: An introduction to the DTT with respect to neural architecture, connectivity, and function is presented. In addition, neurobiologic, neuropathologic, clinical, and cognitive research supporting the application of this model to schizophrenia and anxiety disorders is reviewed. RESULTS: Traditional neuropsychologic models of acquired brain damage have been limited in their ability to explain frontal lobe dysfunction and its consequences in relation to psychopathology. The DTT offers an appropriately general neural-systems framework that may be better able to account for the diversity of symptoms, widespread neuropathology, and developmental abnormalities that are associated with most forms of psychopathology. CONCLUSIONS: Research investigating the neurobiology of psychopathology would benefit from adopting models of brain dysfunction that are consistent with neurodevelopmental pathology and evolution. Such efforts would likely lead to a greater understanding of neurobiologic mechanisms and, ultimately, better treatment strategies.

Arousal↗
PubMed1999

Longitudinal assessment of methylphenidate effects on oral word production and symptoms in first-episode schizophrenia at acute and stabilized phases.

BACKGROUND: Some studies have reported psychotic symptom exacerbation during "pharmacologic challenge" paradigms using dopamine agonists. Few studies, however, have examined the effects of these agonists on neurocognitive functions in patients with schizophrenia. This study assessed the effects of methylphenidate infusion on an oral word production test with demonstrated sensitivity to frontal lobe lesions, and on clinical state. METHODS: Patients were tested at two different phases; at the onset of their first-episode of schizophrenia (acute phase), and then again after they had responded to treatment and were clinically stable (stabilization phase). During each phase, patients were tested prior to and following methylphenidate infusion. Symptom clusters (i.e., positive, negative, and disorganization) were formed from SANS and SADS-C (+PD) ratings at each of these four timepoints. RESULTS: Patients produced significantly more words at preinfusion and while stabilized, suggesting that overall, decreased dopamine activity was associated with better word production. Redundant errors (i.e., perseverations of previously mentioned words and production of multiple words with the same roots) increased significantly following infusion in the stabilized phase. Disorganization symptoms increased significantly following infusion, regardless of study phase. CONCLUSIONS: These findings are consistent with previous theoretical and empirical findings relating dopamine activity to verbal output, a "redundancy bias" in cognitive control, and exacerbation of disorganization symptoms.

Adult↗
PubMed1999

Investigation of frontal lobe subregions in first-episode schizophrenia.

The evidence for frontal lobe structural abnormalities in schizophrenia using magnetic resonance (MR) imaging has been mixed, but most studies used either single slice measures or total volumes of a single frontal region, neither of which is sensitive to potential volume differences in more specific subregions. This study employed reliable methods for parcellation of the frontal lobes from MR images based on the sulcal anatomy. Following a cytoarchitectonic theory that distinguishes dorsomedial (archicortically derived) from ventrolateral (paleocortically derived) frontal subregions, we measured the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal region in 19 first-episode schizophrenia patients and 26 healthy comparison subjects. Results indicated that male patients had significantly larger right orbital frontal volume compared to their left orbital frontal volume and compared to healthy men. Among male patients larger right orbital frontal volume was significantly correlated with smaller right 'archicortical' (i.e. anterior cingulate and superior frontal gyri) volume. Furthermore, the ratio of right orbital frontal to right 'archicortical' volume was significantly and positively correlated with level of delusions among male patients. These findings suggest that there may be reciprocal controls on 'archicortical' and 'paleocortical' neurodevelopment among men with schizophrenia, and that larger paleocortical relative to archicortical volumes may be associated with increased delusions.

Brain↗
PubMed1999

Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder.

BACKGROUND: Functional neuroimaging studies have implicated the frontal lobes and the hippocampus-amygdala complex in the pathophysiology of obsessive-compulsive disorder (OCD). These brain regions have not been well investigated in patients with OCD, however, using magnetic resonance imaging. METHODS: Volumes of the superior frontal gyrus, anterior cingulate gyrus, orbital frontal region, hippocampus, and amygdala were computed from contiguous magnetic resonance images in a sample of 26 patients with OCD and 26 healthy comparison subjects. RESULTS: Patients with OCD had significantly reduced bilateral orbital frontal and amygdala volumes compared with healthy comparison subjects and lacked the normal hemispheric asymmetry of the hippocampus-amygdala complex. Neither brain structure volumes nor asymmetry indices were significantly correlated with total illness duration or length of current OCD episode. CONCLUSIONS: Findings of reduced orbital frontal and amygdala volumes in patients implicate a structural abnormality of these brain regions in the pathophysiology of OCD. Absence of the normal hemispheric asymmetry of the hippocampus-amygdala complex in patients is consistent with an anomalous neurodevelopmental process.

Adult↗
PubMed1999

Cerebral volume asymmetries in schizophrenia and mood disorders: a quantitative magnetic resonance imaging study.

Multiple abnormalities of brain structure have been identified in schizophrenia using in vivo neuroimaging methods, but little is known about the diagnostic specificity of these abnormalities. In a prior study of first-episode schizophrenia we found that this group lacked the normal pattern of cerebral volume asymmetries. Data from that study were combined with data from groups of patients with more chronic schizophrenia, and with bipolar and unipolar mood disorders, to determine the specificity of this abnormality to diagnostic subgroups defined by syndromal status or chronicity. The total sample comprised 235 patients (67 healthy volunteers, 81 patients with mood disorders or schizoaffective disorders, and 87 with schizophrenia or schizophreniform disorders). Asymmetries of regional cerebral volumes were measured on coronal magnetic resonance images with 3.1-mm contiguous slices and nominal in-plane resolution of 1 mm x 1 mm. Asymmetries differed significantly across groups in the occipitoparietal, prefrontal, and temporal regions. These asymmetries, and a composite index of asymmetry across regions ('torque'), all showed the same diagnostic group effect, with the schizophrenia group showing the least normal asymmetry, the mood disorder group intermediate asymmetry, and the control group the most marked asymmetry. No other diagnostic subgroup or chronicity effects were apparent. The findings support a 'continuum' rather than a 'diagnostic specificity' hypothesis, and suggest that the reduction of normal hemispheric asymmetries may mark a neurodevelopmental risk factor for major mental illnesses, and that some syndromal characteristics may be correlated with the degree of deviation from the normal anatomic pattern.

Adolescent↗
PubMed1999

MRI changes during water loading in patients with polydipsia and intermittent hyponatremia.

OBJECTIVE: Patients with polydipsia and intermittent hyponatremia have greater ventricle-brain ratios (VBRs) than matched patients without polydipsia and intermittent hyponatremia and normal subjects. Unlike previous studies, this study controlled for the impact of water loading when examining the volume of intracranial structures. METHOD: Under controlled conditions, eight male schizophrenic patients with polydipsia and intermittent hyponatremia were first assigned to either normal fluid intake or oral water loading and then the alternative condition the following day. Magnetic resonance imaging (MRI) volumetric measurements were made with the use of a standardized protocol. RESULTS: During water loading, total VBR and lateral ventricle volume significantly decreased by 13.1% and 12.6%, respectively. A strong association between change in serum sodium concentration and change in VBR was noted across conditions. CONCLUSIONS: These findings indicate that 1) water loading does not account for the diminished brain volume observed in patients with polydipsia and intermittent hyponatremia in previous studies, and 2) hyponatremia can significantly alter brain morphology on MRI.

Adult↗
PubMed1998

Meta-analysis of symptom factors in schizophrenia.

Factor and correlational analyses have been used to characterize symptom dimensions in schizophrenia, though they have yielded divergent models. This study used meta-analysis of published work to determine the number and composition of symptom dimensions. Principal components analysis of data from 10 empirical studies (pooled n = 896) yielded three factors, 'positive', 'negative' and 'conceptual disorganization'. The findings suggest that a three-factor solution is a relatively stable outcome of studies assessing these symptoms in chronic patients, and that some symptoms (alogia, attentional impairment) are less likely to load uniquely on a single factor.

Behavioral Symptoms↗
PubMed1998

Absence of the adhesio interthalamica as a marker of early developmental neuropathology in schizophrenia: an MRI and postmortem histologic study.

Several recent studies have reported an association between midline cerebral malformations (e.g., corpus callosum, cavum septum pellucidum) and schizophrenia. The authors investigated whether absence of the adhesio interthalamica (AI), a midline structure that develops in concert with prominent features of the ventricular system soon after the bridge from the late embryonic stages to early fetal life, might constitute a marker of early developmental neuropathologic changes in schizophrenia. Eighty-two patients (54 men, 28 women) with a diagnosis of first-episode schizophrenia (FES) were recruited from consecutive admissions to a psychiatric inpatient service. Fifty-two healthy control subjects (30 men, 22 women) were recruited and matched to the patient sample on distributions of sex and age. Magnetic resonance imaging studies were performed, and the presence versus absence of the AI was determined for each subject. The length and volume of the third ventricle were measured for each subject. The AI was found to be absent more often among patients with FES compared with control subjects, and patients without an observable AI also had larger third-ventricle volumes. These differences in presence or absence of the AI observed in vivo (but not in a comparable postmortem sample of histologically fixed and prepared brain slices), which are likely related to third-ventricle enlargement, may represent yet another early developmental marker of cerebral malformation among patients with FES.

Adult↗
PubMed1997

Neurocognitive impairment in schizophrenia and how it affects treatment options.

OBJECTIVE: To review the roles played by neurocognitive assessment in the treatment of schizophrenia and in the design of treatment research strategies. METHOD: A review of the literature and summaries of clinical and research implications are presented, with directions for future research. RESULTS: Neurocognitive deficits are now targets of antipsychotic drug treatment and should increasingly be used to refine both theory and clinical practice by considering the effects of treatments at the level of neural systems. CONCLUSION: Efforts to bridge the gaps between preclinical and clinical assessments should yield large rewards in drug development and individualized treatment strategies. Functional neuroimaging may play a major role in these developments.

Antipsychotic Agents↗