Person:

Seidman, Larry Joel

Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30–100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann’s area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-β) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.

Background: Structural MRI data indicate schizophrenics have reduced left-sided temporal lobe gray matter volumes, especially in the superior temporal gyrus (STG) and medial temporal lobe. Our data further suggest a specificity to schizophrenia spectrum disorders of STG volume reduction. Interpretation of research studies involving schizophrenics may be complicated by the effects of exposure to neuroleptics and chronic illness. Sharing the same genetic diathesis of schizophrenics, subjects with schizotypal personality disorder (SPD) offer a unique opportunity to evaluate commonalities between schizophrenia and SPD, particularly as SPD subjects are characterized by cognitive and perceptual distortions, an inability to tolerate close friendships, and odd behavior, but they are not psychotic and so have generally not been prescribed neuroleptics nor hospitalized. Evaluation of brain structure in SPD may thus offer insight into the “endophenotype” common to both disorders. In addition, differences between groups may suggest which are the brain structures of schizophrenics that contribute to the development of psychosis. Methods: To test the hypothesis of whether SPD subjects might show similar STG abnormalities, STG and medial temporal lobe regions of interest (ROI) were manually drawn on high resolution coronal MRI 1.5 mm thick slices. Images were derived from 16 right-handed male SPD subjects, without regard to family history, and 14 healthy, right-handed, comparison males who did not differ from the SPD group on parental socio-economic status, age, or verbal IQ. Results: As predicted, SPD subjects showed a reduction in left STG gray matter volume compared with age and gender matched comparison subjects. SPD subjects also showed reduced parahippocampal left/right asymmetry and a high degree of disordered thinking. Comparisons with chronic schizophrenics previously studied by us showed the SPD group had a similarity of left STG gray matter volume reduction, but fewer medial temporal lobe abnormalities. Conclusions: These abnormalities strengthen the hypothesis of a temporal lobe abnormality in SPD, and the similarity of STG findings in schizophrenia and SPD suggest that STG abnormalities may be part of the spectrum “endophenotype.” It is also possible that presence of medial temporal lobe abnormalities may help to differentiate who will develop schizophrenia and who will develop the less severe schizophrenia spectrum disorder, SPD.

Objective: This study examined MRI hippocampal volume and cavum septi pellucidi (CSP) in female subjects with schizotypal personality disorder (SPD) and comparison subjects. Method: MRI was performed on 20 SPD and 29 comparison subjects with delineation of left and right hippocampi. Number of slices containing the CSP was counted. Subjects were given a working memory task, the Delayed Alternation task and other measures of working memory including the Wechsler Memory Test-Revised and the California Verbal Learning Test. Clinical measures were derived from the SCID-II. Results: SPD females evinced bilaterally smaller hippocampal volumes compared with non-psychiatric female subjects (15.1% on left, 15.7% on right). Additionally, SPD subjects showed statistically significantly more slices containing CSP, and a trend level difference when large CSP was defined as four or more slices (20% vs. 6.9%). SPD subjects demonstrated more errors, more perseverations, and a trend toward more failure to maintain set on the Delayed Alternating task, which were associated with smaller left hippocampal volumes. There was no difference between groups in logical memory, verbal learning or semantic clustering nor a significant correlation between these measures and hippocampal volumes. Clinically, in SPD subjects, right hippocampal volumes correlated negatively with odd appearance/behavior and positively with suspiciousness/paranoia, and odd speech was positively correlated with the number of slices containing a CSP in exploratory analyses. Conclusions: Female SPD subjects showed bilaterally smaller hippocampal volumes and larger CSP than comparison subjects, similar to what has been shown in schizophrenia. Moreover, these abnormalities have clinically significant associations which may help to explain some of the manifestations of the disorder.

The fusiform gyrus is important for face and object recognition, is abnormal in schizophrenia, but has not been studied in schizotypal personality disorder (SPD). Thin-slice MR images showed no differences, either in right, left or total fusiform gyri volumes, between subjects with SPD (N = 21) and normal controls (N = 19). However, there was a correlation between severity of illusions and magical thinking suffered by the SPD subjects and smaller right fusiform gyrus volumes. This suggests that future studies may be useful in determining the functional competence of this gyrus in SPD.

Background: Reduced, left-lateralized P3 amplitude has been reported in several studies focusing on electrophysiologic function in schizophrenia. Also, several lines of evidence suggest a similarity between schizophrenia and schizotypal personality disorder (SPD). This study was undertaken to determine the replicability of our previous finding of a left-lateralized P3 amplitude deficit in SPD. Methods: We recorded event-related potentials in 21 SPD and 18 normal control subjects in an auditory “oddball” P3 paradigm. Results: In the SPD subjects, but not in the control subjects, there was lower P3 amplitude at T3 compared with T4. Conclusions: These results are similar to the ones in our previous work and further support the presence of a left-lateralized P3 deficit in SPD.

Introduction: Schizotypal personality disorder (SPD) shares with schizophrenia many biological features, yet little is known about the clinical characteristics of persons diagnosed with this disorder. This report describes the clinical, cognitive and socio-occupational characteristics of a community sample of subjects diagnosed with SPD. Method: Sixty-four male and 40 female neuroleptic-naive DSM-IV SPD subjects and 59 male and 51 female comparison subjects were recruited from the community for a total sample of 214 subjects. Demographic and cognitive differences between groups and, within the SPD group, the effect of gender on clinical features, such as the SPD criteria, SAPS, SANS, Schizotypal Personality Questionnaire, and co-morbidity, were examined using ANOVA and Chi-square distributions. Results: SPD subjects, in contrast to comparison subjects, had significantly lower socio-economic status, poorer social relationships and skills, and lower vocabulary scores. Furthermore, SPD subjects demonstrated more impairment on Vocabulary scores than on Block Design, as measured by the WAIS-R, a pattern not seen in comparison subjects. In the SPD cohort, positive symptoms predominated and nearly half were co-morbid for major depression. With respect to gender, male SPD subjects, compared with female SPD subjects, evinced significantly more negative symptoms, fewer friends, had more odd speech, and were more likely to also suffer from paranoid and narcissistic personality disorders. In contrast to male SPD subjects, female SPD subjects perceived themselves to be more disorganized. Conclusions: SPD subjects, similar to schizophrenics, are impaired socially, occupationally, and cognitively, particularly in the area of verbal measures. Moreover, male SPD subjects may be more severely affected than female SPD subjects across multiple domains of functioning.

Background: The goal of the study was to examine mismatch negativity (MMN) in schizotypal personality disorder (SPD) individuals. Abnormal MMN has been a consistent finding in chronic schizophrenia and there are also have been reports of reduced duration MMN in first episode schizophrenia patients (Umbricht & Krljes, 2005), with some studies finding no pitch MMN amplitude differences (Salisbury et al., 2002) while others reporting a modest reduction (Umbricht et al., 2006) in recent onset schizophrenia patients. To our knowledge no reports exist of MMN in SPD individuals. Methods: Twenty six normal (14 females) control and 23 SPD (12 females) individuals were tested using the pitch MMN paradigm. Normal control (NC) and SPD individuals were recruited from the general population and assessed using DSM-IV. SPD individuals were included if they met 5 or more criteria for SPD disorder. The subjects listened to 2000 frequent 1 kHz pure tones and 100 rare 1.2 kHz pure tones while reading a magazine article. MMN was measured from a difference waveform within the latency window of 175–276 msec. Results: Reduced MMN amplitude was found in SPD relative to NC subjects (p< 0.045). Conclusions: These results point to potential differences between SPD and schizophrenia, where no reduction in MMN was found in most studies of first episode patients.