Donna J. Lang

Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins.

Schizophrenia unfolds during the late period of brain maturation, while myelination is still continuing. In the present study, we used MRI and T2 relaxation analysis to measure the myelin water fraction in schizophrenia. In schizophrenia (n=30) compared with healthy subjects (n=27), overall white matter showed 12% lower myelin water fraction (P=0.031), with the most prominent effects on the left genu of the corpus callosum (36% lower, P=0.002). The left anterior genu was affected in both first-episode (P=0.035) and chronic patients (P=0.011). In healthy subjects, myelin water fraction in total white matter and in frontal white matter increased with age, and with years of education, indicating ongoing maturation. In patients with schizophrenia, neither relation was statistically significant. Post-mortem studies of anterior frontal cortex demonstrated less immunoreactivity of two oligodendrocyte-associated proteins in schizophrenia (2′,3′-cyclic nucleotide 3′-phosphodiesterase by 33%, P=0.05; myelin-associated glycoprotein by 27%, P=0.14). Impaired myelination in schizophrenia could contribute to abnormalities of neural connectivity and persistent functional impairment in the illness.

Localization of the Subthalamic Nucleus: Optimization with Susceptibility-Weighted Phase MR Imaging

BACKGROUND AND PURPOSE: On clinical MR images, the subthalamic nuclei (STN) are poorly delineated from adjacent structures, impeding safe direct targeting for placement of electrodes in the treatment of Parkinson disease. Susceptibility-weighted MR phase imaging offers improved contrast and spatial resolution at reduced imaging times relative to clinically used T2-weighted spin-echo imaging for STN visualization. Our purpose was to assess STN visibility by using phase imaging, comparing phase and magnitude images obtained concurrently by using susceptibility-weighted imaging (SWI). The goal was to identify an efficient scanning protocol for high-quality phase images of STN. MATERIALS AND METHODS: Seventy-eight SWI scans were acquired at 3T by using different TEs and acceleration factors. STN visibility and delimitation from adjacent structures were scored from 0 (not interpretable) to 5 (excellent). Regression analyses assessed the relationship of STN visibility to scanning parameters RESULTS: STN were identified at all studied TEs on phase images. Visibility and delimitation of STN were consistently superior on phase images compared with magnitude images. Good visualization (score of ≥4) of STN on phase imaging occurred at a mean TE of 20.0 ms and a sensitivity encoding (SENSE) of 1.40. Scores of STN visualization on phase images were dependent on SENSE (P < .002) and TE (P < .031). Good delimitation of the STN on phase imaging occurred at a mean TE of 21.6 ms and a SENSE of 1.36. CONCLUSIONS: Visualization and delimitation of STN was superior on phase images and was achieved at 3T in <2.5 minutes. A TE of 20 ms and an acceleration factor of ≤1.5 are recommended to visualize STN by using this method,.

Reduced anterior internal capsule and thalamic volumes in first-episode psychosis.

BACKGROUND The thalamus is the gateway for sensory and motor information en route to the cortex. Information is processed via thalamocortical and corticothalamic pathways coursing through the internal capsules. In this study, we investigated the relationship between the anterior limb of the internal capsule, posterior limb of the internal capsule, and thalamus in first-episode psychosis (FEP). METHODS Twenty-nine FEP subjects (26 DSM-IV schizophrenia, 2 schizoaffective disorder, 1 psychosis not otherwise specified) and 22 healthy volunteers participated in this study. Anterior limb of the internal capsule (AIC), posterior limb of the internal capsule (PIC), and the thalamus volumes were manually determined from MRI scans. RESULTS FEP subjects had reduced AIC volumes (F(1,45)=6.18, p=0.017) and thalamic volumes (F(1,45)=8.00, p=0.007) compared to healthy volunteers. PIC volumes did not differ. Significant correlations between AIC volumes and thalamic volumes were observed in subjects with FEP, but not in healthy volunteers. Negative relationships between thalamic volumes and symptom severity were also observed. CONCLUSIONS The AIC and thalamic volumes were reduced in subjects with FEP compared to healthy volunteers. Abnormalities in thalamocortical and orticothalamic pathways may contribute to functional disruption of neural circuits in psychosis.

The Association of Elevated Body Mass Index with Reduced Brain Volumes in First-Episode Mania

BACKGROUND Compared with normal-weight patients, obese patients with bipolar I disorder (BD) suffer more manic and depressive episodes and make more suicide attempts. In the general population, obesity is associated with reduced total brain volume (TBV) and gray matter volume (GMV), but the neurobiology of obesity in BD has not been investigated. METHODS We used magnetic resonance imaging to examine TBV, GMV, white matter volume (WMV), as well as frontal, parietal, occipital, and temporal lobe volumes, in 55 healthy subjects (17 overweight/obese and 38 normal weight) and 57 patients with BD following their first manic episode (20 overweight/obese and 37 normal weight). RESULTS Linear regression analyses demonstrated that when other predictors of brain volume were accounted for, increased body mass index (BMI) in healthy subjects was significantly associated with decreased TBV and GMV. In contrast, increased BMI in patients with BD was significantly associated with decreased WMV and temporal lobe volume, areas of known vulnerability in early BD. CONCLUSIONS This is the first published report to show a relationship between elevated BMI and reduced brain volumes in BD, or any psychiatric illness. Our results suggest that obesity is associated with unique neurobiological changes in BD. They further imply a possible biological mechanism underlying the association between obesity and a more severe illness course in BD.

Developmental abnormalities of the hippocampus in First-Episode schizophrenia

BACKGROUND The human hippocampus becomes visible during the first trimester and folds to form the hippocampal fissure (HF) in the second trimester. The walls of this fissure fuse by 30 weeks, although small residual cavities can occur if development is disrupted. The primary purpose of this study was to determine if hippocampal fissures are evident in schizophrenia. A second goal was to assess the association between HF size and premorbid and clinical features of the illness. METHODS Magnetic resonance imaging scans were obtained on 33 patients with first-episode schizophrenia and 19 healthy volunteers. Hippocampal fissures were measured using semi-automated procedures, and hippocampi were manually traced. Birth history and premorbid functioning were assessed using maternal report. RESULTS Patients had a significantly larger mean HF volume and a nonsignificantly smaller hippocampal volume. Hippocampal fissure size was significantly associated with poor educational achievement and with anxiety-depression symptoms during the onset of illness. Smaller hippocampal size was associated with poor premorbid adjustment. CONCLUSIONS Larger HF size and an association between low educational achievement and enlarged HFs suggest abnormal neurodevelopment in schizophrenia. The association between HF size and anxiety-depression symptoms suggests that hippocampal abnormalities underlying HF dilatation may be a predisposing factor for increased stress sensitivity.

Predictors of persistent psychotic symptoms in persons with methamphetamine abuse receiving psychiatric treatment.

Abstract The objective of this study was to identify predictors of sustained psychotic symptoms after methamphetamine (MA) abuse during the course of 6 months from patterns of MA and other substance use, depressive symptoms, family history of psychosis, antisocial personality disorder, and trauma history. A total of 295 individuals with MA abuse and psychotic symptoms seeking psychiatric services were assessed at baseline and then monthly on symptoms and substance use for 6 months. Trajectory analyses revealed two trajectories of the individuals with positive symptoms, with one group presenting with persistent psychotic symptoms (30% of the sample). Those with persistent psychosis were significantly older, had more severe psychotic symptoms, misused MA for more years, had more antisocial personality traits, and had more sustained depressive symptoms. The strongest predictors of belonging to the persistent psychosis group, via logistic regressions, were more severe psychotic symptoms, longer use of MA, and sustained depressive symptoms. Our results highlight the important comorbidities, especially regarding depressive symptoms and persistent psychosis, in individuals seeking psychiatric help after MA abuse. This study also highlights the importance of identifying people with persistent psychosis within MA users to facilitate rapid and effective treatment of co-occurring psychotic disorder.

The Hotel Study: Multimorbidity in a Community Sample Living in Marginal Housing

OBJECTIVE The health of people living in marginal housing is not well characterized, particularly from the perspective of multimorbid illness. The authors investigated this population in a community sample. METHOD A prospective community sample (N=293) of adults living in single-room occupancy hotels was followed for a median of 23.7 months. Assessment included psychiatric and neurological evaluation, multimodal MRI, and viral testing. RESULTS Previous homelessness was described in 66.6% of participants. Fifteen deaths occurred during 552 person-years of follow-up. The standardized mortality ratio was 4.83 (95% CI=2.91-8.01). Substance dependence was ubiquitous (95.2%), with 61.7% injection drug use. Psychosis was the most common mental illness (47.4%). A neurological disorder was present in 45.8% of participants, with definite MRI findings in 28.0%. HIV serology was positive in 18.4% of participants, and hepatitis C virus serology in 70.3%. The median number of multimorbid illnesses (from a list of 12) was three. Burden of multimorbidity was significantly correlated with lower role functioning score. Comorbid addiction or physical illness significantly decreased the likelihood of treatment for psychosis but not the likelihood of treatment for opioid dependence or HIV disease. Participants who died during follow-up appeared to have profiles of multimorbidity similar to those of the overall sample. CONCLUSIONS This marginally housed cohort had greater than expected mortality and high levels of multimorbidity with adverse associations with role function and likelihood of treatment for psychosis. These findings may guide the development of effective health care delivery in the setting of marginal housing.

A longitudinal study on the effects of typical versus atypical antipsychotic drugs on hippocampal volume in schizophrenia

BACKGROUND Previous studies have reported that hippocampal volumes correlate with symptom severity in schizophrenia. This longitudinal study measured changes in symptoms and hippocampal volume in patients switched from typical antipsychotics to olanzapine. METHODS MRI scans were acquired from patients with chronic schizophrenia (n=10) and healthy volunteers (n=20). At baseline, patients were treated with typical antipsychotics for at least one year, then switched to olanzapine, and rescanned approximately one year later. RESULTS Olanzapine treatment resulted in no significant change in right or left hippocampal volume. Individual changes in right hippocampal volume correlated significantly with changes in symptoms. CONCLUSIONS Hippocampal volume change may serve as a marker of symptom change in patients on olanzapine.

Body Mass Index–Related Regional Gray and White Matter Volume Reductions in First-Episode Mania Patients

BACKGROUND We previously reported that overweight/obese first-episode mania patients had reduced white matter (WM) and temporal lobe volumes compared with normal-weight patients. WM reductions are characteristic of early-stage bipolar disorder (BD), whereas temporal lobe reductions are frequently reported later in the illness. These findings thus suggested a testable hypothesis: that the neuropathology of BD is exacerbated with elevated body mass index (BMI). METHODS We used voxel-based morphometry to examine the relationship between BMI and regional gray matter (GM) and WM volumes in our sample of 57 euthymic first-episode mania patients and 55 healthy subjects. We hypothesized that elevated BMI in patients, but not healthy subjects, would be associated with volume reductions in frontal, temporal, and subcortical limbic brain regions implicated in the pathophysiology of BD. RESULTS At recovery from their first manic episode, patients with higher BMI had GM and WM reductions in the predicted emotion-generating and -regulating regions. In contrast, healthy subjects with higher BMI had reduced occipital lobe GM only. Factorial analyses confirmed significant BMI × diagnosis interactions for the WM reductions. Approximately three-quarters of patients with elevated BMI were overweight rather than obese; thus, weight-related volume reductions were detectable in patients with modestly elevated BMI. CONCLUSIONS This is the first hypothesis-driven test of, and supporting evidence for, our theory that elevated BMI is associated with unique brain changes in BD that have a negative impact on regions believed to be vulnerable in the illness. Our results suggest a neurobiological mechanism to explain the well-validated link between obesity and illness severity in BD.

Effects of eight weeks of atypical antipsychotic treatment on middle frontal thickness in drug-naïve first-episode psychosis patients

Atypical antipsychotic medications generally maintain or increase gray matter amount and functioning. First-episode psychosis patients have lower gray matter volume in the middle frontal gyrus, as well as worse performance on spatial working memory tasks compared to controls. This study investigated the effects of short-term four- and eight-week atypical treatment on middle frontal thickness and spatial working memory in first-episode psychosis patients. Nineteen drug-naïve first-episode psychosis patients treated with risperidone or quetiapine and 26 controls completed structural magnetic resonance imaging, a spatial working memory task, and clinical assessment at three intervals (baseline, four weeks, and eight weeks; all patients and 23 controls completed all three assessments). Caudal and rostral middle frontal thicknesses were measured using the automated program Freesurfer. Positive, negative, and general symptoms of the Positive and Negative Syndrome Scale (PANSS) decreased significantly in patients, with most of the change occurring in the first four weeks of treatment. Patients demonstrated an increase in rostral middle frontal thickness over eight weeks of treatment compared to controls. There was a medium effect size relationship between reduction in negative symptoms at four and eight weeks, and a change in rostral middle frontal thickness over eight weeks. No changes were found in spatial working memory ability. Short-term atypical treatment with risperidone or quetiapine can increase prefrontal cortical thickness in psychosis. These findings are notable given the role of the rostral middle frontal region in cognition and the relationship between better cognitive functioning and better functional outcome in psychosis.