Morphological Abnormalities in Early-Onset Schizophrenia Revealed by Structural Magnetic Resonance Imaging.

Schizophrenia is a pathological condition characterized by delusions, hallucinations, and a lack of motivation. In this study, we performed a morphological analysis of regional biomarkers in early-onset schizophrenia, including cortical thicknesses, surface areas, surface curvature, and volumes extracted from T1-weighted structural magnetic resonance imaging (MRI) and compared these findings with a large cohort of neurotypical controls. Results demonstrate statistically significant abnormal presentation of the curvature of select brain regions in early-onset schizophrenia with large effect sizes, inclusive of the pars orbitalis, pars triangularis, posterior cingulate cortex, frontal pole, orbital gyrus, lateral orbitofrontal gyrus, inferior occipital gyrus, as well as in medial occipito-temporal, lingual, and insular sulci. We also observed reduced regional volumes, surface areas, and variability of cortical thicknesses in early-onset schizophrenia relative to neurotypical controls in the lingual, transverse temporal, cuneus, and parahippocampal cortices that did not reach our stringent standard for statistical significance and should be confirmed in future studies with higher statistical power. These results imply that abnormal neurodevelopment associated with early-onset schizophrenia can be characterized with structural MRI and may reflect abnormal and possibly accelerated pruning of the cortex in schizophrenia.

A morphological study of schizophrenia with magnetic resonance imaging, advanced analytics, and machine learning.

We have performed a morphological analysis of patients with schizophrenia and compared them with healthy controls. Our analysis includes the use of publicly available automated extraction tools to assess regional cortical thickness (inclusive of within region cortical thickness variability) from structural magnetic resonance imaging (MRI), to characterize group-wise abnormalities associated with schizophrenia based on a publicly available dataset. We have also performed a correlation analysis between the automatically extracted biomarkers and a variety of patient clinical variables available. Finally, we also present the results of a machine learning analysis. Results demonstrate regional cortical thickness abnormalities in schizophrenia. We observed a correlation (rho = 0.474) between patients' depression and the average cortical thickness of the right medial orbitofrontal cortex. Our leading machine learning technology evaluated was the support vector machine with stepwise feature selection, yielding a sensitivity of 92% and a specificity of 74%, based on regional brain measurements, including from the insula, superior frontal, caudate, calcarine sulcus, gyrus rectus, and rostral middle frontal regions. These results imply that advanced analytic techniques combining MRI with automated biomarker extraction can be helpful in characterizing patients with schizophrenia.

Identification of association fibers using ex vivo diffusion tractography in Alexander disease brains.

BACKGROUND AND PURPOSE: Alexander disease (AxD) is a neurodegenerative disorder caused by heterozygous Glial Fibrillary Acidic Protein mutation. The characteristic structural findings of AxD, such as leukodystrophic features, are well known, while association fibers of AxD remain uninvestigated. The aim of this study was to explore global and subcortical fibers in four brains with AxD using ex vivo diffusion tractography METHODS: High-angular-resolution diffusion magnetic resonance imaging (HARDI) tractography and diffusion-tensor imaging (DTI) tractography were used to evaluate long and short association fibers and compared to histological findings in brain specimens obtained from four donors with AxD and two donors without neurological disorders RESULTS: AxD brains showed impairment of long association fibers, except for the arcuate fasciculus and cingulum bundle, and abnormal trajectories of the inferior longitudinal and fronto-occipital fasciculi on HARDI tractography and loss of multidirectionality in subcortical fibers on DTI tractography. In histological studies, AxD brains showed diffuse low density on Klüver-Barrera and neurofilament staining and sporadic Rosenthal fibers on hematoxylin and eosin staining CONCLUSIONS: This study describes the spatial distribution of degenerations of short and long association fibers in AxD brains using combined tractography and pathological findings.

Hold-out validation for the assessment of stability and reliability of multivariable regression demonstrated with magnetic resonance imaging of patients with schizophrenia.

Neuroscience studies are very often tasked with identifying measurable differences between two groups of subjects, typically one group with a pathological condition and one group representing control subjects. It is often expected that the measurements acquired for comparing groups are also affected by a variety of additional patient characteristics such as sex, age, and comorbidities. Multivariable regression (MVR) is a statistical analysis technique commonly employed in neuroscience studies to "control for" or "adjust for" secondary effects (such as sex, age, and comorbidities) in order to ensure that the main study findings are focused on actual differences between the groups of interest associated with the condition under investigation. It is common practice in the neuroscience literature to utilize MVR to control for secondary effects; however, at present, it is not typically possible to assess whether the MVR adjustments correct for more error than they introduce. In common neuroscience practice, MVR models are not validated and no attempt to characterize deficiencies in the MVR model is made. In this article, we demonstrate how standard hold-out validation techniques (commonly used in machine learning analyses) that involve repeatedly randomly dividing datasets into training and testing samples can be adapted to the assessment of stability and reliability of MVR models with a publicly available neurological magnetic resonance imaging (MRI) dataset of patients with schizophrenia. Results demonstrate that MVR can introduce measurement error up to 30.06% and, on average across all considered measurements, introduce 9.84% error on this dataset. When hold-out validated MVR does not agree with the results of the standard use of MVR, the use of MVR in the given application is unstable. Thus, this paper helps evaluate the extent to which the simplistic use of MVR introduces study error in neuroscientific analyses with an analysis of patients with schizophrenia.

Reduction of dopamine and glycogen synthase kinase-3 signaling in rat striatum after continuous administration of haloperidol.

BACKGROUND: Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats. METHODS: Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions. RESULTS: In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/ß and an increase in the pGSK-3ß/GSK-3ß ratio, whereas AKT was not changed. CONCLUSIONS: Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS.

Astroglial glutamate transporter 1 and glutamine synthetase of the nucleus accumbens are involved in the antidepressant-like effects of allopregnanolone in learned helplessness rats.

Clinical studies have demonstrated that allopregnanolone (3α5α-tetrahydroprogesterone, ALLO) has antidepressant-like effects on patients with depression. Previous studies have shown alteration of the astroglial glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) in depression, and ALLO is known to modulate glutamate release. The present study aimed to investigate whether astroglial GLT-1 and GS are indeed involved in the antidepressant-like effects of ALLO in learned helplessness (LH) rats, a validated animal model of depression. The results of this study showed that bilateral microinjection of ALLO into the lateral ventricles could normalize the levels of GLT-1 and GS in the nucleus accumbens (NAc) and of GS in the hippocampal CA1 region of LH rats. These results suggest a certain connection between the antidepressant-like effects of ALLO and the astroglial GLT-1/GS system of the NAc in LH rats.

The alterations of glutamate transporter 1 and glutamine synthetase in the rat brain of a learned helplessness model of depression.

BACKGROUND: Although glutamate transmission via astrocytes has been proposed to contribute to the pathophysiology of depression, the precise mechanisms are unknown. Herein, we investigated the levels of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) of astrocytes in learned helplessness (LH) rats (an animal model of depression) and non-LH rats (an animal model of resilience). METHODS: We administered inescapable mild electric shock to rats and then discriminated the LH and non-LH rats by a post-shock test. Almost 55% of the rats acquired LH. We then measured the expressions of GLT-1 and GS in several brain regions of LH and non-LH rats by Western blot analysis. RESULTS: The levels of GLT-1 and GS in the CA-1, CA-3, dentate gyrus (DG), medial prefrontal cortex (mPF), and nucleus accumbens (NAc) of the LH group were significantly higher than those of the control group. The GS levels in the amygdala of the LH rats were significantly decreased compared to the controls. There were significant differences in GLT-1 and GS levels between the non-LH and LH rats in the CA-1 and CA-3. CONCLUSIONS: These results suggest that the LH rats experienced up-regulations of GLT-1 and GS in the CA-1, CA-3, DG, mPF, and NAc and a down-regulation of GS in the amygdala. It is possible that the effects of the GLT-1 and GS levels on astrocytes in the CA-1 and CA-3 are critical for the differentiation of resilience from vulnerability.