Symptom dimensions and brain morphology in schizophrenia and related psychotic disorders

Mental Health Clinical Research Center, Division of Biostatistics, University of Iowa Hospital and Clinics, Univerisity of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
Journal of Psychiatric Research (Impact Factor: 3.96). 07/1995; 29(4):261-276. DOI: 10.1016/0022-3956(94)00046-T


The heterogeneity of symptoms in schizophrenia may reflect heterogeneity of underlying pathophysiological mechanisms. Factor analytic studies have consistently identified three symptom factors, psychotic, negative and disorganized, as independent dimensions of schizophrenic psychopathology. This study examined the relationship of these symptom dimensions with volumes of specific brain regions. One-hundred and sixty-six schizophrenia spectrum patients were clinically evaluated with the Comprehensive Assessment of Symptoms and History (CASH) and scanned with a 1.5 Tesla magnetic resonance imaging scanner. Regions of interest (ROIs) were manually traced on 5 mm and 3 mm coronal slices by a single technician, blind to all aspects of subject identity. Correlations between ROI volumes and indices of symptom severity were determined. Analyses of covariance were then used to test for specific relationships between each of the three symptom dimensions and ROI volumes. Tests were made of each dimension, controlling for all others. Overall symptom severity was significantly correlated with larger ventricle volumes (lateral, third and temporal horns) and smaller temporal lobe, hippocampal and superior temporal gyral volumes. Both psychotic and negative symptom severity predicted increased third ventricular volume. Psychotic symptom severity uniquely predicted decreased superior temporal gyral volume as well as increased temporal horn volume. Within the psychotic symptom dimension, hallucinations alone predicted left superior temporal gyral volume. No significant associations between disorganized symptoms and any ROIs were demonstrated. These results provide clues to the localization of specific brain regions underlying symptom clusters in schizophrenia, and provide further validating evidence for the construct of independent dimensions of psychopathology within schizophrenia and related psychotic disorders.

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    • "Both an abnormal decrease of STG gray matter volume and cortical thinning in the STG, particularly in the left hemisphere (McCarley et al., 1993; Hirayasu et al., 2000; Nesvåg et al., 2008), can be seen in patients with schizophrenia as well as in first-degree relatives of patients with schizophrenia (Kasai et al., 2003; Yoshida et al., 2009; Tang et al., 2012). Reduced STG volume is also associated with auditory hallucinations (Barta et al., 1990; Flaum et al., 1995), a core positive symptom of schizophrenia. Also, Tang et al. found a negative correlation between gray matter volume in left middle and superior temporal gyrus and PANSS-positive symptoms (Tang et al., 2012). "
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    ABSTRACT: Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) grey matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyse the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. No SNP by diagnosis interaction effect reached genome-wide significance (5 × 10(-8)) in our GWA study, but 10 SNPs reached P-values less than 10(-6). The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signalling. Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes.
    The World Journal of Biological Psychiatry 08/2015; 16(6):1-11. DOI:10.3109/15622975.2015.1062915 · 4.18 Impact Factor
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    • "The STG is involved in auditory processing (Chen et al., 2013) and social cognitive processes (Bosia et al., 2012). Previous studies have shown structural alterations of the STG in schizophrenia patients (Edgar et al., 2013; Honea et al., 2005; Kasai et al., 2003; Yoshida et al., 2009), which have also been associated with auditory hallucinations (Barta et al., 1990; Flaum et al., 1995; Nenadic et al., 2010). Another well-studied intermediate phenotype is DLPFC activity during WM processing (Kim et al., 2009; Manoach, 2003; Potkin et al., 2009a; Walton et al., 2013a). "
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    ABSTRACT: Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data 01 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identity markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (ERIIA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; 59. DOI:10.1016/j.pnpbp.2015.01.006 · 3.69 Impact Factor
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    • "Previous studies have found a positive relationship between hippocampal volume and serum levels of BDNF in both chronic and first episode schizophrenia (Erickson et al., 2010; Rizos et al., 2011). In addition, a negative relationship between hippocampal volume and symptom severity has been found in chronic schizophrenia (Flaum et al., 1995; Rajarethinam et al., 2001). "
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    ABSTRACT: Objective The present study was to examine serum levels of brain-derived neurotrophic factor (BDNF), folate, homocysteine (Hcy), and their relationships with hippocampal volume and psychopathology in drug naïve, first episode schizophrenia. Method Drug naïve, first episode schizophrenia patients and healthy controls were enrolled in the study. Serum levels of BDNF, folate and Hcy were measured using enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA), and enzymatic cycling method respectively. Hippocampus was parcellated and bilateral hippocampal volumes were measured using FreeSurfer. Results Forty-six patients with drug naïve, first episode schizophrenia (SZ group) and 30 healthy controls (control group) were enrolled. The SZ group had significantly lower serum levels of BDNF and folate, and significantly higher serum levels of Hcy compared with the control group (p = 0.013, p < 0.001, p = 0.003 respectively). There were no significant differences in hippocampal volumes between the two groups (ps > 0.2). Within the SZ group, there were significant positive relationships between serum levels of BDNF and both left and right hippocampal volumes (r = 0.327, p = 0.026; r = 0.338, p = 0.022 respectively). In contrast, such relationships did not exist in the control group. Within the SZ group, there were significant negative relationships between serum levels of folate and PANSS-total scores and PANSS-negative symptom scores (r = 0.319, p = 0.031; r = 0.321, p = 0.030 respectively); and there was a positive relationship between serum levels of Hcy and PANSS-total scores (r = 0.312, p = 0.035). Controlling for potential confounding variables resulted in similar findings. Conclusions Drug naïve, first episode schizophrenia presents decreased serum levels of BDNF, folate and increased serum levels of Hcy, which may play an important role in the neurodevelopmental process and clinical manifestation of schizophrenia.
    Schizophrenia Research 10/2014; 159(1). DOI:10.1016/j.schres.2014.07.033 · 3.92 Impact Factor
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