Ian T. Mathew

Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.

IMPORTANCE Structural alterations in the hippocampus and other medial temporal lobe regions have been observed in schizophrenia. How these alterations and hippocampal subfields might differ across the psychosis spectrum remains unclear. OBJECTIVES To characterize medial temporal lobe structures, including hippocampal subfields, using magnetic resonance imaging and to examine their relation to psychosis and cognitive function across the psychosis spectrum. DESIGN, SETTING, AND PARTICIPANTS Case-control, cross-sectional neuroimaging study in a large series of probands with psychotic disorders and healthy volunteers as part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Patients with psychotic disorders (schizophrenia, n = 219; schizoaffective disorder, n = 142; and psychotic bipolar disorder, n = 188) and healthy controls (n = 337) were recruited across ambulatory clinics at university health centers in the B-SNIP consortium. MAIN OUTCOMES AND MEASURES Medial temporal lobe and hippocampal subfields were quantified with an automated parcellation approach using FreeSurfer software. Memory and other cognitive parameters were assessed using standardized neuropsychological tests. RESULTS Hippocampal volume reductions were seen in all 3 diagnostic groups when compared with healthy controls; alterations in the entorhinal cortex and parahippocampal regions were limited to schizophrenia and schizoaffective disorders (P < .001). Smaller volumes across the hippocampal subfields were seen in all 3 psychotic disorders, with the most prominent differences being in cornu ammonis 2/3 (P < .001). Hippocampal volumes were positively correlated with psychosis severity, declarative memory, and overall cognitive performance (P < .05). CONCLUSIONS AND RELEVANCE Alterations in the hippocampus were evident across psychotic disorders. Hippocampal subfields that participate in memory-related processes supporting pattern separation and pattern completion might be abnormal and may underlie the pathophysiology of psychosis.

Patient Smartphone Ownership and Interest in Mobile Apps to Monitor Symptoms of Mental Health Conditions: A Survey in Four Geographically Distinct Psychiatric Clinics

Background Despite growing interest in mobile mental health and utilization of smartphone technology to monitor psychiatric symptoms, there remains a lack of knowledge both regarding patient ownership of smartphones and their interest in using such to monitor their mental health. Objective To provide data on psychiatric outpatients’ prevalence of smartphone ownership and interest in using their smartphones to run applications to monitor their mental health. Methods We surveyed 320 psychiatric outpatients from four clinics around the United States in order to capture a geographically and socioeconomically diverse patient population. These comprised a state clinic in Massachusetts (n=108), a county clinic in California (n=56), a hybrid public and private clinic in Louisiana (n=50), and a private/university clinic in Wisconsin (n=106). Results Smartphone ownership and interest in utilizing such to monitor mental health varied by both clinic type and age with overall ownership of 62.5% (200/320), which is slightly higher than the average United States’ rate of ownership of 58% in January 2014. Overall patient interest in utilizing smartphones to monitor symptoms was 70.6% (226/320). Conclusions These results suggest that psychiatric outpatients are interested in using their smartphones to monitor their mental health and own the smartphones capable of running mental healthcare related mobile applications.

Are structural brain abnormalities associated with suicidal behavior in patients with psychotic disorders

Suicide represents a major health problem world-wide. Nevertheless, the understanding of the neurobiological underpinnings of suicidal behavior remains far from complete. We compared suicide attempters to non-attempters, and high vs. low lethality attempters, to identify brain regions associated with suicidal behavior in patients with psychotic disorders. 489 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I and 262 healthy controls enrolled in the B-SNIP study were studied. Groups were compared by attempt history and the highest medical lethality of previous suicide attempts. 97 patients had a history of a high lethality attempt, 51 of a low lethality attempt and 341 had no attempt history. Gray matter volumes were obtained from 3T structural MRI scans using FreeSurfer. ANCOVAs were used to examine differences between groups, followed by Hochberg multiple comparison correction. Compared to non-attempters, attempters had significantly less gray matter volume in bilateral inferior temporal and superior temporal cortices, left superior parietal, thalamus and supramarginal regions, right insula, superior frontal and rostral middle frontal regions. Among attempters, a history of high lethality attempts was associated with significantly smaller volumes in the left lingual gyrus and right cuneus. Compared to non-attempters, low lethality attempters had significant decreases in the left supramarginal gyrus, thalamus and the right insula. Structural brain abnormalities may distinguish suicide attempters from non-attempters and high from low lethality attempters among individuals with psychotic disorders. Regions in which differences were observed are part of neural circuitries that mediate inhibition, impulsivity and emotion, visceral, visual and auditory perception.

Correlations Between Brain Structure and Symptom Dimensions of Psychosis in Schizophrenia, Schizoaffective, and Psychotic Bipolar I Disorders

INTRODUCTION Structural alterations may correlate with symptom severity in psychotic disorders, but the existing literature on this issue is heterogeneous. In addition, it is not known how cortical thickness and cortical surface area correlate with symptom dimensions of psychosis. METHODS Subjects included 455 individuals with schizophrenia, schizoaffective, or bipolar I disorders. Data were obtained as part of the Bipolar Schizophrenia Network for Intermediate Phenotypes study. Diagnosis was made through the Structured Clinical Interview for DSM-IV. Positive and negative symptom subscales were assessed using the Positive and Negative Syndrome Scale. Structural brain measurements were extracted from T1-weight structural MRIs using FreeSurfer v5.1 and were correlated with symptom subscales using partial correlations. Exploratory factor analysis was also used to identify factors among those regions correlating with symptom subscales. RESULTS The positive symptom subscale correlated inversely with gray matter volume (GMV) and cortical thickness in frontal and temporal regions, whereas the negative symptom subscale correlated inversely with right frontal cortical surface area. Among regions correlating with the positive subscale, factor analysis identified four factors, including a temporal cortical thickness factor and frontal GMV factor. Among regions correlating with the negative subscale, factor analysis identified a frontal GMV-cortical surface area factor. There was no significant diagnosis by structure interactions with symptom severity. CONCLUSIONS Structural measures correlate with positive and negative symptom severity in psychotic disorders. Cortical thickness demonstrated more associations with psychopathology than cortical surface area.

Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy

BACKGROUND Proton magnetic resonance spectroscopy ((1)H MRS) enables in-vivo measurement of several relevant brain metabolites and has provided evidence of a range of neurochemical abnormalities in schizophrenia, especially in glutamate and N-acetyl-aspartate (NAA). While individuals at high familial risk for schizophrenia (HR) exhibit some neurobiological findings observed in the disorder, (1)H MRS findings and their clinical correlates are not well characterized in this population. METHODS We compared 23 adolescent and young adult offspring of schizophrenia patients with 24 age- and sex-matched healthy controls using (1)H MRS. We acquired multi-voxel, short TE (1)H MRS measurements at 1.5T and obtained metabolite concentrations of N-acetyl-aspartate (NAA), combined glutamate and glutamine (Glu+Gln) and choline-containing compounds (GPC+PC) for the left and right thalamus, anterior cingulate gyrus, and caudate. We also assessed the relationship between regional metabolite levels, clinical measures and brain volume in a subset of 16 high-risk and 15 control subjects. RESULTS Compared to healthy controls, high-risk subjects showed reductions in NAA levels in all three regions (thalamus, caudate, and anterior cingulate cortex), increases in Glu+Gln in the thalamus and caudate, and increases in GPC+PC in the anterior cingulate. In HR, thalamic Glu+Gln concentration was positively correlated and thalamic NAA inversely correlated with measures of schizotypy. Anterior cingulate GPC+PC and caudate Glu+Gln were significantly correlated with attenuated psychotic symptom severity. Anterior cingulate NAA was correlated with executive function. CONCLUSIONS Our data suggest the occurrence of metabolic alterations in young relatives of schizophrenia patients similar to those seen in patients with established illness. The observed correlations with cognitive deficits and psychosis-related psychopathology suggest that these metabolic measures may have value as biomarkers of risk for schizophrenia.

Local gyrification index in Probands with psychotic disorders and their first-degree relatives

BACKGROUND Psychotic disorders are characterized by aberrant neural connectivity. Alterations in gyrification, the pattern and degree of cortical folding, may be related to the early development of connectivity. Past gyrification studies have relatively small sample sizes, yield mixed results for schizophrenia, and are scant for psychotic bipolar and schizoaffective (SZA) disorders and for relatives of these conditions. Here, we examine gyrification in psychotic disorder patients and their first-degree relatives as a possible endophenotype. METHODS Regional local gyrification index (LGI) values, as measured by FreeSurfer software, were compared between 243 control subjects, 388 psychotic disorder probands, and 300 of their first-degree relatives. For patients, LGI values were examined grouped across psychotic diagnoses and then separately for schizophrenia, SZA, and bipolar disorder. Familiality (heritability) values and correlations with clinical measures were also calculated for regional LGI values. RESULTS Probands exhibited significant hypogyria compared with control subjects in three brain regions and relatives with Axis II cluster A disorders showed nearly significant hypogyria in these same regions. Local gyrification index values in these locations were significantly heritable and uncorrelated with any clinical measure. Observations of significant hypogyria were most widespread in SZA. CONCLUSIONS Psychotic disorders appear to be characterized by significant regionally localized hypogyria, particularly in cingulate cortex. This abnormality may be a structural endophenotype marking risk for psychotic illness and it may help elucidate etiological underpinnings of psychotic disorders.

Alterations in brain structures underlying language function in young adults at high familial risk for schizophrenia

INTRODUCTION Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia. METHODS T1 MRI scans from a 3T Siemens scanner of young adult FHR subjects (N=46) and controls with no family history of illness (i.e. at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. We explored volumetric and lateralization alterations in regions associated with language processing. An extensive neuropsychological battery of language measures was administered. RESULTS No significant differences were observed between groups on any language measures. Controlling intracranial volume, significantly smaller left pars triangularis (PT) (p<0.01) and right pars orbitalis (PO) (p<0.01) volumes and reversal of the L>R pars orbitalis (p<0.001) lateralization were observed in FHR subjects. In addition, the L pars triangularis and R pars orbitalis correlated with performance on tests of linguistic function in the FHR group. CONCLUSIONS Reduced volume and reversed structural asymmetry in language-related regions hypothesized to be altered in SZ are also found in first degree relatives at FHR, despite normal language performance. To clarify if these findings are endophenotypes for Sz, future studies would need to be performed of ill and well family members no longer within the age range of risk for illness to show these deficits segregate with schizophrenia within families. Moreover, measures of complex language need to be studied to determine if FHR individuals manifest impairments in some aspects of language function.

Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder.

Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study.

Schizophrenia (SZ) is a heterogeneous disorder that presents in adolescence, persists into adulthood, and has many clinical features. Recent evidence suggests that abnormalities in inflammatory, neurotrophic, and angiogenic processes may play a role in the etiology of SZ. The identification of molecular biomarkers early in the course of disease is crucial to transforming diagnostic and therapeutic avenues. We investigated 14 molecular analytes focusing on inflammatory, neurotrophic and angiogenic pathways from the plasma of antipsychotic-naïve familial high risk for SZ (FHR; n=35) and first-episode psychosis (FEP; n=45) subjects, in comparison to healthy controls (HC, n=39). We identified distinct alterations in molecular signatures in young relatives at FHR for SZ prior to psychosis onset and FEP subjects. Firstly, the expression of soluble fms-like tyrosine kinase (sFlt-1), an anti-angiogenic factor that binds vascular endothelial growth factor (VEGF), was significantly increased in the FHR group compared to HC, but not in FEP. Secondly, interferon gamma (IFNγ) was significantly reduced in the FEP group compared to HC. Thirdly, network analysis revealed a positive correlation between sFlt-1 and VEGF, suggesting an activation of the angiogenic cascade in the FHR group, which persists in FEP. Our results indicate an angiogenesis and immunological dysfunction early in the course of disease, shifting the balance towards anti-angiogenesis and inflammation.

Callosal Abnormalities Across the Psychosis Dimension: Bipolar Schizophrenia Network on Intermediate Phenotypes

BACKGROUND The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects. METHODS We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale. RESULTS Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality. CONCLUSIONS The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially.