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Mobile and connected devices like smartphones and wearable sensors can facilitate the collection of novel naturalistic and longitudinal data relevant to psychiatry at both the personal and population level. The National Institute of Mental Health’s Research Domain Criteria framework offers a useful roadmap to organize, guide and lead new digital phenotyping data towards research discoveries and clinical advances.

Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) share considerable overlap in clinical features, genetic risk factors and co-occurrence among relatives. The common and unique functional cerebral deficits in these disorders, and in unaffected relatives, remain to be identified. A total of 59 healthy controls, 37 SCZ and 57 PBD probands and their unaffected first-degree relatives (38 and 28, respectively) were studied using resting-state functional magnetic resonance imaging (rfMRI). Regional cerebral function was evaluated by measuring the amplitude of low-frequency fluctuations (ALFF). Areas with ALFF alterations were used as seeds in whole-brain functional connectivity analysis. We then tested whether abnormalities identified in probands were present in unaffected relatives. SCZ and PBD probands both demonstrated regional hypoactivity in the orbital frontal cortex and cingulate gyrus, as well as abnormal connectivity within striatal-thalamo-cortical networks. SCZ probands showed greater and more widely distributed ALFF alterations including the thalamus and bilateral parahippocampal gyri. Increased parahippocampal ALFF was related to positive symptoms and cognitive deficit. PBD patients showed uniquely increased functional connectivity between the thalamus and bilateral insula. Only PBD relatives showed abnormal connectivity within striatal-thalamo-cortical networks seen in both proband groups. The present findings reveal a common pattern of deficits in frontostriatal circuitry across SCZ and PBD, and unique regional and functional connectivity abnormalities that distinguish them. The abnormal network connectivity in PBD relatives that was present in both proband groups may reflect genetic susceptibility associated with risk for psychosis, but within-family associations of this measure were not high.

Our knowledge about the neurobiology of suicide is limited. It has been proposed that suicidal behavior generally requires biological abnormalities concomitant with the personality trait of impulsivity/aggression, besides an acute psychiatric illness or psychosocial stressor. We investigated fronto-limbic anatomical brain abnormalities in suicidal and non-suicidal adult female patients with unipolar depression. Our sample consisted of seven suicidal unipolar patients, 10 non-suicidal unipolar patients and 17 healthy female comparison subjects. The criterion for suicidality was one or more documented lifetime suicide attempts. A 1.5T GE Signa Imaging System running version Signa 5.4.3 software was used to acquire the magnetic resonance imaging images. All anatomical structures were measured blindly, with the subjects’ identities and group assignments masked. We used analysis of covariance with age and intracranial volume as covariates and the Tukey–Kramer procedure to compare suicidal patients, non-suicidal patients and healthy comparison subjects. Suicidal patients had smaller right and left orbitofrontal cortex gray matter volumes compared with healthy comparison subjects. Suicidal patients had larger right amygdala volumes than non-suicidal patients. Abnormalities in the orbitofrontal cortex and amygdala in suicidal patients may impair decision-making and predispose these patients to act more impulsively and to attempt suicide.

Cognitive rehabilitation has emerged as an effective treatment for addressing cognitive impairments and functional disability in schizophrenia; however, the degree to which changes in various social and non-social cognitive processes translate into improved functioning during treatment remains unclear. This research sought to identify the neurocognitive and social-cognitive mechanisms of functional improvement during a 2-year trial of cognitive enhancement therapy (CET) for early-course schizophrenia. Patients in the early course of schizophrenia were randomly assigned to CET (n=31) or an enriched supportive therapy control (n=27) and treated for up to 2 years. A comprehensive neurocognitive assessment battery and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) were completed annually, along with measures of functioning. Mediator analyses using mixed-effects growth models were conducted to examine the effects of neurocognitive and social-cognitive improvement on functional change. Improvements over 2 years in neurocognition and the emotion management branch of the MSCEIT were found to be significantly related to improved functional outcome in early-course schizophrenia patients. Neurocognitive improvement, primarily in executive functioning, and social-cognitive change in emotion management also mediated the robust effects of CET on functioning. Improvements in neurocognition and social cognition that result from cognitive rehabilitation are both significant mediators of functional improvement in early-course schizophrenia. Cognitive rehabilitation programs for schizophrenia may need to target deficits in both social and non-social cognition to achieve an optimal functional response.

Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n =25) and healthy controls (HC, n =30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N -acetylserotonin was increased in FENNS-BL compared with HC ( P =0.0077, which remained nearly significant after Bonferroni correction). N -acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/ N -acetylserotonin ratio was lower in FENNS-BL (all P -values<0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp–5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N -acetylserotonin by serotonin N -acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp–5HIAA correlation. Considering N -acetylserotonin as a potent antioxidant, such increases in N -acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.

Background Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. Methods Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. Results We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right ( p  = 0.03), but not left ( p  = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p  = .00023; p  = .00023) originating in selective PFC subregions. Conclusions In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

Polymorphisms of the gene encoding the regulator of G-protein signaling subtype 4 (RGS4) may confer risk for schizophrenia. 1 DNA microarray studies of postmortem brain samples have shown RGS4 underexpression in the dorsolateral prefrontal cortex (DLPFC, area 9), motor and visual cortices in schizophrenia patients relative to control subjects. 2 Underexpression of RGS4 in DLPFC is pathophysiologically significant because DLPFC pathology in schizophrenia has been supported by neurocognitive, 3 , 4 structural 5 and functional 6 , 7 imaging, postmortem, 8 cellular 9 , 10 and molecular 11 pathological studies. For these reasons, we examined the association of DLPFC gray matter volume with RGS4 polymorphisms in a series of antipsychotic-naïve first-episode schizophrenia patients and control subjects. We hypothesized that volumetric alterations of the DLPFC would be associated with RGS4 polymorphisms and that these differences would be more pronounced in patients than in controls. We observed robust volumetric differences across the genotypes in the pooled sample of patients and control subjects; when separately analyzed, we observed differences within the patient group ( n =30) but not in control subject ( n =27) group. The findings suggest that RGS4 polymorphisms may contribute to structural alterations in the DLPFC.

Background: Anatomical abnormalities in the corpus callosum have been reported in magnetic resonance imaging (MRI) studies in patients with bipolar but not unipolar disorder. MRI signal intensity can be used as a putative index of corpus callosum myelination. Objectives: To measure MRI signal intensity in patients with bipolar and unipolar disorder to investigate abnormalities of corpus callosum myelination. Methods: The study involved 29 DSM-IV bipolar patients (mean (SD) age, 35 (11) years; 16 male, 13 female), 23 DSM-IV unipolar patients (41 (10) years; 4 male, 19 female), and 36 healthy controls (37 (10) years; 23 male, 13 female). A 1.5T GE Signa magnet was employed, with a fast spin echo sequence. Corpus callosum signal intensity was obtained blindly using the semiautomated software NIH Image 1.62. Results: Bipolar patients had lower corpus callosum signal intensity for all callosal subregions (genu, anterior and posterior body, isthmus, splenium) than healthy controls (ANCOVA, age and sex as covariates, p<0.05). No significant differences were found between unipolar and healthy subjects (ANCOVA, age and sex as covariates, p>0.05). Conclusions: The findings suggest abnormalities in corpus callosum white matter in bipolar but not unipolar patients, possibly because of altered myelination. Such abnormalities could lead to impaired interhemispheric communication in bipolar disorder. Longitudinal MRI studies involving first episode and early onset bipolar patients will be necessary for a better understanding of the potential role of abnormalities of corpus callosum myelination in the pathophysiology of bipolar disorder.

IntroductionArea-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with decreased gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC).ObjectivesWe hypothesize that greater ARI will be associated with reduced right posterior CMFG and rACC GMVs.MethodsData were collected at baseline as part of the North American Prodrome Longitudinal Study. Counties where participants resided during childhood were geographically coded using the US Censuses to area-level factors. ARI was defined as the percentage of residents living in a different house five years ago. Generalized linear mixed models tested associations between ARI and GMVs.ResultsThis study included 29 HC and 64 CHR-P individuals who were aged 12 to 24 years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG (adjusted β = -0.258; 95% CI = -0.502 – -0.015) and right rACC volumes (adjusted β = -0.318; 95% CI = -0.612 – -0.023). The interaction terms (ARI X diagnostic group) in the prediction of both brain regions were not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.ConclusionsLike urban upbringing, ARI may be an important social environmental characteristic that adversely impacts brain regions related to schizophrenia.DisclosureNo significant relationships.

Background: Structural alterations in the association cortices as well as in the corpus callosum (CC) have been described in schizophrenia, and have been considered to reflect developmental abnormalities. Areas of primary and association cortices have been topographically mapped in the CC. Objective: To investigate whether, in schizophrenia, there are alterations in CC subdivisions that connect association, but not primary, cortices, and also to see if the normative, developmentally mediated increase in CC size with age is absent in this disorder. Methods: The midsagittal magnetic resonance imaging scans of 31 first episode, neuroleptic naive, schizophrenic patients, 12 non-schizophrenic, psychotic patients, and 31 healthy controls were compared. The total area of CC as well as that of anterior, middle and posterior genu, body, isthmus, and anterior, middle, and posterior splenii were measured. Results: Patients with schizophrenia as a group had a smaller CC, anterior genu, anterior body, isthmus, and anterior splenium than normal controls. Furthermore, the age related increase in CC size seen in normal subjects was absent in the patients. Conclusions: The observed reductions in size in selected regions of CC suggest a reduction in axonal connections between the heteromodal association cortices, which typically involve small diameter fibres. Furthermore, the absence of an age related increase in CC size in patients with schizophrenia suggests a neurodevelopmental abnormality that may extend into adolescence and early adulthood.