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BACKGROUND The relationship between dietary behaviors and depression has been widely studied, yet previous research has relied on self-reported data which is subject to recall bias. Electronic device-based behavioral monitoring offers the potential for objective, real-time data collection of a large amount of continuous, long-term behavior data in naturalistic settings. OBJECTIVE The study aims to characterize digital dietary behaviors in depression, and to determine whether these behaviors could be used to detect depression. METHODS A total of 3310 students (2222 healthy controls, 916 with mild depression, and 172 with moderate-severe depression) were recruited for the study. Daily electronic records of meals consumed over one month were used to analyze differences in dietary behaviors between groups through analyses of covariance. Support vector machine analysis was used to determine if changes in dietary behaviors could detect mild and moderate-severe depression. RESULTS The study found that individuals with moderate-severe depression had more irregular eating patterns, more fluctuated feeding times, spending more money on dinner, less diverse food choices, as well as eating breakfast less frequently and preferred to eat only lunch and dinner, compared to healthy controls. The study found that these changes in digital dietary behaviors were able to detect mild and moderate-severe depression, with better accuracy for detecting moderate-severe depression. CONCLUSIONS This is the first study to develop a profile of changes in digital dietary behaviors in individuals with depression using real-world behavioral monitoring rather than self-reported data. The results suggest that digital markers may be a promising approach for detecting depression.

Multiple genetic variants and their interplay with environmental factors have hindered the progress of mental disease research and the development of effective markers of neuropsychiatric disorders. Intermediate phenotypes like neuroimaging brain patterns offer unique opportunities to understand multifaceted etiologies of neuropsychiatric diseases such as depression. Neuroimaging intermediate phenotypes bridging etiologic differences and disease behavioral features may facilitate translational applications of animal models to humans with depression. We identified cross-species neuroimaging patterns of the amplitude of low-frequency fluctuations (ALFF) that correlated with anhedonia in rodent genetic and stress models of depression and depressed individuals. Compared to controls, converse ALFF patterns in subcortical and sensorimotor regions were found between P11 knockout mice and chronic unpredictable mild stress rats. Similarly, two ALFF subtypes with converse patterns in frontal, subcortical, and sensorimotor regions were identified and validated in two independent human cohorts for depression. Importantly, anhedonia was significantly increased across all rodent models and human subtypes when compared to controls, despite differences in ALFF patterns. Further, anhedonia correlated with subcortical-sensorimotor ALFF in rodent models and human cohorts. Thus, subcortical-sensorimotor ALFF may serve as an intermediate phenotype that bridges etiologic differences and anhedonia in depression. These results deepened our knowledge of disease mechanisms underlying depression which can be explored in translational research and clinical applications treating depression and other psychiatric disorders.

ObjectiveDeveloping a neuroimaging-based precision medicine framework for depression.MethodsThe study was conducted in two stages at two sites: development of a neuroimaging-based subtyping and precise repetitive transcranial magnetic stimulation (rTMS) strategy for depression at Center 1 and its clinical application at Center 2. Center 1 identified depression subtypes and subtype-specific rTMS targets based on amplitude of low frequency fluctuation (ALFF) in a cohort of 238 major depressive disorder patients and 66 healthy controls (HC). Subtypes were identified using a Gaussian Mixture Model, and subtype-specific rTMS targets were selected based on dominant brain regions prominently differentiating depression subtypes from HC. Subsequently, one classifier trained per Center 1 findings for subtyping and subtype-specific rTMS targets were employed to deliver two-week precise rTMS to 72 hospitalized, depressed youths at Center 2. MRI and clinical assessments were obtained at baseline, midpoint, and treatment completion for evaluation.ResultsTwo neuroimaging subtypes of depression, archetypal and atypical depression, were identified based on distinct frontal-posterior functional imbalance patterns as measured by ALFF. The dorsomedial prefrontal cortex was identified as the rTMS target for archetypal depression, and the occipital cortex for atypical depression. Following precise rTMS, ALFF alterations were normalized in both archetypal and atypical depressed youths, corresponding with symptom response of 90.00% in archetypal depression and 70.73% in atypical depression.ConclusionsA precision medicine framework for depression was developed based on frontal-posterior functional imbalance and implemented with promising results. Future randomized controlled trials are warranted.Chinese Clinical Trial Registry identifier: ChiCTR2100045391

Background: Schizophrenia, bipolar disorder and major depressive disorder are increasingly being conceptualized as a transdiagnostic continuum. Disruption of white matter is a common alteration in these psychiatric disorders, but the molecular mechanisms underlying the disruption remain unclear. Neuregulin 1 (NRG1) is genetically linked with susceptibility to schizophrenia, bipolar disorder and major depressive disorder, and it is also related to white matter. Methods: Using a transdiagnostic approach, we aimed to identify white matter differences associated with NRG1 and their relationship to transdiagnostic symptoms and cognitive function. We examined the white matter of 1051 participants (318 healthy controls and 733 patients with major psychiatric disorders: 254 with schizophrenia, 212 with bipolar disorder and 267 with major depressive disorder) who underwent diffusion tensor imaging. We measured the plasma NRG1-β1 levels of 331 participants. We also evaluated clinical symptoms and cognitive function. Results: In the patient group, abnormal white matter was negatively associated with NRG1-β1 levels in the genu of the corpus callosum, right uncinate fasciculus, bilateral inferior fronto-occipital fasciculus, right external capsule, fornix, right optic tract, left straight gyrus white matter and left olfactory radiation. These NRG1-associated white matter abnormalities were also associated with depression and anxiety symptoms and executive function in patients with a major psychiatric disorder. Furthermore, across the 3 disorders we observed analogous alterations in white matter, NRG1-β1 levels and clinical manifestations. Limitations: Medication status, the wide age range and our cross-sectional findings were limitations of this study. Conclusion: This study is the first to provide evidence for an association between NRG1, white matter abnormalities, clinical symptoms and cognition in a transdiagnostic psychiatric cohort. These findings provide further support for an understanding of the molecular mechanisms that underlie the neuroimaging substrates of major psychiatric disorders and their clinical implications.

Objective: Clinical heterogeneity in major depressive disorder likely reflects the range of etiology and contributing factors in the disorder, such as genetic risk. Identification of more refined subgroups based on biomarkers such as white matter integrity and lipid-related metabolites could facilitate precision medicine in major depressive disorder. Methods: A total of 148 participants (15 genetic high-risk participants, 57 patients with first-episode major depressive disorder and 76 healthy controls) underwent diffusion tensor imaging and plasma lipid profiling. Alterations in white matter integrity and lipid metabolites were identified in genetic high-risk participants and patients with first-episode major depressive disorder. Then, shared alterations between genetic high-risk and first-episode major depressive disorder were used to develop an imaging x metabolite diagnostic panel for genetically based major depressive disorder via factor analysis and logistic regression. A fivefold cross-validation test was performed to evaluate the diagnostic panel. Results: Alterations of white matter integrity in corona radiata, superior longitudinal fasciculus and the body of corpus callosum and dysregulated unsaturated fatty acid metabolism were identified in both genetic high-risk participants and patients with first-episode major depressive disorder. An imaging x metabolite diagnostic panel, consisting of measures for white matter integrity and unsaturated fatty acid metabolism, was identified that achieved an area under the receiver operating characteristic curve of 0.86 and had a significantly higher diagnostic performance than that using either measure alone. And cross-validation confirmed the adequate reliability and accuracy of the diagnostic panel. Conclusion: Combining white matter integrity in corpus callosum, superior longitudinal fasciculus and corona radiata, and unsaturated fatty acid profile may improve the identification of genetically based endophenotypes in major depressive disorder to advance precision medicine strategies.

Background The association between executive dysfunction, brain dysconnectivity, and inflammation is a prominent feature across major psychiatric disorders (MPDs), schizophrenia, bipolar disorder, and major depressive disorder. A dimensional approach is warranted to delineate their mechanistic interplay across MPDs. Methods This single site study included a total of 1543 participants (1058 patients and 485 controls). In total, 1169 participants underwent diffusion tensor and resting-state functional magnetic resonance imaging (745 patients and 379 controls completed the Wisconsin Card Sorting Test). Fractional anisotropy (FA) and regional homogeneity (ReHo) assessed structural and functional connectivity, respectively. Pro-inflammatory cytokine levels [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α] were obtained in 325 participants using blood samples collected with 24 h of scanning. Group differences were determined for main measures, and correlation and mediation analyses and machine learning prediction modeling were performed. Results Executive deficits were associated with decreased FA, increased ReHo, and elevated IL-1β and IL-6 levels across MPDs, compared to controls. FA and ReHo alterations in fronto-limbic-striatal regions contributed to executive deficits. IL-1β mediated the association between FA and cognition, and IL-6 mediated the relationship between ReHo and cognition. Executive cognition was better predicted by both brain connectivity and cytokine measures than either one alone for FA-IL-1β and ReHo-IL-6. Conclusions Transdiagnostic associations among brain connectivity, inflammation, and executive cognition exist across MPDs, implicating common neurobiological substrates and mechanisms for executive deficits in MPDs. Further, inflammation-related brain dysconnectivity within fronto-limbic-striatal regions may represent a transdiagnostic dimension underlying executive dysfunction that could be leveraged to advance treatment.

Dynamic functional connectivity (DFC) analysis can capture time‐varying properties of connectivity. However, studies on large samples using DFC to investigate transdiagnostic dysconnectivity across schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are rare. In this study, we used resting‐state functional magnetic resonance imaging and a sliding‐window method to study DFC in a total of 610 individuals (150 with SZ, 100 with BD, 150 with MDD, and 210 healthy controls [HC]) at a single site. Using k‐means clustering, DFCs were clustered into three functional connectivity states: one was a more frequent state with moderate positive and negative connectivity (State 1), and the other two were less frequent states with stronger positive and negative connectivity (State 2 and State 3). Significant 4‐group differences (SZ, BD, MDD, and HC groups; q, We identified three functional connectivity states across multiple psychiatric disorders and healthy controls: one was a more frequent state with weak connectivity, and the other two were less frequent states with strong connectivity. Dysconnectivity in the psychiatric patients was found nearly only in the weak connectivity state. Psychiatric patients spent less time in the weak connectivity state than HC patients.

Converging evidence increasingly implicates shared etiologic and pathophysiological characteristics among major psychiatric disorders (MPDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Examining the neurobiology of the psychotic-affective spectrum may greatly advance biological determination of psychiatric diagnosis, which is critical for the development of more effective treatments. In this study, ensemble clustering was developed to identify subtypes within a trans-diagnostic sample of MPDs. Whole brain amplitude of low-frequency fluctuations (ALFF) was used to extract the low-dimensional features for clustering in a total of 944 participants: 581 psychiatric patients (193 with SZ, 171 with BD, and 217 with MDD) and 363 healthy controls (HC). We identified two subtypes with differentiating patterns of functional imbalance between frontal and posterior brain regions, as compared to HC: (1) Archetypal MPDs (60% of MPDs) had increased frontal and decreased posterior ALFF, and decreased cortical thickness and white matter integrity in multiple brain regions that were associated with increased polygenic risk scores and enriched risk gene expression in brain tissues; (2) Atypical MPDs (40% of MPDs) had decreased frontal and increased posterior ALFF with no associated alterations in validity measures. Medicated Archetypal MPDs had lower symptom severity than their unmedicated counterparts; whereas medicated and unmedicated Atypical MPDs had no differences in symptom scores. Our findings suggest that frontal versus posterior functional imbalance as measured by ALFF is a novel putative trans-diagnostic biomarker differentiating subtypes of MPDs that could have implications for precision medicine.

Schizophrenia (SZ) is a neurodevelopmental disorder. There remain significant gaps in understanding the neural trajectory across development in SZ. A major research focus is to clarify the developmental functional changes of SZ and to identify the specific timing, the specific brain regions, and the underlying mechanisms of brain alterations during SZ development. Regional homogeneity (ReHo) characterizing brain function was collected and analyzed on humans with SZ (hSZ) and healthy controls (HC) cross-sectionally, and methylazoxymethanol acetate (MAM) rats, a neurodevelopmental model of SZ, and vehicle rats longitudinally from adolescence to adulthood. Metabolomic and proteomic profiling in adult MAM rats and vehicle rats was examined and bioanalyzed. Compared to HC or adult vehicle rats, similar ReHo alterations were observed in hSZ and adult MAM rats, characterized by increased frontal (medial prefrontal and orbitofrontal cortices) and decreased posterior (visual and associated cortices) ReHo. Longitudinal analysis of MAM rats showed aberrant ReHo patterns as decreased posterior ReHo in adolescence and increased frontal and decreased posterior ReHo in adulthood. Accordingly, it was suggested that the visual cortex was a critical locus and adolescence was a sensitive window in SZ development. In addition, metabolic and proteomic alterations in adult MAM rats suggested that central carbon metabolism disturbance and mitochondrial dysfunction were the potential mechanisms underlying the ReHo alterations. This study proposed frontal-posterior functional imbalance and aberrant function developmental patterns in SZ, suggesting that the adolescent visual cortex was a critical locus and a sensitive window in SZ development. These findings from linking data between hSZ and MAM rats may have a significant translational contribution to the development of effective therapies in SZ.

BackgroundThe confounding effects of antipsychotics that led to the inconsistencies of neuroimaging findings have long been the barriers to understanding the pathophysiology of schizophrenia (SZ). Although it is widely accepted that antipsychotics can alleviate psychotic symptoms during the early most acute phase, the longer-term effects of antipsychotics on the brain have been unclear. This study aims to look at the susceptibility of different imaging measures to longer-term medicated status through real-world observation.MethodsWe compared gray matter volume (GMV) with amplitude of low-frequency fluctuations (ALFFs) in 89 medicated-schizophrenia (med-SZ), 81 unmedicated-schizophrenia (unmed-SZ), and 235 healthy controls (HC), and the differences were explored for relationships between imaging modalities and clinical variables. We also analyzed age-related effects on GMV and ALFF values in the two patient groups (med-SZ and unmed-SZ).ResultsMed-SZ demonstrated less GMV in the prefrontal cortex, temporal lobe, cingulate gyri, and left insula than unmed-SZ and HC (p < 0.05, family-wise error corrected). Additionally, GMV loss correlated with psychiatric symptom relief in all SZ. However, medicated status did not influence ALFF values: all SZ showed increased ALFF in the anterior cerebrum and decreased ALFF in posterior visual cortices compared with HC (p < 0.05, family-wise error corrected). Age-related GMV effects were seen in all regions, which showed group-level differences except fusiform gyrus. No significant correlation was found between ALFF values and psychiatric symptoms.ConclusionGMV loss appeared to be pronounced to longer-term antipsychotics, whereby imbalanced alterations in regional low-frequency fluctuations persisted unaffected by antipsychotic treatment. Our findings may help to understand the disease course of SZ and potentially identify a reliable neuroimaging feature for diagnosis.

Background Increasing evidence suggests that major psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) share biological, neuropsychological and clinical features, despite the criteria for their respective diagnoses being different. Neuroimaging studies have shown disrupted ‘static’ neural connectivity in these disorders. However, the changes in brain dynamics across the three psychiatric disorders remain unknown. Methods We aim to examine the connections and divergencies of the dynamic amplitude of low-frequency fluctuation (dALFF) in MDD, BD and SZ. In total, 901 participants [MDD, 229; BD, 146; SZ, 142; and healthy controls (HCs), 384] received resting-state functional magnetic resonance imaging. The dALFF was calculated using sliding-window analysis and compared across three psychiatric disorders. Results We found significant increases of dALFF in the right fusiform, right hippocampus, right parahippocampal in participants with MDD, BD and SZ compared to HC. We also found specific increased dALFF changes in caudate and left thalamus for SZ and BD and decreased dALFF changes in calcarine and lingual for SZ and MDD. Conclusion Our study found significant intrinsic brain activity changes in the limbic system and primary visual area in MDD, BD, and SZ, which indicates these areas disruptions are core neurobiological features shared among three psychiatric disorders. Meanwhile, our findings also indicate that specific alterations in MDD, BD, and SZ provide neuroimaging evidence for the differential diagnosis of the three mental disorders.

Dimensional psychopathology and its neurobiological underpinnings could provide important insights into major psychiatric disorders, including major depressive disorder, bipolar disorder and schizophrenia. In a dimensional transdiagnostic approach, we examined depressive symptoms and their relationships with regional homogeneity and leptin across major psychiatric disorders. A total of 728 participants (including 403 patients with major psychiatric disorders and 325 age–gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging at a single site. We obtained plasma leptin levels and depressive symptom measures (Hamilton Depression Rating Scale (HAMD)) within 24 h of scanning and compared the regional homogeneity (ReHo), plasma leptin levels and HAMD total score and factor scores between patients and healthy controls. To reveal the potential relationships, we performed correlational and mediational analyses. Patients with major psychiatric disorders had significant lower ReHo in primary sensory and visual association cortices and higher ReHo in the frontal cortex and angular gyrus; plasma leptin levels were also elevated. Furthermore, ReHo alterations, leptin and HAMD factor scores had significant correlations. We also found that leptin mediated the transdiagnostic relationships among ReHo alterations in primary somatosensory and visual association cortices, core depressive symptoms and body mass index. The transdiagnostic associations we demonstrated support the common neuroanatomical substrates and neurobiological mechanisms. Moreover, leptin could be an important association among ReHo, core depressive symptoms and body mass index, suggesting a potential therapeutic target for dimensional depressive symptoms across major psychiatric disorders.

Brain network alterations have increasingly been implicated in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). However, little is known about the similarities and differences in functional brain networks among patients with SCZ, BD, and MDD. A total of 512 participants (121 with SCZ, 100 with BD, 108 with MDD, and 183 healthy controls, matched for age and sex) completed resting-state functional magnetic resonance imaging at a single site. Four global measures (the clustering coefficient, the characteristic shortest path length, the normalized clustering coefficient, and the normalized characteristic path length) were computed at a voxel level to quantify segregated and integrated configurations. Inter-regional functional associations were examined based on the Euclidean distance between regions. Distance strength maps were used to localize regions with altered distances based on functional connectivity. Patient groups exhibited shifts in their network architectures toward randomized configurations, with SCZ>BD>MDD in the degree of randomization. Patient groups displayed significantly decreased short-range connectivity and increased medium-/long-range connectivity. Decreases in short-range connectivity were similar across the SZ, BD, and MDD groups and were primarily distributed in the primary sensory and association cortices and the thalamus. Increases in medium-/long-range connectivity were differentially localized within the prefrontal cortices among the patient groups. We highlight shared and distinct connectivity features in functional brain networks among patients with SCZ, BD, and MDD, which expands our understanding of the common and distinct pathophysiological mechanisms and provides crucial insights into neuroimaging-based methods for the early diagnosis of and interventions for psychiatric disorders.

Background Alterations of white matter (WM) integrity have been observed in both schizophrenia (SZ) and individuals at genetic high risk for SZ (GHR-SZ); however, the molecular mechanisms underlying WM disruption remain unclear. Cytokines are chemical messengers of the immune system that are closely related to inflammation and neurogenesis in the brain. This study aimed to identify abnormalities in WM integrity, cytokine levels, and their association in SZ and GHR-SZ. Methods A total of 355 participants (126 with SZ, 99 GHR-SZ, and 130 healthy controls [HCs]) were recruited. All participants underwent diffusion tensor imaging and blood samples were obtained from 113 participants within 24 h of imaging. Results In SZ, there was decreased fractional anisotropy(FA) in the genu and body of the corpus callosum (GCC/BCC), anterior corona radiata, anterior and posterior limbs of the internal capsule (ALIC/PLIC), superior fronto-occipital fasciculus, external capsule, and fornix, and elevated IL-6 levels. In both SZ and GHR-SZ, decreased FA in the splenium of the corpus callosum (SCC), posterior corona radiate (PCR), and posterior thalamic radiation (PTR) was observed, and elevated leptin levels were present. Additionally, the IL-6 levels were negatively correlated with FA in the GCC and ALIC in SZ, and leptin levels were negatively correlated with the SCC, PCR, and PTR in SZ and GHR-SZ. Conclusions Abnormal WM integrity in SZ may reflect the state of disease and is associated with increased IL-6 levels. In addition, these leptin-associated WM integrity abnormalities in both SZ and GHR-SZ may reflect a genetic vulnerability to SZ.

Bipolar disorder (BD) is associated with increased suicidal behavior. Understanding the neural features of suicide attempts (SA) in patients with BD is critical to preventing suicidal behavior. The prefrontal cortex (PFC) is a key region related to SA. In this study, forty BD patients with a history of SA (BD+SA), 70 BD patients without a history of SA (BD-SA), and 110 individuals in a healthy control (HC) group underwent structural magnetic resonance imaging (MRI) and resting-state functional MRI. We used voxel-based morphometry (VBM) and amplitude of low frequency fluctuations (ALFF) techniques to examine the gray matter volumes (GMVs) and ALFF values in the PFC. Compared with the HC group, both the BD+SA and BD-SA groups had lower GMVs and higher ALFF values in the medial PFC (MPFC), ventral PFC (VPFC), and dorsolateral PFC (DLPFC). The ALFF values in the MPFC, VPFC, and DLPFC in the BD+SA group were significantly higher than those in the BD-SA group. These findings suggest that BD patients with SA have intrinsic activity abnormalities in PFC regions. This provides potentially identifiable neuroimaging markers in BD patients with SA that could be used to increase our understanding of suicidal behavior.

Background Major depressive disorder (MDD) and bipolar disorder (BD) are major affective disorders associated with high risk for suicide. Neural mechanisms underlying suicide attempts are poorly understood in MDD and BD but likely relate to the structural abnormalities in brain regions. In this study, we explored structural alterations in MDD and BD with prior suicide attempts (SA) using diffusion tensor imaging (DTI). Methods Participants consisted of 27 MDD patients with prior SA (men: 9; age means±sd: 28.04 ± 11.06 years), 49 MDD patients without prior SA (men: 11; age means±sd: 30.03 ± 0.91 years), 25 BD patients with prior SA (men: 7, age means±sd: 27.08 ± 8.40 years), 49 BD patients without prior SA (men: 26, means±sd: 27.69 ± 9.97 years)，and 49 healthy controls (HC) (men: 18, means±sd: 31.12 ± 9.95 years). All participants underwent DTI to examine fractional anisotropy (FA) in brain regions. Results FA in several major white matter (WM) bundles including bilateral inferior fronto-occipital fasciculus (IFOF), bilateral uncinate fasciculus (UF), and the corpus callosum (CC) was shown in MDD with prior SA, compared to MDD without prior SA and HC. Decreased FA was also found in bilateral IFOF, bilateral UF, and CC, as well as other WM bundles, in BD with prior SA, compared to BD without prior SA and HC. Significant diagnostic group by SA effects were shown in bilateral thalami with lowest mean FA values in MDD with prior SA. Conclusions Our findings support the involvement of structural alterations in suicide attempts in major affective disorders. Shared and distinct structural alterations were shown in MDD and BD with prior SA, suggesting common and differential neural pathways for suicide among major affective disorder.

Schizophrenia (SZ) is a highly heritable disease with neurodevelopmental origins and significant functional brain network dysfunction. Functional network is heavily influenced by neurodevelopment processes and can be characterized by the degree of segregation and integration. This study examines functional segregation and integration in SZ and their first-degree relatives (high risk [HR]) to better understand the dynamic changes in vulnerability and resiliency, and disease markers. Resting-state functional magnetic resonance imaging data acquired from 137 SZ, 89 HR, and 210 healthy controls (HCs). Small-worldness σ was computed at voxel level to quantify balance between segregation and integration. Interregional functional associations were examined based on Euclidean distance between regions and reflect degree of segregation and integration. Distance strength maps were used to localize regions of altered distance-based functional connectivity. σ was significantly decreased in SZ compared to HC, with no differences in high risk (HR). In three-group comparison, significant differences were noted in short-range connectivity (primarily in the primary sensory, motor and their association cortices, and the thalamus) and medium/long-range connectivity (in the prefrontal cortices [PFCs]). Decreased short- and increased medium/long-range connectivity was found in SZ. Decreased short-range connectivity was seen in SZ and HR, while HR had decreased medium/long-range connectivity. We observed disrupted balance between segregation and integration in SZ, whereas relatively preserved in HR. Similarities and differences between SZ and HR, specific changes of SZ were found. These might reflect dynamic changes of segregation in primary cortices and integration in PFCs in vulnerability and resilience, and disease markers in SZ.

Background: Cognitive impairment influenced by brain dysconnectivity and inflammatory cytokines has consistently been the most prominent feature across major psychiatric disorders (MPDs) including schizophrenia, bipolar disorder, and major depressive disorder. The commonalities call upon a trans-diagnostic and dimensional approach in delineating the neural mechanisms underlying the relationship between brain connectivity, cognition, and inflammation among MPDs. Methods: 1543 participants, including 1058 with MPDs and 485 healthy controls, from a single site were enrolled in this study. Participants underwent diffusion tensor imaging and resting-state functional magnetic resonance imaging, with the majority of participants (n = 1169, 765 participants with MPDs and 404 healthy controls) also completing the Wisconsin Card Sorting Test (WCST). Blood samples were obtained from 325 participants within 24 h of imaging. Fractional anisotropy (FA) and regional functional connectivity (FC) were used to measure structural and functional connectivity, respectively. Findings: Differences in inflammatory cytokine indices were assessed using IL-1β, IL-6 and TNF-α. WCST deficits were associated with decreased FA; increased regional FC; and elevated IL-1β, IL-6 and TNF-α among MPDs. Overlapping structural and functional dysconnectivity within the frontolimbic-striatal regions contributed to cognitive deficits among MPDs. Mediation analyses revealed that IL-1β mediated the association between FA and WCST and that IL-6 mediated the relationship between regional FC and WCST. Interpretation: Our findings implicate an intriguing mechanism for the effects of inflammation on cognitive function through different molecular-brain-cognition pathways among MPDs. Specific cytokine influences allow for more targeted studies and potentially more targeted interventions that may improve cognition in MPDs. Funding Statement: This study was funded by National Science Fund for Distinguished Young Scholars (81725005 to F.W.), National Natural Science Foundation of China (81571311 to Y.T., 81571331 to F.W.), National Key Research and Development Program (2018YFC1311604 to Y.T., 2016YFC1306900 to Y.T., 2016YFC0904300 to F.W.), National High Tech Development Plan (863) (2015AA020513 to F.W.), Liaoning Science and Technology Project (2015225018 to Y.T.), Liaoning Education Foundation (Pandeng Scholar to F.W.), Innovation Team Support Plan of Higher Education of Liaoning Provience (LT2017007 to F.W.), and Major Special Construction plan of China Medical University (3110117059 to F.W.). Declaration of Interests: The authors report no biomedical financial interests or potential conflicts of interest. Ethics Approval Statement: The study was approved by the Institutional Review Board of China Medical University and was performed in accordance with the Declaration of Helsinki. All experiments and methods were performed in accordance with approved guidelines and regulations. All subjects provided written informed consent.

Background: Dimensional psychopathology and its neurobiological underpinnings could provide important insight into the major psychiatric disorders (MPDs), including major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ). In this study, we examined depressive symptoms and their relationship with functional connectivity (FC) and leptin across MPDs. Methods: A total of 728 participants [healthy controls (HC), n = 325; MDD, n = 153; BPD, n = 123; SCZ, n = 127] underwent resting state functional magnetic resonance imaging at a single site. Plasma leptin levels and depressive symptom measures (Hamilton Depression Rating Scale, HAMD) were obtained within 24 hours of scan. Factor analyses were used to identify HAMD factor scores. Regional FC and plasma leptin levels were compared between MPDs and HC. Mediational analyses were performed to determine the relationship between regional FC, plasma leptin levels, and HAMD factor scores. Findings: We found that depressive symptoms were associated with regional FC decreases in primary sensory and association cortices and thalamus, regional FC increases in the prefrontal cortex and angular gyrus, and elevated leptin levels across MPDs, compared to HC. Mediation analyses showed that plasma leptin level mediates the relationship between regional FC alterations in primary somatosensory cortex and somatic depressive symptoms. Interpretation: Our findings support a role of the primary somatosensory cortex in depressive symptoms across MPDs. Further, leptin appears to be an important link between brain connectivity alterations in this region and somatic depressive symptoms, suggesting a potential therapeutic target for depressive symptoms in patients with MPDs. Funding: This study was funded by National Science Fund for Distinguished Young Scholars (81725005 to F.W.), National Natural Science Foundation of China (81571311 to Y.T., 81571331 to F.W.), National Key Research and Development Program (2018YFC1311604 to Y.T., 2016YFC1306900 to Y.T., 2016YFC0904300 to F.W.), National High Tech Development Plan (863) (2015AA020513 to F.W.), Liaoning Science and Technology Project (2015225018 to Y.T.), Liaoning Education Foundation (Pandeng Scholar to F.W.), Innovation Team Support Plan of Higher Education of Liaoning Provience (LT2017007 to F.W.), and Major Special Construction plan of China Medical University (3110117059 to F.W.). Declaration of Interest: The authors report no biomedical financial interests or potential conflicts of interest. Ethical Approval: The study was approved by the Institutional Review Board of the China Medical University and was conducted in accordance with the Declaration of Helsinki. Participants provided written informed consent. All the experiments and methods were carried out in accordance with approved regulations and guidelines.

Converging lines of evidence implicate structural and functional abnormalities in the cerebellum in schizophrenia (SCZ). The cerebellar vermis is of particular interest given its association with clinical symptoms and cognitive deficits in SCZ and its known connections with cortical regions such as the prefrontal cortex. Prior neuroimaging studies have shown structural and functional abnormalities in the vermis in SCZ. In this study, we examined the cerebellar vermis in 50 individuals with SCZ and 54 healthy controls (HC) using a quantitative volumetric approach. All participants underwent high-resolution structural magnetic resonance imaging (MRI). The vermis was manually traced for each participant, and vermis volumes were computed using semiautomated methods. Volumes for total vermis and vermis subregions (anterior and posterior vermis) were analyzed in the SCZ and HC groups. Significant diagnosis-by-sex interaction effects were found in total vermis and vermis subregion analyses. These effects appeared to be driven by significantly decreased posterior vermis volumes in males with SCZ. Exploratory analyses did not reveal significant effects of clinical variables (FEP status, illness duration, and BPRS total score and subscores) on vermis volumes. The findings herein highlight the presence of neural sex differences in SCZ and the need for considering sex-related factors in studying the disorder.

Converging evidence increasingly implicates shared etiologic and pathophysiological characteristics among major psychiatric disorders (MPDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Examining the neurobiology of the psychotic-affective spectrum may greatly advance biological determination of psychiatric diagnosis, which is critical for the development of more effective treatments. In this study, ensemble clustering was developed to identify subtypes within a trans-diagnostic sample of MPDs. Whole brain amplitude of low-frequency fluctuations (ALFF) was used to extract the low-dimensional features for clustering in a total of 944 participants: 581 psychiatric patients (193 with SZ, 171 with BD, and 217 with MDD) and 363 healthy controls (HC). We identified two subtypes with differentiating patterns of functional imbalance between frontal and posterior brain regions, as compared to HC: (1) Archetypal MPDs (60% of MPDs) had increased frontal and decreased posterior ALFF, and decreased cortical thickness and white matter integrity in multiple brain regions that were associated with increased polygenic risk scores and enriched risk gene expression in brain tissues; (2) Atypical MPDs (40% of MPDs) had decreased frontal and increased posterior ALFF with no associated alterations in validity measures. Medicated Archetypal MPDs had lower symptom severity than their unmedicated counterparts; whereas medicated and unmedicated Atypical MPDs had no differences in symptom scores. Our findings suggest that frontal versus posterior functional imbalance as measured by ALFF is a novel putative trans-diagnostic biomarker differentiating subtypes of MPDs that could have implications for precision medicine.

Background: Growing evidence indicates both shared and distinct features of emotional perception in schizophrenia, bipolar disorder and major depressive disorder. In these disorders, alterations in spontaneous low-frequency fluctuations have been reported in the neural system for emotional perception, but the similarities and differences in the amplitude of low-frequency fluctuation (ALFF) across the 3 disorders are unknown. Methods: We compared ALFF and its signal balance in the neural system for emotional perception at 2 frequency bands (slow-5 and slow-4) in 119 participants with schizophrenia, 100 with bipolar disorder, 123 with major depressive disorder and 183 healthy controls. We performed exploratory Pearson partial correlation analyses to determine the relationship between ALFF signal balance and clinical variables. Results: We observed commonalities in ALFF change patterns across the 3 disorders for emotional perception neural substrates, such as increased ALFF in the anterior cerebrum (including subcortical, limbic, paralimbic and heteromodal cortical regions) and decreased ALFF in the posterior visual cortices. Schizophrenia, bipolar disorder and major depressive disorder showed significantly decreased ALFF signal balance in the neural system for emotional perception at both slow-5 and slow-4 frequency bands, with the greatest alterations for schizophrenia, followed by bipolar disorder and major depressive disorder. We found a negative correlation between ALFF signal balance and negative/disorganized symptoms in slow-4 across the 3 disorders. Limitations The relatively broad age range in our sample and the cross-sectional study design may not account for our findings. Conclusion: The extent of the commonalities we observed further support the concept of core neurobiological disruptions shared among the 3 disorders; ALFF signal balance could be an important neuroimaging marker for the diagnosis and treatment of schizophrenia, bipolar disorder and major depressive disorder.

Background Local functional connectivity (FC) indicates local or short-distance functional interactions and may serve as a neuroimaging marker to investigate the human brain connectome. Local FC alterations suggest a disrupted balance in the local functionality of the whole brain network and are increasingly implicated in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Methods We aim to examine the similarities and differences in the local FC across SZ, BD, and MDD. In total, 537 participants (SZ, 126; BD, 97; MDD, 126; and healthy controls, 188) completed resting-state functional magnetic resonance imaging at a single site. The local FC at resting state was calculated and compared across SZ, BD, and MDD. Results The local FC increased across SZ, BD, and MDD within the bilateral orbital frontal cortex (OFC) and additional region in the left OFC extending to putamen and decreased in the primary visual, auditory, and motor cortices, right supplemental motor area, and bilateral thalami. There was a gradient in the extent of alterations such that SZ > BD > MDD. Limitations This cross-sectional study cannot consider medications and other clinical variables. Conclusions These findings indicate a disrupted balance between network integration and segregation in SZ, BD, and MDD, including over-integration via increased local FC in the OFC and diminished segregation of neural processing with the weakening of the local FC in the primary sensory cortices and thalamus. The shared local FC abnormalities across SZ, BD, and MDD may shed new light on the potential biological mechanisms underlying these disorders.

Background: Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are distinct diagnostic categories in current psychiatric nosology, yet there is increasing evidence for shared clinical and biological features in these disorders. No previous studies have examined brain structural features concurrently in these 3 disorders. The aim of this study was to identify the extent of shared and distinct brain alterations in SZ, BD, and MDD. We examined gray matter (GM) volume and white matter (WM) integrity in a total of 485 individuals (135 with SZ, 86 with BD, 108 with MDD, and 156 healthy controls [HC]) who underwent high-resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at a single site. Results: Significant 4-group (SZ, BD, MDD, and HC groups) differences (P < .05, corrected) in GM volumes were found primarily in the paralimbic and heteromodal corticies. Post hoc analyses showed that the SZ, BD, and MDD groups shared GM volume decreases in 87.9% of the total regional volume with significant 4-group differences. Significant 4-group differences in WM integrity (P < .05 corrected) were found in callosal, limbic-paralimbic-hetermodal, cortico-cortical, thalamocortical and cerebellar WM. Post hoc analyses revealed that the SZ and BD groups shared WM alterations in all regions, while WM alterations were not observed with MDD. Conclusions: Our findings of common alterations in SZ, BD, and MDD support the presence of core neurobiological disruptions in these disorders and suggest that neural structural distinctions between these disorders may be less prominent than initially postulated, particularly between SZ and BD.

Objectives: Bipolar disorder (BD) and schizophrenia (SZ) share structural abnormalities in the anterior insula cortex (AIC). The AIC appears to have a crucial role in emotional processing and regulation and cognitive control in BD and SZ. Methods: Forty-six participants with BD, 68 with SZ and 66 healthy controls (HC) underwent functional magnetic resonance imaging scanning. Resting-state functional connectivity (rsFC) from AIC subregions (ventral and dorsal) was compared among the three groups. Results: Compared to HC group, both BD and SZ groups exhibited increased rsFC from the ventral AIC (vAIC) and dorsal AIC (dAIC) to bilateral frontal pole and thalamus, the left middle frontal gyrus and the hippocampus. Meanwhile, the BD group demonstrated increased rsFC from the vAIC to the perigenual anterior cingulate cortex, the SZ group presented increased rsFC from the vAIC and dAIC to the right caudate. Compared with the BD group, the SZ group showed significantly increased rsFC from the vAIC and dAIC to the left middle frontal gyrus. Conclusions: The shared AIC rsFC abnormalities in both BD and SZ support the importance of the AIC in the common pathophysiology of BD and SZ. There were also disorder-specific features of AIC rsFC, which might implicate potential avenues for differentiating during the early stages.

White matter (WM) neuroimaging studies have shown varied findings at different stages of schizophrenia (SZ). Understanding these variations may elucidate distinct markers of genetic vulnerability and conversion to psychosis. To examine the similarities and differences in WM connectivity between those at-risk for and in early stages of SZ, a cross-sectional diffusion tensor imaging study of 48 individuals diagnosed with first-episode SZ (FE-SZ), 37 nonpsychotic individuals at a high genetic risk of SZ (GHR-SZ), and 67 healthy controls (HC) was conducted. Decreased fractional anisotropy (FA) in the corpus callosum (CC), anterior cingulum (AC), and uncinate fasciculus (UF) was observed in both the GHR-SZ and FE-SZ groups, while decreased FAs in the superior longitudinal fasciculus (SLF) and the fornix were only seen in the FE-SZ participants. Additionally, both GHR-SZ and FE-SZ showed worse executive performance than HC. The left SLF III FA was significantly positively correlated with hallucinations, and right SLF II was positively correlated with thought disorder. The presence of shared WM deficits in both FE-SZ and GHR-SZ individuals may reflect the genetic liability to SZ, while the disparate FA changes in the FE-SZ group may represent symptom-generating circuitry that mediates perceptual and cognitive disturbances of SZ and ultimately culminates in the onset of psychotic episodes.

There are limited resting‐state functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD). Of these studies, functional connectivity analyses are mostly used. However, a new method based on the magnitude of low frequency fluctuation (LFF) during resting‐state fMRI may provide important insight into MDD. In this study, we examined the amplitude of LFF (ALFF) within the whole brain during resting‐state fMRI in 30 treatment‐naïve MDD subjects and 30 healthy control (HC) subjects. When compared with HC, MDD subjects showed increased ALFF in the frontal cortex (including the bilateral ventral/dorsal anterior cingulate cortex, orbitofrontal cortex, premotor cortex, ventral prefrontal cortex, left dorsal lateral frontal cortex, left superior frontal cortex), basal ganglia (including the right putamen and left caudate nucleus), left insular cortex, right anterior entorhinal cortex and left inferior parietal cortex, together with decreased ALFF in the bilateral occipital cortex, cerebellum hemisphere, and right superior temporal cortex. These findings may relate to characteristics of MDD, such as excessive self‐referential processing and deficits in cognitive control of emotional processing, which may contribute to the persistent and recurrent nature of the disorder. Hum Brain Mapp 35:4979–4988, 2014. © 2014 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Background: Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic res onance imaging (fMRI) to investigate amygdala‐PFC functional connectivity during emotional face processing in medication-naive individ uals with MDD. Methods: Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups. Results: Our study included 28 individuals with MDD and 30 controls. Decreased amygdala‐left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition ( p < 0.05, corrected). No significant differences were found in amygdala connectiv ity to any cerebral regions between the MDD and control groups for the happy or neutral conditions. Limitations: All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population. Conclusion: Medicationnaive individuals with MDD showed decreased amygdala‐left rPFC functional connectivity in response to negative emotional stimuli, sug gesting that abnormalities in amygdala‐left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD.

Background Insight into the neural mechanisms underlying the shared and disparate features of schizophrenia (SZ) and bipolar disorder (BD) is limited. The amygdala and prefrontal cortex (PFC) appear to have crucial roles in SZ and BD, yet abnormalities appear to manifest differently in the 2 disorders. Methods Eighteen participants with SZ, 18 participants with BD, and 18 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Resting-state functional connectivity (rsFC) between the PFC and the amygdala divided into 3 subregions (the laterobasal, centromedial, and superficial amygdala) was examined using probabilistic anatomic maps. For each participant, rsFC maps of the 3 amygdala subregions were computed and compared across the 3 groups. Results Compared with the HC group, we found significant differences in rsFC between the amygdala and PFC in the SZ and BD groups. In direct comparison between the SZ and BD groups, distinct patterns of rsFC between the amygdala and PFC were observed, particularly in the superficial amygdala. RsFC between the amygdala and the dorsal lateral PFC was significantly decreased in the SZ group, whereas rsFC between the amygdyala and the ventral PFC was significantly decreased in the BD group. Conclusions These results strongly suggest dorsal vs ventral PFC differentiation in amygdala-PFC neural system abnormalities between SZ and BD. These regional differences in SZ and BD may give rise to the differences in clinical characteristics observed in SZ and BD, and may implicate potential avenues for differentiating the 2 disorders during early stages of illness.

Major depressive disorder (MDD) and schizophrenia (SZ) are considered two distinct psychiatric disorders. Yet, they have considerable overlap in symptomatology and clinical features, particularly in the initial phases of illness. The amygdala and prefrontal cortex (PFC) appear to have critical roles in these disorders; however, abnormalities appear to manifest differently. In our study forty-nine drug-naïve, first-episode MDD, 45 drug-naïve, first-episode SZ, and 50 healthy control (HC) participants from 13 to 30 years old underwent resting-state functional magnetic resonance imaging. Functional connectivity (FC) between the amygdala and PFC was compared among the three groups. Significant differences in FC were observed between the amygdala and ventral PFC (VPFC), dorsolateral PFC (DLPFC), and dorsal anterior cingulated cortex (dACC) among the three groups. Further analyses demonstrated that MDD showed decreased amygdala-VPFC FC and SZ had reductions in amygdala-dACC FC. Both the diagnostic groups had significantly decreased amygdala-DLPFC FC. These indicate abnormalities in amygdala-PFC FC and further support the importance of the interaction between the amygdala and PFC in adolescents and young adults with these disorders. Additionally, the alterations in amygdala-PFC FC may underlie the initial similarities observed between MDD and SZ and suggest potential markers of differentiation between the disorders at first onset.

In the past decade, neuroimaging research has identified key components in the neural system that underlies bipolar disorder (BD). The ventral prefrontal cortex (VPFC) and amygdala are highly interconnected structures that jointly play a central role in emotional regulation. Numerous research groups have reported prominent structural and functional abnormalities within the VPFC and amygdala supporting their essential role in a neural system underlying the emotional dysregulation that is a core feature of BD. Findings in BD also include those in brain regions interconnected with the VPFC and amygdala, including the ventral striatum, hippocampus and the cerebellum. Abnormalities in these regions may contribute to symptoms that reflect disruption in functions sub-served by these structures, including motivational, mnemonic and psychomotor functions.This article will first review leads from behavioural neurology that implicated these neural system abnormalities in BD. It will then review findings from structural and functional imaging studies to support the presence of abnormalities within these neural system components in BD. It will also review new findings from studies using diffusion tensor imaging (DTI) that provide increasing evidence of abnormalities in the connections between these neural system components in BD. Emerging data supporting differences in this neural system during adolescence, as well as potential beneficial effects of treatment on structure and function will also be presented. Finally, the article will discuss the implications for future investigations, including those for early identification and treatment of BD.

Hippocampus volume decreases and verbal memory deficits have been reported in bipolar disorder (BD) as independent observations. We investigated potential associations between these deficits in subjects with BD. Hippocampus volumes were measured on magnetic resonance images of 31 subjects with BD and 32 healthy comparison (HC) subjects. The California Verbal Learning Test-Second Edition (CVLT) assessed verbal memory function in these subjects. Compared to the HC group, the BD group showed both significantly smaller hippocampus volumes and impaired performance on CVLT tests of immediate, short delay and long delay cued and free recall. Further, smaller hippocampus volume correlated with impaired performance in BD. Post-hoc analyses revealed a trend towards improved memory in BD subjects taking antidepressant medications. These results support associations between morphological changes in hippocampus structure in BD and verbal memory impairment. They provide preliminary evidence pharmacotherapy may reverse hippocampus-related memory deficits.

Childhood maltreatment (CM) has been associated with diminished executive functioning in children and adults; however, there is a relative paucity of study of executive function in adolescents exposed to CM. Yet, executive dysfunction in adolescence may have important adverse consequences including increased vulnerability to risky behaviors and impaired school functioning. This study investigates the relationship between self-reported CM and an executive function, cognitive flexibility, in adolescents without identified psychiatric disorders. Effects of physical and emotional, abuse and neglect, maltreatment subtypes were explored. Thirty adolescents ages 12–17 years, 50% females, completed the retrospective self-report Childhood Trauma Questionnaire (CTQ) and were administered the Wisconsin Card Sorting Test (WCST). Correlational analyses assessed the relationship between WCST perseverative error scores norm-referenced for age and education with CTQ total scores. The relationship with non-perseverative errors, as well as with physical and emotional abuse and neglect CM subscores, were explored. Total CTQ scores showed significant associations with perseverative errors on the WCST, but not with non-perseverative errors. Significant associations with perseverative errors were seen for physical abuse and physical neglect among the CTQ subscales. The results suggest both physical abuse and physical neglect are associated with diminished cognitive flexibility in adolescents. These effects were detected in adolescents without identified psychiatric diagnoses suggesting the importance of considering executive dysfunction in adolescents exposed to CM who may not meet diagnostic criteria for an Axis I disorder and that tests of perseverative errors, such as those of the WCST, may be sensitive indicators of this dysfunction.

The olfactocentric paralimbic cortex plays a critical role in the regulation of emotional and neurovegetative functions that are disrupted in core features of bipolar disorder. Adolescence is thought to be a critical period in both the maturation of the olfactocentric paralimbic cortex and in the emergence of bipolar disorder pathology. Together, these factors implicate a central role for the olfactocentric paralimbic cortex in the development of bipolar disorder and suggest that abnormalities in this cortex may be expressed by adolescence in the disorder. We tested the hypothesis that differences in olfactocentric paralimbic cortex structure are a morphological feature in adolescents with bipolar disorder. Subjects included 118 adolescents (41 with bipolar disorder and 77 healthy controls). Cortical grey matter volume differences between adolescents with and without bipolar disorder were assessed with voxel-based morphometry analyses of high-resolution structural magnetic resonance imaging scans. Compared with healthy comparison adolescents, adolescents with bipolar disorder demonstrated significant volume decreases in olfactocentric paralimbic regions, including orbitofrontal, insular and temporopolar cortices. Findings in these regions survived small volume correction (P

The cerebellar vermis is increasingly implicated in bipolar disorder (BD). In this study, we investigated vermis morphology in BD using a quantitative volumetric analysis.Volumes for total vermis and vermis subregions V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were calculated using high-resolution structural magnetic resonance imaging obtained from 44 individuals with BD (25 females and 19 males) and 43 healthy comparison (HC) subjects (26 females and 17 males). Total vermis volumes were compared between the BD and HC groups. Potential effects of vermis subregions and clinical features were explored.Total vermis volumes were significantly larger in the BD group than in the HC group (p = 0.02). There was a significant group-by-sex interaction (p = 0.02). Total vermis volumes were significantly larger in males with BD than HC males (p = 0.004); vermis volumes did not differ significantly between females with and without BD (p = 0.95). Subregion analyses showed a trend-level interaction between diagnosis and subregion (p = 0.07) in which subregion V1 volumes were significantly larger in BD participants (p = 0.001), with differences primarily driven by males (p = 0.001).Our findings demonstrate increases in cerebellar vermis volumes in males with BD. These findings support the presence of structural alterations in the cerebellar vermis in BD and furthermore the influence of sex on such changes.

Objective Previous study supports the presence of reduced volume and elevated response to emotional stimuli in amygdala in adolescents with bipolar disorder (BD). In the present study, structural and functional magnetic resonance imaging scans were obtained during the same neuroimaging session to examine amygdala structure-function relations in adolescents with BD. We hypothesized that amygdala volume would be inversely associated with amygdala response to emotional stimuli, such that BD participants with the smallest amygdala volumes would exhibit the highest amygdala response. Method Fifty-one adolescents (21 with BD I and 30 control adolescents, ages 10-18 years) underwent structural and functional magnetic resonance imaging scans. Amygdala volume ( n = 49) and signal change ( n = 44) during emotional face processing were compared between groups, and structure-function correlations were examined within the BD group ( n = 16). Results Adolescents with BD showed decreased amygdala volume ( p = .009) and increased amygdala response to emotional faces ( p = .043). There was no significant interaction between diagnosis and emotion type. A significant inverse association between amygdala volume and activation during emotional face processing was observed ( r = −0.54, p = .029). Conclusions Decreased volume and increased response to emotional stimuli in the amygdala in adolescents with BD are consistent with previous reports. This study represents the first report, to our knowledge, of the two findings in the same adolescent BD sample and supports an amygdala structure-function relation characterized by an inverse association between volume and response to emotional stimuli. This preliminary finding requires replication and suggests a possible pathophysiological link between abnormalities in amygdala structure and response to emotional stimuli in BD. J. Am. Acad. Child Adolesc. Psychiatry ,2009;48(6):636-642.

BACKGROUND Bipolar disorder is a systemic brain disorder. Accumulated evidence suggested that cortical-subcortical imbalance could be a trait-related pathogenic factor of bipolar disorder. Degree centrality, a robust index of focal connectivity in which the number of direct connections from one node to all nodes is counted, has not previously been studied in bipolar disorder as a whole. METHODS Resting state functional magnetic resonance imaging was performed on 52 patients with DSM-IV bipolar I disorder and 70 healthy controls recruited between September 2009 and July 2014. Degree centrality was calculated within cerebral gray matter for each subject and compared between patients with bipolar disorder and healthy controls. Hub distributions of both groups were explored. Effects of medication exposure and mood state on degree centrality, as well as cortical-subcortical degree centrality correlations, were explored. RESULTS Compared to healthy controls, patients with bipolar disorder exhibited significant decrease in degree centrality in cortical regions, including the middle temporal pole, inferior temporal gyrus, and ventral prefrontal cortex, but showed significant increase in degree centrality mainly in subcortical regions, including caudate, thalamus, parahippocampal gyrus, hippocampi, anterior cingulate, insula, and amygdala, and a small portion of cortical regions, such as superior and middle frontal gyrus (P < .05, corrected). Spatial distributions of the 2 groups were very similar. No significant effects of medication exposure or mood state on degree centrality were found. Patients with bipolar disorder also showed significant decrease in cortical-subcortical degree centrality correlation (P = .003). CONCLUSIONS These findings further contribute to the mounting evidence of cortical-subcortical dissociation in bipolar disorder pathophysiology. In addition, this study supports the continued development and implementation of graph-based techniques to enhance our understanding of the underlying neural mechanisms in mental disorders such as bipolar disorder, which are increasingly viewed as systemic brain disorders rather than disorders arising from disruption within a single structure or a limited number of structures. Due to the heterogeneity of our sample, as well as the small sample size of each medication and mood state subgroups, further investigation is needed to support our findings.

This magnetic resonance imaging study demonstrates increased lateral ventricle volume (LVV) in adolescents and adults with bipolar disorder (BD) with psychotic symptoms, but not without psychosis, compared to healthy adolescents and adults. This suggests LVV is a morphologic feature associated with psychosis in BD, present by adolescence.

In this study, we examined the morphology of the basal ganglia and thalamus in bipolar disorder (BP), schizophrenia-spectrum disorders (SCZ-S), and healthy controls (HC) with particular interest in differences related to the absence or presence of psychosis. Volumetric and shape analyses of the basal ganglia and thalamus were performed in 33 BP individuals [12 without history of psychotic features (NPBP) and 21 with history of psychotic features (PBP)], 32 SCZ-S individuals [28 with SCZ and 4 with schizoaffective disorder], and 27 HC using FreeSurfer-initiated large deformation diffeomorphic metric mapping. Significant volume differences were found in the caudate and globus pallidus, with volumes smallest in the NPBP group. Shape abnormalities showing inward deformation of superior regions of the caudate were observed in BP (and especially in NPBP) compared with HC. Shape differences were also found in the globus pallidus and putamen when comparing the BP and SCZ-S groups. No significant differences were seen in the nucleus accumbens and thalamus. In summary, structural abnormalities in the caudate and globus pallidus are present in BP and SCZ-S. Differences were more apparent in the NPBP subgroup. The findings herein highlight the potential importance of separately examining BP subgroups in neuroimaging studies.