Trait and state-related characteristics of thalamo-cortical circuit disruption in bipolar disorder: a prospective cross-sectional study.

Objective: The purpose of this study is to investigate the shared and distinct thalamic-cortical circuit between bipolar depression and remission, as well as to investigate the trait and state-related characteristics of the abnormal thalamic-cortical circuit in bipolar disorder. Methods: Resting-state functional magnetic resonance imaging was performed on 38 bipolar depression patients, 40 bipolar remission patients, and 39 gender-matched healthy controls (rsfMRI). The thalamic subregions were used as seed points to draw the functional connectivity of the entire brain, and then the shared and distinct thalamic-cortical circuits between bipolar depression and remission were compared. Results: When compared to the healthy group, both groups of patients had significantly lower functional connectivity between the rostral temporal thalamus and the lingual gyrus, the posterior parietal thalamus, the precuneus/cerebellum, and the occipital thalamus and the precuneus; however, functional connectivity between the premotor thalamus and the superior medial frontal was significantly lower in depression. Conclusion: This study discovered that both bipolar depression and remission had abnormal sensorimotor-thalamic functional connectivity, implying that it is a trait-related characteristic of bipolar disorder; however, the decline in prefrontal-thalamic connectivity exists specifically in bipolar depression, implying that it is a state-related characteristic of bipolar disorder.

Evaluating test-retest reliability and sex-/age-related effects on temporal clustering coefficient of dynamic functional brain networks.

The multilayer dynamic network model has been proposed as an effective method to understand the brain function. In particular, derived from the definition of clustering coefficient in static networks, the temporal clustering coefficient provides a direct measure of the topological stability of dynamic brain networks and shows potential in predicting altered brain functions. However, test-retest reliability and demographic-related effects on this measure remain to be evaluated. Using a data set from the Human Connectome Project (157 male and 180 female healthy adults; 22-37 years old), the present study investigated: (1) the test-retest reliability of temporal clustering coefficient across four repeated resting-state functional magnetic resonance imaging scans as measured by intraclass correlation coefficient (ICC); and (2) sex- and age-related effects on temporal clustering coefficient. The results showed that (1) the temporal clustering coefficient had overall moderate test-retest reliability (ICC > 0.40 over a wide range of densities) at both global and subnetwork levels, (2) female subjects showed significantly higher temporal clustering coefficient than males at both global and subnetwork levels, particularly within the default-mode and subcortical regions, and (3) temporal clustering coefficient of the subcortical subnetwork was positively correlated with age in young adults. The results of sex effects were robustly replicated in an independent REST-meta-MDD data set, while the results of age effects were not. Our findings suggest that the temporal clustering coefficient is a relatively reliable and reproducible approach for identifying individual differences in brain function, and provide evidence for demographically related effects on the human brain dynamic connectomes.

Aberrant global and local dynamic properties in schizophrenia with instantaneous phase method based on Hilbert transform.

BACKGROUND: Emerging functional imaging studies suggest that schizophrenia is associated with aberrant spatiotemporal interaction which may result in aberrant global and local dynamic properties. METHODS: We investigated the dynamic functional connectivity (FC) by using instantaneous phase method based on Hilbert transform to detect abnormal spatiotemporal interaction in schizophrenia. Based on resting-state functional magnetic resonance imaging, two independent datasets were included, with 114 subjects from COBRE [51 schizophrenia patients (SZ) and 63 healthy controls (HCs)] and 96 from OpenfMRI (36 SZ and 60 HCs). Phase differences and instantaneous coupling matrices were firstly calculated at all time points by extracting instantaneous parameters. Global [global synchrony and intertemporal closeness (ITC)] and local dynamic features [strength of FC (sFC) and variability of FC (vFC)] were compared between two groups. Support vector machine (SVM) was used to estimate the ability to discriminate two groups by using all aberrant features. RESULTS: We found SZ had lower global synchrony and ITC than HCs on both datasets. Furthermore, SZ had a significant decrease in sFC but an increase in vFC, which were mainly located at prefrontal cortex, anterior cingulate cortex, temporal cortex and visual cortex or temporal cortex and hippocampus, forming significant dynamic subnetworks. SVM analysis revealed a high degree of balanced accuracy (85.75%) on the basis of all aberrant dynamic features. CONCLUSIONS: SZ has worse overall spatiotemporal stability and extensive FC subnetwork lesions compared to HCs, which to some extent elucidates the pathophysiological mechanism of schizophrenia, providing insight into time-variation properties of patients with other mental illnesses.

Treatment Effect of Long-Term Antipsychotics on Default-Mode Network Dysfunction in Drug-Naïve Patients With First-Episode Schizophrenia: A Longitudinal Study.

Background: The maintenance of antipsychotic treatment is an efficient way to prevent the relapse of schizophrenia (SCZ). Previous studies have identified beneficial effects of antipsychotics on brain structural and functional abnormalities during mostly the acute phase in SCZ, but seldom is known about the effects of long-term antipsychotics on the brain. The present study focused on the long-term antipsychotic effect on the default mode network (DMN) dysfunction in SCZ. Methods: A longitudinal study of the functional connectivity (FC) of 11 DMN subdivisions was conducted in 86 drug-naive first-episode patients with SCZ at the baseline and after a long-term atypical antipsychotic treatment (more than 6 months) based on the resting-state functional magnetic resonance image. In total, 52 patients completed the follow-up of clinical and neuroimaging investigations. Results: At the baseline, relative to healthy controls, altered connectivities within the DMN and between the DMN and the external attention system (EAS) were observed in patients. After treatment, along with significant relief of symptoms, most FC alterations between the DMN and the EAS at the baseline were improved after treatment, although the rehabilitation of FC within the DMN was only observed at the link between the posterior cingulate cortex and precuneus. Greater reductions in negative and positive symptoms were both related to the changes of DMN-EAS FC in patients. Conclusion: Our findings provide evidence that maintenance antipsychotics on SCZ is beneficial for the improvement of DMN-EAS competitive imbalance, which may partly contribute to the efficient relapse prevention of this severe mental disorder.

Imbalance Between Prefronto-Thalamic and Sensorimotor-Thalamic Circuitries Associated with Working Memory Deficit in Schizophrenia.

BACKGROUND: Thalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia. METHODS: Both n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis. RESULTS: During both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d' score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively. CONCLUSIONS: The thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function.

Abnormal Large-Scale Network Activation Present in Bipolar Mania and Bipolar Depression Under Resting State.

Introduction: Previous studies have primarily focused on the neuropathological mechanisms of the emotional circuit present in bipolar mania and bipolar depression. Recent studies applying resting-state functional magnetic resonance imaging (fMRI) have raise the possibility of examining brain-wide networks abnormality between the two oppositional emotion states, thus this study aimed to characterize the different functional architecture represented in mania and depression by employing group-independent component analysis (gICA). Materials and Methods: Forty-one bipolar depressive patients, 20 bipolar manic patients, and 40 healthy controls (HCs) were recruited and received resting-state fMRI scans. Group-independent component analysis was applied to the brain network functional connectivity analysis. Then, we calculated the correlation between the value of between-group differences and clinical variables. Results: Group-independent component analysis identified 15 components in all subjects, and ANOVA showed that functional connectivity (FC) differed significantly in the default mode network, central executive network, and frontoparietal network across the three groups. Further post-hoc t-tests showed a gradient descent of activity-depression > HC > mania-in all three networks, with the differences between depression and HCs, as well as between depression and mania, surviving after family wise error (FWE) correction. Moreover, central executive network and frontoparietal network activities were positively correlated with Hamilton depression rating scale (HAMD) scores and negatively correlated with Young manic rating scale (YMRS) scores. Conclusions: Three brain networks heighten activity in depression, but not mania; and the discrepancy regions mainly located in prefrontal, which may imply that the differences in cognition and emotion between the two states is associated with top-down regulation in task-independent networks.

Online Real-Time Monitoring of Exhaled Breath Particles Reveals Unnoticed Transport of Nonvolatile Drugs from Blood to Breath.

We used online secondary electrospray ionization mass spectrometry to measure venlafaxine (VEN), a nonvolatile drug, in the exhaled air of mice intraperitoneally treated with VEN. The breath pharmacokinetic (PK) profile of VEN was recorded, which was in good agreement with that of the blood. Combined with online collection of exhaled breath particles (EBPs), it was shown that VEN existed as part of EBPs rather than gas molecules in the breath. Linear free-energy relationship analysis confirmed that almost completely ionized VEN at physiological conditions unlikely partition from the lung lining fluid (LLF) into breath air. This implies that the occurrence of VEN in exhaled air accompanies the formation of EBPs from the LLF. By comparison with the low breath signals of VEN metabolites, passive membrane permeability and lung/blood partition coefficient are suggested as the main influencing factors for the levels of drugs in the breath. This study advances our knowledge on the mechanism by which nonvolatile drugs are transferred from blood into exhaled breath, providing guidance for breath test-based therapeutic drug monitoring.

Abnormal Thalamocortical Circuit in Adolescents With Early-Onset Schizophrenia.

OBJECTIVE: Thalamic circuit imbalance characterized by increased sensorimotor-thalamic connectivity and decreased prefrontal-thalamic connectivity has been consistently observed in adult-onset schizophrenia (AOS), although it is unclear whether this pattern is also a feature of early-onset schizophrenia (EOS). If this is the case, thalamic circuit imbalance can be considered as a core mechanistic defect in schizophrenia, unconfounded by the age of onset. METHOD: A total of 116 adolescents with EOS (63 drug-naive EOS) and 55 matched healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging scans. To define the specific location of the thalamic subregions in thalamocortical circuit, 16 atlas-based thalamic subdivisions were used in functional connectivity analysis. RESULTS: The EOS group showed increased sensorimotor-thalamic connectivity and decreased prefrontal-cerebello-thalamic connectivity, consistent with AOS. Sensorimotor-thalamic hyperconnectivity was more prominent than prefrontal-thalamic hypoconnectivity, which was circumscribed to the medial prefrontal cortex (mPFC), in EOS. Of note, the EOS group specifically exhibited strengthened thalamic connectivity with the salience network (SN). In addition, the EOS showed a more prominent disruption of the lateral thalamic nuclear connectivity. CONCLUSION: Thalamic dysconnectivity observed in the EOS extends the observations from adult patients. Sensorimotor-thalamic hyperconnectivity is critical for the expression of schizophrenia phenotype irrespective of the age of onset, raising the possibility of aberrant but accelerated functional network maturation in EOS. The specific thalamocortical dysconnectivity involving the SN and mPFC may underlie the distinctive features of multi-modal hallucinations and heightened emotional valence of psychosis seen in EOS.

Comparison of Psychological Stress Levels and Associated Factors Among Healthcare Workers, Frontline Workers, and the General Public During the Novel Coronavirus Pandemic.

Objective: We aimed to conduct a comparative analysis of the psychological stress experienced by healthcare workers, frontline workers, and the general public and to assess the factors associated with psychological stress in each of these groups. Methods: We conducted an online survey targeting healthcare workers, frontline workers, and the general public. Psychological stress was assessed with the revised impact of event scale (IES-R). Univariable and multivariable logistic regression analyses were conducted. Results: We surveyed 1,336 participants (64.6% female; mean age, 36.6). The occupation group distribution of respondents was 50.7% healthcare workers, 27.2% frontline workers, and 22.1% general public. The healthcare (23.6 ± 15.8) and frontline (23.6 ± 17.8) workers had higher IES-R scores than the general public (15.3 ± 10.6; p < 0.01). Poor health perception and perception of infection avoidance were associated with psychological stress in the healthcare and frontline workers, but not in the general public. Conclusion: Both healthcare and frontline workers are suffering elevated psychological stress, compared to the general public, and this elevated stress may be related especially to their perceptions of their own health and infection risk. Interventions addressing these factors should be developed to alleviate psychological stress in these populations, and thus reduce their risk of mental illness pathogenesis.

Reduced Cortical Thickness in the Right Caudal Middle Frontal Is Associated With Symptom Severity in Betel Quid-Dependent Chewers.

BACKGROUND: Findings from brain structural imaging studies on betel quid dependence have supported relations between betel quid chewing and alterations in gray matter volume and white matter integrity. However, the effect of betel quid chewing on cortical thickness and the link between cortical thickness and symptom severity remains unascertained. METHODS: In this observational study, we compared cortical thickness measures from 24 male betel quid-dependent chewers with 27 male healthy controls. Using FreeSufer, we obtained three-dimensional T1-weighted images that were used to compute the thickness of the cerebral cortex throughout the cortical layer. RESULTS: Compared to healthy controls, betel quid dependent chewers displayed significant decreased cortical thickness in the precuneus, entorhinal, right paracentral, middle temporal, and caudal middle frontal gyri. Betel quid dependence scale scores negatively correlated (r = -0.604; p = 0.002) with reduced cortical thickness in the right caudal middle frontal of betel quid-dependent chewers. CONCLUSION: The findings provide evidence for cortical thickness abnormality in betel dependent chewers and further propose that the severity of betel quid symptoms may be a critical aspect associated with the cortical alterations. The observed alterations may serve as potential mechanisms to explain why BQ chewing behavior is persistent among individuals with betel quid dependence.

Schizophrenia patients and their healthy siblings share decreased prefronto-thalamic connectivity but not increased sensorimotor-thalamic connectivity.

The pattern of decreased prefronto-thalamic connectivity and increased sensorimotor-thalamic connectivity has been consistently documented in schizophrenia. However, whether this thalamo-cortical abnormality pattern is of genetic predisposition remains unknown. The present study for the first time aimed to investigate the common and distinct characteristics of this circuit in schizophrenia patients and their unaffected siblings who share half of the patient's genotype. Totally 293 participants were recruited into this study including 94 patients with schizophrenia, 96 their healthy siblings, and 103 healthy controls scanned using gradient-echo echo-planar imaging at rest. By using a fine-grained atlas of thalamus with 16 sub-regions, we mapped the thalamocortical network in three groups. Decreased thalamo-prefronto-cerebellar connectivity was shared between schizophrenia and their healthy siblings, but increased sensorimotor-thalamic connectivity was only found in schizophrenia. The shared thalamo-prefronto-cerebellar dysconnectivity showed an impressively gradient reduction pattern in patients and siblings comparing to controls: higher in the controls, lower in the patients and intermediate in the siblings. Anatomically, the decreased thalamic connectivity mostly centered on the pre-frontal thalamic subregions locating at the mediodorsal nucleus, while the increased functional connectivity with sensorimotor cortices was only observed in the caudal temporal thalamic subregion anchoring at the dorsal and ventral lateral nuclei. Moreover, both decreased thalamo-prefronto-cerebellar connectivity and increased sensorimotor-thalamic connectivity were related to clinical symptoms in patients. Our findings extend the evidence that the decreased thalamo-prefronto-cerebellar connectivity may be related to the high genetic risk in schizophrenia, while increased sensorimotor-thalamic connectivity potentially represents a neural biomarker for this severe mental disorder.

Altered Temporal Variability of Local and Large-Scale Resting-State Brain Functional Connectivity Patterns in Schizophrenia and Bipolar Disorder.

Schizophrenia and bipolar disorder share some common clinical features and are both characterized by aberrant resting-state functional connectivity (FC). However, little is known about the common and specific aberrant features of the dynamic FC patterns in these two disorders. In this study, we explored the differences in dynamic FC among schizophrenia patients (n = 66), type I bipolar disorder patients (n = 53), and healthy controls (n = 66), by comparing temporal variabilities of FC patterns involved in specific brain regions and large-scale brain networks. Compared with healthy controls, both patient groups showed significantly increased regional FC variabilities in subcortical areas including the thalamus and basal ganglia, as well as increased inter-network FC variability between the thalamus and sensorimotor areas. Specifically, more widespread changes were found in the schizophrenia group, involving increased FC variabilities in sensorimotor, visual, attention, limbic and subcortical areas at both regional and network levels, as well as decreased regional FC variabilities in the default-mode areas. The observed alterations shared by schizophrenia and bipolar disorder may help to explain their overlapped clinical features; meanwhile, the schizophrenia-specific abnormalities in a wider range may support that schizophrenia is associated with more severe functional brain deficits than bipolar disorder. Together, these findings highlight the potentials of using dynamic FC as an objective biomarker for the monitoring and diagnosis of either schizophrenia or bipolar disorder.

Connectomic signatures of working memory deficits in depression, mania, and euthymic states of bipolar disorder.

BACKGROUND: Working memory (WM) deficit is a feature persistently reported across mania, depression, and euthymic periods of bipolar disorder (BD). WM capacity relates to distributed brain regions that are systemically organized at the connectome level. It is not clear whether the same disruption of this network-level organization underlies the WM impairment seen in different phases of BD. METHODS: We used graph theory to examine the topology of the functional connectome in different granularity in 143 subjects (72 with BD [32 depression; 15 mania; 25 euthymic] and 71 healthy controls) during a n-back task. Linear regression analysis was used to test associations of altered graph properties, clinical symptoms, and WM accuracy in patients. RESULTS: Altered topological properties characterised by an increase in small-worldness of the whole-brain connectome, were specific for bipolar depressed, but not in manic and euthymic states. Depressed subjects showed a shift in the distribution of the number of connections per brain region (degree) within the connectome during WM task. Increased small-worldness related to worse WM accuracy in patients with more severe depression, anxiety and illness burden. LIMITATIONS: We used only 2-back load, limiting our ability to study the parametric effects of task demand. CONCLUSIONS: We demonstrate a putative state-dependent mechanistic link between connectome topology, hub re-distribution and impaired n-back performance in bipolar disorder. The aberrant task-dependent modulation of the connectome relates to worse WM performance especially when anxiety and depression are prominent in BD.

Acute and Chronic Effects of Betel Quid Chewing on Brain Functional Connectivity.

BACKGROUND: The active alkaloid in Betel quid is arecoline. Consumption of betel quid is associated with both acute effects and longer-term addictive effects. Despite growing evidence that betel quid use is linked with altered brain function and connectivity, the neurobiology of this psychoactive substance in initial acute chewing, and long-term dependence, is not clear. METHODS: In this observational study, functional magnetic resonance imaging in a resting-state was performed in 24 male betel quid-dependent chewers and 28 male controls prior to and promptly after betel quid chewing. Network-based statistics were employed to determine significant differences in functional connectivity between brain networks for both acute effects and in long-term betel users versus controls. A support vector machine was employed for pattern classification analysis. RESULTS: Before chewing betel quid, higher functional connectivity in betel quid-dependent chewers than in controls was found between the temporal, parietal and frontal brain regions (right medial orbitofrontal cortex, right lateral orbital frontal cortex, right angular gyrus, bilateral inferior temporal gyrus, superior parietal gyrus, and right medial superior frontal gyrus). In controls, the effect of betel quid chewing was significantly increased functional connectivity between the subcortical regions (caudate, putamen, pallidum, and thalamus), and the visual cortex (superior occipital gyrus and right middle occipital gyrus). CONCLUSION: These findings show that individuals who chronically use betel quid have higher functional connectivity than controls of the orbitofrontal cortex, and inferior temporal and angular gyri. Acute effects of betel quid are to increase the functional connectivity of some visual cortical areas (which may relate to the acute symptoms) and the basal ganglia and thalamus.

Salience-thalamic circuit uncouples in major depressive disorder, but not in bipolar depression.

BACKGROUND: Bipolar depression (BDD) and major depressive disorder (MDD) are two diseases both characterized by depressed mood and diminished interest or pleasure. Recent neuroimaging studies have implicated the thalamo-cortical circuit in mood disorders, and the present study aimed to map thalamo-cortical connectivity to explore the dissociable and common abnormalities between bipolar and major depression in this circuit. METHOD: Applying resting-state functional magnetic resonance imaging (fMRI), we mapped the thalamo-cortical circuit using a fine-grained thalamic atlas with 8 sub-regions bilaterally in 38 BDD patients, 42 MDD patients and 39 healthy controls (HCs). Correlation analysis was then performed between thalamo-cortical connectivity and clinical variables. RESULT: The findings showed that both patient groups exhibited prefronto-thalamo-cerebellar and sensorimotor-thalamic hypoconnectivity, while the abnormalities in MDD were more extensive. Particularly, MDD group showed decreased thalamic connectivity with the salience network including the insula, anterior cingulate cortex (ACC), and striatum. No correlations were found between the abnormal thalamo-cortical connectivity and clinical symptoms in either patient group. LIMITATION: Most patients in our study were taking drugs at the time of scanning, which may confound our findings. CONCLUSION: Our finding suggest that the thalamo-cortical hypofunction is a common neuro-substrate for BDD and MDD. Specifically, the hypoconnectivity between the thalamus and salience network including the insula, ACC and striatum may be a distinguished biomarker for MDD, which may help to differentiate these two emotional disorders.

Connectomic Underpinnings of Working Memory Deficits in Schizophrenia: Evidence From a replication fMRI study.

BACKGROUND: Working memory (WM) deficit is a key feature of schizophrenia that relates to a generalized neural inefficiency of extensive brain areas. To date, it remains unknown how these distributed regions are systemically organized at the connectome level and how the disruption of such organization brings about the WM impairment seen in schizophrenia. METHODS: We used graph theory to examine the neural efficiency of the functional connectome in different granularity in 155 patients with schizophrenia and 96 healthy controls during a WM task. These analyses were repeated in another independent dataset (81 patients and 54 controls). Linear regression analysis was used to test associations of altered graph properties, clinical symptoms, and WM accuracy in patients. A machine-learning approach was adopted to study the ability of multivariate connectome features from one dataset to discriminate patients from controls in the second dataset. RESULTS: Small-worldness of the whole-brain connectome was significantly increased in schizophrenia during the WM task; this increase is related to better (though subpar) WM accuracy in patients with more severe negative symptom burden. There was a shift in the degree distribution to a more homogeneous form in patients. The machine-learning approach classified a new set of patients from controls with 84.3% true-positivity rate for schizophrenia and 71.6% overall accuracy. CONCLUSIONS: We demonstrate a putative mechanistic link between connectome topology, hub redistribution, and impaired n-back performance in schizophrenia. The task-dependent modulation of the connectome relates to, but remains inefficient in, improving the performance above par in the presence of severe negative symptoms.

Morphological Profiling of Schizophrenia: Cluster Analysis of MRI-Based Cortical Thickness Data.

The diagnosis of schizophrenia is thought to embrace several distinct subgroups. The manifold entities in a single clinical patient group increase the variance of biological measures, deflate the group-level estimates of causal factors, and mask the presence of treatment effects. However, reliable neurobiological boundaries to differentiate these subgroups remain elusive. Since cortical thinning is a well-established feature in schizophrenia, we investigated if individuals (patients and healthy controls) with similar patterns of regional cortical thickness form naturally occurring morphological subtypes. K-means algorithm clustering was applied to regional cortical thickness values obtained from 256 structural MRI scans (179 patients with schizophrenia and 77 healthy controls [HCs]). GAP statistics revealed three clusters with distinct regional thickness patterns. The specific patterns of cortical thinning, clinical characteristics, and cognitive function of each clustered subgroup were assessed. The three clusters based on thickness patterns comprised of a morphologically impoverished subgroup (25% patients, 1% HCs), an intermediate subgroup (47% patients, 46% HCs), and an intact subgroup (28% patients, 53% HCs). The differences of clinical features among three clusters pertained to age-of-onset, N-back performance, duration exposure to treatment, total burden of positive symptoms, and severity of delusions. Particularly, the morphologically impoverished group had deficits in N-back performance and less severe positive symptom burden. The data-driven neuroimaging approach illustrates the occurrence of morphologically separable subgroups in schizophrenia, with distinct clinical characteristics. We infer that the anatomical heterogeneity of schizophrenia arises from both pathological deviance and physiological variance. We advocate using MRI-guided stratification for clinical trials as well as case-control investigations in schizophrenia.

Abnormal Connectivity Within Anterior Cortical Midline Structures in Bipolar Disorder: Evidence From Integrated MRI and Functional MRI.

Background: Aberrant functional and structural connectivity across multiple brain networks have been reported in bipolar disorder (BD). However, most previous studies consider the functional and structural alterations in isolation regardless of their possible integrative relationship. The present study aimed to identify the brain connectivity alterations in BD by capturing the latent nexus in multimodal neuroimaging data. Methods: Structural and resting-state images were acquired from 83 patients with BD and 94 healthy controls (HCs). Combined with univariate methods conducted to detect the dysconnectivity in BD, we also employed a semi-multimodal fusion framework fully utilizing the interrelationship between the two modalities to distinguish patients from HCs. Moreover, one-way analysis of variance was adopted to explore whether the detected dysconnectivity has differences across stages of patients with BD. Results: The semi-multimodal fusion framework distinguished patients from HCs with 81.47% accuracy, 85.42% specificity, and 74.75% sensitivity. The connection between the anterior cingulate cortex (ACC) and superior medial prefrontal cortex (sMPFC) contributed the most to BD diagnosis. Consistently, the univariate method also identified that this ACC-sMPFC functional connection significantly decreased in BD patients compared to HCs, and the significant order of the dysconnectivity is: depressive episode < HCs and remission episode < HCs. Conclusions: Our findings, by adopting univariate and multivariate analysis methods, shed light on the decoupling within the anterior midline brain in the pathophysiology of BD, and this decoupling may serve as a trait marker for this disease.

Longitudinal Trajectories of Psychotic-Like Experiences and Their Relationship to Emergent Mental Disorders Among Adolescents: A 3-Year Cohort Study.

BACKGROUND: Psychotic-like experiences (PLEs) may be important antecedents of psychosis and other mental disorders. OBJECTIVE: To investigate distinct longitudinal trajectories of the frequency of PLEs and their relationship to subsequent development of mental disorders. METHODS: A longitudinal study of self-reported PLEs and concurrent traumatic experiences was conducted among 6,198 adolescents through annual classroom assessments over 3 years (2014-2016) using the Community Assessment of Psychic Experiences and the Trauma History Questionnaire. Diagnoses of mental disorders were based on the Mini-International Neuropsychiatric Interview in the final year. Growth mixture modeling was used to identify distinct growth trajectories in the frequency of PLEs. Logistic regression was then used to explore relationships between different PLE trajectories and emergence of psychiatric disorders, taking account of sociodemographic characteristics and childhood antecedents. RESULTS: Two different PLE trajectories were identified, one characterized by stable low levels of PLE frequency and the other by progressively increasing PLE frequency. Transition to mental disorder occurred in 3.39% of the increasing-frequency group and 1.28% of the stable low-level group. The increasing-frequency group had a significantly higher risk of transition to any psychiatric disorder (OR = 2.7; 95% CI, 1.56-4.66), to a psychotic disorder (OR = 22.14; 95% CI, 2.30-213.25), and to a nonpsychotic psychiatric disorder (OR = 2.28; 95% CI, 1.27-4.10). Besides increasing PLEs (OR = 3.33; 95% CI, 1.55-7.19), other risk factors for any psychiatric disorder included childhood trauma (OR = 1.17; 95% CI, 1.01-1.36), family divorce (OR = 2.86; 95% CI, 1.24-6.61), and minority ethnicity (OR = 2.91; 95% CI, 1.18-7.20). CONCLUSIONS: The pattern of increasing PLEs predominates in predicting emergent mental disorder, particularly psychosis, along with minority status, trauma, and family divorce, suggesting potential targets for preventive intervention.

Abnormal resting-state cerebral-limbic functional connectivity in bipolar depression and unipolar depression.

BACKGROUND: Distinctive patterns of functional connectivity (FC) abnormalities in neural circuitry has been reported in patients with bipolar depression (BD) and unipolar depression (UD). However, it is unclear that whether this distinct functional connectivity patterns are diagnosis specific between BD and UD. This study aimed to compare patterns of functional connectivity among BD, UD and healthy controls (HC) and determine the distinct functional connectivity patterns which can differentiate BD from UD. METHOD: Totally 23 BD, 22 UD, and 24 HC were recruited to undergo resting-state fMRI scanning. FC between each pair of brain regions was calculated and compared among the three groups, the associations of FC with depressive symptom were also analyzed. RESULTS: Both patient groups showed significantly decreased cerebral-limbic FC located between the default mode network [posterior cingulated gyrus (PCG) and precuneus] and limbic regions (hippocampus, amygdala and thalamus) than HC. Moreover, the BD group exhibited more decreased FC mainly in the cortical regions (middle temporal gyrus, PCG, medial superior frontal gyrus, inferior occipital gyrus and superior temporal gyrus), but the UD group is more associated with limbic alterations. These decreased FCs were negatively correlated with HAMD scores in both BD and UD patients. CONCLUSIONS: BD and UD patients demonstrate different patterns of abnormal cerebral-limbic FC, reflected by decreased FC within cerebral cortex and limbic regions in BD and UD, respectively. The distinct FC abnormal pattern of the cerebral-limbic circuit might be applied as biomarkers to differentiate these two depressive patient groups.