Changes in patterns of age-related network connectivity are associated with risk for schizophrenia.

Alterations in fMRI-based brain functional network connectivity (FNC) are associated with schizophrenia (SCZ) and the genetic risk or subthreshold clinical symptoms preceding the onset of SCZ, which often occurs in early adulthood. Thus, age-sensitive FNC changes may be relevant to SCZ risk-related FNC. We used independent component analysis to estimate FNC from childhood to adulthood in 9,236 individuals. To capture individual brain features more accurately than single-session fMRI, we studied an average of three fMRI scans per individual. To identify potential familial risk-related FNC changes, we compared age-related FNC in first-degree relatives of SCZ patients mostly including unaffected siblings (SIB) with neurotypical controls (NC) at the same age stage. Then, we examined how polygenic risk scores for SCZ influenced risk-related FNC patterns. Finally, we investigated the same risk-related FNC patterns in adult SCZ patients (oSCZ) and young individuals with subclinical psychotic symptoms (PSY). Age-sensitive risk-related FNC patterns emerge during adolescence and early adulthood, but not before. Young SIB always followed older NC patterns, with decreased FNC in a cerebellar-occipitoparietal circuit and increased FNC in two prefrontal-sensorimotor circuits when compared to young NC. Two of these FNC alterations were also found in oSCZ, with one exhibiting reversed pattern. All were linked to polygenic risk for SCZ in unrelated individuals (R2 varied from 0.02 to 0.05). Young PSY showed FNC alterations in the same direction as SIB when compared to NC. These results suggest that age-related neurotypical FNC correlates with genetic risk for SCZ and is detectable with MRI in young participants.

Sex dimorphism controls dysbindin-related cognitive dysfunctions in mice and humans with the contribution of COMT.

Cognitive dysfunctions are core-enduring symptoms of schizophrenia, with important sex-related differences. Genetic variants of the DTBPN1 gene associated with reduced dysbindin-1 protein (Dys) expression negatively impact cognitive functions in schizophrenia through a functional epistatic interaction with Catechol-O-methyltransferase (COMT). Dys is involved in the trafficking of dopaminergic receptors, crucial for prefrontal cortex (PFC) signaling regulation. Moreover, dopamine signaling is modulated by estrogens via inhibition of COMT expression. We hypothesized a sex dimorphism in Dys-related cognitive functions dependent on COMT and estrogen levels. Our multidisciplinary approach combined behavioral-molecular findings on genetically modified mice, human postmortem Dys expression data, and in vivo fMRI during a working memory task performance. We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (pBonferroni = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = -3.21; pFDR = 0.004). Dorsolateral PFC activity was associated with lower working memory performance in males only (p = 0.04). Also, male humans showed decreased Dys expression in dorsolateral PFC during adulthood (pFDR = 0.05). Female Dys mice showed preserved cognitive performances with deficits only with a lack of estrogen tested in an ovariectomy model (pBonferroni = 0.0001), suggesting that genetic variants reducing Dys protein expression could probably become functional in females when the protective effect of estrogens is attenuated, i.e., during menopause. Overall, our results show the differential impact of functional variants of the DTBPN1 gene interacting with COMT on cognitive functions across sexes in mice and humans, underlying the importance of considering sex as a target for patient stratification and precision medicine in schizophrenia.

Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

The interplay between mentalization, personality traits and burnout in psychiatry training: Results from a large multicenter controlled study.

BACKGROUND: A better characterization of educational processes during psychiatry training is needed, both to foster personal resilience and occupational proficiency. METHODS: An adequate coverage of medical residents at the national level was reached (41.86% of the total reference population, 29 out of 36 training centers-80.55%). Controls were recruited among residents in other medical specialties. All participants were assessed by questionnaires to evaluate early life experiences, attachment style, personality traits, coping strategies, emotional competencies. A Structural Equation Model (SEM) framework was employed to investigate the interplay between individual factors. RESULTS: A total sample of 936 people was recruited (87.9% response-rate; 645 residents in psychiatry, 291 other medical residents). Psychiatry trainees reported a higher prevalence of adverse childhood experiences (emotional abuse, emotional neglect, physical neglect), greater attachment insecurity (anxious or avoidant) in comparison to other medical trainees. Psychiatry residents also reported higher social support-seeking as a coping strategy, lower problem-orientation, and lower transcendence. Lower neuroticism, higher openness to experience, and higher emotional awareness were also observed in psychiatry trainees. Psychiatry training was associated with a redefinition of conflict management skills as a function of seniority. The SEM model provided support for an interplay between early traumatic experiences, mentalization skills (coping strategies, emotion regulation), interpersonal competencies and occupational distress. CONCLUSIONS: The findings of the present study supported a theoretical model based on mentalization theory for the interactions between personal and relational competencies in psychiatry training, thus providing potential target of remodulation and redefinition of this specific process of education.

Network dysfunction of sadness facial expression processing and morphometry in euthymic bipolar disorder.

Facial emotion recognition (FER), including sadness, is altered in bipolar disorder (BD). However, the relationship between this impairment and the brain structure in BD is relatively unexplored. Furthermore, its association with clinical variables and with the subtypes of BD remains to be clarified. Twenty euthymic patients with BD type I (BD-I), 28 BD type II (BD-II), and 45 healthy controls completed a FER test and a 3D-T1-weighted magnetic resonance imaging. Gray matter volume (GMV) of the cortico-limbic regions implicated in emotional processing was estimated and their relationship with FER performance was investigated using network analysis. Patients with BD-I had worse total and sadness-related FER performance relative to the other groups. Total FER performance was significantly negatively associated with illness duration and positively associated with global functioning in patients with BD-I. Sadness-related FER performance was also significantly negatively associated with the number of previous manic episodes. Network analysis showed a reduced association of the GMV of the frontal-insular-occipital areas in patients with BD-I, with a greater edge strength between sadness-related FER performance and amygdala GMV relative to controls. Our results suggest that FER performance, particularly for facial sadness, may be distinctively impaired in patients with BD-I. The pattern of reduced interrelationship in the frontal-insular-occipital regions and a stronger positive relationship between facial sadness recognition and the amygdala GMV in BD may reflect altered cortical modulation of limbic structures that ultimately predisposes to emotional dysregulation. Future longitudinal studies investigating the effect of mood state on FER performance in BD are warranted.

Diagnostic value of regional homogeneity and fractional amplitude of low-frequency fluctuations in the classification of schizophrenia and bipolar disorders.

Schizophrenia (SCZ) and bipolar disorders (BD) show significant neurobiological and clinical overlap. In this study, we wanted to identify indexes of intrinsic brain activity that could differentiate these disorders. We compared the diagnostic value of the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) estimated from resting-state functional magnetic resonance imaging in a support vector machine classification of 59 healthy controls (HC), 40 individuals with SCZ, and 43 individuals with BD type I. The best performance, measured by balanced accuracy (BAC) for binary classification relative to HC was achieved by a stacking model (87.4% and 90.6% for SCZ and BD, respectively), with ReHo performing better than fALFF, both in SCZ (86.2% vs. 79.4%) and BD (89.9% vs. 76.9%). BD were better differentiated from HC by fronto-temporal ReHo and striato-temporo-thalamic fALFF. SCZ were better classified from HC using fronto-temporal-cerebellar ReHo and insulo-tempo-parietal-cerebellar fALFF. In conclusion, we provided evidence of widespread aberrancies of spontaneous activity and local connectivity in SCZ and BD, demonstrating that ReHo features exhibited superior discriminatory power compared to fALFF and achieved higher classification accuracies. Our results support the complementarity of these measures in the classification of SCZ and BD and suggest the potential for multivariate integration to improve diagnostic precision.

The risk of cannabis use disorder is mediated by altered brain connectivity: A chronnectome study.

The brain mechanisms underlying the risk of cannabis use disorder (CUD) are poorly understood. Several studies have reported changes in functional connectivity (FC) in CUD, although none have focused on the study of time-varying patterns of FC. To fill this important gap of knowledge, 39 individuals at risk for CUD and 55 controls, stratified by their score on a self-screening questionnaire for cannabis-related problems (CUDIT-R), underwent resting-state functional magnetic resonance imaging. Dynamic functional connectivity (dFNC) was estimated using independent component analysis, sliding-time window correlations, cluster states and meta-state indices of global dynamics and were compared among groups. At-risk individuals stayed longer in a cluster state with higher within and reduced between network dFNC for the subcortical, sensory-motor, visual, cognitive-control and default-mode networks, relative to controls. More globally, at-risk individuals had a greater number of meta-states and transitions between them and a longer state span and total distance between meta-states in the state space. Our findings suggest that the risk of CUD is associated with an increased dynamic fluidity and dynamic range of FC. This may result in altered stability and engagement of the brain networks, which can ultimately translate into altered cortical and subcortical function conveying CUD risk. Identifying these changes in brain function can pave the way for early pharmacological and neurostimulation treatment of CUD, as much as they could facilitate the stratification of high-risk individuals.

Effects of electroconvulsive therapy on cortical thickness in depression: a systematic review.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most studied and validated available treatments for severe or treatment-resistant depression. However, little is known about the neural mechanisms underlying ECT. This systematic review aims to critically review all structural magnetic resonance imaging studies investigating longitudinal cortical thickness (CT) changes after ECT in patients with unipolar or bipolar depression. METHODS: We performed a search on PubMed, Medline, and Embase to identify all available studies published before April 20, 2023. A total of 10 studies were included. RESULTS: The investigations showed widespread increases in CT after ECT in depressed patients, involving mainly the temporal, insular, and frontal regions. In five studies, CT increases in a non-overlapping set of brain areas correlated with the clinical efficacy of ECT. The small sample size, heterogeneity in terms of populations, comorbidities, and ECT protocols, and the lack of a control group in some investigations limit the generalisability of the results. CONCLUSIONS: Our findings support the idea that ECT can increase CT in patients with unipolar and bipolar depression. It remains unclear whether these changes are related to the clinical response. Future larger studies with longer follow-up are warranted to thoroughly address the potential role of CT as a biomarker of clinical response after ECT.

The complexity of cortical folding is reduced in chronic cocaine users.

Cocaine use is a worldwide health problem with psychiatric, somatic and socioeconomic complications, being the second most widely used illicit drug in the world. Despite several structural neuroimaging studies, the alterations in cortical morphology associated with cocaine use and addiction are still poorly understood. In this study, we compared the complexity of cortical folding (CCF), a measure that aims to summarize the convoluted structure of the cortex between patients with cocaine addiction (n = 52) and controls (n = 36), and correlated it with characteristics of addiction and impulsivity. We found that patients with cocaine addiction had greater impulsivity and showed reduced CCF in a cluster that encompassed the left insula and the supramarginal gyrus (SMG) and in one in the left medial orbitofrontal cortex. Finally, the CCF in the left medial orbitofrontal cortex was correlated with the age of onset of cocaine addiction and with attentional impulsivity. Overall, our findings suggest that chronic cocaine use is associated with changes in the cortical surface in the fronto-parieto-limbic regions that underlie emotional regulation and these changes are associated with earlier cocaine use. Future longitudinal studies are warranted to unravel the association of these changes with the diathesis for the disorder and with the chronic use of this substance.

Neurochemical Correlates of Cue Reactivity in Individuals with Excessive Smartphone Use.

BACKGROUND: Excessive smartphone use (ESU), that is, a pattern of smartphone use that shows specific features of addictive behavior, has increasingly attracted societal and scientific interest in the past years. On the neurobiological level, ESU has recently been related to structural and functional variation in reward and salience processing networks, as shown by, for example, aberrant patterns of neural activity elicited by specific smartphone cues. OBJECTIVES: Expanding on these findings, using cross-modal correlations of magnetic resonance imaging (MRI)-based measures with nuclear imaging-derived estimates, we aimed at identifying neurochemical pathways that are related to ESU. METHODS: Cross-modal correlations between functional MRI data derived from a cue-reactivity task administered in persons with and without ESU and specific PET/SPECT receptor probability maps. RESULTS: The endogenous mu-opioid receptor (MOR) system was found to be significantly (FDR-corrected) correlated with fMRI data, and z-transformed correlation coefficients showed an association (albeit nonsignificant after FDR-correction) between MOR and the Smartphone Addiction Inventory "withdrawal" dimension. CONCLUSIONS: We could identify the MOR system as a neurochemical pathway associated with ESU. The MOR system is closely linked to the reward system, which has been recognized as a key player in addictive disorders. Together with its potential link to withdrawal, the MOR system hints toward a biologically highly relevant marker, which should be taken into consideration in the ongoing scientific discussion on technology-related addictive behaviors.

Structural and functional features of treatment-resistant depression: A systematic review and exploratory coordinate-based meta-analysis of neuroimaging studies.

OBJECTIVES: A third of people suffering from major depressive disorder do not experience a significant improvement in their symptoms even after adequate treatment with two different antidepressant medications. This common condition, termed treatment-resistant depression (TRD), severely affects the quality of life of millions of people worldwide, causing long-lasting interpersonal problems and social costs. Given its epidemiological and clinical relevance and the little consensus on whether the neurobiological underpinnings of TRD differ from treatment-sensitive depression (TSD), we sought to highlight the convergent morphometric and functional neuroimaging correlates of TRD. METHODS: We systematically reviewed the published literature on structural and resting-state functional neuroimaging of TRD compared to TSD and healthy controls (HC) and performed exploratory coordinate-based meta-analyses (CBMA) of significant results separately for each modality and multimodally ("all-effects"). CBMAs were also performed for each direction and combining both directions of group contrasts. RESULTS: Out of the initial 1929 studies, only eight involving 555 participants (189 patients with TRD, 156 with TSD, and 210 HC) were included. In all-effects CBMA, precentral/superior frontal gyrus showed a significant difference between TRD and HC. Functional and structural imaging meta-analyses did not yield statistically significant results. A marginally significant cluster of altered intrinsic activity was found between TRD and HC in the cerebellum/pons. CONCLUSIONS: Frontal, cerebellar, and brainstem functions can be involved in the pathophysiology of TRD. However, the design and heterogeneity of the (scarce) published literature hinder the generalizability of the findings.

Vagus Nerve Stimulation in Treatment-Resistant Depression: A Case Series of Long-Term Follow-up.

OBJECTIVES: Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (>5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant. METHODS: Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events. RESULTS: The VNS implant was associated with a sustained response (>10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred. CONCLUSIONS: Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Cortical complexity estimation using fractal dimension: A systematic review of the literature on clinical and nonclinical samples.

Fractal geometry has recently been proposed as a useful tool for characterizing the complexity of the brain cortex, which is likely to derive from the recurrence of sulci-gyri convolution patterns. The index used to describe the cortical complexity is called fractal dimensional (FD) and was employed by different research exploring the neurobiological correlates of distinct pathological and nonpathological conditions. This review aims to describe the literature on the application of this index, summarize the heterogeneities between studies and inform future research on this topic. Sixty-two studies were included in the systematic review. The main research lines concern neurodevelopment, aging and the neurobiology of specific psychiatric and neurological disorders. Overall, the included papers indicate that cortical complexity is likely to reduce during aging and in various pathological processes affecting the brain. Nevertheless, the high heterogeneity between studies strongly prevents the possibility of drawing conclusions. Further research considering this index besides other morphological values is needed to better clarify the role of FD in characterizing the cortical structure.

Effects of Mindfulness-Based Interventions on Gray Matter Volume in Patients with Opioid Dependence.

INTRODUCTION: Recently, several mindfulness-based programs showed promising clinical effects in the treatment of psychiatric disorders including substance use disorders. However, very little is known about the effects of mindfulness-based interventions (MBIs) on brain structure in such patients. METHODS: This study aimed to detect changes in gray matter volume (GMV) in opioid-dependent patients receiving MBI during their first month of treatment. Thirty patients were assigned to either 3 weeks of MBI (n = 16) or treatment as usual (TAU, n = 14) and were investigated using structural magnetic resonance imaging before and after treatment. Longitudinal pipeline of the Computational Anatomy Toolbox for SPM (CAT12) was used to detect significant treatment-related changes over time. The identified GMV changes following treatment were related to clinically relevant measures such as impulsivity, distress tolerance, and mindfulness. RESULTS: After treatment, increased mindfulness scores were found in individuals receiving MBI compared to TAU. In the MBI group, there were also significant differences with respect to distress tolerance and impulsivity. Effects on mindfulness, distress tolerance, and impulsivity were also found in the TAU group. Longitudinal within-group analysis revealed increased left anterior insula GMV in individuals receiving MBI. Anterior insula volume increase was associated with decreased impulsivity levels. In the TAU group, significant GMV changes were found in the right lingual gyrus and right entorhinal cortex. DISCUSSION/CONCLUSION: MBI can yield significant clinical effects during early abstinence from opioid dependence. MBI is particularly associated with increased insula GMV, supporting an important role of this region in the context of MBI-induced neural changes.

Characterizing the sensorimotor domain in schizophrenia spectrum disorders.

The rapidly evolving field of sensorimotor neuroscience reflects the scientific and clinical relevance of sensorimotor abnormalities as an intrinsic component of the disease process, e.g., in patients with schizophrenia spectrum disorders (SSD). Despite previous efforts, however, prevalence rates and relationships between different categories of sensorimotor abnormalities in SSD patients are still subject of ongoing debate. In this study, we examined five different categories of the sensorimotor domain (Neurological soft signs (NSS), parkinsonism, catatonia, akathisia, and tardive dyskinesia) according to well-established clinical ratings scales and the respective cut-off criteria in a sample of 131 SSD patients. We used a collection of statistical methods to better understand prevalence, overlap and heterogeneity, as well as psychopathological and cognitive correlates of sensorimotor abnormalities. 97.7% of the SSD patients considered by this study exhibited at least one categorically defined sensorimotor abnormality that tended to co-vary within three different sensorimotor subgroups (moderate, hyperkinetic and hypokinetic). Finally, hyperkinetic and hypokinetic groups differed significantly in their neurocognitive performance compared with the moderate group. The results suggest different patterns of clinical overlap, highlight the relationship between sensorimotor and cognitive domain and provide clues for further neurobiological studies.

Melatonin and melatonin-agonists for metabolic syndrome components in patients treated with antipsychotics: A systematic review and meta-analysis.

OBJECTIVE: Metabolic side effects are a limiting factor in the use of antipsychotics, which remain the cornerstone of long-term management of patients with severe mental illness. There is contrasting evidence on a possible role of melatonin and melatonin-agonists in attenuating antipsychotic-induced metabolic abnormalities. DESIGN: We conducted a systematic review (PubMed, PsycInfo, Cochrane databases, up to August 2020) and a random-effect meta-analysis of double-blind, randomized placebo-controlled trials (RCTs) involving melatonin and melatonin-agonists in the treatment of antipsychotic-induced metabolic changes. The primary outcome was the standardized mean difference (SMD) of composite metabolic outcomes built with metabolic syndrome components. Secondary outcomes were individual metabolic syndrome components, and other anthropometric, glucose metabolism, lipid profile, and psychopathology measures. RESULTS: Out of the initial 41 studies, six documented five separate RCTs randomizing 248 patients (126 to melatonin/ramelteon, 122 to placebo) affected by schizophrenia-spectrum disorders and bipolar disorder. Melatonin/ramelteon outperformed placebo on the primary outcome (SMD -0.28, 95% CI = -0.39 ÷ -0.168), as well as on all individual components of metabolic syndrome (systolic blood pressure MD -3.266, 95% CI = -6.020 ÷ -0.511; fasting glucose MD -3.766, 95% CI = -5.938 ÷ -1.593; triglycerides MD -9.800, 95% CI = -19.431 ÷ -0.169; HDL MD 2.995, 95% CI = 0.567 ÷ 5.423), except waist circumference. CONCLUSIONS: Melatonin/ramelteon augmentation may be beneficial for non-anthropometric metabolic syndrome components in patients treated with antipsychotics.

Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use.

Heavy cannabis use (HCU) is frequently associated with a plethora of cognitive, psychopathological and sensorimotor phenomena. Although HCU is frequent, specific patterns of abnormal brain structure and function underlying HCU in individuals presenting without cannabis-use disorder or other current and life-time major mental disorders are unclear at present. This multimodal magnetic resonance imaging (MRI) study examined resting-state functional MRI (rs-fMRI) and structural MRI (sMRI) data from 24 persons with HCU and 16 controls. Parallel independent component analysis (p-ICA) was used to examine covarying components among grey matter volume (GMV) maps computed from sMRI and intrinsic neural activity (INA), as derived from amplitude of low-frequency fluctuations (ALFF) maps computed from rs-fMRI data. Further, we used JuSpace toolbox for cross-modal correlations between MRI-based modalities with nuclear imaging derived estimates, to examine specific neurotransmitter system changes underlying HCU. We identified two transmodal components, which significantly differed between the HCU and controls (GMV: p = 0.01, ALFF p = 0.03, respectively). The GMV component comprised predominantly cerebello-temporo-thalamic regions, whereas the INA component included fronto-parietal regions. Across HCU, loading parameters of both components were significantly associated with distinct HCU behavior. Finally, significant associations between GMV and the serotonergic system as well as between INA and the serotonergic, dopaminergic and µ-opioid receptor system were detected. This study provides novel multimodal neuromechanistic insights into HCU suggesting co-altered structure/function-interactions in neural systems subserving cognitive and sensorimotor functions.

Secondary Mania induced by TNF-α inhibitors: A systematic review.

A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor necrosis factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes. PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of the initial 75 references, the screening resulted in the inclusion of four case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600-0.53% - experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept. These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania.

White Matter Microstructure Associated with the Antidepressant Effects of Deep Brain Stimulation in Treatment-Resistant Depression: A Review of Diffusion Tensor Imaging Studies.

Treatment-resistant depression (TRD) is a severe disorder characterized by high relapse rates and decreased quality of life. An effective strategy in the management of TRD is deep brain stimulation (DBS), a technique consisting of the implantation of electrodes that receive a stimulation via a pacemaker-like stimulator into specific brain areas, detected through neuroimaging investigations, which include the subgenual cingulate cortex (sgCC), basal ganglia, and forebrain bundles. In this context, to improve our understanding of the mechanism underlying the antidepressant effects of DBS in TRD, we collected the results of diffusion tensor imaging (DTI) studies exploring how WM microstructure is associated with the therapeutic effects of DBS in TRD. A search on PubMed, Web of Science, and Scopus identified 11 investigations assessing WM microstructure in responders and non-responders to DBS. Altered WM microstructure, particularly in the sgCC, medial forebrain bundle, cingulum bundle, forceps minor, and uncinate fasciculus, was associated with the antidepressant effect of DBS in TRD. Overall, the results show that DBS targeting selective brain regions, including the sgCC, forebrain bundle, cingulum bundle, rectus gyrus, anterior limb of the internal capsule, forceps minor, and uncinate fasciculus, seem to be effective for the treatment of TRD.

Structurally constrained effective brain connectivity.

The relationship between structure and function is of interest in many research fields involving the study of complex biological processes. In neuroscience in particular, the fusion of structural and functional data can help to understand the underlying principles of the operational networks in the brain. To address this issue, this paper proposes a constrained autoregressive model leading to a representation of effective connectivity that can be used to better understand how the structure modulates the function. Or simply, it can be used to find novel biomarkers characterizing groups of subjects. In practice, an initial structural connectivity representation is re-weighted to explain the functional co-activations. This is obtained by minimizing the reconstruction error of an autoregressive model constrained by the structural connectivity prior. The model has been designed to also include indirect connections, allowing to split direct and indirect components in the functional connectivity, and it can be used with raw and deconvoluted BOLD signal. The derived representation of dependencies was compared to the well known dynamic causal model, giving results closer to known ground-truth. Further evaluation of the proposed effective network was performed on two typical tasks. In a first experiment the direct functional dependencies were tested on a community detection problem, where the brain was partitioned using the effective networks across multiple subjects. In a second experiment the model was validated in a case-control task, which aimed at differentiating healthy subjects from individuals with autism spectrum disorder. Results showed that using effective connectivity leads to clusters better describing the functional interactions in the community detection task, while maintaining the original structural organization, and obtaining a better discrimination in the case-control classification task.