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Introduction: Cellular prion protein (PrP C ) was implicated in amyloid beta (Aβ)-induced toxicity in Alzheimer's disease (AD), but the precise molecular mechanisms involved in this process are unclear., Methods: Double transgenic mice were generated by crossing Prnp knockout (KO) with 5xFAD mice, and light-sheet microscopy was used for whole brain tissue analyses. PrP C -overexpressing cells were developed for in vitro studies, and microscopy was used to assess co-localization of proteins of interest. Surface-plasmon resonance (SPR) was used to investigate protein-binding characteristics., Results: In vivo, PrP C  levels correlated with reduced lifespan and cognitive and motor function, and its ablation disconnected behavior deficits from Aβ levels. Light-sheet microscopy showed that PrP C  influenced Aβ-plaque burden but not the distribution of those plaques. Interestingly, caveolin-1 (Cav-1) KO neurons significantly reduced intracellular Aβ-oligomer (Aβo) uptake when compared to wild-type neurons., Discussion: The findings shed new light on the relevance of intracellular Aβo, suggesting that PrP C  and Cav-1 modulate intracellular Aβ levels and the Aβ-plaque load., Highlights: PrP C expression adversely affects lifespan and behavior in 5xFAD mice. PrP C increases Aβ1-40 and Aβ1-42 levels and Aβ-plaque load in 5xFAD mice. Cav-1 interacts with both PrP C and Aβ peptides. Knocking out Cav-1 leads to a significant reduction in intracellular Aβ levels., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression., (© 2024. The Author(s).)

Although implicated in unsuccessful treatment, psychomotor deficits and their neurobiological underpinnings in bipolar (BD) and unipolar (UD) depression remain poorly investigated. Here, we hypothesized that motor performance deficits in depressed patients would relate to basal functional coupling of the hand primary motor cortex (M1) and the posterior cingulate cortex (PCC) with the supplementary motor area (SMA). We performed a longitudinal, naturalistic study in BD, UD and matched healthy controls comprising of two resting-state functional MRI measurements five weeks apart and accompanying assessments of motor performance using a finger tapping task (FTT). A subject-specific seed-based analysis describing functional connectivity between PCC-SMA as well as M1-SMA was conducted. The basal relationships with motor performance were investigated using linear regression models and all measures were compared across groups. Performance in FTT was impaired in BD in comparison to HC in both sessions. Behavioral performance across groups correlated significantly with resting state functional coupling of PCC-SMA, but not of M1-SMA regions. This relationship was partially reflected in a reduced PCC-SMA connectivity in BD vs HC in the second session. Exploratory evaluation of large-scale networks coupling (SMN-DMN) exhibited no correlation to motor performance. Our results shed new light on the association between the degree of disruption in the SMA-PCC anticorrelation and the level of motor impairment in BD., (© 2023. The Author(s).)

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects., (© 2024. The Author(s).)

Background: Major depressive disorder [MDD] is expected to be the leading cause of overall global burden of disease by the year 2030 [WHO]. Non-response to first line pharmacological and psychotherapeutic antidepressive treatments is substantial, with treatment-resistant depression [TRD] affecting approximately one third of depressed patients. There is an urgent need for rapid acting and effective treatments in this population. Repetitive Transcranial Magnetic Stimulation [rTMS] is an non-invasive treatment option for patients with MDD or TRD. Recent studies have proposed new paradigms of TMS, one paradigm is accelerated intermittent Theta Burst Stimulation [aiTBS]., Objective: This systematic review assesses the efficacy, safety and tolerability of aiTBS in patients with MDD., Methods: This review was registered with PROSPERO [ID number: 366556]. A systematic literature review was performed using Pubmed, Web of Science and PsycINFO. Case reports/series, open-label and randomized controlled trials [RCTs] were eligible for inclusion if they met the following criteria; full text publication available in English describing a form of aiTBS for MDD or TRD. aiTBS was defined as at least three iTBS treatments sessions per day, during at least four days for one week., Results: 32 studies were identified describing aiTBS in MDD, 13 studies described overlapping samples. Six articles from five unique studies met eligibility criteria; two open-label studies and three RCTs [two double blind and one quadruple blind]. Response rates directly after treatment ranged from 20.0% to 86.4% and remission rates ranged from 10.0 to 86.4%. Four weeks after treatment response rates ranged from 0.0% to 66.7% and remission rates ranged from 0.0% to 57.1%. Three articles described a significant reduction in suicidality scores. aiTBS was well tolerated and safe, with no serious adverse events reported., Conclusions: aiTBS is a promising form of non-invasive brain stimulation [NIBS] with rapid antidepressant and antisuicidal effects in MDD. Additionally, aiTBS was well tolerated and safe. However, the included studies had small samples sizes and differed in frequency, intersession interval, neuro localization and stimulation intensity. Replication studies and larger RCTs are warranted to establish efficacy, safety and long term effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) has gained considerable importance in the treatment of neuropsychiatric disorders, including major depression. However, it is not yet understood how rTMS alters brain's functional connectivity. Here we report changes in functional connectivity captured by resting state functional magnetic resonance imaging (rsfMRI) within the first hour after 10 Hz rTMS. We apply subject-specific parcellation schemes to detect changes (1) in network nodes, where the strongest functional connectivity of regions is observed, and (2) in network boundaries, where functional transitions between regions occur. We use support vector machine (SVM), a widely used machine learning algorithm that is robust and effective, for the classification and characterization of time intervals of changes in node and boundary maps. Our results reveal that changes in connectivity at the boundaries are slower and more complex than in those observed in the nodes, but of similar magnitude according to accuracy confidence intervals. These results were strongest in the posterior cingulate cortex and precuneus. As network boundaries are indeed under-investigated in comparison to nodes in connectomics research, our results highlight their contribution to functional adjustments to rTMS., (© 2023. Springer Nature Limited.)

We aimed to systematically evaluate the clinical efficacy and safety of accelerated intermittent theta burst stimulation (aiTBS) for patients with major depressive disorder (MDD) or bipolar depression (BD). A random-effects model was adopted to analyze the primary and secondary outcomes using the Review Manager, Version 5.3 software. This meta-analysis (MA) identified five double-blind randomized controlled trials (RCTs) comprising 239 MDD or BD patients with a major depressive episode. Active aiTBS overperformed sham stimulation in the study-defined response. This MA found preliminary evidence that active aiTBS resulted in a greater response in treating major depressive episodes in MDD or BD patients than sham stimulation., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in conducting this study or preparing the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is a very prevalent mental disorder that imposes an enormous burden on individuals, society, and health care systems. Most patients benefit from commonly used treatment methods such as pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), and repetitive transcranial magnetic stimulation (rTMS). However, the clinical decision on which treatment method to use remains generally informed and the individual clinical response is difficult to predict. Most likely, a combination of neural variability and heterogeneity in MDD still impedes a full understanding of the disorder, as well as influences treatment success in many cases. With the help of neuroimaging methods like functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the brain can be understood as a modular set of functional and structural networks. In recent years, many studies have investigated baseline connectivity biomarkers of treatment response and the connectivity changes after successful treatment. Here, we systematically review the literature and summarize findings from longitudinal interventional studies investigating the functional and structural connectivity in MDD. By compiling and discussing these findings, we recommend the scientific and clinical community to deepen the systematization of findings to pave the way for future systems neuroscience roadmaps that include brain connectivity parameters as a possible precision component of the clinical evaluation and therapeutic decision., (© 2023. The Author(s).)

Quantifying pathology-related patterns in patient data with pattern expression score (PES) is a standard approach in medical image analysis. In order to estimate the PES error, we here propose to express the uncertainty contained in read-out patterns in terms of the expected squared Euclidean distance between the read-out pattern and the unknown "true" pattern (squared standard error of the read-out pattern, SE 2 ). Using SE 2 , we predicted and optimized the net benefit (NBe) of the recently suggested method controls-based denoising (CODE) by weighting patterns of nonpathological variance (NPV). Multi-center MRI (1192 patients with various neurodegenerative and neuropsychiatric diseases, 1832 healthy controls) were analysed with voxel-based morphometry. For each pathology, accounting for SE 2 , NBe correctly predicted classification improvement and allowed to optimize NPV pattern weights. Using these weights, CODE improved classification performances in all but one analyses, for example, for prediction of conversion to Alzheimer's disease (AUC 0.81 vs. 0.75, p = .01), diagnosis of autism (AUC 0.66 vs. 0.60, p < .001), and of major depressive disorder (AUC 0.62 vs. 0.50, p = .03). We conclude that the degree of uncertainty in a read-out pattern should generally be reported in PES-based analyses and suggest using weighted CODE as a complement to PES-based analyses., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia., Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior., Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments., Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objectives: Suicidality is a serious public health problem and is closely associated with the severity of depression. In this work, we examined the effects of accelerated intermittent theta burst stimulation (iTBS) on suicidal status, risk factors for suicide, and severity of depressive symptoms in subjects with major depressive disorder (MDD)., Methods: We present data from a quadruple-blind (patient, care provider, investigator, rater) sham-controlled crossover randomized clinical trial. During a 6-week observation period, each participant underwent 2 weeks of stimulation - each week with 20 sessions of active or sham iTBS. A suicide score was created using a composite of individual items from Montgomery-Åsberg Depression Scale (MADRS), Hamilton Depression Scale, and Beck Depression Inventory. The severity of depression was determined by MADRS total scores. In addition, we used demographic and Columbia Suicidality Rating Scale information to assess suicide risk., Results: Among 81 participants, we observed a significant reduction in suicidality and this change was positively correlated with a change in depressive symptoms. A significant difference between active and sham iTBS provided evidence for antidepressant effects. Higher changes in levels of anxiety and impulsiviness also correlated with larger changes in suicidality., Conclusions: As neither suicide nor other serious adverse events were evidenced, this intervention was a safe and viable procedure to reduce suicidality and severity of depressive symptoms. Moreover, we identified more pronounced anti-suicidal effects in those with higher risk profiles. Unlike MADRS, composite suicidal scores did not provide evidence of an effect between stimulation conditions in this crossover design study. Even so, based on our promising results, parallel and larger studies could contribute to a better characterization of the anti-suicidal placebo effect and the benefit of using iTBS against suicidal symptoms., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

The exploration of the spatial relationship between gene expression profiles and task-evoked response patterns known to be altered in neuropsychiatric disorders, for example depression, can guide the development of more targeted therapies. Here, we estimated the correlation between human transcriptome data and two different brain activation maps measured with functional magnetic resonance imaging (fMRI) in healthy subjects. Whole-brain activation patterns evoked during an emotional face recognition task were associated with topological mRNA expression of genes involved in cellular transport. In contrast, fMRI activation patterns related to the acceptance of monetary rewards were associated with genes implicated in cellular localization processes, metabolism, translation, and synapse regulation. An overlap of these genes with risk genes from major depressive disorder genome-wide association studies revealed the involvement of the master regulators TCF4 and PAX6 in emotion and reward processing. Overall, the identification of stable relationships between spatial gene expression profiles and fMRI data may reshape the prospects for imaging transcriptomics studies., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Importance: Insufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD., Objective: To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD., Design, Setting, and Participants: The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020., Interventions: Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks., Main Outcomes and Measures: Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales., Results: Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes., Conclusions and Relevance: In this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD., Trial Registration: EU Clinical Trials Register Number: EudraCT 2015-001456-29.

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Brain structural abnormalities and low educational attainment are consistently associated with major depressive disorder (MDD), yet there has been little research investigating the complex interaction of these factors. Brain structural alterations may represent a vulnerability or differential susceptibility marker, and in the context of low educational attainment, predict MDD. We tested this moderation model in a large multisite sample of 1958 adults with MDD and 2921 controls (aged 18 to 86) from the ENIGMA MDD working group. Using generalized linear mixed models and within-sample split-half replication, we tested whether brain structure interacted with educational attainment to predict MDD status. Analyses revealed that cortical thickness in a number of occipital, parietal, and frontal regions significantly interacted with education to predict MDD. For the majority of regions, models suggested a differential susceptibility effect, whereby thicker cortex was more likely to predict MDD in individuals with low educational attainment, but less likely to predict MDD in individuals with high educational attainment. Findings suggest that greater thickness of brain regions subserving visuomotor and social-cognitive functions confers susceptibility to MDD, dependent on level of educational attainment. Longitudinal work, however, is ultimately needed to establish whether cortical thickness represents a preexisting susceptibility marker. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior., Methods: Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects., Results: We identified 25 regions of interest with statistically significant (false discovery rate < .05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe., Conclusions: This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases. Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups. Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode. Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hansen, Singh, Bartels, Brosseron, Buerger, Cetindag, Dobisch, Dechent, Ertl-Wagner, Fliessbach, Haynes, Heneka, Janowitz, Kilimann, Laske, Metzger, Munk, Peters, Priller, Roy, Scheffler, Schneider, Spottke, Spruth, Teipel, Tscheuschler, Vukovich, Wiltfang, Duezel, Jessen and Goya-Maldonado.)

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., Design, Setting, and Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., Main Outcomes and Measures: Interregional profiles of group difference in cortical thickness between cases and controls., Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., Conclusions and Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.

Understanding the mechanisms by which intermittent theta burst stimulation (iTBS) protocols exert changes in the default-mode network (DMN) is paramount to develop therapeutically more effective approaches in the future. While a full session (3000 pulses) of 10 Hz repetitive transcranial magnetic stimulation (HF-rTMS) reduces the functional connectivity (FC) of the DMN and the subgenual anterior cingulate cortex, the current understanding of the effects of a single session of iTBS on the DMN in healthy subjects is limited. Here, we use a previously validated target selection approach for an unprecedented investigation into the effects of a single session (1800 pulses) of iTBS over the DMN in healthy controls. Twenty-six healthy subjects participated in a double-blind, crossover, sham-controlled study. After iTBS to the personalized left dorsolateral prefrontal cortex (DLPFC) targets, we investigated the time lapse of effects in the DMN and its relationship to the harm avoidance (HA) personality trait measure (Temperament and Character Inventory/TCI). Approximately 25-30 min after stimulation, we observed reduced FC between the DMN and the rostral and dorsal anterior cingulate cortex (dACC). About 45 min after stimulation the FC of rostral and dACC strongly decreased further, as did the FC of right anterior insula (AI) with the DMN. Also, we report a positive correlation between the FC decrease in the rostral ACC and the HA domain of TCI, indicating that the HA scores can potentially predict iTBS response. Overall, our results show the time lapse by which iTBS at left-DLPFC targets reduces the FC between DMN and the dACC and right AI, regions typically described as nodes of the salience network.

Noninvasive neuromodulation, including repetitive trans-cranial magnetic stimulation (rTMS) and direct current stimulation (tDCS), provides researchers and health care professionals with the ability to gain unique insights into brain functions and treat several neurological and psychiatric conditions. Undeniably, the number of published research and clinical papers on this topic is increasing exponentially. In parallel, several methodological and scientific caveats have emerged in the transcranial stimulation field; these include less robust and reliable effects as well as contradictory clinical findings. These inconsistencies are maybe due to the fact that research exploring the relationship between the methodological aspects and clinical efficacy of rTMS and tDCS is far from conclusive. Hence, additional work is needed to understand the mechanisms underlying the effects of magnetic stimulation and low-intensity transcranial electrical stimulation (TES) in order to optimize dosing, methodological designs, and safety aspects., (© 2019 S. Karger AG, Basel.)

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects., Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T 1 -weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1., Results: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset., Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

High frequency repetitive transcranial magnetic stimulation (HF-rTMS) delivered to the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment option for treatment resistant depression. However, the underlying mechanisms of a full session of HF-rTMS in healthy volunteers have not yet been described. Here we investigated, with a personalized selection of DLPFC stimulation sites, the effects driven by HF-rTMS in healthy volunteers (n = 23) over the default mode network (DMN) in multiple time windows. After a complete 10 Hz rTMS (3000 pulses) session, we observe a decrease of functional connectivity between the DMN and the subgenual Anterior Cingulate Cortex (sgACC), as well as the ventral striatum (vStr). A negative correlation between the magnitude of this decrease in the right sgACC and the harm avoidance domain measure from the Temperament and Character Inventory was observed. Moreover, we identify that coupling strength of right vStr with the DMN post-stimulation was proportional to a decrease in self-reports of negative mood from the Positive and Negative Affect Schedule. This shows HF-rTMS attenuates perception of negative mood in healthy recipients in agreement with the expected effects in patients. Our study, by using a personalized selection of DLPFC stimulation sites, contributes understanding the effects of a full session of rTMS approved for clinical use in depression over related brain regions in healthy volunteers.

A growing body of evidence indicates that the neuropeptide oxytocin (OT) alters the neural correlates of socioemotional and salience processing. Yet the effects of OT over important large-scale networks involved in these processes, such as the default mode (DM), ventral attention (VA), and cingulo-opercular (CO) networks, remain unknown. Therefore, we conducted a placebo-controlled crossover study with intranasal 24 IU OT in 38 healthy male subjects using a resting-state functional magnetic resonance imaging paradigm to investigate its impact over these three networks candidates. To understand the underlying mechanisms of the neuropeptide, we compared the intranetwork connectivity for each network candidate and also the internetwork connectivity across all networks between both treatment conditions. Based on the relevance of interindividual factors for OT effects, we correlated individual network changes with behavioral performance in a decision-making task and with impulsivity scores. Our results show that OT mainly alters connectivity in the VA, on one side reducing the coupling to regions that typically form the nodes of DM, an introspective and self-referential network, and on the other side increasing the coupling to the edges of the CO, which is involved in salience processing. The results of the internetwork analyses confirmed the specificity of the OT effects. Indeed, we observed significant correlations with the erroneous performance during decision-making but not with the obtained impulsivity scores. Overall, our data support that the modulation of functional connectivity within the VA is a basic mechanism by which OT directs attentional resources from internal to external cues, preparing the brain for context-dependent salience processing.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN (P < 0.001), and in particular from the left SMG (P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG (P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG (P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG (P = 0.005) and to the negative symptom score on the PANSS scale (P = 0.001, r = -0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741-1750, 2017. © 2017 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Major depressive disorder (MDD) involves impairment in cognitive and interpersonal functioning. The right temporoparietal junction (RTPJ) is a key brain region subserving cognitive-attentional and social processes. Yet, findings on the involvement of the RTPJ in the pathophysiology of MDD have so far been controversial. Recent connectivity-based parcellation data revealed a topofunctional dualism within the RTPJ, linking its anterior and posterior part (aRTPJ/pRTPJ) to antagonistic brain networks for attentional and social processing, respectively. Comparing functional resting-state connectivity of the aRTPJ and pRTPJ in 72 MDD patients and 76 well-matched healthy controls, we found a seed (aRTPJ/pRTPJ) × diagnosis (MDD/controls) interaction in functional connectivity for eight regions. Employing meta-data from a large-scale neuroimaging database, functional characterization of these regions exhibiting differentially altered connectivity with the aRTPJ/pRTPJ revealed associations with cognitive (dorsolateral prefrontal cortex, parahippocampus) and behavioral (posterior medial frontal cortex) control, visuospatial processing (dorsal visual cortex), reward (subgenual anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex), as well as memory retrieval and social cognition (precuneus). These findings suggest that an imbalance in connectivity of subregions, rather than disturbed connectivity of the RTPJ as a whole, characterizes the connectional disruption of the RTPJ in MDD. This imbalance may account for key symptoms of MDD in cognitive, emotional, and social domains. Hum Brain Mapp 37:2931-2942, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Cyclic AMP response element-binding protein (CREB) contributes to adaptation of mesocorticolimbic networks by modulating activity-regulated transcription and plasticity in neurons. Activity or expression changes of CREB in the nucleus accumbens (NAc) and orbital frontal cortex (OFC) interact with behavioral changes during reward-motivated learning. However, these findings from animal models have not been evaluated in humans. We tested whether CREB1 genotypes affect reward-motivated decisions and related brain activation, using BOLD fMRI in 224 young and healthy participants. More specifically, participants needed to adapt their decision to either pursue or resist immediate rewards to optimize the reward outcome. We found significant CREB1 genotype effects on choices to pursue increases of the reward outcome and on BOLD signal in the NAc, OFC, insula cortex, cingulate gyrus, hippocampus, amygdala, and precuneus during these decisions in comparison with those decisions avoiding total reward loss. Our results suggest that CREB1 genotype effects in these regions could contribute to individual differences in reward- and associative memory-based decision-making., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Misdiagnosing bipolar depression can lead to very deleterious consequences of mistreatment. Although depressive symptoms may be similarly expressed in unipolar and bipolar disorder, changes in specific brain networks could be very distinct, being therefore informative markers for the differential diagnosis. We aimed to characterize specific alterations in candidate large-scale networks (frontoparietal, cingulo-opercular, and default mode) in symptomatic unipolar and bipolar patients using resting state fMRI, a cognitively low demanding paradigm ideal to investigate patients., Methods: Networks were selected after independent component analysis, compared across 40 patients acutely depressed (20 unipolar, 20 bipolar), and 20 controls well-matched for age, gender, and education levels, and alterations were correlated to clinical parameters., Results: Despite comparable symptoms, patient groups were robustly differentiated by large-scale network alterations. Differences were driven in bipolar patients by increased functional connectivity in the frontoparietal network, a central executive and externally-oriented network. Conversely, unipolar patients presented increased functional connectivity in the default mode network, an introspective and self-referential network, as much as reduced connectivity of the cingulo-opercular network to default mode regions, a network involved in detecting the need to switch between internally and externally oriented demands. These findings were mostly unaffected by current medication, comorbidity, and structural changes. Moreover, network alterations in unipolar patients were significantly correlated to the number of depressive episodes., Conclusion: Unipolar and bipolar groups displaying similar symptomatology could be clearly distinguished by characteristic changes in large-scale networks, encouraging further investigation of network fingerprints for clinical use. Hum Brain Mapp 37:808-818, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Schizophrenia and depression are prevalent psychiatric disorders, but their underlying neural bases remains poorly understood. Neuroimaging evidence has pointed towards the relevance of functional connectivity aberrations in default mode network (DMN) hubs, dorso-medial prefrontal cortex and precuneus, in both disorders, but commonalities and differences in resting state functional connectivity of those two regions across disorders has not been formally assessed. Here, we took a transdiagnostic approach to investigate resting state functional connectivity of those two regions in 75 patients with schizophrenia and 82 controls from 4 scanning sites and 102 patients with depression and 106 controls from 3 sites. Our results demonstrate common dysconnectivity patterns as indexed by a significant reduction of functional connectivity between precuneus and bilateral superior parietal lobe in schizophrenia and depression. Furthermore, our findings highlight diagnosis-specific connectivity reductions of the parietal operculum in schizophrenia relative to depression. In light of evidence that points towards the importance of the DMN for social cognitive abilities and well documented impairments of social interaction in both patient groups, it is conceivable that the observed transdiagnostic connectivity alterations may contribute to interpersonal difficulties, but this could not be assessed directly in our study as measures of social behavior were not available. Given the operculum's role in somatosensory integration, diagnosis-specific connectivity reductions may indicate a pathophysiological mechanism for basic self-disturbances that is characteristic of schizophrenia, but not depression.

Depression is a debilitating psychiatric disorder characterized among other aspects by the inability to properly experience or respond to reward. However, it remains unclear whether patients with depression present impaired reward system due to abnormal modulatory mechanisms. We investigated the activation of the nucleus accumbens (NAcc), a crucial region involved in reward processing, with functional magnetic resonance imaging using the desire-reason-dilemma paradigm. This task allows tracking the activity of the NAcc during the acceptance or the rejection of previously conditioned reward stimuli. Patients were assigned into subgroups of lower (LA) or higher (HA) NAcc activation according to beta weights. LA patients presented significant hypoactivation in the ventral tegmental area in addition to bilateral ventral striatum, confirming impairments in the bottom-up input to the NAcc. Conversely, HA patients presented significant hyperactivation in prefrontal areas such as the rostral anterior cingulate cortex and the anterior ventral prefrontal cortex in addition to bilateral ventral striatum, suggesting disturbances in the top-down regulation of the NAcc. Demographic and clinical differences explaining the abnormal co-activations of midbrain and prefrontal regions were not identified. Therefore, we provide evidence for dysfunctional bottom-up processing in one potential neurobiological subtype of depression (LA) and dysfunctional top-down modulation in another subtype (HA). We suggest that the midbrain and prefrontal regions are more specific pathophysiological substrates for each depression subtype. Above all, our results encourage the segregation of patients by similar dysfunctional mechanisms of the dopaminergic system, which would finally contribute to disentangle more specific pathogeneses and guide the development of more personalized targets for future therapies.

Background: Overnight memory consolidation is disturbed in both depression and schizophrenia, creating an ideal situation to investigate the mechanisms underlying sleep-related consolidation and to distinguish disease-specific processes from common elements in their pathophysiology., Methods: We investigated patients with depression and schizophrenia, as well as healthy control subjects (each n = 16), under a motor memory consolidation protocol with functional magnetic resonance imaging and polysomnography., Results: In a sequential finger-tapping task associated with the degree of hippocampal-prefrontal cortex functional connectivity during the task, significantly less overnight improvement was identified as a common deficit in both patient groups. A task-related overnight decrease in activation of the basal ganglia was observed in control subjects and schizophrenia patients; in contrast, patients with depression showed an increase. During the task, schizophrenia patients, in comparison with control subjects, additionally recruited adjacent cortical areas, which showed a decrease in functional magnetic resonance imaging activation overnight and were related to disease severity. Effective connectivity analyses revealed that the hippocampus was functionally connected to the motor task network, and the cerebellum decoupled from this network overnight., Conclusions: While both patient groups showed similar deficits in consolidation associated with hippocampal-prefrontal cortex connectivity, other activity patterns more specific for disease pathology differed., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)