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Objective: Evaluation of acute soft tissue injury of the temporomandibular joint (TMJ) with type I–VI fractures immediately after trauma and investigation of the longitudinal evolution including response to conservative treatment using MRI. Methods: The joints of 24 patients with 33 condylar fractures (15 unilateral, nine bilateral) were imaged on a 1 Tesla MR system within the first 24 h post-trauma. 12 of these patients with 16 condylar fractures (eight unilateral, four bilateral) were clinically re-evaluated using MRI after 3 months of closed treatment. The position, morphology, and signal intensities of the disc, capsule, retrodiscal tissue, and osseous structures were documented. Results: In the acute phase, disc displacements (DDs) were diagnosed in 8 out of 33 joints with fracture, including posterior DDs in two joints and tears of the inferior retrodiscal lamina in 11 joints. The follow-up MRI in 12 patients revealed new DD in four joints on the fractured side (FS) including a posterior DD and an increased degree of displacement, and new DDs in two joints in the non-fractured side (NFS). Conclusion: Preexisting and traumatic DD and soft tissue injuries are frequent findings in patients with condylar fracture. Independent of the degree of trauma, condylar fractures may determine the subsequent development of DD on both FS and NFS. Early MR imaging may help initiate well-directed specific measures for better outcomes in the acutely injured TMJ.

Exact histological clot composition remains unknown. The purpose of this study was to identify the best imaging variables to be extrapolated on clot composition and clarify variability in the imaging of thrombi by non-contrast CT. Using a CT-phantom and covering a wide range of histologies, we analyzed 80 clot analogs with respect to X-ray attenuation at 24 and 48 h after production. The mean, maximum, and minimum HU values for the axial and coronal reconstructions were recorded. Each thrombus underwent a corresponding histological analysis, together with a laboratory analysis of water and iron contents. Decision trees, a type of supervised machine learning, were used to select the primary variable altering attenuation and the best parameter for predicting histology. The decision trees selected red blood cells (RBCs) for correlation with all attenuation parameters (p

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = −0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, pspin = 0.006), BD (rho = −0.672, pspin = 0.009), and MDD (rho = −0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

BackgroundElectroconvulsive therapy (ECT) is a fast-acting intervention for major depressive disorder. Previous studies indicated neurotrophic effects following ECT that might contribute to changes in white matter brain structure. We investigated the influence of ECT in a non-randomized prospective study focusing on white matter changes over time.MethodsTwenty-nine severely depressed patients receiving ECT in addition to inpatient treatment, 69 severely depressed patients with inpatient treatment (NON-ECT) and 52 healthy controls (HC) took part in a non-randomized prospective study. Participants were scanned twice, approximately 6 weeks apart, using diffusion tensor imaging, applying tract-based spatial statistics. Additional correlational analyses were conducted in the ECT subsample to investigate the effects of seizure duration and therapeutic response.ResultsMean diffusivity (MD) increased after ECT in the right hemisphere, which was an ECT-group-specific effect. Seizure duration was associated with decreased fractional anisotropy (FA) following ECT. Longitudinal changes in ECT were not associated with therapy response. However, within the ECT group only, baseline FA was positively and MD negatively associated with post-ECT symptomatology.ConclusionOur data suggest that ECT changes white matter integrity, possibly reflecting increased permeability of the blood–brain barrier, resulting in disturbed communication of fibers. Further, baseline diffusion metrics were associated with therapy response. Coherent fiber structure could be a prerequisite for a generalized seizure and inhibitory brain signaling necessary to successfully inhibit increased seizure activity.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3,004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r=.07, pFDR=.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r=.33, pspin=.01), but not BD (r=.19, pspin=.16) or MDD (r=-.22, pspin=.10). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho=-.65, pspin=.01), BD (rho=-.63, pspin=.01), and MDD (rho=-.69, pspin=.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Novelty seeking (NS) has previously been identified as a personality trait that is associated with elevated body mass index (BMI) and obesity. Of note, both obesity and reduced impulse control - a core feature of NS - have previously been associated with grey matter volume (GMV) reductions in the orbitofrontal cortex (OFC). Yet, it remains unknown, if body weight-related grey matter decline in the OFC might be explained by higher levels of NS. To address this question, we studied associations between NS, BMI and brain structure in 355 healthy subjects. Brain images were pre-processed using voxel-based morphometry (VBM). BMI was calculated from self-reported height and weight. The Tridimensional Personality Questionnaire (TPQ) was used to assess NS. NS and BMI were associated positively (r = .137, p = .01) with NS being a significant predictor of BMI (B = 0.172; SE B = 0.05; s = 0.184; p = 0.001). Significant associations between BMI and GMV specifically in the OFC (x = -44, y = 56, z = -2, t(350) = 4.34, k = 5, pFWE = 0.011) did not uphold when correcting for NS in the model. In turn, a significant negative association between NS and OFC GMV was found independent of BMI (x = -2, y = 48, z = -10, t(349) = 4.42, k = 88, pFWE = 0.008). Body mass-related grey matter decrease outside the OFC could not be attributed to NS. Our results suggest that body-weight-related orbitofrontal grey matter reduction can at least partly be linked to higher levels of NS. Given the pivotal role of the OFC in overweight as well as cognitive domains such as impulse inhibition, executive control and reward processing, its association with NS seems to provide a tenable neurobiological correlate for future research.

BackgroundChildhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5-HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5-HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample.

Objectives Combinations of resting-state fMRI and machine-learning techniques are increasingly employed to develop diagnostic models for mental disorders. However, little is known about the neurobiological heterogeneity of depression and diagnostic machine learning has mainly been tested in homogeneous samples. Our main objective was to explore the inherent structure of a diverse unipolar depression sample. The secondary objective was to assess, if such information can improve diagnostic classification. Materials and methods We analyzed data from 360 patients with unipolar depression and 360 non-depressed population controls, who were subdivided into two independent subsets. Cluster analyses (unsupervised learning) of functional connectivity were used to generate hypotheses about potential patient subgroups from the first subset. The relationship of clusters with demographical and clinical measures was assessed. Subsequently, diagnostic classifiers (supervised learning), which incorporated information about these putative depression subgroups, were trained. Results Exploratory cluster analyses revealed two weakly separable subgroups of depressed patients. These subgroups differed in the average duration of depression and in the proportion of patients with concurrently severe depression and anxiety symptoms. The diagnostic classification models performed at chance level. Limitations It remains unresolved, if subgroups represent distinct biological subtypes, variability of continuous clinical variables or in part an overfitting of sparsely structured data. Conclusions Functional connectivity in unipolar depression is associated with general disease effects. Cluster analyses provide hypotheses about potential depression subtypes. Diagnostic models did not benefit from this additional information regarding heterogeneity.

Adolescent-onset major depressive disorder (MDD) is associated with an increased risk of recurrent depressive episodes, suicidal behaviors, and psychiatric morbidity throughout the lifespan. The objective of the present study was to investigate brain structural and functional changes in adolescent patients with MDD. Furthermore, we aimed to clarify the influence of early-life stress on brain function and structure. The study investigated adolescent patients with severe MDD (n=20, mean age=16.0, range=15-18 years) and a control sample of matched healthy adolescents (n=21, mean age=16.6, range=15-18 years). Functional MRI data were obtained using a face-matching paradigm to investigate emotion processing. Structural MRI data were analyzed using voxel-based morphometry (VBM). In line with previous studies on adult MDD, adolescent patients showed elevated amygdala activity to negative and reduced amygdala activity to positive emotional stimuli. Furthermore, MDD patients showed smaller hippocampal volumes compared to healthy adolescents. Higher levels of childhood maltreatment were associated with smaller hippocampal volumes in both depressed patients and healthy controls, whereby no associations between amygdala reactivity and childhood maltreatment were found. Our results suggest that hippocampal alterations in youth MDD patients may at least partly be traced back to higher occurrence of early-life adverse experiences. Regarding the strong morphometric impact of childhood maltreatment and its distinctly elevated prevalence in MDD populations, this study provides an alternative explanation for frequently observed limbic structural abnormalities in depressed patients.

Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Distinguishing bipolar disorder from major depressive disorder is a major challenge in psychiatric treatment. Consequently, there has been growing interest in identifying neuronal biomarkers of disorder-specific pathophysiological processes to differentiate affective disorders. Thirty-six depressed bipolar patients, 36 depressed unipolar patients, and 36 matched healthy controls (HCs) participated in an fMRI experiment. Emotional faces served as stimuli in a matching task. We investigated neural activation towards angry, fearful, and happy faces focusing on prototypical regions related to emotion processing, ie, the amygdala and the anterior cingulate gyrus (ACG). Furthermore, we employed a whole-brain and a multivariate pattern classification analysis. Unipolar patients showed abnormally reduced ACG activation toward happy and fearful faces compared with bipolar patients and HCs respectively. Furthermore, the whole-brain analysis revealed significantly increased activation in bipolar patients compared with unipolar patients in the fearful condition in the right frontal and parietal cortex. Moreover, the multivariate pattern classification analysis yielded significant classification rates of up to 72% based on ACG activation elicited by fearful faces. Our results question the rather ‘amygdalocentric' neurobiological models of mood disorders. We observed patterns of abnormally reduced ventral and supragenual ACG activation, potentially indicating impaired bottom-up emotion processing and automatic emotion regulation specifically in unipolar but not in bipolar individuals.

Objective The absence of neurobiological diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We investigated if changes in fractional anisotropy (FA) could help to differentiate BD from UD in the state of depression. Methods Using diffusion tensor imaging (DTI) we employed a voxel-based analysis approach to examine fractional anisotropy (FA) in 86 patients experiencing an acute major depressive episode according to DSM-IV (N=39 BD, mean age 39.2 years; N=43 UD, mean age 39.0 years), and 42 healthy controls (HC, mean age 36.1 years). The groups did not differ in sex, age or total education time. FA was investigated in white matter (FA >.2) and hypothesis-driven anatomically defined tracts (region-of-interest [ROI] analysis). Additionally, an exploratory gray matter FA analysis was performed. Results White matter analysis showed decreased FA in the right corticospinal tract in UD vs HC and in the right corticospinal tract/superior longitudinal fascicle in BD vs HC and also in BD vs UD. ROI analysis revealed decreased FA in BD vs UD in the corpus callosum and in the cingulum. Gray matter exploratory analysis revealed decreased FA in the left middle frontal gyrus and in the right inferior frontal gyrus in UD vs HC, and in the left superior medial gyrus in BD vs HC. Conclusion This is one of very few studies directly showing differences in FA between BD and UD. Gray matter FA changes in prefrontal areas might be precursors for future prefrontal gray matter abnormalities in these disorders.

In small, selected samples, an approach combining resting-state functional connectivity MRI and multivariate pattern analysis has been able to successfully classify patients diagnosed with unipolar depression. Purposes of this investigation were to assess the generalizability of this approach to a large clinically more realistic sample and secondarily to assess the replicability of previously reported methodological feasibility in a more homogeneous subgroup with pronounced depressive symptoms. Two independent subsets were drawn from the depression and control cohorts of the BiDirect study, each with 180 patients with and 180 controls without depression. Functional connectivity either among regions covering the gray matter or selected regions with known alterations in depression was assessed by resting-state fMRI. Support vector machines with and without automated feature selection were used to train classifiers differentiating between individual patients and controls in the entire first subset as well as in the subgroup. Model parameters were explored systematically. The second independent subset was used for validation of successful models. Classification accuracies in the large, heterogeneous sample ranged from 45.0 to 56.1% (chance level 50.0%). In the subgroup with higher depression severity, three out of 90 models performed significantly above chance (60.8-61.7% at independent validation). In conclusion, common classification methods previously successful in small homogenous depression samples do not immediately translate to a more realistic population. Future research to develop diagnostic classification approaches in depression should focus on more specific clinical questions and consider heterogeneity, including symptom severity as an important factor.

Attention-deficit/hyperactivity disorder (ADHD) is closely linked to the dysregulation of dopaminergic and noradrenergic neurotransmission in the fronto-striatal neural network, including the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). Additionally, increasing evidence supports the involvement of the glutamatergic system in the pathophysiology of ADHD. Impulsivity, a core symptom in patients with ADHD, has been repeatedly associated with glutamatergic neurotransmission, and pharmacological treatment of ADHD has been shown to reduce glutamate levels in the prefrontal cortex.We investigated glutamate levels in the ACC and the DLPFC in 30 adults with ADHD and 30 healthy controls using single-voxel proton magnetic resonance spectroscopy on a 3T scanner.The ADHD group showed a significant increase in glutamate in the ACC compared to controls, no significant differences in metabolites were observed in the DLPFC. Overall, glutamate levels in the ACC were positively correlated with ADHD symptomatology, especially hyperactivity and impulsivity symptoms.Increased levels of glutamate in the ACC, which were positively correlated with hyperactivity and impulsivity, support the hypothesis that dysfunctional glutamatergic neurotransmission is at least partially responsible for ADHD symptomatology. Modulation of glutamatergic neurotransmission might therefore be a promising avenue for future pharmacological interventions.

Background Regulation of emotional arousal is a relevant factor for mental health. The investigation of neural underpinnings of regulation styles in healthy individuals may provide important insights regarding potential risk factors. To fill the gap of structural correlates of regulation styles and to expand previous results, we focused on the association between brain structure, neural responsiveness and vigilant/avoidant regulation style. Methods In n = 302 healthy individuals regulation style was assessed with the Mainz Coping Inventory (MCI). Participants underwent structural and functional MRI during an emotion-processing paradigm. Structural MRI (voxel-based morphometry) and functional MRI were analysed in two regions of interest (amygdala and anterior cingulate cortex [ACC]). Results Regulation styles did not show an association with brain structure after correction for gender, age, trait anxiety, depressive symptoms. During emotion processing, a vigilant regulation style was negatively associated with ACC activation. Limitations The cross-sectional study in a non-pathological sample is not adequate to unveil causalities or draw conclusions regarding prevention interventions. Conclusion Regulation styles are associated with specific neural activation patterns. The association of a high-vigilant regulation style and low ACC activation during emotion processing in healthy participants might be a potential risk factor.

BACKGROUND: Cross-sectional studies have repeatedly shown impaired white matter integrity in patients with major depressive disorder. Longitudinal analyses are missing from the current research and are crucial to elucidating the impact of disease trajectories on white matter impairment in major depressive disorder. METHODS: Fifty-nine patients with major depressive disorder receiving inpatient treatment, as well as 49 healthy controls, took part in a prospective study. Participants were scanned twice (baseline and follow-up), approximately 2.25 years apart, using diffusion tensor imaging. We analyzed diffusion metrics using tract-based spatial statistics. RESULTS: At baseline, patients had higher mean diffusivity in a large bilateral frontal cluster comprising the body and genu of the corpus callosum, the anterior and superior corona radiata, and the superior longitudinal fasciculus. A significant group × time interaction revealed a decrease of mean diffusivity in patients with major depressive disorder over time, abolishing group differences at follow-up. This effect was observed irrespective of disease course in the follow-up period. LIMITATIONS: Analyzing the course of illness is challenging because of recollection biases in patients with major depressive disorder. CONCLUSION: This study reports follow-up diffusion tensor imaging data in patients with major depressive disorder after an acute depressive episode. We demonstrated impaired prefrontal white matter microstructure (higher mean diffusivity) at baseline in patients with major depressive disorder, which normalized at follow-up after 2 years, irrespective of disease course. This might have been due to a general treatment effect and might have reflected recovery of white matter integrity.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD);\ud however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical\ud heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with\ud BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered\ud individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean\ud fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and\ud meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD\ud compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and\ud cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to\ud higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities\ud in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD.\ud These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel-based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.

Background: Poor social relating is a prominent feature of schizophrenia. The amygdala has been suggested as an important node in social brain networks. Methods: By using structural magnetic resonance imaging, this study examined, for the first time, the relationship between amygdalar gray matter (GM) volume and social relating in 35 schizophrenia patients. Social anhedonia, interaction anxiety, extraversion, and sociable tendencies were assessed as indices of social relating. Results: A correlation between GM volume in the amygdala and enhanced social relating was revealed. Conclusion: These findings indicate that volumetric decreases in the amygdala are related to impoverished sociability in schizophrenia.

Introduction Since numerous studies have found that exposure to early life stress leads to increased peripheral inflammation and psychiatric disease, it is thought that peripheral immune activation precedes and possibly mediates the onset of stress-associated psychiatric disease. Despite early studies, IFNγ has received little attention relative to other inflammatory cytokines in the context of the pathophysiology of affective disorders. Neuroimaging endophenotypes have emerged recently as a promising means of elucidating these types of complex relationships including the modeling of the interaction between environmental factors and genetic predisposition. Here we investigate the GxE relationship between early-life stress and genetic variants of IFNγ on emotion processing. Methods To investigate the impact of the relationship between genetic variants of IFNγ (rs1861494, rs2069718, rs2430561) and early life stress on emotion processing, a sample of healthy adults ( n = 409) undergoing an emotional faces paradigm in an fMRI study were genotyped and analysed. Information on early life stress was obtained via Childhood Trauma Questionnaire (CTQ). Results A positive association between early life stress and amygdala reactivity was found. Specifically, the main effect of genotype of rs1861494 on amygdala reactivity indicates a higher neural response in C allele carriers compared to T homozygotes, while we did not find main effects of rs2069718 and rs2430561. Importantly, interaction analyses revealed a specific interaction between IFNγ genotype (rs1861494) and early life stress affecting amygdala reactivity to emotional faces, resulting from a positive association between CTQ scores and amygdala reactivity in C allele carriers while this association was absent in T homozygotes. Conclusions Our findings indicate that firstly the genetic variant of IFNγ (rs1861494) is involved with the regulation of amygdala reactivity to emotional stimuli and secondly, that this genetic variant moderates effects of early life stress on emotion processing. These findings reiterate the importance that inflammatory genes play in the interaction with early life stress and the regulation of emotion processing.

Summary Background Childhood maltreatment is a leading environmental risk factor for an unfavourable course of disease in major depressive disorder. Both maltreatment and major depressive disorder are associated with similar brain structural alterations suggesting that brain structural changes could mediate the adverse influence of maltreatment on clinical outcome in major depressive disorder. However, longitudinal studies have not been able to confirm this hypothesis. We therefore aimed to clarify the relationship between childhood trauma, brain structural alterations, and depression relapse in a longitudinal design. Methods We recruited participants at the Department of Psychiatry, University of Munster, Germany, from the Munster Neuroimage Cohort for whom 2-year longitudinal clinical data were available. Baseline data acquisition comprised clinical assessments, structural MRI, and retrospective assessment of the extent of childhood maltreatment experiences using the Childhood Trauma Questionnaire. Clinical follow-up assessments were conducted in all participants 2 years after initial recruitment. Findings Initial recruitment was March 21, 2010–Jan 29, 2016; follow-up reassessment Sept 7, 2012–March 9, 2018. 110 patients with major depressive disorder participated in this study. 35 patients were relapse-free, whereas 75 patients had experienced depression relapse within the 2-year follow-up period. Childhood maltreatment was significantly associated with depression relapse during follow-up (odds ratio [OR] 1·035, 95% CI 1·001–1·070; p=0·045). Both previous childhood maltreatment experiences and future depression relapse were associated with reduced cortical surface area (OR 0·996, 95% CI 0·994–0·999; p=0·001), primarily in the right insula at baseline (r=−0·219, p=0·023). Insular surface area was shown to mediate the association between maltreatment and future depression relapse (indirect effect: coefficient 0·0128, SE 0·0081, 95% CI 0·0024–0·0333). Interpretation Early life stress has a detrimental effect on brain structure, which increases the risk of unfavourable disease courses in major depression. Clinical and translational research should explore the role of childhood maltreatment as causing a potential clinically and biologically distinct subtype of major depressive disorder. Funding The German Research Foundation, the Interdisciplinary Centre for Clinical Research, and the Deanery of the Medical Faculty of the University of Munster.

Obesity is a clinically relevant and highly prevalent somatic comorbidity of major depression (MDD). Genetic predisposition and history of childhood trauma have both independently been demonstrated to act as risk factors for obesity and to be associated with alterations in reward related brain structure and function. We therefore aimed to investigate the influence of childhood maltreatment and genetic risk for obesity on structural and functional imaging correlates associated with reward processing in MDD. 161 MDD patients underwent structural and functional MRI during a frequently used card guessing paradigm. Main and interaction effects of a polygenic risk score for obesity (PRS) and childhood maltreatment experiences as assessed using the Childhood Trauma Questionnaire (CTQ) were investigated. We found that maltreatment experiences and polygenic risk for obesity significantly interacted on a) body mass index b) gray matter volume of the orbitofrontal cortex as well as on c) BOLD response in the right insula during reward processing. While polygenic risk for obesity was associated with elevated BMI as well as with decreased OFC gray matter and increased insular BOLD response in non-maltreated patients, these associations were absent in patients with a history of childhood trauma. No significant main effect of PRS or maltreatment on gray matter or BOLD response could be detected at the applied thresholds. The present study suggests that childhood maltreatment moderates the influence of genetic load for obesity on BMI as well as on altered brain structure and function in reward related brain circuits in MDD.

Individual differences in sensitivity to pain are large and have clinical and scientific importance. Although heavily influenced by situational factors, they also relate to genetic factors and psychological traits, and are reflected by differences in functional activation in pain-related brain regions. Here, we used voxel-based morphometry to investigate if individual pain sensitivity is related to local gray matter volumes. Pain sensitivity was determined using (1) index finger pressure pain thresholds (PPTs) and (2) pain intensity ratings of imagined painful situations as assessed by the Pain Sensitivity Questionnaire (PSQ) in 501 population-based subjects participating in the BiDirect Study. Pain Sensitivity Questionnaire scores were positively associated with gray matter in 2 symmetrical clusters, with a focus on the parahippocampal gyrus, extending to the hippocampus, fusiform gyrus, BA19, putamen, and insula (P < 0.05 corrected), but the effect was small (R-2 = 0.045-0.039). No negative associations with the PSQ and no associations with the PPT reached significance. Parahippocampal activation during pain and altered parahippocampal gray matter in chronic pain have been reported, which would be consistent with positive associations with PSQ scores. Alternatively, associations of PSQ scores with the parahippocampal and fusiform gray matter could relate to the visual imagination of painful situations required by the PSQ, not to pain sensitivity itself. Regarding PPTs, the present data obtained in a large sample strongly suggest an absence of associations of this parameter with gray matter volume. In conclusion, the present results argue against a strong association between pain sensitivity and local gray matter volumes.

BackgroundPatients with major depression show reduced hippocampal volume compared to healthy controls. However, the contribution of patients’ cumulative illness severity to hippocampal volume has rarely been investigated. It was the aim of our study to find a composite score of cumulative illness severity that is associated with hippocampal volume in depression.MethodsWe estimated hippocampal gray matter volume using 3-tesla brain magnetic resonance imaging in 213 inpatients with acute major depression according to DSM-IV criteria (employing the SCID interview) and 213 healthy controls. Patients’ cumulative illness severity was ascertained by six clinical variables via structured clinical interviews. A principal component analysis was conducted to identify components reflecting cumulative illness severity. Regression analyses and a voxel-based morphometry approach were used to investigate the influence of patients’ individual component scores on hippocampal volume.ResultsPrincipal component analysis yielded two main components of cumulative illness severity: Hospitalization and Duration of Illness. While the component Hospitalization incorporated information from the intensity of inpatient treatment, the component Duration of Illness was based on the duration and frequency of illness episodes. We could demonstrate a significant inverse association of patients’ Hospitalization component scores with bilateral hippocampal gray matter volume. This relationship was not found for Duration of Illness component scores.ConclusionsVariables associated with patients’ history of psychiatric hospitalization seem to be accurate predictors of hippocampal volume in major depression and reliable estimators of patients’ cumulative illness severity. Future studies should pay attention to these measures when investigating hippocampal volume changes in major depression.

ObjectiveaaEarly neuroimaging studies have demonstrated amygdala hypoactivation in schizophrenia but more recent research based on paradigms with minimal cognitive loads or examining automatic processing has observed amygdala hyperactivation. Hyperactivation was found to be related to affective flattening. In this study, amygdala responsivity to threat-related facial expression was investigat ed in patients as a function of automatic versus controlled processing and patients’ flat affect. MethodsaaFunctional magnetic resonance imaging was used to measure amygdala activation in 36 patients with schizophrenia and 42 healthy controls. During scanning, a viewing task with masked and unmasked fearful and neutral faces was presented. ResultsaaPatients exhibited increased amygdala response to unmasked fearful faces. With respect to masked fearful faces, no betweengroup differences emerged for the sample as a whole but a subsample of patients with flat affect showed heightened amygdala activation. The amygdala response to masked fearful faces was positively correlated with the degree of flat affect. Conversely, amygdala response to unmasked fearful faces was negatively correlated to the severity of affective flattening. In patients, amygdala responses to masked and unmasked fearful faces showed an inverse correlation. ConclusionaaOur findings suggest that amygdala hyperresponsivity to unmasked fearful faces might be a functional characteristic of schizophrenia. Amygdala hyperresponsivity to masked fearful faces might be a specific characteristic of patients with affective flattening. A model of flat affect as a response mechanism to emotional overload is proposed.

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene ( NPSR1 ) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected ( p =.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5 min after injection ( p =.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.

BackgroundNeuroimaging traits of either familial or environmental risk for major depressive disorder (MDD) have been interpreted as possibly useful vulnerability markers. However, the simultaneous occurrence of familial and environmental risk might prove to be a major obstacle in the attempt of recent studies to confine the precise impact of each of these conditions on brain structure. Moreover, the exclusive use of group-level analyses does not permit prediction of individual illness risk which would be the basic requirement for the clinical application of imaging vulnerability markers. Hence, we aimed to distinguish between brain structural characteristics of familial predisposition and environmental stress by using both group- and individual-level analyses.MethodWe investigated grey matter alterations between 20 healthy control subjects (HC) and 20 MDD patients; 16 healthy first-degree relatives of MDD patients (FH+) and 20 healthy subjects exposed to former childhood maltreatment (CM+) by using a combined VBM/pattern recognition approach.ResultsWe found similar grey matter reductions in the insula and the orbitofrontal cortex in patients and FH+ subjects and in the hippocampus in patients and CM+ subjects. No direct overlap in grey matter alterations was found between FH+ and CM+ subjects. Pattern classification successfully detected subjects at risk for the disease even by strictly focusing on morphological traits of MDD.ConclusionsFamilial and environmental risk factors for MDD are associated with differing morphometric anomalies. Pattern recognition might be a promising instrument in the search for and future application of vulnerability markers for MDD.

Background Processes of phasic fear responses to threatening stimuli are thought to be distinct from sustained, anticipatory anxiety toward an unpredicted, potential threat. There is evidence for dissociable neural correlates of phasic fear and sustained anxiety. Whereas increased amygdala activity has been associated with phasic fear, sustained anxiety has been linked with activation of the bed nucleus of stria terminalis (BNST), anterior cingulate cortex (ACC), and the insula. So far, only a few studies have focused on the dissociation of neural processes related to both phasic and sustained fear in specific phobia. We suggested that first, conditions of phasic and sustained fear would involve different neural networks and, second, that overall neural activity would be enhanced in a sample of phobic compared to nonphobic participants. Methods Pictures of spiders and neutral stimuli under conditions of either predicted (phasic) or unpredicted (sustained) fear were presented to 28 subjects with spider phobia and 28 nonphobic control subjects during functional magnetic resonance imaging (fMRI) scanning. Results Phobic patients revealed significantly higher amygdala activation than controls under conditions of phasic fear. Sustained fear processing was significantly related to activation in the insula and ACC, and phobic patients showed a stronger activation than controls of the BNST and the right ACC under conditions of sustained fear. Functional connectivity analysis revealed enhanced connectivity of the BNST and the amygdala in phobic subjects. Conclusions Our findings support the idea of distinct neural correlates of phasic and sustained fear processes. Increased neural activity and functional connectivity in these networks might be crucial for the development and maintenance of anxiety disorders.

Background Obesity has been characterized by alterations in brain structure and function associated with emotion processing and regulation. Particularly, aberrations in food-related reward processing have been frequently demonstrated in obese subjects. However, it remains unclear whether reward-associated functional aberrations in obesity are specific for food-related stimuli or represent a general deficit in reward processing, extending to other stimulus domains. Given the crucial role of rewarding effects in the development of obesity and the ongoing discussion on overlapping neurobiological traits of obesity and psychiatric disorders such as depression and substance-related disorders, this study aimed to investigate the possibility of altered reward processing in obese subjects to occur in the absence of food-related stimuli during a monetary reward condition. Methods Twenty-nine healthy obese subjects (body mass index >30) and 29 healthy, age-, and sex-matched control subjects of normal weight underwent functional MRI during a frequently used card guessing paradigm. A Group × Condition (win vs. loss) ANOVA was conducted to investigate differences between obese and normal-weight subjects. Results We found significant Group × Condition interaction effects in brain areas involved in emotion regulation and reward processing including the insula, the striatum, and the orbitofrontal cortex (OFC). This interaction was predominantly driven by a significant increase in blood oxygenation level dependent (BOLD) response in obese individuals while experiencing reward. Conclusions Enhanced neural activation in obesity during reward processing seems to be apparent even in the absence of food-related stimuli and, thus, might point to generalized dysfunctions in reward-related brain circuits in obese individuals. Hum Brain Mapp 36:2330–2337, 2015. © 2015 Wiley Periodicals, Inc.

BACKGROUND Susceptibility weighted imaging and assessment of intratumoral susceptibility signal (ITSS) morphology is used to identify high-grade glioma (HGG) in patients with suspected brain neoplasm. PURPOSE The aim of this study was to outline variations in ITSS-morphology and their relationship to location as well as volume of the lesion in patients with glioblastoma (GB). MATERIALS AND METHODS Contrast-enhanced SWI (CE-SWI) images of 40 patients with histologically confirmed GB were analyzed retrospectively with particular attention to ITSS-morphology dividing all lesions into two groups. Considering the location of the lesion within brain parenchyma, lesions with and without involvement of the subventricular zone (SVZ+/SVZ−) were discerned. Additionally, the contrast-enhancing tumor volume was evaluated. Statistical analysis was based on a classification analysis resulting in a classification rule (tree) as well as Mann-Whitney-U test. RESULTS The distribution of ITSS-scores showed differences between the SVZ+ and SVZ− groups. While SVZ-GB showed only fine-linear or dot-like ITSS, in SVZ+ GB the ITSS-morphology changed with the tumor volume, that is, in larger tumors dense and conglomerated ITSS were the predominant finding. CONCLUSION Our findings indicate that ITSS-morphology is not a random phenomenon. Location of GB, as well as tumor volume, appear to be factors contributing to ITSS morphology.

Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approach-investigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (p

Background FDG-PET detects hypometabolism in premanifest and symptomatic Huntington's disease (HD). A cross-sectional study suggested that whole-brain FDG-PET is capable to detect a phenotype in transgenic (tg) HD rats. Recently, a longitudinal follow-up study showed no FDG-PET changes in tgHD rats. Both studies applied small sample sizes and analysis was limited to whole-brain or striatum. Objective We therefore performed a follow-up study in a larger cohort of tgHD and wild-type (wt) rats encompassing several pre-defined regions of interest (ROIs) and hypothesis free voxel-by-voxel SPM analysis to clarify whether FDG-PET can detect a phenotype in tgHD rats and to determine onset …and effect sizes of changes over time. Methods N = 19 tgHD- and n = 20 wt-rats, mixed gender, were included. Repeated small animal FDG-μPET and MRI were performed at 5,10,15, and 20 months of age. ROIs encompassing entire brain, cortex, striatum, thalamus, subventricular-zone, and cerebellum were placed manually on the MRI and transferred to the co-registered μPET. Mean and maximal FDG-PET activities within ROIs were calculated and normalized to cerebellar FDG uptake. Activity and spatially normalized FDG-μPET were compared between groups on a hypothesis-free voxel-by-voxel basis using SPM. Results FDG uptake showed changes over time in both tgHD- and wt-rats, however, there was no consistent difference between tgHD- and wt-rats in both the manual ROI and SPM analysis. Conclusions In this transgenic rat model of HD FDG-μPET imaging does not detect significant alterations at the ages investigated. Further investigations are warranted employing other age groups and alternative imaging biomarkers for neuronal degeneration, respectively.

Obesity is one of the most prevalent somatic comorbidities of major depressive disorder (MDD). Both disorders rank among the leading challenges in public health and have been independently characterized by gray matter alterations in partly overlapping brain structures. Hence, it appears crucial to investigate the possibility of a shared neurostructural correlate of this frequent comorbidity as well as its clinical implications. One hundred and fourty-four patients suffering from acute MDD and 141 healthy control subjects underwent structural MRI. Imaging data were analyzed using voxel-based morphometry (VBM). Body-mass-index (BMI) as well as state and course of disease were assessed. Higher BMI was associated with a highly comparable pattern of gray matter reductions in the medial prefrontal cortex, the orbitofrontal cortex, the caudate nucleus and the thalamus in MDD patients and healthy controls alike. In MDD-patients, BMI was associated with a more chronic course of disease and both BMI and chronicity of disorder were related to similar morphometric anomalies in medial prefrontal areas. In MDD, obese subjects might be characterized by a more chronic course of disease. Moreover, obesity and chronicity of disorder seem to share overlapping neurostructural anomalies in prefrontal areas involved in emotion regulation and impulse control. Hence, our data provide evidence for specific morphological alterations underlying this prevalent comorbidity. It further underlines the clinical importance of preventive measures against obesity accompanying MDD treatment.

The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression.

BackgroundElectroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects.MethodIn a non-randomized prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained.ResultsBefore therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (rspearman = −0.48, p = 0.044), and by tendency also for the MED sample (rspearman = −0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample.ConclusionsIn sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.

Major depression, currently the world's primary cause of disability, leads to profound personal suffering and increased risk of suicide. Unfortunately, the success of antidepressant treatment varies amongst individuals and can take weeks to months in those who respond. Electroconvulsive therapy (ECT), generally prescribed for the most severely depressed and when standard treatments fail, produces a more rapid response and remains the most effective intervention for severe depression. Exploring the neurobiological effects of ECT is thus an ideal approach to better understand the mechanisms of successful therapeutic response. Though several recent neuroimaging studies show structural and functional changes associated with ECT, not all brain changes associate with clinical outcome. Larger studies that can address individual differences in clinical and treatment parameters may better target biological factors relating to or predictive of ECT-related therapeutic response. We have thus formed the Global ECT-MRI Research Collaboration (GEMRIC) that aims to combine longitudinal neuroimaging as well as clinical, behavioral and other physiological data across multiple independent sites. Here, we summarize the ECT sample characteristics from currently participating sites, and the common data-repository and standardized image analysis pipeline developed for this initiative. This includes data harmonization across sites and MRI platforms, and a method for obtaining unbiased estimates of structural change based on longitudinal measurements with serial MRI scans. The optimized analysis pipeline, together with the large and heterogeneous combined GEMRIC dataset, will provide new opportunities to elucidate the mechanisms of ECT response and the factors mediating and predictive of clinical outcomes, which may ultimately lead to more effective personalized treatment approaches., Highlights • A global collaboration for longitudinal neuroimaging of ECT was established. • A secure data portal with individual-patient level data. • The feasibility of a standardized image analysis pipeline is demonstrated.

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.