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Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

Contains fulltext : 220907.pdf (Publisher’s version ) (Open Access) Background and Aims: The regular use of gamma-hydroxybutyrate acid (GHB) can induce GHB-induced comas. Other substance use disorders are associated with alterations in brain structure and impulsivity. Here we aim to investigate if these are also modulated by either regular GHB use or GHB-induced comas. Methods: In a sample of human males, structural and diffusion neuroimaging data were collected for 27 GHB users with >/=4 GHB-induced comas (GHB-Coma), 27 GHB users without GHB-induced comas (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). The structural brain parameters were analyzed macroscopically using voxel-based morphometry and microscopically using tract-based spatial statistics (TBSS) and tractography. Impulsivity was assessed with the Barrat Impulsivity Scale. Results: In comparison to the other two groups, the GHB-Coma group showed a higher fractional anisotropy in the body of the corpus callosum and a lower mean diffusivity in the forceps minor (i.e., whole-brain TBSS analysis). No macrostructural differences nor microstructural differences, as assessed with tractography, were observed. The GHB-Coma group also reported higher impulsivity, which was more strongly associated with white matter volume and fractional anisotropy in tracts involved in impulse control (post-hoc analysis). GHB use per se was associated neither with differences in brain structure nor with impulsivity. Conclusions: The results suggest that multiple GHB-induced comas, but not GHB use per se, are associated with microstructural alterations in white matter and with higher self-reported impulsivity, which in turn was associated with white matter tracts involved in impulse control. 11 p.

Background: Adequate and timely identification of depression is essential to improve patient care. A potential method to achieve this is by using neuroimaging. Many neuroimaging studies have revealed widespread abnormalities in brain structure and function in patients with depression, but in most studies only single neuroimaging modalities were used. Links between abnormalities in brain structure and function need to be therefore further explored in order to define diagnostic and therapeutic applications. Methods: A systematic literature review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines was conducted. Results: Out of 2,516 articles, only 14 studies were eligible to be included. These studies combined structural and functional neuroimaging methods in depressed patients compared to controls. Four studies reported a negative relationship between brain structure and function within the default mode network: reduced gray or white matter integrity in depressed patients compared to healthy controls was associated with enhanced neural activity or connectivity. The other studies reported positive relationships (two studies), mixed relationships (two studies), or no link (six studies) between structural and functional brain abnormalities. Conclusion: This systematic literature review revealed no robust relationship between abnormalities in brain structure and function in patients with depression. Remarkably, only 14 studies could be included and four of these suggested enhanced default mode network connectivity associated with reduced structural brain integrity. In the ongoing development of the diagnostic and treatment applications of neuroimaging, large-scale studies that combine structural with functional neuroimaging are required to determine the relationship between structural and functional abnormalities in depression.

Objective: Brain imaging communities focusing on different diseases have increasingly started to collaborate and to pool data to perform well-powered meta- and mega-analyses. Some methodologists claim that a one-stage individual-participant data (IPD) mega-analysis can be superior to a two-stage aggregated data meta-analysis, since more detailed computations can be performed in a mega-analysis. Before definitive conclusions regarding the performance of either method can be drawn, it is necessary to critically evaluate the methodology of, and results obtained by, meta- and mega-analyses. Methods: Here, we compare the inverse variance weighted random-effect meta-analysis model with a multiple linear regression mega-analysis model, as well as with a linear mixed-effects random-intercept mega-analysis model, using data from 38 cohorts including 3,665 participants of the ENIGMA-OCD consortium. We assessed the effect sizes and standard errors, and the fit of the models, to evaluate the performance of the different methods. Results: The mega-analytical models showed lower standard errors and narrower confidence intervals than the meta-analysis. Similar standard errors and confidence intervals were found for the linear regression and linear mixed-effects random-intercept models. Moreover, the linear mixed-effects random-intercept models showed better fit indices compared to linear regression mega-analytical models. Conclusions: Our findings indicate that results obtained by meta- and mega-analysis differ, in favor of the latter. In multi-center studies with a moderate amount of variation between cohorts, a linear mixed-effects random-intercept mega-analytical framework appears to be the better approach to investigate structural neuroimaging data.

Background and Aims Childhood trauma is associated with increased levels of anxiety later in life, an increased risk for the development of substance use disorders as well as neurodevelopmental abnormalities in the amygdala and frontostriatal circuitry. The aim of this study was to investigate the (neurobiological) link between childhood trauma, state anxiety and amygdala-frontostriatal activity in response to cocaine cues in regular cocaine users. Methods In this study we included 59 non-treatment seeking regular cocaine users 58 non-drug using controls. Blood oxygenation level dependent (BOLD) responses were measured using functional Magnetic Resonance Imaging (fMRI) while subjects performed a cue-reactivity paradigm with cocaine and neutral cues. Psychophysiological interaction analyses were applied to assess functional connectivity between the amygdala and other regions in the brain. Self-report questionnaires were used to measure childhood trauma, state anxiety, drug use, drug use severity and craving. Results Neural activation was increased during the presentation of cocaine cues, in a widespread network including the frontostriatal circuit and amygdala in cocaine users but not in controls. Functional coupling between the amygdala and medial prefrontal cortex was reduced in response to cocaine cues, in both cocaine users and controls, which was further diminished with increasing state anxiety. Importantly, amygdala-striatal connectivity was positively associated with childhood trauma in regular cocaine users, while there was a negative association in controls. At the behavioral level, state anxiety was positively associated with cocaine use severity and craving related to negative reinforcement. Conclusions Childhood trauma is associated with enhanced amygdala-striatal connectivity during cocaine cue-reactivity in regular cocaine users, which may contribute to increased habit behavior and poorer cognitive control. While we cannot draw conclusions on causality, this study provides novel information on how childhood trauma may contribute to the development and persistence of cocaine use disorder. Keywords: cocaine addiction; anxiety; childhood trauma; functional connectivity; ventral striatum; amygdala; dorsal medial prefrontal cortex; negative reinforcement

Objective: Brain imaging studies of structural abnormalities in OCD have yielded inconsistent results, partly because of limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and mega-analyses comprising the largest study of cortical morphometry in OCD ever undertaken. Method: T1-weighted MRI scans of 1,905 OCD patients and 1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness and surface area. Effect sizes for differences between patients and controls, and associations with clinical characteristics, were calculated using linear regression models controlling for age, sex, site, and intracranial volume. Results: In adult OCD patients versus controls, we found a significantly lower surface area for the transverse temporal cortexand a thinner inferiorparietalcortex.Medicated adult OCD patients also showed thinner cortices throughout the brain. In pediatric OCD patients compared with controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed showedsignificant differences in surface area. However, medicated pediatric OCD patients had lower surface area in frontal regions. Cohen's d effect sizes varied from 20.10 to 20.33. Conclusions: The parietal cortex was consistently implicated in both adults and children with OCD. More widespread cortical thickness abnormalities were found in medicated adult OCD patients, and more pronounced surface area deficits (mainly in frontal regions) were found in medicated pediatric OCD patients. These cortical measures represent distinct morphological features and may be differentially affected during different stages of development and illness, and possibly moderated by disease profile and medication.

Relapse of fear after successful treatment is a common phenomenon in patients with anxiety disorders. Animal research suggests that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) plays a key role in the maintenance of extinguished fear. Here, we combined magnetic resonance spectroscopy and functional magnetic resonance imaging to investigate the role of GABA in fear recovery in 70 healthy male participants. We associated baseline GABA levels in the dorsal anterior cingulate cortex (dACC) to indices of fear recovery as defined by changes in skin conductance responses (SCRs), blood oxygen level dependent responses, and functional connectivity from fear extinction to fear retrieval. The results showed that high GABA levels were associated with increased SCRs, enhanced activation of the right amygdala, and reduced amygdala-ventromedial prefrontal cortex connectivity during fear recovery. Follow-up analyses exclusively for the extinction phase showed that high GABA levels were associated with reduced amygdala activation and enhanced amygdala-ventromedial prefrontal cortex connectivity, despite the absence of correlations between GABA and physiological responses. Follow-up analyses for the retrieval phase did not show any significant associations with GABA. Together, the association between GABA and increases in SCRs from extinction to retrieval, without associations during both phases separately, suggests that dACC GABA primarily inhibits the consolidation of fear extinction. In addition, the opposite effects of GABA on amygdala activity and connectivity during fear extinction compared to fear recovery suggest that dACC GABA may initially facilitate extinction learning

Contains fulltext : 154946.pdf (Publisher’s version ) (Open Access) Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission after various treatment options and develop treatment resistant depression (TRD). So far, little is known about the pathophysiology of TRD. Studies in MDD patients showed aberrant functional connectivity (FC) of three "core" neurocognitive networks: the salience network (SN), cognitive control network (CCN), and default mode network (DMN). We used a cross-sectional design and performed resting-state FC MRI to assess connectivity of the SN, CCN, and both anterior and posterior DMN in 17 severe TRD, 18 non-TRD, and 18 healthy control (HC) subjects. Relative to both non-TRD and HC subjects, TRD patients showed decreased FC between the dorsolateral prefrontal cortex and angular gyrus, which suggests reduced FC between the CCN and DMN, and reduced FC between the medial prefrontal cortex and precuneus/cuneus, which suggests reduced FC between the anterior and posterior DMN. No significant differences in SN FC were observed. Our results suggest that TRD is characterized by a disturbance in neurocognitive networks relative to non-TRD and HC.