Translational Psychiatry www.nature.com/tp ARTICLE OPEN The thalamus and its subnuclei—a gateway to obsessive- compulsive disorder ✉ Cees J. Weeland 1 , Selina Kasprzak1, Niels T. de Joode1, Yoshinari Abe 2, Pino Alonso3,4,5, Stephanie H. Ameis 6,7,8, Alan Anticevic , Paul D. Arnold 10,11, Srinivas Balachander12, Nerisa Banaj13, Nuria Bargallo14,15, Marcelo C. Batistuzzo 16,17, 9 Francesco Benedetti 18,19, Jan C. Beucke20,21,22,23, Irene Bollettini 24, Vilde Brecke25, Silvia Brem26,27, Carolina Cappi28, Yuqi Cheng29, Kang Ik K. Cho30,31, Daniel L. C. Costa 32, Sara Dallaspezia33, Damiaan Denys34, Goi Khia Eng35,36, Sónia Ferreira37,38,39, Jamie D. Feusner40,41, Martine Fontaine42, Jean-Paul Fouche43, Rachael G. Grazioplene44, Patricia Gruner44, Mengxin He 29, Yoshiyuki Hirano 45,46, Marcelo Q. Hoexter16, Chaim Huyser 47,48, Hao Hu49, Fern Jaspers-Fayer50,51, Norbert Kathmann20, Christian Kaufmann20, Minah Kim 52,53, Kathrin Koch54,55, Yoo Bin Kwak31, Jun Soo Kwon 31,53,56,57, Luisa Lazaro58,59, Chiang- shan R. Li 4, Christine Lochner 60, Rachel Marsh 42, Ignacio Martínez-Zalacaín 3,5, David Mataix-Cols 21,61, Jose M. Menchón 3,4,5, Luciano Minnuzi62,63, Pedro Silva Moreira37,38,64, Pedro Morgado 37,38,65,66, Akiko Nakagawa45, Takashi Nakamae 67, Janardhanan C. Narayanaswamy12, Erika L. Nurmi68, Ana E. Ortiz69,70, Jose C. Pariente14, John Piacentini 71, Maria Picó-Pérez37,38,39, Fabrizio Piras 13, Federica Piras13, Christopher Pittenger 72, Y. C. Janardhan Reddy12, Daniela Rodriguez- Manrique55,73,74, Yuki Sakai 2,75, Eiji Shimizu45, Venkataram Shivakumar76, Helen Blair Simpson77,78, Noam Soreni62,79, Carles Soriano- Mas 3,4,80, Nuno Sousa 37,38,39, Gianfranco Spalletta 81,82, Emily R. Stern35,36, Michael C. Stevens 83,84, S. Evelyn Stewart 50,51,85, Philip R. Szeszko86,87, Jumpei Takahashi88, Tais Tanamatis16, Jinsong Tang89,90, Anders Lillevik Thorsen 25,91, David Tolin84,92, 1234567890();,: Ysbrand D. van der Werf1, Hein van Marle1, Guido A. van Wingen 34, Daniela Vecchio13, G. Venkatasubramanian 93, Susanne Walitza26,27, Jicai Wang29, Zhen Wang 49, Anri Watanabe 2, Lidewij H. Wolters48,94, Xiufeng Xu29, Je-Yeon Yun 95,96, Qing Zhao49, ENIGMA OCD Working Group, Tonya White97,98, Paul M. Thompson99, Dan J. Stein 100, Odile A. van den Heuvel 1,101 and Chris Vriend 1,101 © The Author(s) 2022 Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1- weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered (https://osf.io/73dvy) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = −0.15 to −0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status. Translational Psychiatry (2022)12:70 ; https://doi.org/10.1038/s41398-022-01823-2 INTRODUCTION planning ability, response inhibition, habitual behaviour, and Obsessive-compulsive disorder (OCD) is a debilitating mental emotion regulation [2]. The thalamus lies at the core of these disorder with a lifetime prevalence of 1.3% that often starts during functionally segregated CSTC circuits. Previous work from the childhood and follows a chronic course [1]. Structural and ENIGMA-OCD Working Group revealed that the thalamus is larger functional differences in cortico-striato-thalamo-cortical (CSTC) in unmedicated pediatric OCD patients compared with controls [3] circuits have been linked to commonly observed affective and and shows more leftward asymmetry [4]. The former finding was cognitive deficits, including fear conditioning and extinction, corroborated in the population-based Generation R study, A full list of author affiliations appears at the end of the paper. Received: 24 December 2021 Revised: 6 January 2022 Accepted: 20 January 2022 C.J. Weeland et al. 2 showing that school-aged children with symptoms above a clinical disease onset, and symptom severity. Based on the literature, we cut-off had a larger thalamus than symptom-free children [5]. expected that pediatric OCD patients would show larger nuclei Thalamus structure is not uniform and consists of several nuclei volumes compared with healthy controls, mostly driven by larger with distinct connectivity and functions [6]. The anterior nucleus volume of the anterior and ventral thalamus. Furthermore, adult connects fronto-limbic regions including the medial orbitofrontal OCD patients were expected to have lower pulvinar volumes and ventromedial prefrontal cortex [7]. The mediodorsal nucleus compared with healthy controls [13]. Based on our previous is involved in both emotional and cognitive processing, including analyses on subcortical and cortical morphology, we expected reward devaluation, fear extinction, working memory, beha- that volume enlargement in children would be driven by vioural flexibility, and goal-directed behaviour [8, 9]. The pulvinar unmedicated patients and lower volume in adults by medicated nucleus functions as an association nucleus involved in attribut- patients [3, 15]. We also expected that adult OCD patients with a ing salience to visual stimuli and modulating attention and childhood onset would show larger nuclei volumes than patients behaviour accordingly [9, 10]. The ventral thalamus includes the with adult-onset OCD. ventral anterior and ventral lateral nucleus, which are involved in motor control [9]. Functional deficits in all of the aforementioned domains and their associated circuits have been implicated in the MATERIALS AND METHODS neurobiological model of OCD [2]. Therefore, larger thalamus Samples volume in OCD may reflect structural or functional changes The ENIGMA-OCD working group is a collaboration of 29 international within these circuits that are expressed in enlarged volume of research institutes that provided in total 50 samples of structural brain specific nuclei. imaging and clinical data from OCD patients and control participants Few studies have investigated OCD-related morphological without psychopathology. These samples partly overlap with the previous cortical and subcortical mega-analyses performed by this group [3, 15]. We differences of the thalamus at the subregional level. Shape divided the participants into three age groups: children under 12 years, analysis has found increased surface area of the anterior and adolescents aged 12–17 years, and adults aged 18 years and older. After pulvinar nuclei in adult OCD patients compared with controls [11]. excluding 45 participants based on poor segmentations, the dataset Within school-aged children from the Generation R study, all included 5423 participants, among which 2678 OCD patients (96 children, thalamic nuclei except the pulvinar trended towards larger 317 adolescents, 2265 adults) and 2746 healthy controls (90 children, 254 volumes in the clinical symptom group compared with children adolescents, 2402 adults). The institutional review boards of each without symptoms [12]. The ventral nucleus group showed the participating site permitted the analysis of measures extracted from largest difference, though this was no longer significant after coded, de-identified individual participant data. correction for multiple comparisons [12]. Another recent study found that adult patients compared with controls had lower Image acquisition and processing volumes of the left posterior thalamus, which includes the T1-weighted structural brain magnetic resonance imaging (MRI) scans of pulvinar and geniculate nuclei, and smaller posterior thalamus the participants were acquired at each site and processed using the latest volume was also associated with a later age of onset of OCD [13]. stable release of FreeSurfer (version 7.1.1) for segmentation of the whole A limitation of previous literature is the focus on a specific age thalamus. Next, the pipeline of Iglesias and colleagues [14] was used to segment the thalamus into 25 nuclei, which we grouped into five different group, limiting the ability to explore differences across the subregions per hemisphere: anterior, lateral, ventral, intralaminar/medial lifespan. The datasets of ENIGMA-OCD allow comparison across and pulvinar (see Fig. 1 for an overview of the subdivision and Fig. S1 for a larger age range, including children, adolescents and adults. an in vivo example). A containerized version (Singularity) of the pipeline We performed mega- and meta-analyses comparing thalamic was created to facilitate cross-platform compatibility at each site (http:// nuclei volume between OCD patients and healthy controls across datasets.datalad.org/?dir=/shub/chrisvriend/ENIGMA_subthal) and allow 29 sites worldwide. We used the automated segmentation standardized quality inspection of the segmentation by means of algorithm implemented in FreeSurfer 7.1.1 that uses a histology- custom-made Python and shell scripts. All segmentations were visually based probabilistic atlas created by Iglesias and colleagues [14]. inspected and investigated for statistical outliers. Full details of the image exclusion criteria and quality assessments are described in Supplementary We also examined the effects of medication status, age, sex, age of Section S1. Fig. 1 Schematic representation of thalamic nuclei grouping. Figure adapted from Thalamic Subregions and Obsessive-Compulsive Symptoms in 2500 Children From the General Population by Weeland et al., 2021, Journal of the American Academy of Child and Adolescent Psychiatry. Translational Psychiatry (2022)12:70 C.J. Weeland et al. 3 Table 1. Pooled descriptive statistics of obsessive-compulsive patients and healthy control participants for the adult (age 18 or higher), adolescent (age 12–17) and child (age under 12) age groups. Variables Adult OCD Adult HC Adolescent OCD Adolescent HC Pediatric OCD Pediatric HC n = 2265 n = 2402 n = 317 n = 254 n = 96 n = 90 Age (y) Mean, SD 31.9 (9.9)* 30.7 (9.9) 14.8 (1.7) 14.6 (1.7) 10.0 (1.3) 9.6 (1.4) Range 18–67 18–69 12–17.9 12–17.5 5–11.6 6–11.9 (C)Y-BOCS Mean, SD 24.5 (6.6) – 22.7 (7.2) – 21.9 (6.9) – Range 3–46 – 0–40 – 0–36 – Education (y) Mean, SD 13.6 (3.1)* 15.1 (3.0) 9.2 (1.8) 8.8 (1.9) 5.0 (1.5) 4.1 (1.6) Range 0–26 0–28 5–14 4–14 0–9 0–7 Female (%) 50.3% 50.4% 45.3% 48.6% 47.9% 55.6% Medicated (%) 52.4% – 40.6% – 19.8% – Child-onset (%) 45.4% – – – – – Comorbid depressive 26.8% – 35.9% – 17.5% – disorder (%) Comorbid anxiety 24.7.0% – 46.4% – 41.7% – disorder (%) OCD obsessive-compulsive disorder, HC healthy control, y years, SD standard deviation, (C)Y-BOCS (Child version) Yale-Brown Obsessive-Compulsive Scale. *Statistically significant group difference (p < 0.05). Fig. 2 Volumetric differences between obsessive-compulsive patients and healthy controls by age group. *puncorrected < 0.05; **pFDR < 0.05; volumetric differences are adjusted for age, sex and intracranial volume. Thal Thalamus. Statistical analysis We computed Cohen’s d (d) effect sizes using the t-statistic of the main We conducted both mega- and meta-analyses. Statistical analyses were predictor variable in the regression models. Medication effects were conducted in accordance with statistical protocols of the ENIGMA investigated by conducting stratified analyses comparing medicated Consortium (http://enigma.ini.usc.edu/). We pre-registered our analysis versus unmedicated OCD patients with the healthy control group. plan and hypotheses prior to conducting any analyses (https://osf.io/ Similarly, we conducted stratified analyses for the adult-onset and child- 73dvy). Mega-analyses were performed by pooling the extracted volume onset (onset before age 18 years) groups to study the influence of time of measures for each participant across all sites. The data were harmonized to onset (age at diagnosis). We also investigated the continuous association adjust for possible cross-site batch effects using a modified version of the of subregional volume with illness severity, expressed in terms of the total ComBat function [16]. Multiple linear regression models were run on the severity score of the adult and child versions of the Yale-Brown Obsessive harmonized data. We conducted separate analyses for children, adoles- Compulsive Scale (Y-BOCS) [17, 18]. In post hoc (i.e. not pre-registered) cents and adults. The bilateral mean volumes of the five subregions served analyses, lateralization of volume differences was assessed in children and as the main outcome measures. Diagnosis was used as a binary predictor adults by computing an asymmetry index ([L – R]/([L + R]/2)) for each in all analyses. All models were adjusted for age, sex, and total intracranial subregion [4]. We further explored subregional volume differences volume (ICV). We additionally investigated the interaction of age, age- relative to the whole thalamus by post hoc adjustment for whole squared, sex or sex-by-age. Details of the meta-analysis are described in thalamus volume. Since subregions and whole thalamus are highly Supplementary Section S2. correlated, we evaluated variance inflation factors to rule out any Translational Psychiatry (2022)12:70 C.J. Weeland et al. 4 Table 2. Multiple linear regression output of volumetric difference between obsessive-compulsive patients and healthy controls for children (<12 years), adolescents (12–17 years) and adults (age 18 or higher). Cohen’s d [95% CI] p-value p-value (FDR) n (OCD) n (HC) Children Ventral 0.28 [−0.009, 0.575] 0.061 0.102 94 88 Pulvinar 0.28 [−0.008, 0.576] 0.060 0.102 94 88 Medial 0.22 [−0.07, 0.515] 0.143 0.178 94 87 Lateral 0.37 [0.081, 0.664] 0.014 0.068 95 89 Anterior 0.16 [−0.133, 0.445] 0.297 0.297 95 90 Whole Thal 0.32 [0.032, 0.611] 0.032 – 96 90 Adolescents Ventral −0.076 [−0.241, 0.09] 0.374 0.467 314 253 Pulvinar −0.012 [−0.178, 0.154] 0.884 0.884 312 252 Medial −0.08 [−0.245, 0.086] 0.348 0.467 316 253 Lateral −0.16 [−0.322, 0.01] 0.067 0.334 316 252 Anterior −0.086 [−0.253, 0.08] 0.311 0.467 311 251 Whole Thal −0.069 [−0.234, 0.096] 0.416 – 317 254 Adults Ventral −0.075 [−0.133, −0.017] 0.011 0.011 2200 2383 Pulvinar −0.093 [−0.151, −0.035] 0.002 0.003 2211 2381 Medial −0.10 [−0.159, −0.043] 0.001 0.002 2198 2390 Lateral −0.08 [−0.134, −0.019] 0.010 0.011 2201 2402 Anterior −0.15 [−0.206, −0.09] 5.66E−07 2.82E−06 2195 2400 Whole Thal −0.11 [−0.165, −0.05] 0.0003 – 2265 2402 Models were adjusted for age, sex, and intracranial volume. 95% CI 95% confidence interval, FDR false discovery rate, n number of participants, OCD obsessive-compulsive disorder, HC healthy controls, Thal Thalamus. multicollinearity in the models. Here, we also statistically compared effect Adults (18–69 years): Whole thalamus volume was smaller in sizes between subregions using Z-tests. The main analyses were corrected adult OCD patients (n = 2265) compared with controls (n = for multiple comparisons by applying a Benjamini–Hochberg false 2402) (d = −0.11 [−0.17, −0.05], p = 0.001). All subregions had discovery rate correction (q = 0.05) across the five subregions tested. smaller volume in adult OCD patients compared with healthy We also report uncorrected results throughout the manuscript. controls (d = −0.08 [−0.133, −0.017] to −0.15 [−0.21, −0.09], pFDR = <0.001 to 0.011, Fig. 2 and Table 2) and in the whole thalamus. In addition, anterior volume relative to whole RESULTS thalamus volume was significantly smaller in adults patients Table 1 provides an overview of the demographic and clinical (d = −0.10 [−0.16, −0.05], pFDR = 0.003, Table S4). We ruled out characteristics of the pooled samples for each age group. The multicollinearity of these models by inspecting variance demographic and clinical characteristics of the separate samples inflation factors, which all remained below 2. Formal compar- are displayed in Table S1 in the data supplement. isons of effect sizes between the anterior thalamus and other subregions revealed statistically significant or nearly significant Mega-analysis differences with the pulvinar (Z = −2.45, p = 0.0144), ventral Thalamic subregional volume differences between OCD patients and (Z = −3.75, p < 0.001), lateral (Z = −1.92, p = 0.0546) and medial controls (Z = −1.94, p = 0.0658) thalamus. Children (<12 years): Consistent with previous findings, larger volume between children with OCD (n = 96) compared with Influence of medication status. Figure 3 visualizes the volumetric controls (n = 90) of the whole thalamus (d = 0.32 [0.03, 0.61], p = differences between medicated patients, unmedicated patients 0.03). Larger volume was observed in children with OCD and healthy controls in relation to age and sex. compared with healthy controls in the lateral subregion (d = 0.37 [0.08, 0.66], p = 0.01, pFDR = 0.08), but the difference did not Children: Unmedicated children with OCD (n = 75) compared survive correction for multiple comparisons. The other subregions with healthy controls (n = 88) had a larger lateral volume (d = 0.46 trended towards increased volume in OCD patients compared [0.15, 0.77], pFDR = 0.02). At an unadjusted significance threshold, with controls (d = 0.16 [−0.133, 0.445] to 0.28 [−0.008, 0.576], patients had a larger ventral subregion (d = 0.35 [0.04, 0.66], unadjusted p = 0.06 to 0.30, pFDR = 0.10 to 0.30) (see Fig. 2 and p = 0.03, pFDR = 0.07) and pulvinar (d = 0.33 [0.02, 0.64], p = 0.03, Table 2). We found no significant differences in subregional pFDR = 0.07) (see Table S5). We found no significant volume volume after adjusting for whole thalamus volume (see Table S2). differences between medicated children with OCD and healthy controls or between medicated and unmedicated children with Adolescents (12–17 years): There were no significant volume OCD (see Tables S6 and S7). differences of the thalamus as a whole or subregions between adolescent OCD patients (n = 317) and healthy controls (n = 354) Adolescents: We found no significant differences between (see Fig. 2 and Table 2). There was also no group differences in medicated adolescents with OCD (n = 186), unmedicated relative thalamus volume (Table S3). Translational Psychiatry (2022)12:70 C.J. Weeland et al. 5 Fig. 3 Age trajectory of thalamus subregion volume for medicated obsessive-compulsive patients, unmedicated patients and healthy controls, split by sex and diagnosis. Adjusted for intracranial volume. Shading represents error margins. OCD obsessive-compulsive disorder. adolescent OCD patients (n = 128) and healthy controls (n = 254) were no significant differences between unmedicated adult OCD (see Tables S8–S10). patients (n = 1000) and healthy controls (n = 2402 (Table S12) or between medicated and unmedicated patients (Table S13). Adults: Medicated adults with OCD (n = 1091) compared with healthy controls (n = 2402) exhibited a significantly smaller Influence of age and sex on OCD-related differences in thalamic volume of all thalamic subregions (d = −0.09 [−0.16, −0.01] to nuclei volume. Results of the interaction models are displayed in −0.17 [−0.24, −0.10], pFDR = <0.001 to 0.02) (Table S11), but there Tables S14–S25. In children, we found an age-by-diagnosis Translational Psychiatry (2022)12:70 C.J. Weeland et al. 6 interaction for the medial (Cohen’s d = 0.30 [0.01, 0.60], p = 0.046, that OCD-related thalamic volume differences are global and not pFDR = 0.076), pulvinar (d = 0.31 [0.02, 0.60], p = 0.041, pFDR = driven by particular subregions and that the direction of effects 0.076), ventral (d = 0.36 [0.07, 0.65], p = 0.018, pFDR = 0.076) nuclei are explained by both age and medication status. and for the whole thalamus (d = 0.36 [0.07, 0.65], p = 0.017). This The current study further elucidates the strongly age- indicates larger volume with age in patients versus lower volume dependent nature of the link between OCD and thalamic with age in controls (see Table S15). We also found an age-by-sex- morphology. In line with our prior work, we found the whole by-diagnosis interaction in the anterior (d = −0.32 [−0.61, −0.03], thalamus was larger in the pediatric patient group [3]. However, pFDR = 0.045), medial (d = −0.40 [−0.70, −0.11], pFDR = 0.026), a crucial difference is that we split the pediatric group into pulvinar (d = −0.39 [−0.69, −0.10], pFDR = 0.026), ventral (d = children (<12 years) and adolescents (12–17 years). This revealed −0.34 [−0.63, −0.05], pFDR = 0.045) subregions and for the whole that OCD-related thalamic volume differences appear during thalamus (d = −0.42 [−0.71, −0.13], p = 0.006) (see Table S17), childhood and already attenuate during adolescence. Comple- indicative of larger volume in male pediatric OCD patients with mentary to the pediatric findings and in contrast with our age, but lower volume with age in female OCD patients and previous work, we found significantly smaller volumes across all healthy controls. We found no such interactions in adolescents subregions in adult OCD patients compared with controls. This (Table S18–S21). novel finding relative to previous work is likely explained by In adults, we found a sex-by-diagnosis interaction in the anterior increased power from the larger sample size and use of the subregion (d = −0.07 [−0.12, −0.01]; p = 0.03, pFDR = 0.13) (see ComBat algorithm to adjust for batch effects [16], as well as the Table S22), indicating stronger volume differences between OCD more sensitive thalamic segmentation method [14]. Taken patients and healthy controls among females. We found no other together, we robustly show that thalamic volume differences, interactions (see Tables S23–S25). regardless of subregions, follow an opposite trajectory from larger to smaller volumes across age in patients compared with Influence of time of disease onset on thalamic subregional volume in controls. This is consistent with the significant interactions with adults. Compared with healthy controls (n = 2402), adult-onset age and age-by-sex we found in the pediatric sample. However, OCD patients (n = 1000) had a smaller medial (d = −0.10 [−0.17, we are cautious to interpret the pediatric interaction analyses −0.02], pFDR = 0.026) and anterior (d = −0.14 [−0.21, −0.07], due to the low sample size and skewed age distribution in this pFDR = 0.001) thalamic volume. The ventral and lateral subregions group. Conversely, the sufficiently powered adult sample size did were smaller at unadjusted p-value < 0.05 (see Table S26). There not show a significant interaction with age or age-by-sex. This were no differences between adult patients with a child-onset could indicate that differences in volume trajectories across age (n = 850) and controls (see Table S27) or between child-onset and between patients and controls that appear in the plot are adult-onset patients (see Table S28). challenging to model with formal testing. However, we did find a sex-by-diagnosis interaction in adults for the anterior subregion Association between illness severity and thalamic subregional (see Table S3), indicating that OCD-related volume differences volume. Medication use was associated with higher YBOCS are on average stronger in females than males. We should note scores (t = 2.23, p = 0.026) and the presence of comorbid that our findings in adults are partly consistent with recent work depressive disorders (t = 3.13, p = 0.002) but not comorbid from Jurng et al. in a sample that was also included in the current anxiety disorders (t = 0.59, p = 0.56). We therefore additionally analysis [13]. While the current study found lower volumes of all adjusted the severity analyses for medication use and comorbid subregions in adult OCD patients, Jurng et al. found significant depressive disorders. There was no relationship between symp- differences only in the posterior thalamus region that includes tom severity and subregional volume in pediatric (n = 83) and the pulvinar [13]. This difference is most likely explained by adolescent OCD patients (n = 301) (see Table S29 and S30). differences in sample size and the fact that only unmedicated Conversely, symptom severity in adult OCD patients (n = 2106) patients were included in the Jurng et al. sample. was negatively associated with volume in all subregions (r = −0.04 Given that specific thalamic subregions play a key role in OCD- and −0.06) and whole thalamus volume (r = −0.07) (see Table relevant circuitry [2], we hypothesized morphometric differences S31). in these subregions in OCD. Thalamic subregions have been more intensively studied in relation to schizophrenia and have Volume asymmetry group differences between patients and controls. repeatedly shown subregional volume differences [19], includ- We found no significant thalamic subregional volume asymmetry ing recently by using the same Iglesias et al. segmentation tool in child, adolescent and adult OCD patients compared with [20, 21]. Participants at high risk of developing schizophrenia controls (see Tables S32–S34). with auditory hallucinations had a smaller volume of the medial geniculate nucleus and a steeper volume decrease over time Meta-analysis compared with symptom-free controls, accompanied by func- Methods and results of the meta-analysis are displayed in tional connectivity differences in related circuits [21]. This Supplementary Section S1 and Table S35 and Fig. S1. The results suggests that subregional volume changes might be related to of the meta-analysis corroborate the mega-analysis results. specific symptoms. OCD-related symptom dimensions have also been related to distinct structural changes [22]. In the current study, we only had data on global symptom severity and not DISCUSSION specific symptom dimensions. Given the heterogeneity of the We performed a mega- and meta-analysis investigating differ- OCD phenotype and the many circuits involved, this could ences in thalamic subregion volume between OCD patients and explain why the shrinkage of the thalamus was distributed healthy controls across the lifespan. While unmedicated pediatric across all subregions. patients had significantly larger lateral volumes and larger Conversely, thalamus volume was larger rather than smaller in pulvinar, ventral and whole thalamus volumes at uncorrected the child sample, suggesting another process may be at play. For significance thresholds compared with controls, adult OCD instance, the larger overall thalamus volume could reflect broad patients had smaller volumes across all subregions, which was neurodevelopmental differences between patients and controls mostly driven by medicated and adult-onset patients. No volume that predispose to developing OCD. During early childhood and differences were found in adolescent OCD patients. Furthermore, adolescence, thalamo-cortical circuits undergo a process of most subregional group differences did not persist after adjusting myelination, synaptic remodelling and pruning that give rise to for whole thalamus volume. Together, this provides new insight a mature thalamus [23]. Recent work showed that compulsivity Translational Psychiatry (2022)12:70 C.J. Weeland et al. 7 and impulsivity are related to reduced myelin-related growth in despite adjustment for batch effects, we are not able to overcome cortico-striatal regions in adolescents [24]. Although disagreement all effects that arise from scanner and site differences. Since all exists on the trajectory of normative thalamic development, sites included both patient and control groups, large effects of site relative thalamus size has been described to increase until 4 years differences are, however, not expected. Despite the large sample of age [25], followed by either a steady decrease [26] or size, adults form the majority of participants and pediatric stabilization [25] during childhood and adolescence. The larger participants are relatively underrepresented. It is important to volumes observed in our pediatric OCD patients aged 6–12 years emphasize that because of this not all findings in the pediatric may therefore reflect altered neurodevelopment. The association sample survived multiple comparisons. Fortunately, the ENIGMA- was strongest in unmedicated children, indicating that medication OCD Working Group continues to grow, and future analyses will normalizes thalamic volume. This is consistent with the report by enable us to balance out the age distribution in favour of younger Gilbert et al. [27], that revealed enlargement of the thalamus in participants. We should also acknowledge that the internal pediatric patients that normalized after 12-week-treatment with borders of the thalamus on T1 images are difficult to discern paroxetine. Since neurodevelopment is governed by both genetic with visual checks and could not be used to visually verify the [28] and environmental influences [29], longitudinal studies anatomical correctness of the segmentations. Despite this, the integrating these aspects can offer insight into the altered pipeline’s validity has been thoroughly evaluated with histological neurodevelopment in OCD. comparison, across different field strengths (1.5T and 3T) and has Thalamic volume declines with healthy ageing [30] and shows successfully detected subregional differences across different enhanced decline in various brain disorders [31, 32]. Likewise, OCD disorders and age groups [12, 14, 20, 21]. patients may exhibit a more rapid decline in thalamic volume Despite these limitations, our results provide the first robust through various mechanisms. Glutamatergic neurons fulfil an findings on OCD-related volume differences in the thalamus across important role within the CSTC circuits. Several studies have found different developmental stages. In contrast with our hypotheses, we alterations in glutamatergic systems in OCD, indicating possible observed mostly global thalamic rather than region-specific volume glutamatergic dysregulation [33, 34]. Excitotoxic effects of differences, suggesting that the relationship with OCD is not driven glutamate have been proposed as a mechanism for local structural by changes of a particular subregion but overall thalamus volume. loss in schizophrenia [35]. Alternatively, the presence of auto- Future endeavours should focus on disentangling longitudinal age- antibodies in conjunction with increased excitatory metabolites in related and medication-related effects to determine what drives adult OCD suggest activity of autoimmune processes [34]. these global differences. Furthermore, multimodal approaches Our results suggest that medication status largely drives including resting-state functional MRI and diffusion-weighted volumetric differences in adult OCD. Selective serotonin reuptake imaging could bolster our understanding of thalamic connectivity inhibitors (SSRIs) have been reported to induce both neurogenesis and its involvement in OCD, preferably at higher field strengths to and neuronal elimination in the hippocampus [36, 37]. In vitro attain optimal contrast for high-quality images. studies have linked antidepressant exposure to non-neuronal and neuronal apoptosis or death [38, 39], providing a possible mechanism for volume decline of brain structures. However, to REFERENCES our knowledge, such effects have not been described in the 1. Fawcett EJ, Power H, Fawcett JM. Women are at greater risk of OCD than men: a thalamus. In another study, a single dose of SSRIs caused meta-analytic review of OCD prevalence worldwide. J Clin Psychiatry. 2020;81. widespread decreases in subcortical and cortical connectivity as 2. 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Amsterdam Neuroscience (CIA-2019-03-A to O.A. van den Heuvel, Amsterdam 20. Anna S, Huang PD, Baxter P, Rogers PD, Julia M, Sheffield PD, et al. Thalamic Neuroscience Alliance Project to G.A. van Wingen). Supported by the Japan Society nuclei volumes in psychotic disorders and in youths with psychosis spectrum for the Promotion of Science (JSPS; KAKENHI Grants No. 18K15523 to Y. Abe, No. symptoms. Am J Psychiatry. 2020;177:1159–67. 19K03308 to Y. Hirano and A. Nakagawa, No. 16K04342 to A. Nakagawa); National 21. Mancini V, Zöller D, Schneider M, Schaer M, Eliez S. Abnormal development and Institute of Mental Health (NIMH; Grant no. 5R01MH116038 to A. Anticevic, No. dysconnectivity of distinct thalamic nuclei in patients with 22q11.2 deletion R01MH085900 to J.D. Feusner, No. K23 MH115206 to P. Gruner, No. R01MH104648 syndrome experiencing auditory hallucinations. Biol Psychiatry Cogn Neurosci and No. R21MH101441 to R. Marsh, No. R01MH085900 and No. R01MH081864 to Neuroimaging. 2020;5:875–90. J. O’Neill, No. 1R01MH081864 to J. Piacentini, No. K24 MH121571 to C. Pittenger, No. 22. van den Heuvel OA, Remijnse PL, Mataix-Cols D, Vrenken H, Groenewegen HJ, R01 MH074934, No. R21/R33MH107589 and No. R01MH111794 to E.R. Stern, No. R01 Uylings HB, et al. The major symptom dimensions of obsessive-compulsive MH074934 to D. Tolin); the Alberta Innovates Translational Health Chair in Child and disorder are mediated by partially distinct neural systems. Brain. Youth Mental Health and the Ontario Brain Institute funding P.D. Arnold; Swiss 2009;132:853–68. National Science Foundation (Grant No. 320030_130237) and the Hartmann Müller 23. Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsycho- Foundation (Grant No. 1460) to S. Brem; Fundação Faculdade de Medicina (Grant No. pharmacology. 2010;35:147–68. 86.768 to D.L.C. Costa); the Japan Agency for Medical Research and Development 24. Ziegler G, Hauser TU, Moutoussis M, Bullmore ET, Goodyer IM, Fonagy P, et al. (AMED Brain/MINDS Beyond program Grant No. JP21dm0307002 to Y. Hirano, No. Compulsivity and impulsivity traits linked to attenuated developmental fron- JP21dm0307008 to Y. Sakai); Michael Smith Foundation for Health Research to tostriatal myelination trajectories. Nat Neurosci. 2019;22:992–9. F. Jaspers-Fayer; the Deutsche Forschungsgemeinschaft (DFG; to D. Rodriguez- 25. Tutunji R, El Homsi M, Saaybi S, Al Arab N, Tamim H, Makki M, et al. Thalamic Manrique, Grant No. DFG 815/6-1 to N. Kathmann, No. KO 3744/11-1 to K. Koch); The volume and dimensions on MRI in the pediatric population: normative values and Basic Science Research Program through the National Research Foundation of Korea correlations: a cross sectional study. Eur J Radiol. 2018;109:27–32. (NRF) (Grant no. 2019R1A2B5B03100844 to J.S. Kwon); the Marató TV3 Foundation 26. Sussman D, Leung RC, Chakravarty MM, Lerch JP, Taylor MJ. The developing (Grant No. 01/2010 and No. 091710 to L. Lazaro); the National Research Foundation of human brain: age-related changes in cortical, subcortical, and cerebellar anat- South Africa to C. Lochner; the Portuguese Foundation for Science and Technology omy. Brain and Behavior. 2016;6:e00457. (Fundação para a Ciência e a Tecnologia; FCT; Project No. UIDB/50026/2020 and No. 27. Gilbert AR, Moore GJ, Keshavan MS, Paulson LA, Narula V, Mac Master FP, UIDP/50026/2020 to P. Morgado and N. Sousa); the ICVS Scientific Microscopy et al. Decrease in thalamic volumes of pediatric patients with obsessive- Platform, member of the national infrastructure PPBI - Portuguese Platform of compulsive disorder who are taking paroxetine. Arch Gen Psychiatry. Bioimaging (Grant No. PPBI-POCI-01-0145-FEDER-022122); the Norte Portugal 2000;57:449–56. Regional Operational Programme (NORTE 2020; Grant No. NORTE-01-0145-FEDER- 28. Mataix-Cols D, Boman M, Monzani B, Rück C, Serlachius E, Långström N, et al. 000039 to P. Morgado and N. Sousa), under the PORTUGAL 2020 Partnership Population-based, multigenerational family clustering study of obsessive- Agreement, through the European Regional Development Fund (ERDF); the FLAD compulsive disorder. JAMA Psychiatry. 2013;70:709–17. Science Award Mental Health 2021 to P. Morgado and N. Sousa; the Government of 29. Brander G, Rydell M, Kuja-Halkola R, Fernandez de la Cruz L, Lichtenstein P, India grants from the Department of Science and Technology (Grants No. SR/S0/HS/ Serlachius E, et al. Association of perinatal risk factors with obsessive-compulsive 0016/2011 to Y.C. Janardhan Reddy, and DST INSPIRE faculty grant -IFA12-LSBM-26 to disorder: a population-based birth cohort, sibling control study. JAMA Psychiatry. J.C. Narayanaswamy) and from the Department of Biotechnology (Grants No. BT/ 2016;73:1135–44. PR13334/Med/30/259/2009 to Y.C. Janardhan Reddy, and No. BT/06/IYBA/2012 to 30. Van Der Werf YD, Tisserand DJ, Visser PJ, Hofman PAM, Vuurman E, Uylings HBM, Dr. Janardhanan C. Narayanaswamy, and Accelerator Program for Discovery in Brain et al. Thalamic volume predicts performance on tests of cognitive speed and Disorders using Stem cells (ADBS), Grant No. BT/PR17316/MED/31/326/2015 to decreases in healthy aging: a magnetic resonance imaging-based volumetric S. Balachander); the Italian Ministry of Health (Grant No. RC19-20-21 to Fabrizio Piras, analysis. Cognitive Brain Res. 2001;11:377–85. No. RC18-19-20-21/A to G. Spalletta); the Wellcome Trust-DBT India Alliance (Grant 31. de Jong LW, van der Hiele K, Veer IM, Houwing JJ, Westendorp RGJ, Bollen E, et al. No. 500236/Z/11/Z to G. Venkatasubramanian, Early Career Fellowship Grant No. IA/ Strongly reduced volumes of putamen and thalamus in Alzheimer’s disease: an CPHE/18/1/503956 to. V. Shivakumar); the Carlos III Health Institute (Grant No. PI16/ MRI study. 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Anti-brain autoantibodies and altered excitatory neurotransmitters in Council (SAMRC) to D.J. Stein; the Dutch Brain Foundation (Nederlandse Hersen- obsessive-compulsive disorder. Neuropsychopharmacology. 2009;34:2489–96. stichting; Grant No. HA-2017-00227 to C. Vriend). 35. Plitman E, Patel R, Chung JK, Pipitone J, Chavez S, Reyes-Madrigal F, et al. Glu- tamatergic metabolites, volume and cortical thickness in antipsychotic-naive patients with first-episode psychosis: implications for excitotoxicity. Neu- AUTHOR CONTRIBUTIONS ropsychopharmacology. 2016;41:2606–13. Cees J. Weeland: Conceptualization, methodology, formal analysis, resources, data 36. Sairanen M, Lucas G, Ernfors P, Castrén M, Castrén E. Brain-derived neurotrophic curation, writing—original draft, writing—review and editing, visualization; Selina factor and antidepressant drugs have different but coordinated effects on neu- Kasprzak: Conceptualization, methodology, resources, data curation, writing— ronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci. original draft, writing—review and editing; Niels T. de Joode, Yoshinari Abe, Pino 2005;25:1089–94. Alonso, Stephanie H. Ameis, Alan Anticevic, Paul D. Arnold, Srinivas Balachander, Translational Psychiatry (2022)12:70 C.J. Weeland et al. 9 Nerisa Banaj, Nuria Bargallo, Marcelo C. Batistuzzo, Francesco Benedetti, Jan C. Association for serving as Associate Editor of JAMA-Psychiatry; Susanne Walitza Beucke, Irene Bollettini, Vilde Brecke, Silvia Brem, Carolina Cappi, Yuqi Cheng, Kang Ik received no funds of Industry Outside professional activities and interests are K. Cho, Daniel L.C. Costa, Sara Dallaspezia, Damiaan Denys, Goi Khia Eng, Sónia declared under the link of the University of Zurich www.uzh.ch/prof/ssl-dir/ Ferreira, Jamie D. Feusner, Martine Fontaine, Jean-Paul Fouche, Rachael G. interessenbindungen/client/web/. Her work was supported in the last 5 years by Grazioplene, Patricia Gruner, Mengxin He, Yoshiyuki Hirano, Marcelo Q. Hoexter, the Swiss National Science Foundation (SNF), diverse EU FP7s, Gesundheitsförderung Hao Hu, Chaim Huyser, Fern Jaspers-Fayer, Norbert Kathmann, Christian Kaufmann, Schweiz, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Minah Kim, Kathrin Koch, Yoo Bin Kwak, Jun Soo Kwon, Luisa Lazaro, Chiang-shan R. Thalmann, Vontobel, Unicentia, Erika Schwarz Fonds. Paul M. Thompson received Li, Christine Lochner, Rachel Marsh, Ignacio Martínez-Zalacaín, David Mataix-Cols, partial research support from Biogen, Inc., for research unrelated to this manuscript; Jose M. Menchón, Luciano Minnuzi, Pedro Silva Moreira, Pedro Morgado, Akiko Chris Vriend is listed as an inventor on a patent licensed to General Electronic Nakagawa, Takashi Nakamae, Janardhanan C. Narayanaswamy, Erika L. Nurmi, Joseph (WO2018115148A1). Odile A. van den Heuvel received a consultation honorarium O’Neill, Ana E. Ortiz, Jose C. Pariente, John Piacentini, Maria Picó-Pérez, Federica Piras, from Lundbeck. All other authors from the ENIGMA OCD working group have no Fabrizio Piras, Christopher Pittenger, Y.C. Janardhan Reddy, Daniela Rodriguez- conflicts of interest related to this study. Manrique, Yuki Sakai, Eiji Shimizu, Venkataram Shivakumar, Helen Blair Simpson, Noam Soreni, Carles Soriano-Mas, Nuno Sousa, Gianfranco Spalletta, Emily R. Stern, Michael C. Stevens, S. Evelyn Stewart, Philip R. Szeszko, Jumpei Takahashi, Tais ADDITIONAL INFORMATION Tanamatis, Anders Lillevik Thorsen, David Tolin, Ysbrand D. van der Werf, Hein van Supplementary information The online version contains supplementary material Marle, Guido A. van Wingen, Daniela Vecchio, Venkatasubramanian G., Susanne available at https://doi.org/10.1038/s41398-022-01823-2. Walitza, Jicai Wang, Zhen Wang, Anri Watanabe, Lidewij H. Wolters, Xiufeng Xu, Je- Yeon Yun, Qing Zhao and Tonya White: Resources, data curation, writing—review Correspondence and requests for materials should be addressed to Cees J. Weeland. and editing; Paul M. Thompson: Conceptualization, resources, data curation, writing —original draft, writing—review and editing, project administration, funding Reprints and permission information is available at http://www.nature.com/ acquisition; Dan J. Stein: Conceptualization, resources, data curation, writing— reprints original draft, writing—review and editing, project administration; Odile A van den Heuvel: Conceptualization, methodology, resources, data curation, writing—original Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims draft, writing—review and editing, supervision, project administration, funding in published maps and institutional affiliations. acquisition; Chris Vriend: Conceptualization, methodology, software, resources, data curation, writing—original draft, writing—review and editing, supervision, project administration, funding acquisition. Open Access This article is licensed under a Creative Commons COMPETING INTERESTS Attribution 4.0 International License, which permits use, sharing, Alan Anticevic is a shareholder and member of the technology advisory board for adaptation, distribution and reproduction in any medium or format, as long as you give RBNC Therapeutics. Jamie D. Feusner is affiliated with NOCD, LLC; Prof. Mataix-Cols appropriate credit to the original author(s) and the source, provide a link to the Creative receives personal fees from UpToDate, Inc and Elsevier, both outside the current Commons license, and indicate if changes were made. The images or other third party work; Pedro Morgado has received in the past 3 years grants, CME-related honoraria, material in this article are included in the article’s Creative Commons license, unless or consulting fees from Angelini, AstraZeneca, Bial Foundation, Biogen, DGS-Portugal, indicated otherwise in a credit line to the material. If material is not included in the FCT, FLAD, Janssen-Cilag, Gulbenkian Foundation, Lundbeck, Springer Healthcare, article’s Creative Commons license and your intended use is not permitted by statutory Tecnimede and 2CA-Braga; Erika L. Nurmi served on the Scientific Advisory Board of regulation or exceeds the permitted use, you will need to obtain permission directly Myriad Genetics and Medical Advisory Board of Tourette Association of America and from the copyright holder. To view a copy of this license, visit http://creativecommons. Teva Pharmaceuticals; Christopher Pittenger is a consultant for Biohaven, CH-TAC, org/licenses/by/4.0/. Lundbeck (not relevant to this work); in the last 3 years, Dr. Simpson has received research support from Biohaven for a multi-site clinical trial, royalties from Cambridge University Press and UpToDate, Inc, and a stipend from the American Medical © The Author(s) 2022 1 Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Department of Anatomy & Neurosciences, Amsterdam, The Netherlands. 2Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. 3Bellvitge Biomedical Research Insitute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain. 4CIBERSAM, Barcelona, Spain. 5Department of Clinical Sciences, University of Barcelona, Barcelona, Spain. 6Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada. 7Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. 8Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada. 9Departments of Psychiatry and Neuroscience, Yale University, New Haven, CT, USA. 10 The Mathison Centre for Mental Health Research & Education, Departments of Psychiatry and Medical Genetics, Calgary, Canada. 11Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. 12OCD clinic, Department of Psychiatry, National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India. 13 Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy. 14Magnetic Resonance Image Core Facility, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 15Image Diagnostic Center, Hospital Clinic, Barcelona, Spain. 16Departamento de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. 17Department of Methods and Techniques in Psychology, Pontificial Catholic University of Sao Paulo, Sao Paulo, SP, Brazil. 18Vita-Salute San Raffaele University, Milano, Italy. 19Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano, Italy. 20Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany. 21Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet, Stockholm, Sweden. 22Department of Medical Psychology, Medical School Hamburg, Hamburg, Germany. 23Institute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany. 24Psychiatry and Clinical Psychobiology, Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy. 25Bergen Center for Brain Plasticity, Haukeland University Hospital, Bergen, Norway. 26Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland. 27 Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland. 28Icahn School of Medicine at Mount Sinai Department of Psychiatry, New York, NY, USA. 29Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China. 30Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 31Department of Brain and Cognitive Sciences, Seoul National University College of Natural Science, Seoul, Republic of Korea. 32Obsessive-Compulsive Spectrum Disorders Program, Departamento e Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP, Brazil. 33IRCCS Ospedale San Raffaele, Milano Italy Psychiatry, Milano, Italy. 34Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, Amsterdam, The Netherlands. 35Department of Psychiatry, New York University School of Medicine, New York, NY, USA. 36Clinical Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA. 37Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. 38ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal. 39Clinical Academic Center - Braga, Braga, Portugal. 40Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Canada. 41Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA. 42Columbia University Medical College, Columbia University, New York, NY, USA. 43Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. 44Department of Psychiatry, Yale University, New Haven, CT, USA. 45Research Center for Child Mental Development, Chiba University, Chiba, Japan. 46United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Japan. 47Levvel, Academic Center for Child and Adolescent Translational Psychiatry (2022)12:70 C.J. Weeland et al. 10 Psychiatry, Amsterdam, the Netherlands. 48Amsterdam UMC, Department of Child and Adolescent Psychiatry, Amsterdam, the Netherlands. 49Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 50Department of Psychiatry, University of British Columbia, Vancouver, Canada. 51British Columbia Children’s Hospital Research Institute, Vancouver, Canada. 52Seoul National University Hospital, Department of Neuropsychiatry, Seoul, Republic of Korea. 53Seoul National University College of Medicine, Department of Psychiatry, Seoul, Republic of Korea. 54Department of Neuroradiology, Klinikum rechts der Isar, Technische Universität, München, Germany. 55TUM-Neuroimaging Center (TUM-NIC) of Klinikum rechts der Isar, Technische Universität München, München, Germany. 56Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea. 57Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea. 58Department of Child and Adolescent Psychiatry and Psychology, Hospital Clinic, IDIBAPS, Barcelona, Spain. 59Department of Medicine, University of Barcelona, Barcelona, Spain. 60 Stellenbosch University, SAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch, South Africa. 61Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden. 62Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada. 63Offord Centre for Child Studies, Hamilton, Ontario, Canada. 64Psychological Neuroscience Lab, CIPsi, School of Psychology, University of Minho, Braga, Portugal. 65Clinical Academic Center- Braga (2CA), Braga, Portugal. 66Hospital de Braga, Braga, Portugal. 67Graduate School of Medical Science Kyoto Prefectural University of Medicine, Department of Psychiatry, Kyoto, Japan. 68Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. 69Department of Child and Adolescent Psychiatry and Psychology, Institute of Neuroscience, Hospital Clinic, Barcelona, Spain. 70Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 71 UCLA Semel Institute, Division of Child and Adolescent Psychiatry, Los Angeles, CA, USA. 72Department of Psychiatry and Yale Child Study Center, Yale University, New Haven, CT, USA. 73Department of Diagnostic and Interventional Neuroradiology, School of Medicine, Technical University of Munich, Munich, Germany. 74Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximilians-Universität, Munich, Germany. 75Department of Neural Computation for Decision-Making, Advanced Telecommunications Research Institute International Brain Information Communication Research Laboratory Group, Kyoto, Japan. 76Department of Integrative Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. 77Columbia University Irving Medical College, Columbia University, New York, NY, USA. 78 New York State Psychiatric Institute, New York, NY, USA. 79Pediatric OCD Consultation Team, Anxiety Treatment and Research Center, Hamilton, Ontario, Canada. 80 Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Barcelona, Spain. 81IRCCS Santa Lucia Foundation, Laboratory of Neuropsychiatry, Rome, Italy. 82Baylor College of Medicine, Department of Psychiatry and Behavioral Sciences, Houston, TX, USA. 83Institute of Living, Hartford, CT, USA. 84 Yale University School of Medicine, New Haven, CT, USA. 85BC Mental Health and Substance Use Services Research Institute, Vancouver, Canada. 86Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 87James J. Peters VA Medical Center, Mental Illness Research, Education and Clinical Center, Bronx, NY, USA. 88Department of Child Psychiatry, Chiba University Hospital, Chiba, Japan. 89Department of Psychiatry, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 90Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. 91Centre for Crisis Psychology, University of Bergen, Bergen, Norway. 92Institute of Living/Hartford Hospital, Hartford, CT, USA. 93National Institute of Mental Health And Neurosciences, Department of Psychiatry, Bengaluru, India. 94 Levvel, Academic Center for Child and Adolescent Psychiatry, Post Box 303, 1115 ZG Duivendrecht, the Netherlands. 95Seoul National University Hospital, Seoul, Republic of Korea. 96Yeongeon Student Support Center, Seoul National University College of Medicine, Seoul, Republic of Korea. 97Erasmus Medical Center, Department of Child and Adolescent Psychiatry/Psychology, Wytemaweg 8, 3015 GD Rotterdam, the Netherlands. 98Department of Radiology and Nuclear Medicine, University of Southern California, Los Angeles, CA, USA. 99Imaging Genetics Center, Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 100SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa. 101 These authors contributed equally: Odile A. van den Heuvel, Chris Vriend. A full list of members and their affiliations appears in the Supplementary Information. ✉email: c.j.weeland@amsterdamumc.nl Translational Psychiatry (2022)12:70