Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Adolescence

Objective Associations between psychiatric problems and white matter (WM) microstructure have been reported in childhood and adolescence. Yet, a deeper understanding of this relation has been hampered by a dearth of well-powered longitudinal studies and a lack of explicit examination of the bidirectional associations between brain and behavior. We investigated the temporal directionality of WM microstructure and psychiatric symptom associations from late childhood to early adolescence. Methods In this observational study, we leveraged the world’s largest single- and multi-site cohorts of neurodevelopment: the Generation R and Adolescent Brain Cognitive Development Studies (total n scans = 11,400). We assessed psychiatric symptoms with the Child Behavioral Checklist as broad-band Internalizing and Externalizing scales, and as syndrome scales (e.g., Anxious/Depressed). We quantified WM with Diffusion Tensor Imaging, globally and at a tract level. We used cross-lagged panel models to test bidirectional associations of global and specific measures of psychopathology and WM microstructure, meta-analyzed results across cohorts, and used linear mixed-effects models for validation. Results We did not identify any robust longitudinal associations of global WM microstructure with internalizing or externalizing problems across cohorts (confirmatory analyses). We observed similar findings for longitudinal associations between tract-based microstructure with internalizing and externalizing symptoms, and for global WM microstructure with specific syndromes (exploratory analyses). Conclusion Uni- or bi-directionality of longitudinal associations between WM and psychiatric symptoms was not robustly identified. We propose several explanations for these findings, including interindividual differences, the use of longitudinal approaches, and smaller effects than expected. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development(ABCD)Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9-10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The Generation R Study is supported by Erasmus MC, Erasmus University Rotterdam, the Rotterdam Homecare Foundation, the Municipal Health Service Rotterdam area, the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, the Netherlands Organization for Health Research and Development (ZonMw), and the Ministry of Health, Welfare and Sport. Neuroimaging informatics and image analysis was supported by the Sophia Foundation (S18-20, RLM). Netherlands Organization for Scientific Research (Exacte Wetenschappen) and SURFsara (Cartesius Compute Cluster, www.surfsara.nl) supported the Supercomputing resources. LDA, BX, and HT were supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) while RLM was supported by the Sophia Foundation S18-20 and Erasmus MC Fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was received from the institutional review boards of the University of California (San Diego) and of each of the 21 data collection sites for ABCD, and the Medical Ethics Committee of Erasmus MC, University Medical Centre (Rotterdam) for GenR. Informed consent or assent has been received from the included participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data for the Generation R Study is available upon request to Prof. Vincent Jaddoe (email: v.jaddoe@erasmusmc.nl). In line with the European Data Protection Regulation, The Generation R Study data is protected under the General Data Protection Regulation (GDPR). Data for The ABCD Study is already open and available in the NIMH Data Archive (NDA) (nda.nih.gov) to eligible researchers within NIH-verified institutions. Data can be accessed following a data request to the NIH data access committee (https://nda.nih.gov/), which should include information on the planned topic of study. The request is valid for one year. Data use should be in line with the NDA Data Use Certification.