Shared vulnerability for connectome alterations across psychiatric and neurological brain disorders

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Macroscale white matter pathways are the infrastructure for large-scale communication in the human brain and a prerequisite for healthy brain function. Disruptions in the brain’s connectivity architecture play an important role in many psychiatric and neurological brain disorders. Here we show that connections important for global communication and network integration are particularly vulnerable to brain alterations across multiple brain disorders. We report on a cross-disorder connectome study comprising in total 1,033 patients and 1,154 matched controls across 8 psychiatric and 4 neurological disorders. We extracted disorder connectome fingerprints for each of these 12 disorders and combined them into a ‘cross-disorder disconnectivity involvement map’ describing the level of cross-disorder involvement of each white matter pathway of the human brain network. Network analysis revealed connections central to global network communication and integration to display high disturbance across disorders, suggesting a general cross-disorder involvement and the importance of these pathways in normal function.

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Fig. 1: Cross-disorder involvement.
Fig. 2: Edge-wise network measures.
Fig. 3: Rich-club organization.
Fig. 4: Cross-disorder hyperconnectivity.
Fig. 5: Overlap disorder disconnectivity with the cross-disorder involvement map.
Fig. 6: Cross-comparison of cross-disorder grey matter abnormalities and region-wise cross-disorder white matter disconnectivity.

Data availability

The reference connectome dataset was based on data from the HCP, which are available from The datasets ASD II, ASD III and ASD IV were obtained from the ABIDE II database and are available from The datasets Alzheimer’s disease II, MCI II and PTSD II were obtained from the ADNI and DOD ADNI database and are available from The dataset Schizophrenia III was obtained from the COBRE database and is available from The datasets ADHD I, ALS, Alzheimer’s disease I, ASD I, Bipolar disorder, MCI I, MDD, Obesity, OCD, PLS, PTSD I, Schizophrenia I and Schizophrenia II are subject to specific data-sharing restrictions. To inquire about access to the restricted datasets, please contact the corresponding author.

Code availability

All codes used are available from the corresponding author on reasonable request.


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M.P.v.d.H. was funded by an ALW open (ALWOP.179) and VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and a Fellowship of MQ. The Muenster Depression Cohort was funded by the German Research Foundation (DFG; grant FOR2107 DA1151/5-1 and DA1151/5-2 to U.D.); SFB-TRR58 (projects C09 and Z02 to U.D.) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to U.D.). K.K. was funded by the DFG (grant KO3744/7-1). N.E.M.v.H. was supported by the VIDI grant 452-11-014 from the NWO. M.H.J.H. received research support from The European Community’s Health Seventh Framework Programme (grant agreement no. F2-2008-222968), NARSAD Brain and Behavior Foundation (grant no. 20244) and The Netherlands Organization for Health Research and Development (MARIO grant no. 636100004). Data collection and sharing for this project were funded by the ADNI (National Institutes of Health (NIH) grant U01 AG024904) and Department of Defense ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica; Biogen; Bristol-Myers Squibb; CereSpir; Cogstate; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Lumosity; Lundbeck; Merck & Co.; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH ( The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California (Los Angeles, CA, USA). ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. COBRE data were downloaded from the Collaborative Informatics and Neuroimaging Suite Data Exchange tool (COINS;, and data collection was performed at the Mind Research Network and funded by the Center of Biomedical Research Excellence (COBRE) grant 5P20RR021938/P20GM103472 from the NIH to V. Calhoun. Data obtained from the SchizConnect database were funded by the NIMH cooperative agreement 1U01 MH097435. The database ABIDE II is primarily funded by NIMH 5R21MH107045. Data were provided in part by the HCP, WU-Minn Consortium (Principal Investigators: D. V. Essen and K. Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University (St. Louis, MO, USA). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

M.P.v.d.H. conceived the project. S.C.d.L. analysed the data. M.P.v.d.H. and S.C.d.L. wrote the manuscript. L.H.S. provided expertise and feedback on the manuscript. L.H.v.d.B., M.P.B., M.B., W.C., U.D., S.D., E.G., N.E.M.v.H, M.H.J.H., K.K., M.A.J., M.M., I.M.-I., S.M., R.A.O., T.J.R., J.R. and R.S.K. contributed data and provided feedback on the manuscript. Data used in preparation of this article were obtained from the ADNI database ( As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete list of the ADNI investigators can be found at:

Correspondence to Martijn P. van den Heuvel.

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Competing interests

L.H.v.d.B. serves on scientific advisory boards for Orion, Biogen and Cytokinetics; received an educational grant from Baxalta; serves on the editorial boards of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and the Journal of Neurology, Neurosurgery, and Psychiatry; and receives research support from the Prinses Beatrix Spierfonds, the Netherlands ALS Foundation, The European Community’s Health Seventh Framework Programme (grant agreement no. 259867) and The Netherlands Organization for Health Research and Development (Vici Scheme, JPND (SOPHIA, STRENGTH, ALSCare)). All other authors declare no competing interests.

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Supplementary Methods 1–3, Supplementary Results 1–12, Supplementary Note, Supplementary References, Supplementary Figs. 1–12 and Supplementary Tables 1–6.

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