Identification of neurobehavioural symptom groups based on shared brain mechanisms

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Abstract

Most psychopathological disorders develop in adolescence. The biological basis for this development is poorly understood. To enhance diagnostic characterization and develop improved targeted interventions, it is critical to identify behavioural symptom groups that share neural substrates. We ran analyses to find relationships between behavioural symptoms and neuroimaging measures of brain structure and function in adolescence. We found two symptom groups, consisting of anxiety/depression and executive dysfunction symptoms, respectively, that correlated with distinct sets of brain regions and inter-regional connections, measured by structural and functional neuroimaging modalities. We found that the neural correlates of these symptom groups were present before behavioural symptoms had developed. These neural correlates showed case–control differences in corresponding psychiatric disorders, depression and attention deficit hyperactivity disorder in independent clinical samples. By characterizing behavioural symptom groups based on shared neural mechanisms, our results provide a framework for developing a classification system for psychiatric illness that is based on quantitative neurobehavioural measures.

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Fig. 1: Results of the first msCCA-regression analysis showing relationships between anxiety/depression psychiatric symptoms and neuroimaging measures in the IMAGEN sample.
Fig. 2: Results of the second msCCA-regression analyses showing relationships between executive dysfunction symptoms and neuroimaging measures in the IMAGEN sample, following the removal of the first canonical relation.
Fig. 3: Longitudinal analysis of canonical correlates.
Fig. 4: Differences in the grey matter correlates of anxiety/depression and executive dysfunction psychiatric symptoms between cases and controls for a range of psychiatric illnesses.

Data availability

The IMAGEN data used in this investigation will be made available on reasonable request to the corresponding author. All other data are available on reasonable request to the appropriate study leader.

Code availability

The core code used to run the analyses reported in this study are available as Supplementary Software. The supporting code can be found at: https://github.com/alexjamesing/mscca-regression-code.

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Acknowledgements

This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (reinforcement-related behaviour in normal brain function and psychopathology; grant no. LSHM-CT-2007-037286), the Horizon 2020-funded ERC Advanced Grant STRATIFY (brain-network-based stratification of reinforcement-related disorders; grant no. 695313), ERANID (understanding the interplay between cultural, biological and subjective factors in drug use pathways; grant no. PR-ST-0416-10004), BRIDGET (JPND: brain imaging, cognition, dementia and next generation genomics; grant no. MR/N027558/1), the Human Brain Project (HBP SGA 2, grant no. 785907), the FP7 project MATRICS (grant no. 603016), the Medical Research Council Grant c-VEDA (Consortium on Vulnerability to Externalizing Disorders and Addictions; grant no. MR/N000390/1), the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministerium für Bildung und Forschung (BMBF grant nos. 01GS08152 and 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B, 01ZX1314G, 01GS08147), the Deutsche Forschungsgemeinschaft (DFG grant nos. SM 80/7-2, SFB 940/2), the Medical Research Foundation and Medical Research Council (grant nos. MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH)-funded ENIGMA (grant nos. 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: ANR (project AF12-NEUR0008-01-WM2NA and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the NIH, Science Foundation Ireland (grant no. 16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; grant no. RO1 MH085772-01A1) and NIH Consortium grant no. U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. A.M. gratefully acknowledges funding from the Netherlands Organization for Scientific Research via the Vernieuwingsimpuls VIDI programme (grant no. 016.156.415). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

A.I., C.C., I.M.V., P.G.S., H.L., T.J. and G.R. preprocessed the data. A.I. and P.G.S. analysed the data. A.I., G.S., F.B. and P.G.S. wrote the manuscript. A.I., G.S., T.W.R., A.M., J.A. and E.B. conceptualized the study. N.T., E.B.Q., T.W., S.D., T.B., A.L.W.B., U.B., C.B., P.C., T.F., H.F., V.F., H.G., P.S., P.G., Y.G., A.H., B.I., V.K., J.-L.M., A.M.-L., F.N., B.v.N., D.P.O., M.-L.P.M., S.M., J.P., L.P., M.S., A.S., M.N.S., H.W., R.W., O.A.A., I.A., E.D.B. and J.B. collected data. A.I. and N.T. prepared the figures. All authors revised the manuscript.

Correspondence to Gunter Schumann.

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Competing interests

T.B. served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH and Shire. He received conference support or a speaker’s fee from Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire and Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien and Oxford University Press. The present work is unrelated to the above grants and relationships. E.D.B. received honoraria from General Electric Healthcare for teaching on scanner programming courses and acts as a consultant for IXICO. O.A.A. received a speaker’s honorarium from Lundbeck. G.R. received financial support from scientific meetings (Janssen & Janssen, Otsuka−Lundbeck). A.M.-L. received consultant fees from Boehringer Ingelheim, Brainsway, Elsevier, Lundbeck Int. Neuroscience Foundation and Science Advances. The other authors declare no competing interests.

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Supplementary Information

Supplementary Information

Supplementary Figs. 1−10, and Tables 1−9, and Supplementary Note (containing the list of authors for the IMAGEN Consortium).

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Supplementary Software

This msCCA script forms the basis of the msCCA-regression approach used in the present investigation.

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Ing, A., Sämann, P.G., Chu, C. et al. Identification of neurobehavioural symptom groups based on shared brain mechanisms. Nat Hum Behav 3, 1306–1318 (2019) doi:10.1038/s41562-019-0738-8

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