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ABSTRACT Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether

these circuits converge, we studied depression severity after brain lesions (_n_ = 461, five datasets), transcranial magnetic stimulation (_n_ = 151, four datasets) and deep brain

stimulation (_n_ = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (_P_ < 

0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (_P_ < 0.0005), as were circuits derived from patients with major

depression versus other diagnoses (_P_ < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain

stimulation sites (_P_ < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson’s disease (_P_ < 

0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other

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CONTENT BEING VIEWED BY OTHERS CLOSING THE LOOP IN PSYCHIATRIC DEEP BRAIN STIMULATION: PHYSIOLOGY, PSYCHOMETRICS, AND PLASTICITY Article 06 July 2023 ELECTROCONVULSIVE THERAPY-INDUCED

VOLUMETRIC BRAIN CHANGES CONVERGE ON A COMMON CAUSAL CIRCUIT IN DEPRESSION Article Open access 20 November 2023 TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) IN DEPRESSION INDUCES

STRUCTURAL PLASTICITY Article Open access 17 February 2023 DATA AVAILABILITY STATEMENT This paper used de-identified data from 14 different datasets collected by 14 different teams of

investigators at various institutions across four different countries. Each dataset is available upon reasonable request from each respective team of investigators. Data sharing will be

subject to the policies and procedures of the institution where each dataset was collected as well as the laws of the country where each dataset was collected. CODE AVAILABILITY STATEMENT

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Scholar  Download references ACKNOWLEDGEMENTS The authors thank all research participants, funding bodies, allied health staff and other research staff that made this work possible. The

present work was supported by the Sidney R. Baer Foundation (S.H.S., J.L.P., M.D.F.), the Brain & Behavior Research Foundation (SHS) and the National Institute of Mental Health (grant

no. K23MH121657 to S.H.S.; grant nos. R01MH113929 and R01MH115949 to M.D.F.). The funders were not directly involved in the conceptualization, design, data collection, analysis, decision to

publish or preparation of the manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Brain Circuit Therapeutics, Brigham and Women’s Hospital, Boston, MA, USA Shan H. Siddiqi, 

Frederic L. W. V. J. Schaper, Andreas Horn, Jaya L. Padmanabhan & Michael D. Fox * Department of Psychiatry, Harvard Medical School, Boston, MA, USA Shan H. Siddiqi & Darin D.

Dougherty * Department of Neurology, Harvard Medical School, Boston, MA, USA Frederic L. W. V. J. Schaper, Andreas Horn, Alvaro Pascual-Leone & Michael D. Fox * Department of Neurology,

Maastricht University Medical Center, Maastricht, the Netherlands Frederic L. W. V. J. Schaper & Rob P. W. Rouhl * Movement Disorders and Neuromodulation Unit, Department for Neurology,

Charité University Medicine Berlin, Berlin, Germany Andreas Horn & Andrea A. Kuhn * University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Joey Hsu * Melbourne Neuropsychiatry

Centre, The University of Melbourne, Melbourne, Victoria, Australia Amy Brodtmann, Robin F. H. Cash & Andrew Zalesky * Department of Biomedical Engineering, The University of Melbourne,

Melbourne, Victoria, Australia Robin F. H. Cash & Andrew Zalesky * Department of Neuroscience, Padova Neuroscience Center (PNC), Venetian Institute of Molecular Medicine (VIMM),

University of Padova, Padova, Italy Maurizio Corbetta * Departments of Neurology, Radiology, Bioengineering, and Neuroscience, Washington University, St. Louis, MO, USA Maurizio Corbetta *

Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA Ki Sueng Choi & Helen S. Mayberg * Department of Psychiatry,

Massachusetts General Hospital, Boston, MA, USA Darin D. Dougherty * Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Victoria, Australia Natalia Egorova * The

Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia Natalia Egorova * Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University

Department of Psychiatry, Camberwell, Victoria, Australia Paul B. Fitzgerald * Brain Stimulation Laboratory, Psychiatry Department, Medical University of South Carolina, Charleston, SC, USA

Mark S. George * Ralph H. Johnson VA Medical Center, Charleston, SC, USA Mark S. George * Department of Neurology, Monash Health and Department of Medicine, School of Clinical Sciences,

Monash University, Clayton, Victoria, Australia Sophia A. Gozzi & Thanh G. Phan * Department of Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität

Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany Frederike Irmen * School of Medicine, Florida State University, Tallahassee, FL, USA Kevin A. Johnson *

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Andrew M. Naidech, Joel L. Voss & Jordan H. Grafman * Hinda and Arthur Marcus Institute for Aging Research and

Center for Memory Health, Hebrew SeniorLife, Boston, MA, USA Alvaro Pascual-Leone * Guttmann Brain Health Institut, Universitat Autonoma, Barcelona, Spain Alvaro Pascual-Leone * School for

Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands Rob P. W. Rouhl * Academic Center for Epileptology Kempenhaeghe/Maastricht University Medical Center,

Maastricht, the Netherlands Rob P. W. Rouhl * Department of Psychiatry, University of Michigan School of Medicine, Ann Arbor, MI, USA Stephan F. Taylor * Shirley Ryan AbilityLab, Chicago,

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 Google Scholar CONTRIBUTIONS Conception and design of study: S.H.S., A.H. and M.D.F. Design of analytical procedures: S.H.S. and M.D.F. Neuroimaging analyses and statistical analyses:

S.H.S. Preprocessing and preparation of data for analysis: S.H.S., A.H., J.H., J.L.P. and F.S. Contribution of data: A.H., F.S., R.F.H.C., A.B., K.A.J., N.E., A.M.N., S.G., T.G.P., K.S.C.,

F.I., A.K., P.B.F., M.S.G., R.P.W.R., S.F.T., A.Z., J.L.V., M.C., D.D.D., A.P.-L., J.H.G., H.S.M. and M.D.F. Writing of manuscript: S.H.S. and M.D.F. with input from all authors.

CORRESPONDING AUTHOR Correspondence to Shan H. Siddiqi. ETHICS DECLARATIONS COMPETING INTERESTS S.H.S. serves as a clinical consultant for Kaizen Brain Center. S.H.S. and M.D.F. have jointly

received investigator-initiated research support from Neuronetics. None of these organizations were involved in the present work. S.H.S. and M.D.F. each own independent intellectual

property on the use of brain network mapping to target neuromodulation. The present work did not utilize any of this intellectual property. The authors report no other conflicts of interest

related to the present work. ADDITIONAL INFORMATION PEER REVIEW INFORMATION _Nature Human Behaviour_ thanks Nolan Williams and the other, anonymous, reviewer(s) for their contribution to the

peer review of this work. PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION

SUPPLEMENTARY INFORMATION Supplementary Tables 1 and 2 and Supplementary Figs. 1–5. REPORTING SUMMARY RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Siddiqi, S.H., Schaper, F.L.W.V.J., Horn, A. _et al._ Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease. _Nat Hum Behav_ 5, 1707–1716 (2021).

https://doi.org/10.1038/s41562-021-01161-1 Download citation * Received: 30 December 2020 * Accepted: 11 June 2021 * Published: 08 July 2021 * Issue Date: December 2021 * DOI:

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