Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease

S.H. Siddiqi*, F.L.W.V.J. Schaper, A. Horn, J. Hsu, J.L. Padmanabhan, A. Brodtmann, R.F.H. Cash, M. Corbetta, K.S. Choi, D.D. Dougherty, N. Egorova, P.B. Fitzgerald, M.S. George, S.A. Gozzi, F. Irmen, A.A. Kuhn, K.A. Johnson, A.M. Naidech, A. Pascual-Leone, T.G. PhanR.P.W. Rouhl, S.F. Taylor, J.L. Voss, A. Zalesky, J.H. Grafman, H.S. Mayberg, M.D. Fox

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Web of Science)


Which brain circuits are causally involved in depression? Using the human connectome as a wiring diagram, Siddiqi et al. combine data from lesions, deep brain stimulation and transcranial magnetic stimulation studies to show that these three methods converge in identifying a single depression circuit.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 disorders.
Original languageEnglish
Pages (from-to)1707-1716
Number of pages13
JournalNature human behaviour
Issue number12
Early online date8 Jul 2021
Publication statusPublished - Dec 2021


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