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


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.

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Fig. 1: Lesion locations and brain stimulation sites across 14 datasets.
Fig. 2: Identifying depression circuit maps for each cohort.
Fig. 3: Depression circuit maps are similar across 14 datasets (n = 713).
Fig. 4: Depression circuit maps are similar across lesions, neuromodulation and diagnoses.
Fig. 5: Combining all circuit maps and predicting clinical variance.

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

All custom MATLAB code used in this study is available upon reasonable request from the corresponding author.


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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.

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Authors and Affiliations



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.

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Correspondence to Shan H. Siddiqi.

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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.

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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.

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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).

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