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Cited by 375Transcranial Magnetic Stimulation StudiesNeurological disorders and treatmentsTreatment of Major Depression

Distinct symptom-specific treatment targets for circuit-based neuromodulation

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Siddiqi, Shan H., Taylor, Stephan F., Cooke, Danielle, Pascual-Leone, Alvaro, George, Mark S., Fox, Michael D.·2020·American Journal of Psychiatry
DOI 10.1176/appi.ajp.2019.19090915PMC PMC8396109
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Abstract

OBJECTIVE: Treatment of different depression symptoms may require different brain stimulation targets with different underlying brain circuits. The authors sought to identify such targets, which could improve the efficacy of therapeutic brain stimulation and facilitate personalized therapy. METHODS: The authors retrospectively analyzed two independent cohorts of patients who received left prefrontal transcranial magnetic stimulation (TMS) for treatment of depression (discovery sample, N=30; active replication sample, N=81; sham replication sample, N=87). Each patient's TMS site was mapped to underlying brain circuits using functional connectivity MRI from a large connectome database (N=1,000). Circuits associated with improvement in each depression symptom were identified and then clustered based on similarity. The authors tested for reproducibility across data sets and whether symptom-specific targets derived from one data set could predict symptom improvement in the other independent cohort. RESULTS: The authors identified two distinct circuit targets effective for two discrete clusters of depressive symptoms. Dysphoric symptoms, such as sadness and anhedonia, responded best to stimulation of one circuit, while anxiety and somatic symptoms responded best to stimulation of a different circuit. These circuit maps were reproducible, predicted symptom improvement in independent patient cohorts, and were specific to active compared with sham stimulation. The maps predicted symptom improvement in an exploratory analysis of stimulation sites from 14 clinical TMS trials. CONCLUSIONS: Distinct clusters of depressive symptoms responded better to different TMS targets across independent retrospective data sets. These symptom-specific targets can be prospectively tested in a randomized clinical trial. This data-driven approach for identifying symptom-specific targets may prove useful for other disorders and facilitate personalized neuromodulation therapy.

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  • Most clinical rTMS treatments for MDD occur daily and are applied using scalp-based targeting of DLPFC; these standard treatments are only modestly effective, even in the general MDD population.

    “Most clinical rTMS treatments for MDD occur daily (one rTMS session per day) and are applied using scalp-based targeting of DLPFC. These standard treatments are only modestly effective, even in the general MDD population (17, 24–31).”

    From Adaptive trial for the treatment of depressive symptoms associated with concussion using accelerated intermittent theta burst stimulation (ADEPT): rationale, design and methods (2025) · cites this paper as [30]

    The paper says clinical TMS targeting is usually based on scalp measurements, and Methods > Subjects and Data Collection describes stimulation of the left DLPFC in two cohorts with treatment-resistant depression (page unavailable). It does not establish that most clinical treatments involve one session per day or that standard treatments are only modestly effective in the general MDD population; searches for daily scheduling and modest efficacy did not resolve those points. (LLM, conf=0.84)

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Authors
Siddiqi, S. H., Taylor, S. F., Cooke, D., Pascual-Leone, A., George, M. S., & Fox, M. D.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Department of Psychiatry (Siddiqi) and Department of Neurology (Pascual-Leone, Fox), Harvard Medical School, Boston; Berenson-Allen Center for Noninvasive Brain Stimulation (Siddiqi, Cooke, Fox), and Cognitive Neurology Unit, Department of Neurology (Siddiqi), Beth Israel Deaconess Medical Center, Boston; Division of Neurotherapeutics, McLean Hospital, Belmont, Mass. (Siddiqi); Department of Psychiatry, Washington University School of Medicine, St. Louis (Siddiqi); Center for Neuroscience and...
ORCID
Venue
American Journal of Psychiatry
Publisher
American Psychiatric Association Publishing
Published
2020-05-01
Volume
177
Issue
5
Pages
435-446
ISSN
  • 0002-953X (ISSN-L)
  • 1535-7228
DOI
10.1176/appi.ajp.2019.19090915
PMC
PMC8396109
OpenAlex
W3011443824
Cited by
375
References
66
Citations by year
2026: 64 · 2025: 78 · 2024: 66 · 2023: 51 · 2022: 46 · 2021: 49 · 2020: 20 · 2019: 1
FWCI
16.07
Type
journal article
Language
en
Open access
Locations
  • American Journal of Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01MH113929)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P2CHD086844)
Topics
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
depression, transcranial magnetic stimulation, brain circuits, functional connectivity MRI, connectome, dysphoric symptoms, anhedonia, anxiety symptoms, somatic symptoms, personalized neuromodulation, left prefrontal cortex
MeSH terms
Brain Mapping, Depression, Humans, Neural Pathways, Retrospective Studies, Cohort Studies, Cluster Analysis, Treatment Outcome, Transcranial Magnetic Stimulation, Datasets as Topic

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