Targeting Brain Circuits in TMS May Relieve Specific Symptoms of Depression

Transcranial magnetic stimulation (TMS). A magnetic pulse is painlessly applied to the skull by means of a coil. The magnetic flux induces an electric field that modifies the activity of neurons in the brain. Repetitive stimulation emits a series of pulses during a given time interval with the intention of significantly altering the activity of the target area in the brain. This technique is used for therapeutic purposes to treat neurological disorders, such as depression, fibromyalgia, schizophrenia, and hallucinations.
The findings suggest that TMS efficacy may improve when therapy is tailored to patient symptoms, whether dysphoric, anxiety-related, or somatic.

Distinct clusters of depression symptoms responded well to certain transcranial magnetic stimulation (TMS) targets in a study published in the American Journal of Psychiatry. The findings suggest that TMS efficacy may improve when therapy is tailored to patient symptoms, whether dysphoric, anxiety-related, or somatic.

Shan Siddiqi, MD, from the Berenson-Allen Center for Noninvasive Brain Stimulation, Harvard Medical School in Boston, Massachusetts, and colleagues retrospectively analyzed 2 independent cohorts of patients who received TMS for treatment-resistant depression. The discovery cohort comprised 30 patients who received a 4- to 6-week course of clinical TMS. To capture symptom improvements during treatment, the investigators administered the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAM-D).

The replication cohort comprised an active TMS arm (n=81) and a sham arm (n=87), with HAM-D score improvements as the primary outcome. Patients were randomly assigned to receive 3 weeks of either TMS or placebo, followed by optional, open-label TMS for an additional 3 weeks. The researchers mapped the samples’ TMS sites to underlying brain circuits based on resting-state functional magnetic resonance imaging (fMRI) data from a connectome database (n=1000). They clustered stimulation site connectivity maps based on similarities to achieve discrete “symptom-response” circuits and analyzed cluster reproducibility.

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In the discovery dataset, a total of 21 symptom-response maps were computed for each symptom listed on the BDI. Overall, 2 clusters of symptoms emerged: “dysphoric” symptoms, including sadness, anhedonia, and suicidality; and “anxiosomatic” symptoms, including irritability, sexual disinterest, and insomnia. This 2-cluster solution accounted for 73% of the variance across clusters.

A similar 2-cluster solution was observed in the TMS arm of the replication cohort, despite use of a different symptom scale for outcome measures. These symptom-specific circuit maps were not observed in the sham condition, where an optimal 6-cluster solution was observed instead. The dysphoric and anxiosomatic cluster maps were highly reproducible, maintaining significance across 100,000 permutations. In addition, the ratio of dysphoric to anxiosomatic symptom improvement (P <.0001) could be predicted in the discovery cohort using a targeting atlas derived from the replication cohort. The predictive capacity of data derived from the TMS arm was significantly stronger than data derived from the sham arm of the replication set (P <.001).

Overall, symptom-specific circuits were robust and highly reproducible across independent discovery and replication cohorts. As study limitations, the investigators cited the use of separate instruments across study cohorts and inconsistent classification of some symptoms as anxiosomatic vs dysphoric. Nonetheless, they noted that their “approach provides a framework for empirical derivation of symptom-specific treatment targets that may prove useful in other disorders and for other types of focal neuromodulation.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry.

Please see the original reference for a full list of authors’ disclosures.


Siddiqi SH, Taylor SF, Cooke D, Pascual-Leone A, George MS, Fox MD. Distinct symptom-specific treatment targets for circuit-based neuromodulation [published online March 12, 2020]. Am J Psychiatry. doi: 10.1176/appi.ajp.2019.19090915