Acute Perturbations of Whole-Brain and Triple-Network Connectivity During Low- Frequency-Right TMS for Treatment...

Concurrent transcranial magnetic stimulation and functional magnetic resonance imaging (TMS-fMRI) provides a mechanism for assessing the acute effects of transcranial magnetic stimulation (TMS) on functional connectivity (FC), allowing a unique perspective of how TMS induces antidepressant effects over the course of treatment. The aim of this secondary analysis of clinical trial data was to interrogate the relevance of the triple network theory in low-frequency TMS to the right dorsolateral prefrontal cortex (DLPFC) (low-frequency repetitive TMS [LFR]) by assessing perturbations in salience (SN), control (CN), and default mode (DMN) networks during TMS-fMRI.

A total of 38 subjects with treatment-resistant depression underwent one session of concurrent TMS-fMRI at 1 Hz to the right DLPFC (LFR), with resting-state scans acquired immediately before and after. Patients subsequently underwent a four-week treatment course using the same protocol. Whole-brain FC was computed, as well as within- and between- network FC for the SN, CN, and DMN for each scan. FC modulation scores were computed to capture changes between resting-state and TMS-fMRI and were used to test for relationships between acute changes in FC during a single repetitive TMS treatment and clinical outcomes after a course of treatment.

Whole-brain FC decreased during the TMS-fMRI scan, as did within- and between-network FC for the SN, CN, and DMN. Resting-state scans acquired immediately before and after TMS-fMRI showed no differences in FC. After the four-week treatment course, eight subjects were classified as remitters (21%), eight subjects were responders but fell short of remission (21%), with the remaining 22 subjects (58%) showing nonresponse. FC modulation scores for the whole-brain were significantly associated with decreased depression scores at the end of treatment. Between-network FC modulation was initially correlated with clinical improvement, but these correlations did not persist when controlling for whole-brain FC modulation. When tested using predictive modeling, both whole-brain and network-level data significantly predicted treatment outcomes, with modulation involving SN predicting outcomes as effectively as whole-brain models.

LFR acutely disrupts FC at a global, whole-brain level that encompasses the triple networks. Modulation of the SN-CN and SN-DMN connectivity hold predictive value for clinical improvement comparable with that of global, whole-brain connectivity. This widespread global disruption may be an important mechanism through which TMS exerts antidepressant effects. Limitations include the use of atlas-based network definitions, small sample, and generalizability limited to LFR protocols only.