Functional Connectivity Mapping for rTMS Target Selection in Depression
Publication: American Journal of Psychiatry
Abstract
Objective:
Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cortex (sgACC) functional connectivity to individualize treatment targets. However, the efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site’s functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression.
Methods:
The reliability and accuracy of estimating sgACC functional connectivity were validated with data from individuals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations between sgACC-StimFC and clinical improvement using standardized assessments and to evaluate sources of heterogeneity.
Results:
An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=−0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=−0.49).
Conclusions:
Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration-related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ∼3% of the variance in outcomes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true—albeit small—effect and highlight opportunities for incorporating additional functional connectivity measures to generate models of rTMS response with enhanced predictive power.
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History
Received: 5 April 2022
Revision received: 9 August 2022
Revision received: 27 September 2022
Accepted: 17 October 2022
Published online: 1 March 2023
Published in print: March 01, 2023
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Funding Information
Supported by a grant from the Canadian Institutes of Health Research (CIHR) (MOP-136801) and by the Temerty Family Foundation, the Grant Family Foundation, and the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH) and Tina Buchan and the Buchan Family Fund through the University Health Network (Drs. Blumberger and Downar). This work was also supported by grants from the Foundation for OCD Research, the Hope for Depression Research Foundation, NIDA (DA047851), NIMH (MH109685, MH118451, MH118388, and MH123154), and the Rita Allen Foundation (Dr. Liston). MagVenture provided in-kind equipment support in the form of two coils and two high-performance coolers at each site.Dr. Downar has received research support from the Arrell Family Foundation, Brain Canada, the Buchan Family Foundation, the Canadian Biomarker Integration Network in Depression, CIHR, the Klarman Family Foundation, NIH, the Ontario Brain Institute, the Toronto General and Western Hospital Foundation, and the Weston Family Foundation; he has received travel stipends from ANT Neuro and Lundbeck; he has served as an adviser for BrainCheck, Restorative Brain Clinics, and TMS Neuro Solutions; and he has equity ownership in Neurostim TMS Centers, Restorative Brain Clinics, and Salience Neuro Health. Dr. Vila-Rodriguez has received research support from Brain Canada, CIHR, the Michael Smith Foundation for Health Research, the Vancouver Coastal Health Research Institute, and the Weston Brain Institute for investigator-initiated research; he has received philanthropic support from the Seedlings Foundation; he has received in-kind equipment support for this investigator-initiated trial from MagVenture; and he has received honoraria for participation on an advisory board for Janssen. Dr. Daskalakis has received research and equipment in-kind support for an investigator-initiated study through BrainsWay and MagVenture and industry-initiated trials through Magnus Medical; he has received research support from Brain Canada, CIHR, and NIMH and from the Temerty Family Foundation and the Grant Family Foundation through the CAMH Foundation and the Campbell Institute; and he has served on the scientific advisory board for BrainsWay. Dr. Blumberger has received research support from Brain Canada, CIHR, NIH, and the Temerty Family Foundation through the CAMH Foundation and Campbell Institute; he has received research support and in-kind equipment support and was the site principal investigator for sponsor-initiated studies from BrainsWay; he has received in-kind equipment support from MagVenture for investigator-initiated studies; he has received medication supplies for an investigator-initiated trial from Indivior; and he has served on advisory boards for Janssen and Welcony. Dr. Liston has received research support from the Foundation for OCD Research, the Hope for Depression Research Foundation, NIDA, NIMH, and the Rita Allen Foundation; he is listed as an inventor for Cornell University patent applications on neuroimaging biomarkers for depression that are pending or in preparation; and he has served as a scientific adviser or consultant for Brainify.AI, Compass Pathways, Delix Therapeutics, and Magnus Medical. The other authors report no financial relationships with commercial interests.
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