Targeting location relates to treatment response in active but not sham rTMS stimulation

A C Rosen; J V Bhat; V A Cardenas; T J Ehrlich; A M Horwege; D H Mathalon; B J Roach; G H Glover; B W Badran; S D Forman; M S George; M E Thase; D Yurgelun-Todd; M E Sughrue; S P Doyen; P J Nicholas; J C Scott; L Tian; J A Yesavage

doi:10.1016/j.brs.2021.04.010

Targeting location relates to treatment response in active but not sham rTMS stimulation

Brain Stimul. 2021 May-Jun;14(3):703-709. doi: 10.1016/j.brs.2021.04.010. Epub 2021 Apr 15.

Authors

A C Rosen¹, J V Bhat², V A Cardenas³, T J Ehrlich⁴, A M Horwege³, D H Mathalon⁵, B J Roach⁶, G H Glover⁷, B W Badran⁸, S D Forman⁹, M S George¹⁰, M E Thase¹¹, D Yurgelun-Todd¹², M E Sughrue¹³, S P Doyen¹⁴, P J Nicholas¹⁴, J C Scott¹¹, L Tian¹⁵, J A Yesavage¹⁶

Affiliations

¹ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry, Stanford University, Stanford, CA, 94305, USA. Electronic address: rosena@stanford.edu.
² Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, 94304, USA.
³ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
⁴ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; University of Michigan, Ann Arbor, USA.
⁵ Mental Health Service, San Francisco Veterans Affairs Health Care System, University of California, San Francisco, CA, USA; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA.
⁶ Mental Health Service, San Francisco Veterans Affairs Health Care System, University of California, San Francisco, CA, USA; Northern California Institute for Research and Education, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.
⁷ Department of Radiology, Stanford University, Stanford, CA, USA.
⁸ Brain Stimulation Division, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
⁹ Department of Veterans Affairs, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁰ Brain Stimulation Division, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA; Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
¹¹ VISN4 Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Rocky Mountain Network Mental Illness Research Education and Clinical Centers (VISN 19), VA Salt Lake City Health Care System, Salt Lake City, UT, USA; Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹³ Omniscient Neurotechnologies, Sydney, Australia; Prince of Wales Hospital, Randwick, NSW, Australia.
¹⁴ Omniscient Neurotechnologies, Sydney, Australia.
¹⁵ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry, Stanford University, Stanford, CA, 94305, USA.

Abstract

Background: Precise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression.

Objective: To use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations.

Methods: An imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks.

Results: The average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P < .001) while the nonresponder location did not (P = .17), a finding replicated in independent cohorts of 84 depressed and 35 neurotypical participants. The responder and nonresponder stimulation locations evoked different seed based networks (FDR corrected clusters, all P < .03), revealing additional brain regions related to rTMS treatment outcome.

Conclusion: These results provide evidence from a randomized controlled trial that clinical response to rTMS is related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate. These results support the validity of a neuro-functionally informed rTMS therapy target in Veterans.

Keywords: Depression; Dorsolateral prefrontal cortex; Resting-state fMRI networks; Subgenual cingulate; Targeting; rTMS.

Publication types

Randomized Controlled Trial
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Brain / diagnostic imaging
Depressive Disorder, Treatment-Resistant*
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Prefrontal Cortex
Transcranial Magnetic Stimulation*
Treatment Outcome

Abstract

Publication types

MeSH terms

Grants and funding