Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression

Leanne M. Williams, John T. Coman, Patrick C. Stetz, Nicole C. Walker, F. Andrew Kozel, Mark S. George, Jong Yoon, Laura M. Hack, Michelle R. Madore, Kelvin O. Lim, Noah S. Philip, Paul E. Holtzheimer

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background: Although repetitive transcranial magnetic stimulation (‘TMS’) is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran’s Health Administration. Methods: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at ‘baseline’ pre-TMS commencement, ‘first week’ after initiation of TMS (targeting five sessions) and ‘post-treatment’ at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age. Discussion: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment. Trial registration: NCT04663481, December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

Original languageEnglish (US)
Article number35
JournalBMC Psychiatry
Issue number1
StatePublished - Jan 13 2021

Bibliographical note

Funding Information:
Bryon Mueller from Center for Magnetic Resonance Research at the University of Minnesota and Adam Kerr and Hua Wu from the Center for Cognitive and Neurobiological Imaging at Stanford University helped to harmonize the protocols between the GE and Siemens scanners.

Funding Information:
This study is funded by the National Institutes of Mental Health (NIMH), Grant number R01MH120126. The NIMH has approved this study but was not involved in its planning or design and will not play any role in study management, data analysis, interpretation or publication of its findings.

Publisher Copyright:
© 2021, The Author(s).


  • Biomarker
  • Cognitive control network
  • Default mode network (DMN)
  • Dorsolateral prefrontal cortex (DLPFC)
  • Functional magnetic resonance imaging (fMRI)
  • Major depressive disorder (MDD)
  • Neuroimaging
  • Repetitive Transcranial magnetic stimulation (TMS)
  • Treatment resistant depression (TRD)
  • Veterans

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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