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. 2021 Jan 13;21(1):35.
doi: 10.1186/s12888-020-03030-z.

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  1   2 , John T Coman  3   4 , Patrick C Stetz  3   4 , Nicole C Walker  4 , F Andrew Kozel  5   6 , Mark S George  7   8 , Jong Yoon  3   4 , Laura M Hack  3   4 , Michelle R Madore  3   4 , Kelvin O Lim  9   10 , Noah S Philip  11   12 , Paul E Holtzheimer  13   14
Affiliations

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 et al. BMC Psychiatry. .

Abstract

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: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

Keywords: 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.

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Conflict of interest statement

LMW, LMH, MRM, KOL, JHY, JTC, PCS and NCW have no competing interests. NSP served as an unpaid advisory board member for Microtransponder Neuronetics. FAK was an unpaid consultant for Microtransponder Neuronetics. MSG was a consultant for Puretech Ventures and unpaid consultant for Microtransponder Neuronetics, Mecta, Magstim and Brainsway. MSG served as a Journal Editor for Elsevier Press and as a Data Safety Monitoring Board member for Microtransponder Neuronetics. PEH is a consultant for Abbot and receives royalties from UpToDate and Oxford University Press.

Figures

Fig. 1
Fig. 1
Procedural Diagram. All veterans that consent to research and meet eligibility criteria will follow this procedural diagram. Veterans will attend four research assessment sessions (highlighted in orange). ‘Baseline’ refers to the research assessment session prior to commencement of TMS treatment, ‘1 Week’ to the assessment session undertaken after a target of five sessions of TMS treatment, and ‘Post-treatment’ to assessment sessions undertaken following the completion of the full course of TMS treatment which is typically 30 treatment sessions.*The MINI-7 is the only Sample Characteristic and Eligibility Measure that will be given at the Enrollment Visit instead of the Baseline research session
Fig. 2
Fig. 2
GoNoGo and N-Back Tasks. A visual summary of the GoNoGo paradigm [38] (left) and the N-Back working memory paradigm [39] (right) for probing the cognitive control network during functional neuroimaging
See this image and copyright information in PMC

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