Leanne M Williams1,2, John T Coman3,4, Patrick C Stetz3,4, Nicole C Walker4, F Andrew Kozel5,6, Mark S George7,8, Jong Yoon3,4, Laura M Hack3,4, Michelle R Madore3,4, Kelvin O Lim9,10, Noah S Philip11,12, Paul E Holtzheimer13,14. 1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA, 94304, USA. leawilliams@stanford.edu. 2. Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA, 94304, USA. leawilliams@stanford.edu. 3. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA, 94304, USA. 4. Mental Illness Research, Education and Clinical Center, VA Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA, 94304, USA. 5. Department of Behavioral Sciences and Social Medicine, Florida State University, 1115 W Call St, Tallahassee, FL, 32304, USA. 6. Department of Psychiatry and Behavioral Neurosciences, University of South Florida, 3515 E Fletcher Ave, Tampa, FL, 33613, USA. 7. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 96 Jonathan Lucas St. Ste. 601, MSC 617, Charleston, SC, 29425, USA. 8. Ralph H. Johnson VA Medical Center, Charleston, SC, USA. 9. Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN, 55455, USA. 10. Minneapolis VA Health Care System, 1 Veterans Dr, Minneapolis, MN, 55417, USA. 11. Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, 345 Blackstone Boulevard, Providence, RI, 02908, USA. 12. VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Ave, Providence, RI, 02908, USA. 13. Departments of Psychiatry and Surgery, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH, 03756, USA. 14. Executive Division, National Center for PTSD, White River Junction VA Medical Center, 215 North Main St., White River Junction, VT, 05009, USA.
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.
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.
Entities:
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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