Transcranial magnetic stimulation (TMS) to the left dorsal-lateral prefrontal cortex (DLPFC) can be useful in the treatment of depression, and the Neuronetics(R)'Neurostar TMS protocol was approved in October of 2008 by the Food and Drug Administration for therapy of certain forms of medication-resistant depression. However, clinical responses are heterogeneous and effect size can be limited. One factor known to contribute to this response variability is differences in the specific site of stimulation in and around the DLPFC. Recent evidence from our lab suggests that the efficacy of different DLPFC targets is related to the connectivity of each target site with deeper limbic regions, specifically the subgenual cingulate. Based on these findings, we have proposed a novel connectivity-based targeting approach to identify the optimal stimulation site in individual patients to maximize antidepressant response. The goal of this project is to empirically validate this approach in actual patients undergoing TMS for depression. Patients referred for treatment by their psychiatrist and found eligible for the FDA-approved Neurostar TMS protocol will be eligible for the study. Participants will undergo an MRI scan including sequences specific to resting state functional connectivity MRI (rs-fcMRI) prior to a four week TMS treatment course (daily sessions Monday to Friday on four consecutive weeks) using FDA approved parameters. The site of TMS administration in each patient will be defined according to the FDA approved Neurostar protocol, but recorded with a noninvasive stereotactic registration system. Clinical antidepressant response to the TMS treatment paradigm will be assessed using the Hamilton Depression Rating Scale (HDRS). Upon completion of the TMS treatment course, clinical response (change in HDRS) will be evaluated as a function of the functional connectivity of the stimulation site as characterized by rs-fcMRI. Our hypothesis is that patients with better clinical response (greater change in HDRS) will show stronger functional connectivity between the stimulation site and deep limbic regions, especially the subgenual. Further, we hypothesize that patients with better clinical response will show a closer approximation between their actual stimulation site and their "optimal" stimulation site identified with our connectivity-based targeting technique. Should these hypotheses prove correct, the results would lend important insight into the antidepressant mechanism of TMS in depression and provide the foundation for a larger randomized clinical trial to better individually tailor TMS and thus improve its antidepressant efficacy across patients.

Public Health Relevance

In October of 2008, the Food and Drug Administration approved transcranial magnetic stimulation (TMS) using the Neuronetics(R)'Neurostar protocol for the treatment of certain forms of medication-resistant major depressive disorder (MDD). Since there has been a rapid increase in its use, but the efficacy of TMS for MDD remains variable across patients and can be of limited clinical significance. Recent work suggests that an important factor underlying response variability is differences in stimulation site and the connectivity of these sites to deeper limbic regions such as the subgenual cingulate. We propose a novel connectivity-based targeting approach for TMS to optimize the stimulation site and thus antidepressant response in individual patients. The aim of the present application is to validate this approach in actual patients undergoing TMS for depression. We hypothesize that among patients undergoing TMS following the approved FDA protocol, those with better antidepressant response will show (1) greater connectivity between their specific stimulation site and the subgenual cingulate and (2) closer approximation between their actual stimulation site and an optimal site identified with our novel targeting technique. We propose to test these hypotheses with resting state functional connectivity magnetic resonance imaging (MRI) in patients receiving therapeutic TMS following the FDA approved protocol at one of two established clinical programs (Berenson-Allen Center at BIDMC or McLean Hospital). Experimental support for our hypotheses will validate our connectivity-based targeting strategy and set the stage for a randomized clinical trial to improve antidepressant response to TMS.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Interventions Committee for Adult Disorders (ITVA)
Program Officer
Rumsey, Judith M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Halko, Mark A; Farzan, Faranak; Eldaief, Mark C et al. (2014) Intermittent theta-burst stimulation of the lateral cerebellum increases functional connectivity of the default network. J Neurosci 34:12049-56
Fox, Michael D; Buckner, Randy L; Liu, Hesheng et al. (2014) Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proc Natl Acad Sci U S A 111:E4367-75
Oberman, Lindsay M; Pascual-Leone, Alvaro (2014) Hyperplasticity in Autism Spectrum Disorder confers protection from Alzheimer's disease. Med Hypotheses 83:337-42