Joshua C. Brown, MD, PhD
Medical Director, Transcranial Magnetic Stimulation (TMS) Service
Director of Transcranial Magnetic Stimulation Research, Division of Depression and Anxiety Disorders
Director, Brain Stimulation Mechanisms Laboratory
- Member of the Faculty of Psychiatry
Joshua C. Brown, MD, PhD, is a psychiatrist and neurologist. He is medical director of the Transcranial Magnetic Stimulation (TMS) Service and director of TMS research in the Division of Depression and Anxiety Disorders at McLean Hospital. Dr. Brown is also director of the Brain Stimulation Mechanisms Laboratory at McLean. TMS is a safe and effective tool for treatment-resistant depression and obsessive compulsive disorder and has the potential to treat any brain disorder involving cortical networks.
Dr. Brown is working to advance TMS through service on the Clinical TMS Society board of directors and as research committee co-chair. He directs research focused on determining the synaptic-level mechanisms of rTMS, which in turn, can help guide TMS parameter selection and augmentation strategies to maximize TMS benefits for brain disorders. His research uses neurophysiology, including neurophysiology, neuroimaging, and neurobehavioral tasks, to measure TMS effects in combination with relevant receptor-modulation drugs in human subjects.
Dr. Brown directs the Brain Stimulation Mechanisms Laboratory (BSML) at McLean Hospital, which is focused on understanding the neuronal mechanisms of transcranial magnetic stimulation (TMS) and leveraging these mechanisms to improve TMS effectiveness through parameter selection and pharmacologic augmentation strategies.
TMS is a tool capable of modulating brain activity in targeted networks, most likely subserved by changes in the synapse, such as long-term potentiation (LTP) and long-term depression (LTD). Dr. Brown’s lab has done much of the seminal work to understand the synaptic mechanisms of standard-of-care 10-Hz rTMS in humans.
Using neurophysiology and pharmacology, his lab found that 10-Hz rTMS exhibits properties consistent with LTP, including excitatory shifts in input-output curves, apparent occlusion of compound facilitation during intracortical facilitation protocols and homeostatic depression in response to intracortical inhibition protocols, all with sustained potentiation during NMDA receptor activation.
Towards the end of improving TMS effectiveness, their seminal finding that TMS effects could be enhanced with d-cycloserine, an NMDA receptor partial agonist, preceded the transformative clinical trial showing marked improvement in remission and response rates for depression, carried out by collaborator Alex McGirr.
These mechanistic studies are an extension of his earlier mechanistic work demonstrating a critical role for BRAG1, a causal protein in X-linked intellectual disorder (XLID), as a molecular consolidator of memory through removal of less-stable GluA1-type AMPA receptors while concurrently increasing (and possibly replacing) the more stable GluA2-type AMPA receptor expression.
Further work with mice overexpressing neurogranin, a protein causally implicated in schizophrenia and Alzheimer’s disease (AD), set the stage for enhancing TMS effects. These mice developed supraphysiologic memory traits—above that of wild-type mice—suggesting not only an ability to restore, but to enhance brain function.
Neurogranin works by localizing calmodulin within dendritic spines in a manner preferential for LTP, and can be increased by retinol, or vitamin A, suggesting a potential novel therapeutic mechanism for these disorders.
Current work aims to test the role of NMDA and GABA receptors in rTMS modulation with EMG-based motor-evoked potentials (MEPs) and EEG-based TMS-evoked potentials; cortical function through neurobehavioral tasks; and neurotransmitter levels through magnetic resonance spectroscopy (MRS)
Collaborative work further aims to characterize network-level changes through advanced imaging techniques. Preliminary findings have shed light on the comparative role of NMDA and GABA receptors in the two FDA-cleared TMS protocols: 10-Hz and intermittent theta burst (iTBS).
Further, efforts are underway to better understand how rTMS causes brain changes after repeated series of TMS treatments, including accelerated protocols, and to expand the mechanistic work done in the motor cortex of healthy subjects to the dorsolateral prefrontal cortex of depressed brains.
- Prayushi Sharma, Clinical Research Assistant
- Tracy Barbour, MD, Massachusetts General Hospital
- Joan Camprodon, MD, PhD, Massachusetts General Hospital
- Linda Carpenter, MD, Butler Hospital/Brown University School of Medicine
- Kevin Caulfield, PhD, Medical University of South Carolina
- Leo Chen, MD, Melbourne University, Australia
- Jeff Daskalakis, MD, PhD, University of California San Diego
- Nick Folk, PhD, Beth Israel Deaconess Medical Center
- Michael Fox, MD, PhD, Brigham and Women’s Hospital
- Michael Frank, PhD, Brown University
- Pete Fried, PhD, Beth Israel Deaconess Medical Center
- Andy Fukuda, MD, PhD, Butler Hospital/Brown University School of Medicine
- Mark George, MD, Medical University of South Carolina
- Benjamin Greenberg, MD, PhD, Butler Hospital/Brown University School of Medicine
- Carolina Haass-Koffler, PharmD, PhD, Brown University
- Mark A. Halko, PhD, McLean Hospital
- Colleen Hanlon, PhD, Brainsway Health Technology Company
- Stephanie Jones, PhD, Brown University
- Alex McGirr, MD, PhD, University of Calgary, Canada
- Lisa McTeague, PhD, Brigham and Women’s Hospital
- Dost Öngür, MD, PhD, McLean Hospital
- Frederike Petschner, PhD, Brown University
- Noah Philip, MD, Providence VA Medical Center, Brown University School of Medicine
- Diego A. Pizzagalli, PhD, McLean Hospital
- Kerry J. Ressler, MD, PhD, McLean Hospital
- Mo Shafi, MD, PhD, Beth Israel Deaconess Medical Center
- Mohamed Sherif, MD, PhD, Brown University School of Medicine
- Shan Siddiqi, MD, Brigham and Women’s Hospital
- Joe Taylor, MD, PhD, Brigham and Women’s Hospital
- Brian Theyel, MD, PhD, Brown University School of Medicine
- Jenna M. Traynor, PhD, McLean Hospital
- Andreas Vlachos, MD, PhD, University of Freiburg, Germany
- Nolan Williams, MD, Stanford University
Brown JC, Petersen, A, Zhong L, Himelright, ML, Murphy, JA, Walikonis RS, Gerges NZ. Bi-directional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression. Nature Communications. 2016;24:7:11080.
Brown JC, DeVries WH, Korte JE, Sahlem GL, Bonilha L, Short EB, George MS. NMDA receptor partial agonist, d-cycloserine, enhances 10 Hz rTMS-induced motor plasticity, suggesting long-term potentiation (LTP) as underlying mechanism. Brain Stimulation. 2020;13:530-532.
Brown JC, Higgins ES, George MS. Synaptic plasticity 101: The story of the AMPA receptor for the brain stimulation practitioner. Neuromodulation. 2021;25(8):1289-1298.
Education & Training
- 2002 BS in Psychology, University of Utah
- 2013 PhD in Neurobiology, Medical College of Wisconsin
- 2014 MD, Medical College of Wisconsin
- 2014-2015 Internship, Internal Medicine, Medical University of South Carolina
- 2015-2020 Residency in Psychiatry and Neurology, Medical University of South Carolina
- 2017-2020 Residency Interventional Psychiatry Track, Medical University of South Carolina
- 2018-2020 DART Research Fellowship, Brain Stimulation Laboratory, Medical University of South Carolina
- 2016 Medical License, State of South Carolina
- 2020 Medical License, State of Rhode Island and Providence Plantations
- 2022 Psychiatry, American Board of Psychiatry and Neurology
- 2023 Medical License, Board of Registration in Medicine, Commonwealth of Massachusetts