#67: Jonathan Downar – TMS for Depression: Towards a One-Day protocol

Today we had the privilege of speaking with a true pioneer in the field of neuropsychiatry and brain stimulation— Dr. Harold Sackeim.Dr. Sackeim is perhaps best known for his extensive research on electroconvulsive therapy (ECT), but his contributions span a wide range of topics from treatment-resistant depression to the placebo effect in neurostimulation. As a founding figure in modern ECT research, he has played a central role in shaping both the science and the clinical practice of brain stimulation therapies.In this episode, we explored the history and future of ECT, the controversies surrounding it, and Dr. Sackeim’s insights on the direction of neuromodulation. He explains how ECT has long been the most effective treatment for severe, treatment-resistant depression. While once overlooked in favor of medication, we now know that both the placement and intensity of stimulation are key—challenging the old belief that seizures alone drive its effects.

In this episode, we journey through the remarkable career of Dr. Rees Cosgrove—a trailblazer in functional neurosurgery, Director of Epilepsy and Functional Neurosurgery at Brigham and Women’s Hospital, and Professor of Neurosurgery at Harvard Medical School.Dr. Cosgrove reflects on his formative years training in the very halls that were roamed by legends such as Wilder Penfield at the Montreal Neurological Institute, and takes us through pivotal chapters of his career leading programs at Massachusetts General Hospital, Brown University, and now the Brigham. With a repertoire that spans from the golden era of ablative neurosurgery to modern deep brain stimulation and MR-guided focused ultrasound—where he has performed over 600 sonications—Dr. Cosgrove provides a unique perspective on how the field has transformed over the past several decades.Throughout the conversation, we delve into the history and resurgence of surgical lesions for psychiatric and neurological conditions, the nuances of neuromodulation technologies, and the evolution of imaging that now defines precision in brain surgery. Dr. Cosgrove also shares his views on mentorship, the transmission of surgical wisdom, and how we can preserve the disappearing art of lesioning in an age increasingly dominated by stimulation.Whether you're a neurosurgeon, neuroscientist, or simply curious about how we interface with the brain to treat disease, this episode is a rare and insightful look into the mind of one of the field’s most experienced and thoughtful pioneers.

In this episode we will dive deep into the minds of leading researchers and clinicians in the field of neuromodulation. Today, we are thrilled to have Dr. Terry Sanger with us.Dr. Sanger is a renowned pediatric neurologist, engineer, and Chief Scientific Officer at CHOC, where he focuses on improving the lives of children with movement disorders—especially dystonia. He’s well known for combining deep computational approaches with cutting-edge neuromodulation techniques.In this episode, we’ll uncover how his background in engineering, neuroscience, and clinical practice converges to shape new possibilities for treating complex movement disorders in children. From pioneering multi-electrode deep brain stimulation for pediatric dystonia to his latest forays in closed-loop stimulation research, Dr. Sanger is truly expanding the boundaries of what’s possible in pediatric care.

In this episode, we have the privilege of speaking with Dr. Todd Herrington, a leading neurologist and director of the Deep Brain Stimulation (DBS) program at Massachusetts General Hospital. Dr. Herrington specializes in movement disorders such as Parkinson’s disease, tremor, and dystonia, and his research focuses on the motor, cognitive, and psychiatric effects of DBS, leveraging intraoperative and noninvasive neurophysiology and neuroimaging to advance neuromodulation therapies.Today, we’ll explore his key role in the ADAPT PD trial, a groundbreaking multicenter study evaluating the safety and efficacy of adaptive DBS for Parkinson’s disease. This trial, led by Dr. Helen Brontë-Stewart at Stanford, introduced a neurostimulator capable of sensing local field potentials and dynamically adjusting stimulation in real time based on a patient’s brain activity. We’ll discuss how this technology represents a shift toward personalized DBS therapy and what it means for the future of neuromodulation.In the second part of our conversation, we’ll delve into broader topics, including the mechanism of action of DBS, novel neuromodulation approaches, and the potential role of stem cell therapy in movement disorders. Dr. Herrington shares his expert insights on how these advancements shape both our scientific understanding and the clinical application of DBS. From improving motor and non-motor symptoms in Parkinson’s disease to pioneering adaptive neurostimulation, his work is at the forefront of innovation in the field.

In this episode, we’re joined by Dr. Jonathan Downar, a psychiatrist and neuroscientist based in Toronto, renowned for his pioneering research in transcranial magnetic stimulation (TMS) for depression. You may recognize him from his landmark work on the Three-D Trial, which helped establish intermittent theta-burst stimulation (iTBS) as a rapid and effective alternative to standard repetitive TMS.Recently, Jonathan has been pushing the boundaries of TMS with accelerated treatment protocols, including the One-D Study, which tested the feasibility of delivering an entire TMS course in a single day.In our conversation, we explore his scientific journey, the future of brain stimulation, and his bold approach to innovation—what he calls “TMS in SpaceX mode.” We also discuss the vision for achieving a billion depression patient remissions in our lifetime.Tune in for an inspiring and insightful discussion with one of the leaders in neuromodulation research.

In this episode, we have a privilege to talk with Dr. Roxanne Lofredi, a prominent researcher investigating movement disorders and deep brain stimulation (DBS). Dr. Lofredi is based at Charité – Universitätsmedizin Berlin and is widely recognized for her groundbreaking contributions to understanding how basal ganglia networks drive motor symptoms in conditions such as dystonia and Parkinson’s disease. Today, we’ll explore two fascinating studies led by Dr. Lofredi. The first focuses on how subthalamic nucleus stimulation impairs stopping of ongoing movements in Parkinson’s disease. This work, published in Brain, was inspired by a foundational basic science study from Aron and Poldrack (2006), which first implicated the subthalamic nucleus as a critical node for motor inhibition within the hyperdirect pathway of the basal ganglia. We’ll discuss how these findings translated to her DBS study and how they may impact DBS therapy. The second part of our conversation will cover her recent publication in Nature Communications, where Dr. Lofredi and her team demonstrate a clear link between striato-pallidal oscillatory connectivity and symptom severity in dystonia. This work highlights the pathophysiological role of the direct pathway within the basal ganglia and opens up new possibilities for targeted therapeutic approaches. In conclusion, Dr. Lofredi shares key insights from her research, bridging the gap between basic neuroscience and clinical application. From understanding motor inhibition in Parkinson's disease to exploring striato-pallidal connectivity in dystonia, her work advances our knowledge and paves the way for more effective DBS therapies.

In this episode of Stimulating Brains, we're thrilled to have Jim McNasby join us. Jim is a deep brain stimulation (DBS) patient and the Chief Counsel at the Michael J. Fox Foundation. Jim has an inspiring story, not just as a DBS patient but also as a legal professional working at the forefront of Parkinson’s research advocacy. We’ll dive into his personal experience with DBS—how it has shaped his life since his diagnosis in 2000 and his surgery in 2019—and explore his crucial role at the Michael J. Fox Foundation, where he helps drive forward their mission to find a cure for Parkinson’s disease. I had the pleasure of hearing Jim speak at the Neuromodec Conference, where he shared a powerful story of how DBS transformed his life, even showing a video that vividly captured its positive effects. We’ll talk about that, his DBS wishlist, and the work he’s doing to advocate for patients and drive research. In this episode, we explore his personal experiences, the impact of DBS, and his role in advancing Parkinson's research and advocacy at the foundation. Jim also reflects on the transformative moment when his DBS was first activated and discusses his vision for the future of patient care and innovation in the field.

Today, we have the pleasure of speaking with Dr. Bálint Várkuti, a distinguished expert in the field of neuromodulation. Dr. Várkuti is the founder and CEO of CereGate, a pioneering company developing brain-computer interface technologies—referred to as computer-brain interface technologies—that aim to enhance neuromodulation therapies. Before founding CereGate, Dr. Várkuti made significant contributions to image-guided DBS programming solutions at Brainlab. With over a decade of experience in neurotechnology and the medical device industry, his work focuses on designing innovative interfaces between technology and the human brain to improve patient outcomes. For those familiar with DBS, you’ll understand the nuances here: when stimulation of the super-dynamic nucleus in DBS is set too high, patients often experience a tingling or irritating sensation due to overstimulation of sensory fibers. Typically, this side effect is avoided. However, Dr. Várkuti had a groundbreaking insight: This sensation represented a channel of information with the brain – and one could make use of it! In a nutshell, CereGate leverages these overlooked pathways, using them in a patterned and complex way to transmit information that the brain can decode. This approach opens up new possibilities for interfacing with the brain, which we find truly fascinating: This concept that CereGate is exploring might just be the start of a much larger field of innovation.

In this episode, we have the pleasure of hosting Mark McAuley, a deep brain stimulation (DBS) patient and the CEO of Astronomy Australia Limited, and Dr. Susan Boehnke, an Associate Professor at Queen’s University in Canada and director of the Neurotech Microcredential Program and the Neurotech Discovery Lab. Together, they've been part of remarkable efforts that not only focus on the practical and ethical aspects of neurotechnology but also engage students in real-time research. Mark brings over thirty years of experience in research and development, with a remarkable track record of securing $300 million in Australian Government grants for major research infrastructure projects. Holding degrees in astrophysics, ancient history, and an MBA—where he was awarded the Vice-Chancellor’s medal as the university's highest-achieving postgraduate student—Mark was diagnosed with Parkinson’s disease in 2010 and received a DBS implant in 2020. Post-surgery, he's been a passionate advocate for better patient care and improved DBS programming to enhance clinical outcomes. Dr. Susan Boehnke completed her PhD in Neuroscience at Dalhousie University and has an extensive background in auditory neuroscience and primate neurophysiology. She led the creation of one of the first non-human primate models of Alzheimer’s disease and established Canada's first non-human primate biobank. In response to the explosion of interest in neurotechnology, she's now pioneering a micro-credential program in neurotech and exploring the ethical issues surrounding it. She's also leading the Training Committee for Connected Minds, a significant research initiative between York and Queen’s Universities. At the recent Neuromodec conference in New York, Mark and Susan presented their work, which emphasizes patient inclusion in research—a theme Dr. Boehnke passionately advocates for—and provides transformative learning experiences for students. Today, we'll dive into their journeys, the science behind their projects, and explore potential insights into the future of patient-led research and education in neurotechnology.

In today’s episode, we dive deep into two groundbreaking studies led by Daniela and Clément. We explore their 2022 Nature Communications paper on using cerebellar stimulation to alleviate levodopa-induced dyskinesias in Parkinson’s disease and discuss their 2023 paper uncovering the cerebellum’s role in regulating fear extinction through its connections with the thalamo-prefrontal cortex pathway. Along the way, we discuss how these discoveries may open up exciting new possibilities for treating both motor and emotional disorders. Tune in for an insightful conversation packed with cutting-edge science and exciting future perspectives!