Stimulating Brains

It was my great pleasure to talk with Nolan Williams, who is the mind behind the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol for treatment of depression. In this drastically intensified protocol, Fifty sessions of 1,800 pulses are delivered as 10 daily sessions over just 5 days – condensing what usually takes months to a single week. After making hands-on experience with deep brain stimulation, Nolan wanted to first work with this invasive technique in depression. His mentors told him that it wasn't a good time for DBS in depression, given two randomized trials had just failed, so he turned to noninvasive stim and realized, that – in comparison to DBS – we were heavily understimulating the brain, i.e., by far not delivering as many pulses in a given time interval. He also realized that the optimal targeting could not be determined by electrophysiology, but gladly Mike Fox had worked out a good method using resting-state fMRI. This way, the SAINT protocol was born, leapfrog-jumping the way we apply TMS to treat depression. After undergoing SAINT, 19 of 21 patients (90.5%) met remission criteria after a single week of TMS.

The tenth DBS Think Tank is about to happen in Gainesville, Florida next month – so it's timely to talk with the masterminds behind it: Michael Okun and Kelly Foote need no introduction in the field & represent a role-model power-couple of how neurosurgery and neurology can join forces to build something unique. In Gainesville, they built one of the most important DBS programs in the world, essentially from scratch, after setting their minds to this goal during residency. We talk the concepts behind the Think Tank, their work on the DBS Tourette's Disease registry, the importance of collaborations in the field and future / (present?) concepts such as adaptive DBS, their «tick detector» (about which we could already hear in episode #21 between Aysegul Gunduz and Julian Neumann) and the general future of the field.

Following a fascinating talk Aryn gave at OptoDBS 2022, we talk about her work on optogenetically inspired deep brain stimulation for Parkinson's Disease. In a first paper (2017 Nature Neuroscience), Aryn's lab could establish that a specific lineage of cells in the external pallidum needed to be stimulated (or a second one suppressed) to achieve symptom relief in the 6-OHDA mouse model of Parkinson's Disease. Crucially, these effects outlasted the stimulation, sometimes by up to eight hours. In a second paper (2021 Science), her team was able to mimick the exact same effect using a very creative form of deep brain stimulation to the entopeduncular nucleus. I am convinced that these results could transform the way we apply DBS in humans and they form a template of successful translation from optogenetics to electical stimulation. In a way, Aryn's story of discovery very much resemble the ones by Anne Young (previous episode), both were puzzled that differentially modulating specific – not all – cells (for Anne D1 vs. D2 cells in the striatum & Aryn Pv+ vs. Lhx6+ cells in the pallidum) would have an effect on Parkinsonism. I hope you will be as fascinated by the conversation I had with Aryn, as I was!

In this episode, I had the tremendous honor of speaking with Anne Young about the many highlights of her career, including key evidence that established Glutamate as a neurotransmitter, as well as her work on Huntington's Disease. Directly building upon the preceding episode with Mahlon DeLong, we now hear about the Ann Arbor Side of the so-called “Albin-Delong” model, which was equally informed by the team of Anne Young & her late husband John Penney alongside Roger Albin. In 1991, Dr. Young was appointed chief of neurology at Massachusetts General Hospital and  with that the first female service chief in the hospital's 180-year history and the first female chief of neurology at a teaching hospital in the United States. During her career, she was president of both the American Neurological Association and the Society for Neuroscience – which so far nobody else has achieved. We take these unique achievements as examples to talk about success, leadership and career advice, while also covering a bit of the struggles and challenges associated with a clinician-scientist career.

In this episode, I had the great pleasure of speaking with Mahlon DeLong about the past and future of our field, the most influential model of the basal ganglia circuitry, microexciteable zones in the striatum, the role of the nucleus basalis in Alzheimer’s Disease and many other topics. We also touch upon the role of the basal ganglia model for psychiatry, more recent topics such as psychedelics or how instrumental the MPTP model for Parkinson’s Disease in nonhuman primates was. Mahlon needs no introduction and can certainly be seen as one of the key founding fathers of modern basal ganglia research and together with Hagai Bergman and Thomas Wichmann directly paved the way to establish deep brain stimulation to the subthalamic nucleus. The episode is enriched by guest questions from Marwan Hariz and Hagai Bergman, as well as planning input from Helen Mayberg. I hope you enjoy the episode with Mahlon as much as I did and thank you for tuning in!

In this episode, Aysegul Gunduz & Julian Neumann speak about Ayse's exciting work on closed-loop DBS in tremor, their tic-detector, and thriving as an engineer in a medical field such as DBS. They also touch upon minority groups in the field. The main focus of their 2020 Science Translational Medicine study, in which Ayse's team developed and studied a chronically embedded cortico-thalamic closed-loop deep brain stimulation system for treatment of essential tremor – clearly a landmark study in the field that brought together advances in engineering and medical research. Ayse also speaks about industry collaborations and the value of novel devices that enable scientific studies that had not been possible, in the past. I hope you enjoy the conversation between Ayse and Julian as much as I did and thank you for tuning in!

In this episode I had the honor to speak with Christian Lüscher about his exciting work on neuromodulation in addiction as well as the upcoming OptoDBS conference which he has been organizing since 2015 in Geneva. We cover Christian's milestone works in creating and refining a model of addiction in the brain, ways to counteract addiction using both optogenetics and DBS and why only about twenty percent of mice with unlimited access to drugs will become addicted. We discuss examples of optogenetically informed DBS by the Lüscher lab and recent milestone work by Aryn Gittis. OptoDBS has unique setup of joint sessions with similar topics by speakers from the optogenetics & DBS fields, respectively. The aim is to derive at optogenetically informed concepts for DBS – which could be implemented to change clinical practice. I have the great honor to co-host this years' conference and we discuss the anticipated highlights of OptoDBS and what we are most excited about. I hope you enjoy the conversation with Christian as much as I did and we both hope to see you this June in Geneva for OptoDBS 2022!

In this episode I had the honor to speak with Sameer Sheth about recent advances in deep brain stimulation for psychiatric indications. We focus on two recent publications, a paper published in Biological Psychiatry that introduced a revolutionary novel concept of treating depression by inserting stereo-EEG electrodes to determine the individual circuitry involved in each patient's disease. The second was published in Nature Medicine and involved long-term local field potential recordings carried out during daily live in patients with obsessive compulsive disorder. It was a very unique opportunity to learn more about the background on how these studies originated, how they were carried out, and what the future may bring for this exciting field & I hope you enjoy the conversation I had with Sameer as much as I did.

In this guest episode, Jeffrey Hausdorff and Nathan Morelli speak about transcranial direct current stimulation (tDCS), its mechanisms of action, current application in research, and where the field is going in the future. In this discussion, we cover many topics which will give you insight into this area of brain stimulation. We begin with the basics of tDCS from its historic origins and therapy fundamentals. Our discussion then progresses to a deep-dive inside some of Prof. Hausdorff's most recent works in collaboration with many world renowned researchers in neurodegenerative disease – notably including recent findings in using tDCS to mitigate freezing of gait in patients with Parkinson’s disease. We close with a look into the future of tDCS in research and clinical practice. Given Prof. Hausdorff’s expertise there are few people in the world more qualified to speak on Parkinson’s disease and non-invasive brain stimulation. As such, it is our immense privilege to present this interview to you.

In this episode, Hagai Bergman and I talk about his new book, The Hidden Life of the Basal Ganglia: At the Base of Brain and Mind. We cover some of the many highlights of his life in basal ganglia and deep brain stimulation research. This includes his crucial discovery that paved the way to subthalamic deep brain stimulation during his work at John Hopkins together with Mahlon DeLong and Thomas Wichmann. We talk about his three-layer model of the basal ganglia, one of the first proof-of-principle demonstrations of closed-loop DBS, his work on the basal ganglia as a dimensionality reduction system and his newer interest in asleep DBS (and basal ganglia electrophysiology during sleep). We also talk about collaborations and friendships between academia and industry, as his research has found commercial applications such as in the HaGuide algorithm in the NeuroOmega system by AlphaOmega. Together with the surgeon of his center, Zvi Israel, Hagai has carried out over seven hundred DBS surgeries as a pair of two – and he has further studied DBS electrophysiology in numerous experiments in the macaque model. Likely, there are few if no people around that know the basal ganglia as well as Prof. Bergman. Hence, it was a true privilege to carry out this in-depth conversation about the key concepts of his research with him.