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!
More episodes from "Stimulating Brains"
#31: Veerle Visser-Vandewalle – Operating on the first neuropsychiatric DBS case in the modern era
1:12:41It was my great pleasure to talk with Veerle Visser-Vandewalle, who is the Head of the Department of Stereotactic and Functional Neurosurgery at University Hospital of Cologne. As a unique setup, she chairs the stereotactic department with access to their own operating theaters in which they have carried out a wide variety of surgeries, including DBS for Parkinson's, Tremor, Dystonia, OCD, Alzheimer's Disease and Pain; as well as spinal chord stimulation and even brachytherapy as one of the few centers in Germany. At age 34, Veerle published the first neuropsychiatric DBS case in the Lancet, 1999, operating on a 42-year old man with Gilles de la Tourette's Syndrome and self-injurious behavior. It was a good year for DBS: Soon after Veerle, Bart Nuttin published the first case series of OCD-DBS (also in the Lancet) and in the same year, Joachim Krauss published the first three Dystonia DBS cases (also in the Lancet). We discuss how DBS for Tourette's has evolved since the first case and what are next steps to come. Currently, Veerle focuses on fornix-DBS in Alzheimer's Disease, taking part as a key center in the ADvance II trial and was able to report some interesting insights. Finally, we talk about the crisis of access to DBS in diseases with low numbers, such as OCD (based on her recent Nature Medicine commentary), her being a knight of Leopold the II and the book she wrote for her son's 18th birthday, “Plato & Cola or the secret of your brain”, that unfortunately, so far, he didn't read (we are sure that one day, he will!)
#30: Suzanne Haber – Anatomists, an endangered species & their importance for DBS
1:04:10It was my great honor to talk with Suzanne Haber about the importance of anatomy in neurosurgery and neuromodulation as a whole. Among many other topics, we discussed her seminal work on the subthalamic nucleus, the anterior limb of the internal capsule and briefly present work on the zona incerta, also in synopsis with earlier work from Mahlon DeLong (#22) and Anne Young (#23). Crucially, Suzanne is not only an anatomist but one with a particular interest in deep brain stimulation. She leads a Conte center with the NIMH focused on Obsessive Compulsive Disorders and has carried out seminal work about the striatal system. One key area Suzanne has worked on lately was the comparison between noninvasive imaging (diffusion-MRI based tractography) and tract tracing data. Together with Anastasía Yendiki (Martinos Center Boston), she runs the "iron tract challenge", in which tractography methods folk competes to reconstruct tracts from diffusion data as best they can – which are then compared to the ground truth from tracing data. Together with Cameron McIntyre (#10), alongside three other anatomists, Suzanne recently created the basal ganglia pathway atlas which represents a unique dataset to study connectomic deep brain stimulation data.
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#29: Mike Fox – Finding Therapeutic Treatment Targets using Causal Brain Connectomics
1:40:13Mike Fox leads the Center for Brain Circuit Therapeutics at the Brigham & Women's Hospital at Harvard Medical School in Boston. The center is unique in that it houses colleagues from neurosurgery, neurology, psychiatry and neuroradiology under the same roof – with the aim to collaboratively work on novel neuromodulation treatments. It is a great honor to interview Mike about his earlier work with Marc Raichle on anticorrelated networks in the brain, his work on TMS network mapping, lesion network mapping and DBS network mapping. Our conversation was enriched by guest questions of many friends and members of the center, Shan Siddiqi, Aaron Boes, Michael Ferguson, Fred Schaper and Dan Corp. We cover how lesion network mapping originated, why effective invasive and noninvasive neuromodulation targets must be linked by brain networks and ways Mike has taken to uncover those relationships. We talk about what makes causal sources of inference – brain lesions and neuromodulation targets – so unique to study the brain, treatment concepts that can be traced back to basic science work in animals vs. serendipitous findings in humans and discuss why and how brain lesions are set for a comeback – both for treatment and investigation.
#28: Marie Krüger – Segmented Contacts & DBS for Dental Pain
1:24:13It was my great pleasure to talk with Marie Krüger, who is currently leading the stereotactic surgery unit in St. Gallen but is on her move to join the team at UCL / Queensquare London. Marie trained in Freiburg, Germany, with Volker Coenen and Peter Reinacher, where she ran multiple studies about segmented electrodes and how to localize their directionality. After that, she carried out a fellowship with Chris Honey in Vancouver, where she developed a protocol of DBS for dental pain and was involved in studies about DBS for spasmodic dysphonia. Her concept of treating dental pain was creative: Since it was not exactly known, which nucleus would result in the best benefit, she implanted segmented leads into the triangle border between three adjacent thalamic nuclei. That way, she could probe exactly which one would deliver best therapeutic benefit. In London, she will work on establishing the new MRgFUS device to treat patients without the need for incisions or anaesthesia.
#27: Joshua Gordon – Neuromodulation from genes to cells to circuits to behavior
1:01:29One of five adults in the United States suffers from a diagnosable mental illness at any one point in time. The burden of psychiatric diseases is massive on both personal and economic levels. It was a great honor to talk to Dr. Joshua Gordon, director of the National Institute of Mental Health. We covered finding a balance between i) running this entity with a budget of 1.6 billion USD and 3000 grants at any one time and ii) pursuing his own research using optogenetic methods to dynamically modulate circuits in the brain. We talked about key strategies of the NIMH, such as the Research Domain Criteria Framework (RDoC) and it's evolution over the last decade up to the present day, the importance to balance between predictive and normativ/generative models, the importance of studying dynamics and to map symptoms to circuits in the brain. There are few if not any critically useful biomarkers we have in the field of psychiatry – we discussed why that is the case. Also, we dived into basic science vs. serendipitous discoveries and the power of either one (or the combination of the two) to move our field forward. Covering Dr. Gordon's own scientific agenda, we discussed the work of his lab on the dynamics between the prefrontal cortex and hippocampus, as well as the significance of this work for models of anxiety and schizophrenia.
#26: Nolan Williams – A Noninvasive Neuromodulation Revolution?
1:49:30It 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.
#25: Michael Okun & Kelly Foote – DBS Think Tank, Connectedness, Closed-Loop & Tic-Detectors
1:36:37The 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.
#24: Aryn Gittis – Optogenetically inspired DBS for Parkinson's Disease
1:32:02Following 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!
#23: Anne Young – Basal Ganglia Circuitry, Glutamate & Leadership
1:05:01In 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.
#22: Mahlon DeLong – The Basal Ganglia in Health & Disease
1:30:18In 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!