Jun 12-14, 2024
OptoDBS 2024: Exploring the Future of Neuromodulation
Translational conference on clinical and underlying mechanisms of DBS across disease entities
12-14 June 2024 at the Campus Biotech in Geneva, Switzerland
Under the slogan “reinventing neuromodulation”, OptoDBS 2024 translational conference in Geneva, Switzerland, discussed the state of the art of current therapies for DBS across disease entities and asked how a better understanding of neural circuit dysfunction in pathology could inspire novel protocols. Experts of transregional collaborative research center (TRR 295) ReTune were actively involved by presenting their research at the event.
Deep brain stimulation is an effective therapy for Parkinson’s disease, dystonia and essential tremor. The most important questions in DBS therapy are: Where to stimulate? When to stimulate? How to stimulate? Andrea Kühn, Professor and Head of Movement Disorders and Neuromodulation Unit, Department of Neurology at Charité Berlin and spokesperson of TRR 295 is currently focusing her work on the question of when to stimulate with the higher goal towards so-called adaptive deep brain stimulation. In adaptive DBS, the stimulation is applied based on specific disease states, which are fluctuating not only during the day (microstates) but also during the entire course of the disease (macro states).
Biomarkers for adaptive DBS
In order to reliably stimulate when it is most needed, robust biomarkers are necessary for the identification of relevant disease states. These biomarkers consist of electrophysiological signals derived from the target nucleus using DBS electrodes with sensing capability. One established biomarker in Parkinson’s disease is a signal within the subthalamic nucleus in the beta frequency range, which occurs when bradykinesia is most present and is suppressed by effective therapy (DBS and dopamine). Another emerging biomarker is gamma activity inside the STN and motor cortex, signaling the onset of troublesome dyskinesia. In addition, a signal in the gamma frequency range can be detected, which only occurs after stimulation and successful alleviation of symptoms (Mathioupolou et al., 2024). This gamma signal is entrained by the stimulation itself and can be a reliable marker for successful symptom alleviation.
In conclusion, many factors have to be considered for adaptive DBS. New biomarkers show promise for reliable adaptive DBS in the future.
Andreas Horn at OptoDBS 2024
Mapping human dysfunctional circuits using DBS
Andreas Horn is Scientist at the Department of Neurology at Charité Berlin, Associate Professor for Neurology at Harvard Medical School and director of deep brain stimulation research within the Center for Brain Circuit Therapeutics at Brigham & Women’s Hospital in Boston. The ReTune Project Leader is an expert in structural imaging and noninvasive connectivity measures derived from functional and diffusion-weighted MRI. The human connectome represents the link between invasive and non-invasive neuromodulatory targets. By using the connectome, one can identify optimal stimulation sites for invasive and non-invasive neuromodulation techniques alike and develop targeted circuit therapies.
In a recent study, the concept of human dysfunctional circuits was established (Hollunder et al., 2024) in a large dataset of patients with various disorders – Parkinson’s disease, Dystonia, OCD and Tourette Syndrome – all treated with subthalamic DBS. They could show that each disorder had a special pathway that had to be modulated in order to achieve optimal clinical effects – thus the hypothesis that this pathway is somehow dysfunctional and has to be retuned in order for the network to work properly again. In addition, recent work could show – in the case of Parkinson’s disease – that specific symptoms are also represented by specific pathways, which have to be modulated for optimal clinical effects. On the basis of this symptom-specific tract atlas, an algorithm called Cleartune, which suggests stimulation contacts based on the symptom-specific tract atlas was developed, which was shown to be superior to standard settings in a first set of patients. Lastly, using the information from invasive neuromodulation (DBS) a study was conducted targeting the cortical networks associated with optimal DBS improvement using non-invasive neuromodulation (multifocal-tDCS). Patients receiving tDCS treatment showed significantly better motor scores compared to patients receiving sham stimulation.
Poster of Mehmet Tuncer at OptoDBS 2024
Mehment Tuncer, Medical Doctor at the Movement Disorders and Neuromodulation Unit, Department of Neurology at Charité Berlin, presented his research on the role of cerebrovascular white matter lesions in the therapeutic efficacy of subthalamic deep brain stimulation for Parkinson’s disease. He could show that higher lesion burden inside the white matter is associated with suboptimal clinical response to stimulation. The researchers additionally built a lesion-adapted prediction model of optimal therapeutic tracts, in which the individual lesion maps of patients are incorporated. The lesion-adapted model showed higher prediction accuracy compared to traditional approaches. In conclusion, vascular white matter lesions can affect the efficacy of subthalamic DBS by disrupting key white matter tracts.
Longer-lasting effects of burst stimulation
At the OptoDBS conference 2024 cutting-edge optogenetic presentations interleaved with clinical studies from leading experts.
Aryn Gittis, Professor in the Department of Biological Sciences and the Neuroscience Institute at Cernegie Mellon University in Pittsburgh, USA, talked about her research in mice, where she studies the physiology of basal ganglia circuits using optogenetics in Parkinson’s disease mouse models with emphasis on possible new approaches to neuromodulatory therapies. Her work could show that the burst stimulation of certain types of neurons within the globus pallidum can produce longer-lasting positive effects on movements, even when stimulation is off for hours. This inspired the clinical translation of burst stimulation in humans with deep brain stimulation implants instead of the classical continuous high-frequency stimulation paradigm.
Nader Pouratian, Professor and Chair of Neurological Surgery at UT Southwestern Medical Center in Dallas, USA, already conducted a clinical study with burst DBS, showing its feasibility and non-inferiority to continuous stimulation. In addition, there is also first evidence of longer-lasting clinical effects using burst stimulation in humans.
This collaborative talk shows the great potential of clinical translation of animal research and the collaboration between clinicians and basic researchers, which encapsulates perfectly the theme of the OptoDBS conference.
Treatment of Alzheimer’s Disease with DBS
Andrew Sharott, associate professor at the MRC Brain Network Dynamics Unit at the University of Oxford presented new research on treatment of Alzheimer’s Disease with DBS. Current approaches rely on classical stimulation paradigms using high-frequency stimulation. Can the effectiveness of forniceal DBS in Alzheimer’s Disease be improved by adjusting the stimulation paradigm on the internal dynamics of hippocampal circuits? The idea is to directly target sharp wave ripples inside the hippocampus responsible for memory consolidation. Phase-dependent stimulation shows promise in mice to be effective also in the long term. This work shows that hippocampal theta activity combined with sharp wave ripples may serve as an adequate sensing signal for adaptive deep brain stimulation of the fornix in Alzheimer’s disease.
© Pictures: TRR 295 ReTune
