The cellular and network mechanisms of deep brain stimulation
Embargo Date
2028-05-29
OA Version
Citation
Abstract
Deep Brain Stimulation (DBS) effectively treats movement disorders, which has prompted its use for treating other neurological and psychiatric diseases. However, the therapeutic mechanisms of DBS remain unclear. Thus, clinicians often choose stimulation parameters based on precedent rather than biological inspiration or preclinical support despite differences in target brain region structure and neuropathology. Consequently, the same stimulation parameters - designed to suppress tremors - are often applied to prevent seizures, improve memory, regulate mood, etc., and lead to suboptimal patient outcomes. As clinicians increasingly look to DBS as an alternative treatment method for more neurological disorders, such as depression, epilepsy, Alzheimer’s Disease (AD), and dementia, it is important to support clinical exploration of the parameter space with preclinical investigation of the therapeutic biophysical and biochemical mechanisms of DBS. By understanding how DBS works at the cellular level, we can design more effective, targeted therapies to improve patient care.To address this mechanistic understanding gap, I use cutting edge single-cell imaging techniques in a preclinical mouse model to monitor how neurons respond to electrical stimulation in real-time, enabling systematic parameter exploration to inform clinical and preclinical experimental design. Calcium imaging enables prolonged monitoring of the cellular activity of hundreds of neurons simultaneously, while voltage imaging provides access to the membrane potential dynamics of several neurons simultaneously with millisecond-precision.
Using these tools, I discovered that neurons exhibit similar biochemical responses to DBS regardless of stimulation frequency, including in the supraphysiological kilohertz range, but through potentially different network mechanisms. I also shed light on the profound influence that stimulation intensity has on the biophysical and biochemical responses of neurons and reveal that when DBS intensity is sufficiently low, neurons and their network adapt to the stimulus over clinically relevant time scales. Together, these findings reveal that neuromodulation effects are highly dependent on both frequency and amplitude, with distinct mechanisms engaged under different conditions. By leveraging complementary strengths of calcium and voltage imaging, my research provides unprecedented mechanistic clarity on how electrical stimulation parameters shape neural circuit behavior, laying the groundwork for more precise and effective therapeutic interventions that could transform treatment for thousands of patients with neurological disorders.
Description
2026