CTN Seminar Milad Lankarany E5 2004

Milad Lankarany, Krembil Research Institute

Title: Using Computational Neuroscience and Neuromodulation Techniques to Uncover Mechanisms of Neural Systems

Abstract: Deep brain stimulation, as an invasive neuromodulation technique, has been successfully used to reduce symptoms of movement disorders by delivering electrical pulses to the substructures of the basal ganglia and thalamus. Existing efforts to understand the mechanisms of action of DBS rely on detecting biomarkers during (or after) delivering clinically approved high-frequency pulses and assessing their clinical outcomes. However, less consideration has been given to how DBS modulates information processing in the human brain. Specifically, it is not yet discovered how modulated neural activities observed in a sub-cortical region represent dynamics of underlying circuitry. Building on our published data of in-vivo single-unit recordings in patients with Essential Tremor (n = 20), we discovered that neuronal dynamics (in the sense of instantaneous firing rate) of thalamic ventral intermediate nucleus (Vim) in response to various frequencies of deep brain stimulation (DBS) can be explained by Balanced Amplification mechanism, an established theoretical framework that suggests the large amplification of excitation — caused by either strong external input or positive recurrent circuitry — can be balanced by strong feedback inhibition. We developed a network rate model, together with a sequential optimization algorithm, that accurately reproduces the instantaneous firing rate of Vim neurons, the primary surgical target of DBS for reducing symptoms of essential tremor, in response to low- and high-frequency DBS. Our study revealed that the computer simulation of a single population of Vim neurons (appeared in our recent publication PMID: 37140523) cannot capture the dynamics of the firing rate, thus the presence of other neuronal populations is essential to track the firing rate reliably and mechanistically. Interestingly, our work suggests, in an unsupervised manner, that the presence of an inhibitory neuronal population is necessary to replicate Vim firing rates across different DBS frequencies. We anticipate that our study provides a conceptual modeling framework to uncover mechanisms of information processing in different DBS-modulated sub-cortical regions in the human brain.