Voltage imaging development and investigation of neuromodulation mechanisms
OA Version
Citation
Abstract
Intracranial electrical neuromodulation is effective at managing various neurological and psychiatric diseases, but the underlying neurophysiological mechanisms remain unknown. Since electrical stimulation produces electrical artifacts on conventional electrode-based recording techniques, it has been particularly difficult to characterize the real time effect of electrical neuromodulation to understand the therapeutic mechanisms. In order to measure neural activity with simultaneous electrical stimulation, we apply voltage imaging to measure single cell signals without stimulation artifact. In this dissertation, we first improve the capabilities of voltage imaging with the development of a digital-micromirror-device-based targeted illumination strategy to enable high-speed voltage imaging of many neurons simultaneously over a large anatomical area. We then applied voltage imaging to understand the mechanisms of high frequency electrical neuromodulation by recording the real time effect of intracranial stimulation on individual neurons in the awake mammalian brain. Since most mammalian neurons cannot support high frequency dynamics, it is thought that stimulation at high frequencies, over a hundred hertz, could disrupt pathological dynamics and create functional informational lesions. However, some brain cells, especially fast spiking interneurons (FSIs), can support rapid firing, which may be selectively recruited by high frequency stimulation to exert powerful inhibitory effects. To under how high frequency electrical stimulation impacts FSIs, we measured the stimulation evoked membrane voltage changes in parvalbumin positive interneurons, known to be fast spiking, in motor and visual cortices in awake mice. We found that high frequency, specifically 140 Hz, stimulation heterogeneously modulated individual FSIs in both cortices, similar to lower frequency, 40 Hz, stimulation, leading to complex temporal dynamics that evolve throughout the stimulation duration. While motor cortex FSIs exhibited minimal entrainment by 140 Hz stimulation, visual cortical FSIs were readily entrained by 140 Hz stimulation. Intriguingly, even though stimulation consistently reduced the response amplitude of visual cortex FSIs to synaptic inputs from visual stimuli, response timing precision was bidirectionally modulated with many exhibiting improved tracking of input timing. Thus, high frequency electrical stimulation mediates brain region and cell type specific entrainment and bidirectionally modulates cellular information processing in FSI, highlighting the potential of selectively engaging inhibitory circuits via tuning stimulation parameters. Overall, this dissertation demonstrates continued improvement of high-speed voltage imaging through simple implementation of digital-micromirror-device based targeted illumination strategy, and the application of voltage imaging on probing the mechanisms of electrical neuromodulation. These advances highlight the exciting potential of single cell voltage imaging in studying the cellular and network mechanisms of clinical neuromodulation through simultaneous recording of many neurons in a large field of view.
Description
2025
License
Attribution 4.0 International