Noninvasive, Cell-Specific Ultrasound Neuromodulation in Temporal Lobe Epilepsy
Murphy KR, Farrell JS, Gomez JL, Stedman QG, Li N, Leung SA, Good CH, Qiu Z, Firouzi K, Butts Pauly K, Khuri-Yakub BPT, Michaelides M, Soltesz I, de Lecea L. A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy. Proc Natl Acad Sci USA 2022;119(46):e2206828119. doi: 10.1073/pnas.2206828119.
Background: Temporal lobe epilepsy often resists drug treatment, creating a need for noninvasive approaches to control deep brain activity. Focused ultrasound (FUS) offers a promising tool for neuromodulation, but its effects on specific neuronal cell types are unclear. Since activating hippocampal parvalbumin (PV) interneurons can suppress seizures, determining whether FUS can selectively modulate inhibitory versus excitatory neurons is key to developing targeted therapies.
Hypothesis: This study tested the hypothesis that FUS can modulate neural activity in a cell type–specific manner and that optimized parameters could preferentially activate inhibitory PV interneurons while suppressing excitatory neurons, thereby reducing epileptiform activity.
Methods: Based on an FP3002 system the authors developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) that combines optical recording with ultrasound stimulation in freely moving mice. Using genetically encoded calcium indicators, they simultaneously monitored activity of excitatory and inhibitory neurons in the hippocampus during varied FUS protocols. Whole-brain metabolic effects were assessed with positron emission tomography (PET), and therapeutic efficacy was tested in a kainate model of chronic temporal lobe epilepsy.
Results: PhoCUS allowed precise monitoring of FUS-induced activity. A 900 Hz, 20% duty cycle protocol selectively increased PV interneuron activity while suppressing excitatory neurons. PET imaging confirmed localized inhibition within the hippocampus, and the same protocol significantly reduced epileptiform spikes in epileptic mice.
Conclusions: Focused ultrasound can achieve cell type–specific neuromodulation and suppress epileptiform activity. PhoCUS provides a versatile platform for developing noninvasive, targeted ultrasound therapies for epilepsy and other brain disorders.
