Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus

Abstract

Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3–12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion.

Unraveling the therapeutic mechanism of deep-brain stimulation

“…Remarkably, in most regions, excitation and inhibition were relatively balanced (i.e., equal numbers of excited and inhibited neurons). Consistent with a recent study that reported DBS-evoked membrane depolarization that interfered with somatic action potentials 46 , this questions the DBS ‘ inhibition hypothesis ’ . 6) At therapeutic intensities (i.e., medium- and high-intensity DBS), only partially overlapping neuron populations were recruited.…”

Ultrasound pulse repetition frequency preferentially activates different neuron populations independent of cell type

“…140 Hz is widely used in deep brain stimulation, which leads to better therapeutic outcomes than lower frequency stimulations. Our recent studies demonstrated that 140 Hz electrical stimulation robustly depolarized membrane voltage, scrambled spike timing and led to informational lesion 38 Consistent with our analysis of the Allen Brain Institute's single cell sequencing results showing prevalent and heterogeneous expression of many mechanosensitive channels across individual neurons, we detected diverse US-mediated cellular calcium responses across neurons, with many reliably activated. US-evoked calcium events in individual neurons exhibit the same characteristics as those naturally occurring during increased spiking probability, suggesting that US increases neuronal activity.…”

“…For example, in deep brain stimulation, pulse frequency is a critical consideration. We recently showed that 40 Hz electrical stimulation paced membrane potential and spike timing, but when electrical stimulation reached 140 Hz, spiking output failed to track stimulation pulses temporally 38 . To gain a deeper understanding of how neurons cellular properties influence US-evoked activities, we analyzed the neuronal response to US delivered at biophysically relevant frequencies.…”

“…Many neurons have intrinsic biophysical properties that render them more sensitive to stimulation at certain physiologic frequencies of a few hertz to tens of hertz. We recently demonstrated that when electrical stimulation frequency reaches 140 Hz, membrane voltage was poorly paced by individual electrical pulses 38 . Thus far, most studies have delivered US at PRFs on the order of kilohertz.…”

Injectable Fluorescent Neural Interfaces for Cell-Specific Stimulating and Imaging

“…Emerging from the convergence of multiple disciplines and meeting current needs, a significant advancement in the field of neural interface monitoring and modulation is the development of minimally invasive and retrievable chronic brain implants. These devices offer high-resolution monitoring and modulation of neural activity, marking a significant improvement over traditional methods such as low-resolution, noninvasive electroencephalography (EEG), invasive intracortical electrocorticography (ECoG) , or deep brain stimulation (DBS) electrodes, , and time-uncontrolled bioabsorbable brain implants . Notably, these devices can be injected and later removed post-treatmentan essential feature for targeted interventions, allowing for the modulation of neuronal activity over extended periods.…”