(43) Low-intensity Pulsed Ultrasound Reduces Microglia Activation at the Electrode Interface and Increases Chronic Recording Yield

Introduction: Chronically implanted silicon shank electrodes induce vascular hemorrhage, cell lysis, and tissue deformation at the implant site. This perturbation initiates a chronic injury response in both neurons and microglia with morphological changes to microglia being observed within minutes following implantation. Reactive microglia amplify the injury response by activating astrocytes and recruiting macrophages. Neural injury and microglia reactivity are the initiating events, which underlie the chronic foreign body response (FBR) and limits the longevity of implanted recording and stimulating electrodes. Consequently, methods to reduce microglial activation and attenuate chronic inflammation hold significant promise for improving the long-term viability of implanted neural electrodes. Transcranial focused ultrasound (tFUS) has recently evolved as a non-invasive method to regionally modulate synaptic and non-synaptic mechanisms of neuron and glial cell activity. Previous research has demonstrated neuroprotective and anti-inflammatory effects of tFUS in traumatic brain injury and neurodegenerative disease models.

Methods: We investigated whether the neuroprotective effects of tFUS could reduce microglia reactivity and preserve electrophysiological measures of neural activity in rodent models using chronically implanted silicon shank electrodes. We developed a reusable head-mounted device that delivered low-intensity pulsed ultrasound (LIPUS) to investigate the effects of tFUS on the activation of microglia across the first post-operative month and the relationship between microglial activity and single-unit recording yield of implanted electrodes. Periodic (15 min/day) LIPUS treatment was delivered around electrodes followed by in vivo electrophysiology and two-photon microscopy to assay neural activity and microglia reactivity. Treatment frequency and duration was varied over the course of the post-operative recording period to determine whether LIPUS delivery is required for the duration of the recording period or if treatment in the acute post-injury phase is sufficient to maintain implant patency.

Results: Our in vivo experiments demonstrate that periodic treatment with high frequency (~1MHz) LIPUS alters microglia migration velocity and timing compared to untreated controls and that cellular encapsulation of electrodes is reduced in subjects receiving LIPUS treatment. Single unit recordings of neural activity in subjects receiving LIPUS treatment demonstrated an increase in electrode impedance, greater signal-to-noise ratios, and more identifiable single units across a greater number of electrode channels compared to control subjects. These results demonstrate the validity of tFUS for modulation of microglia and suppression of the FBR and provide a device for simplified non-invasive modulation.

Conclusion: LIPUS is a promising approach for mitigating the FBR in a neural implant