Authors: Suematsu N, Vazquez AL, Kozai TD
Abstract
Understanding the chronic effects of intracortical microstimulation (ICMS) and device implantation on cortical function is essential for the development of stable neuroprosthetics. We chronically implanted penetrating microelectrodes into Thy1-GCaMP6s mice and conducted longitudinal mesoscopic widefield and two-photon Ca imaging alongside intrinsic optical signal recordings over 12 weeks. Six ICMS frequencies (10-500 Hz) and contralateral visual LED stimuli were delivered in repeated sessions. Oxygen extraction fraction (OEF) was estimated from dual-wavelength reflectance, and hemodynamic response functions (HRFs) were derived via regularized deconvolution. Over the chronic period, 25-Hz ICMS evoked progressively larger Ca responses with extending duration, while spatial spread remained stable after the first few days. Low-frequency ICMS preserved stable Ca depression, whereas high-frequency ICMS and visual stimulation showed partial declines in depression magnitude and spatial extent. Two-photon imaging revealed that somatic and neuropil compartments followed distinct activation and depression trajectories, with somatic ICMS responses declining then recovering while neuropil activation tracked mesoscale trends. Concurrently, OEF reductions deepened, reflecting increased relative blood supply, and the spatial extent of OEF signals contracted in the first week before expanding by day 21. Epileptiform Ca events emerged in nearly half of mice, predominantly under 25-Hz ICMS. HRF peak amplitude increased between day 0 and days 7-21, with latency decreasing. Spontaneous neural and hemodynamic activity near the probe was suppressed acutely but recovered over weeks. Chronic ICMS induces progressive potentiation of neuronal and vascular responses alongside local neurovascular uncoupling on day 0 and sustained silencing of spontaneous activity near the implant. These dynamics stabilized 6-7 weeks after implantation. The frequency-dependent epileptiform susceptibility, coupled with persistent focal neurovascular deficits, underscores the need for adaptive stimulation strategies during the pre-stabilization period and electrode designs that mitigate local suppression to ensure long-term stability of cortical neuroprostheses.
PMID: 42097024