Low-threshold, high-resolution, chronically stable intracortical microstimulation by ultraflexible electrodes.

Intracortical microstimulation (ICMS) enables applications ranging from neuroprosthetics to causal circuit manipulations. However, the resolution, efficacy, and chronic stability of neuromodulation is often compromised by the adverse tissue responses to the indwelling electrodes. Here we engineer ultraflexible stim-Nanoelectronic Threads (StimNETs) and demonstrate low activation threshold, high resolution, and chronically stable ICMS in awake, behaving mouse models. In vivo two-photon imaging reveals that StimNETs remain seamlessly integrated with the nervous tissue throughout chronic stimulation periods and elicit stable, focal neuronal activation at low currents of 2 µA. Importantly, StimNETs evoke longitudinally stable behavioral responses for over eight months at markedly low charge injection of 0.25 nC/phase. Quantified histological analysis show that chronic ICMS by StimNETs induce no neuronal degeneration or glial scarring. These results suggest that tissue-integrated electrodes provide a path for robust, long-lasting, spatially-selective neuromodulation at low currents which lessen risks of tissue damage or exacerbation of off-target side-effects.

Low-threshold, high-resolution, chronically stable intracortical microstimulation by ultraflexible electrodes.

Intracortical microstimulation (ICMS) enables applications ranging from neuroprosthetics to causal circuit manipulations. However, the resolution, efficacy, and chronic stability of neuromodulation are often compromised by adverse tissue responses to the indwelling electrodes. Here we engineer ultraflexible stim-nanoelectronic threads (StimNETs) and demonstrate low activation threshold, high resolution, and chronically stable ICMS in awake, behaving mouse models. In vivo two-photon imaging reveals that StimNETs remain seamlessly integrated with the nervous tissue throughout chronic stimulation periods and elicit stable, focal neuronal activation at low currents of 2 µA. Importantly, StimNETs evoke longitudinally stable behavioral responses for over 8 months at a markedly low charge injection of 0.25 nC/phase. Quantified histological analyses show that chronic ICMS by StimNETs induces no neuronal degeneration or glial scarring. These results suggest that tissue-integrated electrodes provide a path for robust, long-lasting, spatially selective neuromodulation at low currents, which lessens risk of tissue damage or exacerbation of off-target side effects.

Longitudinal neural and vascular recovery following ultraflexible neural electrode implantation in aged mice.

Flexible neural electrodes improve the recording longevity and quality of individual neurons by promoting tissue-electrode integration. However, the intracortical implantation of flexible electrodes inevitably induces tissue damage. Understanding the longitudinal neural and vascular recovery following the intracortical implantation is critical for the ever-growing applications of flexible electrodes in both healthy and disordered brains. Aged animals are of particular interest because they play a key role in modeling neurological disorders, but their tissue-electrode interface remains mostly unstudied. Here we integrate in-vivo two-photon imaging and electrophysiological recording to determine the time-dependent neural and vascular dynamics after the implantation of ultraflexible neural electrodes in aged mice. We find heightened angiogenesis and vascular remodeling in the first two weeks after implantation, which coincides with the rapid increase in local field potentials and unit activities detected by electrophysiological recordings. Vascular remodeling in shallow cortical layers preceded that in deeper layers, which often lasted longer than the recovery of neural signals. By six weeks post-implantation vascular abnormalities had subsided, resulting in normal vasculature and microcirculation. Putative cell classification based on firing pattern and waveform shows similar recovery time courses in fast-spiking interneurons and pyramidal neurons. These results elucidate how structural damages and remodeling near implants affecting recording efficacy, and support the application of ultraflexible electrodes in aged animals at minimal perturbations to endogenous neurophysiology.