Delivery of Low-Intensity Pulsed Ultrasound in the Cortex to Improve Longevity and Performance of Neural Interfaces

 NN TIRKO, AS ALSUBHI, JK GREASER, RS CLEMENT, KA SNOOK, RB BAGWELL, ML MULVIHILL
Actuated Medical, Inc., Bellefonte, PA

Chronic neural implants hold great potential for illuminating features of neural function, treating neurological disorders, and enabling the next generation of neuroprosthetics. Penetrating electrode arrays provide direct access to neural signals across the central and peripheral nervous system with high temporospatial resolution. However, a consistent point of failure for chronically implanted microelectrode arrays is poor longevity and variability in functionality of these devices. The foreign body response (FBR) can cause glial scarring and neural cell loss near the electrode sites. The FBR begins with electrode insertion, when damage to the blood brain barrier activates astrocytes and microglia and continues throughout the lifetime of the implant due to the persistent presence of the foreign material in the tissue. Significant efforts have been made to reduce the FBR, both at the outset of implantation by limiting initial insertion damage and over the long-term by reducing the mechanical mismatch between brain and implant, or long-term use of exogenous chemicals to suppress the FBR.

Rather than relying on temporary interventions to limit the FBR, we proposed a method to harness endogenous cortical function to improve the long-term neural interface microenvironment. Low-intensity pulsed ultrasound (LIPUS) has recently been shown to have protective and healing effects in models of cerebral disease and injury, through promotion of brain-derived neurotrophic factor (BDNF) and other neurotrophic factors that affect the anti-inflammatory response of microglia and other cells. Here, we investigate the use of sub-threshold LIPUS focused directly at the neural electrode interface to improve tissue health and increase the quality and longevity of neural recordings. A study was undertaken in which silicon shank electrodes (A4x4-5mm-100-125-703-CM16LP, NeuroNexus, Inc.) oriented at 45º from horizontal, were chronically implanted into cortical layers II/III of the motor or somatosensory cortex of rats (N=8). The effects of LIPUS on neural recording quality over 6 weeks post-implant were studied (n=4) with respect to Sham treatment (n=4). Nominal conditions used were based on the prior LIPUS research on disease and injury; stimulation (0.5 W/cm² intensity, 1.1 MHz, 15 min. total treatment at 4% duty cycle) was administered daily Week 1, and twice weekly for Weeks 2-6 and coupled with electrophysiology recording sessions (SmartBox Pro Allego, NeuroNexus). Single unit analysis of electrophysiological data reveals strong trends in signal quality improvements in the LIPUS-treated group. More than double the electrode channels remained active throughout the 6 weeks in subjects in the LIPUS stimulation group as compared to Sham (p<0.01). Also, the channels that remained active maintained an average 4 dB higher signal-to-noise ratio (SNR) over the same time period (p<0.01). Our studies demonstrate that periodic application of localized LIPUS to tissue at the neural interface has potential to improve electrophysiology signal quality. Implications for future studies will be discussed.

Microelectrode Arrays Insertion System Using Ultrasonic Vibration to Improve Insertion Mechanics and Reduce Tissue Dimpling and Trauma in the Cortex

NN TIRKO, RS CLEMENT, JK GREASER, AS ALSUBHI, EM STEFFAN, RB BAGWELL, ML MULVIHILL

Actuated Med. Inc., Bellefonte, PA

S LEE, HJ KIM, MF AGHA

University of North Carolina, Chapel Hill, NC

Abstract:

Intracortical Electrode Arrays (IEAs) provide direct access to extracellular neural signals in the brain with high temporal and spatial resolution. Unfortunately, chronically implanted IEAs have limited functional lifespans that impede significant clinical translation. The host tissue reaction is a major contributor to neural interface failure, causing formation of glial scars and loss of neurons at electrode sites. Studies suggest that the initial insertion trauma alone is responsible for significant damage. The forces applied to the cortical tissue during insertion can deform tissue, causing strain and membrane disruptions in underlying neurons and vasculature. While insertion is a technical hurdle common to all IEA types, high-density multi-shank arrays have uniquely significant insertion challenges. Following insertion, the IEA chronic interface can be degraded due to mechanical mismatch between the IEA and the cortical tissue. Superior tissue response and device longevity has been demonstrated with ultra-fine microwire (<15 µm diameter) and flexible (e.g., polyimide) arrays. However, given their tendency to buckle/break during insertion they struggle to penetrate meningeal layers and temporary support structures, shuttles, or dissolvable stiffeners are often necessary for mechanical reinforcement during insertion. This increases the complexity and time of the surgery and insertion process, and may limit reliable electrode performance and adaptation of these arrays.

Ultrasonic vibration of IEAs represents a promising approach to reduce frictional and penetration forces associated with insertion. We have demonstrated that this approach has implantation capability of both rigid, multi-shank arrays and mechanically soft microwire or polymer-based arrays. In the case of rigid arrays (i.e. silicon shanks from NeuroNexus, Blackrock and microwires from MicroProbes, Tucker Davis Technologies) vibration-assisted insertion reduces insertion force 61-82% relative to standard insertion via stereotaxic equipment when using an agar model (0.5% base, 1.5% top layer). In vivo studies demonstrated a significant (p<0.01) reduction in cortical surface dimpling/compression with vibration during insertion of silicon arrays (NeuroNexus H-series) into rat cortex, as well as successful insertion through the dura. Electrodes inserted with vibration have no detriment to electrophysiology signal quality.

In the case of flexible arrays, vibration-assisted insertion both reduces insertion force and improves insertion trajectory. Polyimide thin-film single-shanks probes were inserted in rat nucleus accumbens without vibration (n=6), with vibration through pia (n=10) and with vibration through dura (n=5). Using T2-weighted MRI, insertion accuracy was measured; targeting success was improved with vibration (through pia: 70%, through dura: 83%) as compared to Control (50%; p>0.05 due to limited sample size). Ten days after surgery, neuromodulation outcomes (evoked response patterns, as measured through fMRI) were increased with the vibration-inserted electrodes (through pia: 100%, through dura: 80%) versus Control (66%). Additionally, histological evaluation of the implantation site (4 weeks post-op) revealed that the intensity of glial scaring (visualized via glial fibrillary acidic protein immunohistochemistry) was significantly reduced when electrodes were inserted with vibration (p<0.05) relative to Control. Together, these benchtop insertion studies in agar and ex vivo tissue models, as well as in vivo insertion studies support the potential of vibrated insertion for improved outcomes for studies using IEAs, specifically for flexible electrodes.