Therapeutic hypothermia reduces cortical inflammation associated with utah array implants

Abstract

Objective. Neuroprosthetics hold tremendous promise to restore function through brain-computer interfaced devices. However, clinical applications of implantable microelectrodes remain limited given the challenges of maintaining neuronal signals for extended periods of time and with multiple biological mechanisms negatively affecting electrode performance. Acute and chronic inflammation, oxidative stress, and blood brain barrier disruption contribute to inconsistent electrode performance. We hypothesized that therapeutic hypothermia (TH) applied at the microelectrode insertion site will positively modulate both inflammatory and apoptotic pathways, promoting neuroprotection and improved performance in the long-term. Approach. A custom device and thermoelectric system were designed to deliver controlled TH locally to the cortical implant site at the time of microelectrode array insertion and immediately following surgery. The TH paradigm was derived from in vivo cortical temperature measurements and finite element modeling of temperature distribution profiles in the cortex. Male Sprague-Dawley rats were implanted with non-functional Utah microelectrodes arrays (UMEA) consisting of 4 × 4 grid of 1.5 mm long parylene-coated silicon shanks. In one group, TH was applied to the implant site for two hours following the UMEA implantation, while the other group was implanted under normothermic conditions without treatment. At 48 h, 72 h, 7 d and 14 d post-implantation, mRNA expression levels for genes associated with inflammation and apoptosis were compared between normothermic and hypothermia-treated groups. Main results. The custom system delivered controlled TH to the cortical implant site and the numerical models confirmed that the temperature decrease was confined locally. Furthermore, a one-time application of TH post UMEA insertion significantly reduced the acute inflammatory response with a reduction in the expression of inflammatory regulating cytokines and chemokines. Significance. This work provides evidence that acutely applied hypothermia is effective in significantly reducing acute inflammation post intracortical electrode implantation.

Transcriptional response to mild therapeutic hypothermia in noise-induced cochlear injury

“…Compared with post-noise normothermia, post-noise cochlear mild hypothermia therapy to 33°C post-noise showed reduced levels of multiple important cytokines and chemokines, such as Cxcl9, Cxcl10, Cxcl11, Timp1, and Osmr. Our observations are consistent with the literature on cytokine regulation with hypothermic intervention in the central nervous system ( Truettner et al, 2005 ; Dugan et al, 2020 ). Furthermore, in the cochlea, our hypothermic intervention produced a strong downregulation of DEGs with immune host defense-related roles that have been frequently associated with early stress response (Lcn2, Timp1, Kng2, Vmo1, Il17rb, Mx2, Hpx, and Csf2rb).…”

Targeted therapeutic hypothermia protects against noise induced hearing loss

“…MTH may also directly promote the reduction of inflammatory cytokines. One study showed that MTH significantly down-regulated pro-inflammatory interleukins, such as TNF-α, and beneficially up-regulated BCL-2 in a cortical microelectrode implant model ( Dugan et al, 2020 ). Bcl-2 promotes cell survival and inhibits apoptosis by inhibiting free radical production, preventing mitochondrial cytochrome c release, and blocking caspase activation.…”

Recent Advances in In Vivo Neurochemical Monitoring

“…Anti-inflammatory drugs such as dexamethasone [228,238], antioxidants such as melatonin [239] or superoxide dismutase mimics [240,241], and nitric oxide [242] have been employed as anti-inflammatory strategies for neural implants. A recent study applied therapeutic hypothermia after microelectrode implantation and significantly reduced the expression of inflammatory regulating cytokines and chemokines [243]. A further strategy to reduce inflammation is microfabricating ultrasmall sensors [244].…”