Mitochondrial responses to intracellular Ca2+ release following infrared stimulation.

Many studies of Ca2+ effects on mitochondrial respiration in intact cells have used electrical and/or chemical stimulation to elevate intracellular [Ca2+], and have reported increases in [NADH] and increased ADP/ATP ratios as dominant controllers of respiration. This study tested a different form of stimulation: brief temperature increases produced by pulses of infrared light (IR, 1,863 nm, 8-10°C for ∼5 s). Fluorescence imaging techniques applied to single PC-12 cells in low µM extracellular [Ca2+] revealed IR stimulation-induced increases in both cytosolic (fluo5F) and mitochondrial (rhod2) [Ca2+]. IR stimulation increased O2 consumption (porphyrin fluorescence), and produced an alkaline shift in mitochondrial matrix pH (Snarf1), indicating activation of the electron transport chain (ETC). The increase in O2 consumption persisted in oligomycin, and began during a decrease in NADH, suggesting that the initial increase in ETC activity was not driven by increased ATP synthase activity or an increased fuel supply to ETC complex I. Imaging with two potentiometric dyes [tetramethyl rhodamine methyl ester (TMRM) and R123] indicated a depolarizing shift in ΔΨm that persisted in high [K+] medium. High-resolution fluorescence imaging disclosed large, reversible mitochondrial depolarizations that were inhibited by cyclosporin A (CSA), consistent with the opening of transient mitochondrial permeability transition pores. IR stimulation also produced a Ca2+-dependent increase in superoxide production (MitoSox) that was not inhibited by CSA, indicating that the increase in superoxide did not require transition pore opening. Thus, the intracellular Ca2+ release that follows pulses of infrared light offers new insights into Ca2+-dependent processes controlling respiration and reactive oxygen species in intact cells.NEW & NOTEWORTHY Pulses of infrared light (IR) provide a novel method for rapidly transferring Ca2+ from the endoplasmic reticulum to mitochondria in intact cells. In PC12 cells the resulting ETC activation was not driven by increased ATP synthase activity or NADH. IR stimulation produced a Ca2+-dependent, reversible depolarization of ΔΨm that was partially blocked by cyclosporin A, and a Ca2+-dependent increase in superoxide that did not require transition pore opening.

Risk-taking propensity as a risk factor for noise-induced hearing loss in the general population.

OBJECTIVES: To examine general risk propensity in relation to perceptions of noise, risk behaviour, and hearing loss in the general population. DESIGN: Participants completed an online survey using the Amazon Mechanical Turk crowdsourcing platform. STUDY SAMPLE: The sample comprised 1274 adults from the United States. RESULTS: Higher general risk propensity was associated with an increased likelihood to engage in noise-risk behaviours. Lower general risk propensity was associated with increased knowledge of noise risks and an increased perception of noise as risky. The frequency of self-reported exposures to hazardous noise resulted in estimated annual noise doses exceeding standard hazard limits in 40% of the surveyed population. CONCLUSIONS: Results revealed limited knowledge of the risks and associated health consequences of noise exposure in the general population Results of this study suggest a high rate of self-exposure to hazardous noise by the general population. Those with higher general risk propensity are more likely to engage in risky noise behaviour. Risky noise behaviour is associated with age, gender, race, ethnicity, and general risk propensity. Intervention programs to modify risky noise behaviour in the general population should focus on both increasing knowledge and establishing accurate perceptions of risk.

Pulsed infrared releases Ca2+ from the endoplasmic reticulum of cultured spiral ganglion neurons.

Inner ear spiral ganglion neurons were cultured from day 4 postnatal mice and loaded with a fluorescent Ca2+ indicator (fluo-4, -5F, or -5N). Pulses of infrared radiation (IR; 1,863 nm, 200 µs, 200-250 Hz for 2-5 s, delivered via an optical fiber) produced a rapid, transient temperature increase of 6-12°C (above a baseline of 24-30°C). These IR pulse trains evoked transient increases in both nuclear and cytosolic Ca2+ concentration ([Ca2+]) of 0.20-1.4 µM, with a simultaneous reduction of [Ca2+] in regions containing endoplasmic reticulum (ER). IR-induced increases in cytosolic [Ca2+] continued in medium containing no added Ca2+ (±Ca2+ buffers) and low [Na+], indicating that the [Ca2+] increase was mediated by release from intracellular stores. Consistent with this hypothesis, the IR-induced [Ca2+] response was prolonged and eventually blocked by inhibition of ER Ca2+-ATPase with cyclopiazonic acid, and was also inhibited by a high concentration of ryanodine and by inhibitors of inositol (1,4,5)-trisphosphate (IP3)-mediated Ca2+ release (xestospongin C and 2-aminoethoxydiphenyl borate). The thermal sensitivity of the response suggested involvement of warmth-sensitive transient receptor potential (TRP) channels. The IR-induced [Ca2+] increase was inhibited by TRPV4 inhibitors (HC-067047 and GSK-2193874), and immunostaining of spiral ganglion cultures demonstrated the presence of TRPV4 and TRPM2 that colocalized with ER marker GRP78. These results suggest that the temperature sensitivity of IR-induced [Ca2+] elevations is conferred by TRP channels on ER membranes, which facilitate Ca2+ efflux into the cytosol and thereby contribute to Ca2+-induced Ca2+-release via IP3 and ryanodine receptors. NEW & NOTEWORTHY Infrared radiation-induced photothermal effects release Ca2+ from the endoplasmic reticulum of primary spiral ganglion neurons. This Ca2+ release is mediated by activation of transient receptor potential (TRPV4) channels and involves amplification by Ca2+-induced Ca2+-release. The neurons immunostained for warmth-sensitive channels, TRPV4 and TRPM2, which colocalize with endoplasmic reticulum. Pulsed infrared radiation provides a novel experimental tool for releasing intracellular Ca2+, studying Ca2+ regulatory mechanisms, and influencing neuronal excitability.

Theoretical Evaluation and Experimental Validation of Localized Therapeutic Hypothermia Application to Preserve Residual Hearing After Cochlear Implantation.

OBJECTIVES: Cochlear implantation surgery has been shown to result in trauma to inner ear sensory structures, resulting in loss of residual hearing. Localized therapeutic hypothermia has been shown in clinical care to be a neuroprotective intervention. Previously, we have shown in an experimental model that localized hypothermia protects cochlear hair cells and residual hearing function against surgical and cochlear implantation trauma. Using experimental temperature measurements carried out in human cadaver temporal bones and a finite element model of the inner ear, the present study examined the temperature distribution of a custom-designed hypothermia delivery system in the human inner ear organs. DESIGN: The efficacy of the hypothermia probe and resulting heat distribution across human cochlea and surrounding tissues were modeled in three-dimensional in COMSOL. The geometry and dimensions of inner ear and temporal bones were derived from computed tomographic and magnetic resonance imaging images. Model predictions were compared with experimental observations from five human temporal bones. RESULTS: In both the modeling and experimental studies, the cochlear temperature was lowered by 4 to 6 °C on the round window from a baseline of 37 °C within 16 to 18 minutes. The model simulations showed uniformly distributed cooling across the cochlea. This study provides insight for design, operation, and protocols for efficacious delivery of mild therapeutic hypothermia to the human cochlea that may significantly benefit patients undergoing surgical cochlear implantation by preserving residual hearing. CONCLUSION: There was a close correlation between the results of the numerical simulations and experimental observations in this study. Our custom-designed system is capable of effectively providing mild therapeutic hypothermia locally to the human cochlea. When combined with results from in vivo animal experiments, the present study suggests that the application of localized therapeutic hypothermia may hold potential for patients with an aim to preserve residual hearing after cochlear implantation.

Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling.

Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca(2+) imaging. Both types of neurons responded consistently with robust intracellular Ca(2+) ([Ca(2+)]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25-1 pps). Radiant exposures of ∼637 mJ/cm(2) resulted in continual neuronal activation. Temperature or [Ca(2+)] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca(2+) involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na(+), K(+), and Ca(2+) plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca(2+) cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca(2+)]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca(2+) release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses.

Prevalence of Hearing Loss and Perceptions of Hearing Health and Protection among Florida Firefighters.

Firefighters are exposed to extensive hazardous noise while on the job, both during routine tasks at the station and when responding to calls. However, little is known about firefighters' occupational noise hazards. This study employed mixed methods, including focus groups, a survey, and audiometric testing, to identify sources of noise in the firefighters' work environment, determine hearing protective strategies, discern firefighters' perceptions of occupational noise exposure and impacts to their health, and quantify the prevalence of hearing loss among South Florida firefighters. A total of 6 senior officers served in an expert panel, 12 participated in focus groups, 300 completed the survey, and 214 received audiometric tests. Most firefighters were unaware of the risk and their departments' policies, and did not participate in hearing protection practices and avoided using hearing protection devices, which they believed impede team communication and situational awareness. Nearly 30% of participating firefighters showed mild to profound hearing loss, a prevalence that is considerably worse than expected by normal aging alone. Educating firefighters about noise-induced hearing loss early in their careers may have significant health implications for their future. These findings provide insights for developing technologies and programs to mitigate the effects of noise exposure in the firefighting population.

A reliable and reproducible protocol for sound-evoked vestibular myogenic potentials in rattus norvegicus.

Introduction: Cervical vestibular evoked myogenic potentials (cVEMPs) provide an objective measure of the integrity of the sacculo-collic pathway leading to their widespread use as a clinical tool in the diagnostic vestibular test battery. Though the application of cVEMPs in preclinical models to assess vestibular function, as performed in relevant clinical populations, remains limited. The present study aimed to establish a rodent model of cVEMP with standardized methods and protocols, examine the neural basis of the responses, and characterize and validate important features for interpretation and assessment of vestibular function. Methods: We compared air-conducted sound (ACS)-evoked VEMPs from the sternocleidomastoid muscles in naïve Brown Norway rats. A custom setup facilitated repeatable and reliable measurements which were carried out at multiple intensities with ACS between 1 and 16 kHz and over 7 days. The myogenic potentials were identified by the presence of a positive (P1)-negative (N1) waveform at 3-5 ms from the stimulus onset. Threshold, amplitude, and latency were compared with intensity- and frequency-matched responses within and between animals. Results: cVEMP responses were repeatedly evoked with stimulus intensities between 50-100 dB SPL with excellent test-retest reliability and across multiple measurements over 7 days for all frequencies tested. Suprathreshold, cVEMP responses at 90 dB SPL for 6-10 kHz stimuli demonstrated significantly larger amplitudes (p < 0.01) and shorter latencies (p < 0.001) compared to cVEMP responses for 1-4 kHz stimuli. Latency of cVEMP showed sex-dependent variability, but no significant differences in threshold or amplitude between males and females was observed. Discussion: The results provide a replicable and reliable setup, test protocol, and comprehensive characterization of cVEMP responses in a preclinical model which can be used in future studies to elucidate pathophysiological characteristics of vestibular dysfunctions or test efficacy of therapeutics.

The effects of hearing protection devices on spatial awareness in complex listening environments.

Hearing protection devices (HPDs) remain the first line of defense against hazardous noise exposure and noise-induced hearing loss (NIHL). Despite the increased awareness of NIHL as a major occupational health hazard, implementation of effective hearing protection interventions remains challenging in at-risk occupational groups including those in public safety that provide fire, emergency medical, or law enforcement services. A reduction of situational awareness has been reported as a primary barrier to including HPDs as routine personal protective equipment. This study examined the effects of hearing protection and simulated NIHL on spatial awareness in ten normal hearing subjects. In a sound-attenuating booth and using a head-orientation tracker, speech intelligibility and localization accuracy were collected from these subjects under multiple listening conditions. Results demonstrate that the use of HPDs disrupts spatial hearing as expected, specifically localization performance and monitoring of speech signals. There was a significant interaction between hemifield and signal-to-noise ratio (SNR), with speech intelligibility significantly affected when signals were presented from behind at reduced SNR. Results also suggest greater spatial hearing disruption using over-the-ear HPDs when compared to the removal of high frequency cues typically associated with NIHL through low-pass filtering. These results are consistent with reduced situational awareness as a self-reported barrier to routine HPD use, and was evidenced in our study by decreased ability to make accurate decisions about source location in a controlled dual-task localization experiment.

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

Introduction: Prevention or treatment for acoustic injury has been met with many translational challenges, resulting in the absence of FDA-approved interventions. Localized hypothermia following noise exposure mitigates acute cochlear injury and may serve as a potential avenue for therapeutic approaches. However, the mechanisms by which hypothermia results in therapeutic improvements are poorly understood. Methods: This study performs the transcriptomic analysis of cochleae from juvenile rats that experienced noise-induced hearing loss (NIHL) followed by hypothermia or control normothermia treatment. Results: Differential gene expression results from RNA sequencing at 24 h post-exposure to noise suggest that NIHL alone results in increased inflammatory and immune defense responses, involving complement activation and cytokine-mediated signaling. Hypothermia treatment post-noise, in turn, may mitigate the acute inflammatory response. Discussion: This study provides a framework for future research to optimize hypothermic intervention for ameliorating hearing loss and suggests additional pathways that could be targeted for NIHL therapeutic intervention.

Monitoring Occupational Noise Exposure in Firefighters Using the Apple Watch.

Occupational noise exposure and hearing loss are prominent in the fire service. Firefighters are routinely exposed to hazardous levels of noise arising from the tools and equipment they use, from sirens and alarm tones to the emergency response vehicles they drive. The present study utilized the Apple Watch to continuously measure environmental noise levels for on-duty firefighters. Participants included 15 firefighters from the metropolitan South Florida area, and 25 adult non-firefighter control subjects. Firefighters were recruited from a variety of roles across two stations to ensure noise exposure profiles were appropriately representative of exposures in the fire service. All participants wore an Apple Watch for up to three separate 24 h shifts and completed a post-shift survey self-reporting on perceived exposures over the 24 h study period. Cumulative exposures were calculated for each shift and noise dose was calculated relative to the NIOSH recommended exposure limit of 85 dBA as an 8 h time-weighted average. The maximum dBA recorded on the Apple Watches was statistically significant between groups, with firefighters experiencing a median of 87.79 dBA and controls a median of 77.27 dBA. Estimated Exposure Time at 85 dBA (EET-85) values were significantly higher for firefighters when compared to controls: 3.97 h (range: 1.20-14.7 h) versus 0.42 h (range: 0.05-8.21 h). Only 2 of 16 firefighters reported the use of hearing protection devices during their shifts. Overall, our results highlight the utility of a commonly used personal device to quantify noise exposure in an occupationally at-risk group.

Mild therapeutic hypothermia protects against inflammatory and proapoptotic processes in the rat model of cochlear implant trauma.

OBJECTIVE: Mild therapeutic hypothermia (MTH) has been demonstrated to prevent residual hearing loss from surgical trauma associated with cochlear implant (CI) insertion. Here, we aimed to characterize the mechanisms of MTH-induced hearing preservation in CI in a well-established preclinical rodent model. APPROACH: Rats were divided into four experimental conditions: MTH-treated and implanted cochleae, cochleae implanted under normothermic conditions, MTH only cochleae and un-operated cochleae (controls). Auditory brainstem responses (ABRs) were recorded at different time points (up to 84 days) to confirm long-term protection and safety of MTH locally applied to the cochlea for 20 min before and after implantation. Transcriptome sequencing profiling was performed on cochleae harvested 24 h post CI and MTH treatment to investigate the potential beneficial effects and underlying active gene expression pathways targeted by the temperature management. RESULTS: MTH treatment preserved residual hearing up to 3 months following CI when compared to the normothermic CI group. In addition, MTH applied locally to the cochleae using our surgical approach was safe and did not affect hearing in the long-term. Results of RNA sequencing analysis highlight positive modulation of signaling pathways and gene expression associated with an activation of cellular inflammatory and immune responses against the mechanical damage caused by electrode insertion. SIGNIFICANCE: These data suggest that multiple and possibly independent molecular pathways play a role in the protection of residual hearing provided by MTH against the trauma of cochlear implantation.

Targeted therapeutic hypothermia protects against noise induced hearing loss.

Introduction: Exposure to occupational or recreational loud noise activates multiple biological regulatory circuits and damages the cochlea, causing permanent changes in hearing sensitivity. Currently, no effective clinical therapy is available for the treatment or mitigation of noise-induced hearing loss (NIHL). Here, we describe an application of localized and non-invasive therapeutic hypothermia and targeted temperature management of the inner ear to prevent NIHL. Methods: We developed a custom-designed cooling neck collar to reduce the temperature of the inner ear by 3-4°C post-injury to deliver mild therapeutic hypothermia. Results: This localized and non-invasive therapeutic hypothermia successfully mitigated NIHL in rats. Our results show that mild hypothermia can be applied quickly and safely to the inner ear following noise exposure. We show that localized hypothermia after NIHL preserves residual hearing and rescues noise-induced synaptopathy over a period of months. Discussion: This study establishes a minimally-invasive therapeutic paradigm with a high potential for rapid translation to the clinic for long-term preservation of hearing health.

Subclinical Hearing Deficits in Noise-Exposed Firefighters.

Noise-induced hearing loss (NIHL) is the most prevalent occupational disease in the world and firefighters are at increased risk of NIHL due to their frequent exposure to hazardous levels of noise during service. Adverse effects of NIHL include acceleration of age-related hearing loss and an increased risk of cognitive decline. A critical challenge in addressing NIHL is the delayed clinical presentation of symptoms and lack of sensitive tools for early detection. To study the early clinical symptoms of NIHL in this high-risk group, we collected hearing function data including behavioral audiometric thresholds and distortion product otoacoustic emissions (DPOAEs) in 176 firefighters during annual physical assessments. Results revealed significant deficits in cochlear outer hair cell function in the presence of normal audiograms. Additionally, 55% of firefighters self-reported changes in hearing, while 20% self-reported concerns about their balance. This study is the first to characterize DPOAEs in firefighters who display decreased DPOAE amplitudes with increasing years in the fire service. These effects were observed even when controlling for hearing loss and age and are suggestive of a link between hearing loss and occupational exposure to hazardous noise.

Intracellular calcium transients evoked by pulsed infrared radiation in neonatal cardiomyocytes.

Neonatal rat ventricular cardiomyocytes were used to investigate mechanisms underlying transient changes in intracellular free Ca2+ concentration ([Ca2+]i) evoked by pulsed infrared radiation (IR, 1862 nm). Fluorescence confocal microscopy revealed IR-evoked [Ca2+]i events with each IR pulse (3-4 ms pulse⁻¹, 9.1-11.6 J cm⁻² pulse⁻¹). IR-evoked [Ca2+]i events were distinct from the relatively large spontaneous [Ca2+]i transients, with IR-evoked events exhibiting smaller amplitudes (0.88 ΔF/F0 vs. 1.99 ΔF/F0) and shorter time constants (τ =0.64 s vs. 1.19 s, respectively). Both IR-evoked [Ca2+]i events and spontaneous [Ca2+]i transients could be entrained by the IR pulse (0.2-1 pulse s⁻¹), provided the IR dose was sufficient and the radiation was applied directly to the cell. Examination of IR-evoked events during peak spontaneous [Ca2+]i periods revealed a rapid drop in [Ca2+]i, often restoring the baseline [Ca2+]i concentration, followed by a transient increase in [Ca2+]i.Cardiomyocytes were challenged with pharmacological agents to examine potential contributors to the IR-evoked [Ca2+]i events. Three compounds proved to be the most potent, reversible inhibitors: (1) CGP-37157 (20 µM, n =12), an inhibitor of the mitochondrial Na+/Ca2+ exchanger (mNCX), (2) Ruthenium Red (40 µM, n =13), an inhibitor of the mitochondrial Ca2+ uniporter (mCU), and (3) 2-aminoethoxydiphenylborane (10 µM, n =6), an IP3 channel antagonist. Ryanodine blocked the spontaneous [Ca2+]i transients but did not alter the IR-evoked events in the same cells. This pharmacological array implicates mitochondria as the major intracellular store of Ca2+ involved in IR-evoked responses reported here. Results support the hypothesis that 1862 nm pulsed IR modulates mitochondrial Ca2+ transport primarily through actions on mCU and mNCX.

Infrared photostimulation of the crista ampullaris.

The present results show that the semicircular canal crista ampullaris of the toadfish, Opsanus tau, is sensitive to infrared radiation (IR) applied in vivo. IR pulse trains (∼1862 nm, ∼200 µs pulse⁻¹) delivered to the sensory epithelium by an optical fibre evoked profound changes in phasic and tonic discharge rates of postsynaptic afferent neurons. Phasic afferent responses to pulsed IR occurred with a latency of <8 ms while tonic responses developed with a time constant (τ) of 7 ms to 10 s following the onset or cessation of the radiation. Afferents responded to direct optical radiation of the sensory epithelium but did not respond to thermal stimuli that generated nearly equivalent temperature increases of the whole organ. A subset of afferent neurons fired an action potential in response to each IR pulse delivered to the sensory epithelium, at phase-locked rates up to 96 pulses per second. The latency between IR pulses and afferent nerve action potentials was much greater than synaptic delay and spike generation, demonstrating the presence of a signalling delay interposed between the IR pulse and the action potential. The same IR stimulus applied to afferent nerve axons failed to evoke responses of similar magnitude and failed to phase-lock afferent nerve action potentials. The present data support the hypothesis that pulsed IR activates sensory hair cells, thus leading to modulation of synaptic transmission and afferent nerve discharge reported here.

Additive Protective Effects of Delayed Mild Therapeutic Hypothermia and Antioxidants on PC12 Cells Exposed to Oxidative Stress.

Mild therapeutic hypothermia is protective against several cellular stresses, but the mechanisms underlying this protection are not completely resolved. In the present study, we used an in vitro model to investigate whether therapeutic hypothermia at 33°C applied following a peroxide-induced oxidative stress would protect PC12 cells. A 1-hour exposure to tert-butyl peroxide increased cell death measured 24 hours later. This cell death was dose-dependent in the range of 100-1000 µM tert-butyl peroxide with ∼50% cell death observed at 24 hours from 500 µM peroxide exposure. Cell survival/death was measured with an alamarBlue viability assay, and propidium iodide/Hoechst imaging for counts of living and dead cells. Therapeutic hypothermia at 33°C applied for 2 hours postperoxide exposure significantly increased cell survival measured 24 hours postperoxide-induced stress. This protection was present even when delayed hypothermia, 15 minutes after the peroxide washout, was applied. Addition of any of the three FDA-approved antioxidants (Tempol, EUK134, Edaravone at 100 µM) in combination with hypothermia improved cell survival. With the therapeutic hypothermia treatment, a significant downregulation of caspases-3 and -8 and tumor necrosis factor-α was observed at 3 and 24 hours poststress. Consistent with this, a cell-permeable pan-caspase inhibitor Z-VAD-FMK applied in combination with hypothermia significantly increased cell survival. Overall, these results suggest that the antioxidants quenching of reactive oxygen species likely works with hypothermia to reduce mitochondrial damage and/or apoptotic mechanisms. Further studies are required to confirm and extend these results to other cell types, including neuronal cells, and other forms of oxidative stress as well as to optimize the critical parameters of hypothermia treatment such as target temperature and duration.

Pulsed Infrared Stimulation of Vertical Semicircular Canals Evokes Cardiovascular Changes in the Rat.

A variety of stimuli activating vestibular end organs, including sinusoidal galvanic vestibular stimulation, whole body rotation and tilt, and head flexion have been shown to evoke significant changes in blood pressure (BP) and heart rate (HR). While a role for the vertical semicircular canals in altering autonomic activity has been hypothesized, studies to-date attribute the evoked BP and HR responses to the otolith organs. The present study determined whether unilateral activation of the posterior (PC) or anterior (AC) semicircular canal is sufficient to elicit changes in BP and/or HR. The study employed frequency-modulated pulsed infrared radiation (IR: 1,863 nm) directed via optical fibers to PC or AC of adult male Long-Evans rats. BP and HR changes were detected using a small-animal single pressure telemetry device implanted in the femoral artery. Eye movements evoked during IR of the vestibular endorgans were used to confirm the stimulation site. We found that sinusoidal IR delivered to either PC or AC elicited a rapid decrease in BP and HR followed by a stimulation frequency-matched modulation. The magnitude of the initial decrements in HR and BP did not correlate with the energy of the suprathreshold stimulus. This response pattern was consistent across multiple trials within an experimental session, replicable, and in most animals showed no evidence of habituation or an additive effect. Frequency modulated electrical current delivered to the PC and IR stimulation of the AC, caused decrements in HR and BP that resembled those evoked by IR of the PC. Frequency domain heart rate variability assessment revealed that, in most subjects, IR stimulation increased the low frequency (LF) component and decreased the high frequency (HF) component, resulting in an increase in the LF/HF ratio. This ratio estimates the relative contributions of sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) activities. An injection of atropine, a muscarinic cholinergic receptor antagonist, diminished the IR evoked changes in HR, while the non-selective beta blocker propranolol eliminated changes in both HR and BP. This study provides direct evidence that activation of a single vertical semicircular canal is sufficient to activate and modulate central pathways that control HR and BP.

Spatiotemporal properties of vestibular responses in area MSTd.

Recent studies have shown that many neurons in the primate dorsal medial superior temporal area (MSTd) show spatial tuning during inertial motion and that these responses are vestibular in origin. Given their well-studied role in processing visual self-motion cues (i.e., optic flow), these neurons may be involved in the integration of visual and vestibular signals to facilitate robust perception of self-motion. However, the temporal structure of vestibular responses in MSTd has not been characterized in detail. Specifically, it is not known whether MSTd neurons encode velocity, acceleration, or some combination of motion parameters not explicitly encoded by vestibular afferents. In this study, we have applied a frequency-domain analysis to single-unit responses during translation in three dimensions (3D). The analysis quantifies the stimulus-driven temporal modulation of each response as well as the degree to which this modulation reflects the velocity and/or acceleration profile of the stimulus. We show that MSTd neurons signal a combination of velocity and acceleration components with the velocity component being stronger for most neurons. These two components can exist both within and across motion directions, although their spatial tuning did not show a systematic relationship across the population. From these results, vestibular responses in MSTd appear to show characteristic features of spatiotemporal convergence, similar to previous findings in the brain stem and thalamus. The predominance of velocity encoding in this region may reflect the suitability of these signals to be integrated with visual signals regarding self-motion perception.

Therapeutic hypothermia reduces cortical inflammation associated with utah array implants.

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.

I-Corps@NCATS trains clinical and translational science teams to accelerate translation of research innovations into practice.

INTRODUCTION: A key barrier to translation of biomedical research discoveries is a lack of understanding among scientists regarding the complexity and process of implementation. To address this challenge, the National Science Foundation's Innovation Corps™ (I-Corps™) program trains researchers in entrepreneurship. We report results from the implementation of an I-Corps™ training program aimed at biomedical scientists from institutions funded by the National Center for Advancing Translational Sciences (NCATS). METHODS: National/regional instructors delivered 5-week I-Corps@NCATS short courses to 62 teams (150 individuals) across six institutions. Content included customer discovery, value proposition, and validating needs. Teams interviewed real-life customers and presented the value of innovations for specific end-users weekly, culminating in a "Finale" featuring their refined business thesis and business model canvas. Methodology was developed to evaluate the newly adapted program. National mixed-methods evaluation assessed program implementation, reach, effectiveness using observations of training delivery and surveys at Finale (n = 55 teams), and 3-12 months post-training (n = 34 teams). RESULTS: Innovations related to medical devices (33%), drugs/biologics (20%), software applications (16%), and diagnostics (8%). An average of 24 interviews was conducted. Teams reported increased readiness for commercialization over time (83%, 9 months; 14%, 3 months). Thirty-nine percent met with institutional technology transfer to pursue licensing/patents and 24% pursued venture capital/investor funding following the short courses. CONCLUSIONS: I-Corps@NCATS training provided the NCATS teams a rigorous and repeatable process to aid development of a business model based on customer needs. Outcomes of this pilot program support the expansion of I-Corps™ training to biomedical scientists for accelerating research translation.