Translation of an existing implantable cardiac monitoring device for measurement of gastric electrical slow-wave activity.

BACKGROUND: Despite evidence that slow-wave dysrhythmia in the stomach is associated with clinical conditions such as gastroparesis and functional dyspepsia, there is still no widely available device for long-term monitoring of gastric electrical signals. Actionable biomarkers of gastrointestinal health are critically needed, and an implantable slow-wave monitoring device could aid in the establishment of causal relationships between symptoms and gastric electrophysiology. Recent developments in the area of wireless implantable gastric monitors demonstrate potential, but additional work and validation are required before this potential can be realized. METHODS: We hypothesized that translating an existing implantable cardiac monitoring device, the Reveal LINQ™ (Medtronic), would present a more immediate solution. Following ethical approval and laparotomy in anesthetized pigs (n = 7), a Reveal LINQ was placed on the serosal surface of the stomach, immediately adjacent to a validated flexible-printed-circuit (FPC) electrical mapping array. Data were recorded for periods of 7.5 min, and the resultant signal characteristics from the FPC array and Reveal LINQ were compared. KEY RESULTS: The Reveal LINQ device recorded slow waves in 6/7 subjects with a comparable period (p = 0.69), signal-to-noise ratio (p = 0.58), and downstroke width (p = 0.98) to the FPC, but with reduced amplitude (p = 0.024). Qualitatively, the Reveal LINQ slow-wave signal lacked the prolonged repolarization phase present in the FPC signals. CONCLUSIONS & INFERENCES: These findings suggest that existing cardiac monitors may offer an efficient solution for the long-term monitoring of slow waves. Translation toward implantation now awaits.

Sensing in Sacral Neuromodulation: A Feasibility Study in Subjects With Urinary Incontinence and Retention.

OBJECTIVES: Sacral neuromodulation (SNM) therapy standard of care relies on visual-motor responses and patient-reported sensory responses in deciding optimized lead placement and programming. Automatic detection of stimulation responses could offer a simple, consistent indicator for optimizing SNM. The purpose of this study was to measure and characterize sacral evoked responses (SERs) resulting from sacral nerve stimulation using a commercial, tined SNM lead. MATERIALS AND METHODS: A custom external research system with stimulation and sensing hardware was connected to the percutaneous extension of an implanted lead during a staged (tined lead) evaluation for SNM. The system collected SER recordings across a range of prespecified stimulation settings (electrode configuration combinations for bipolar stimulation and bipolar sensing) during intraoperative and postoperative sessions in 21 subjects with overactive bladder (OAB) and nonobstructive urinary retention (NOUR). Motor and sensory thresholds were collected during the same sessions. RESULTS: SERs were detected in all 21 subjects. SER morphology (number of peaks, magnitude, and timing) varied across electrode configurations within and across subjects. Among subjects and electrode configurations tested, recordings contained SERs at motor threshold and/or sensory threshold in 75% to 80% of subjects. CONCLUSIONS: This study confirmed that implanted SNM leads can be used to directly record SERs elicited by stimulation in subjects with OAB and NOUR. SERs were readily detectable at typical SNM stimulation settings and procedural time points. Using these SERs as possible objective measures of SNM response has the capability to automate patient-specific SNM therapy, potentially providing consistent lead placement, programming, and/or closed-loop therapy.

Rationale and design of an implant procedure and pivotal study to evaluate safety and effectiveness of Medtronic's tibial neuromodulation device.

Percutaneous tibial neuromodulation is a medical guideline recommended therapy for treating symptoms of overactive bladder. Stimulation is delivered to the tibial nerve via a thin needle placed percutaneously for 30 min once a week for 12-weeks, and monthly thereafter. Studies have shown that this therapy can effectively relieve symptoms of overactive bladder; however, the frequent office visits present a barrier to patients and can impact therapy effectiveness. To mitigate the burden of frequent clinic visits, small implantable devices are being developed to deliver tibial neuromodulation. These devices are implanted during a single minimally invasive procedure and deliver stimulation intermittently, similar to percutaneous tibial neuromodulation. Here, we describe the implant procedure and design of a pivotal study evaluating the safety and effectiveness for an implantable tibial neuromodulation device. The Evaluation of Implantable Tibial Neuromodulation (TITAN 2) pivotal study is a prospective, multicenter, investigational device exemption study being conducted at up to 30 sites in the United States and enrolling subjects with symptoms of overactive bladder.

Gradients of response latencies and temporal precision of auditory neurons extend across the whole inferior colliculus.

Neural responses to acoustic stimulation have long been studied throughout the auditory system to understand how sound information is coded for perception. Within the inferior colliculus (IC), a majority of the studies have focused predominantly on characterizing neural responses within the central region (ICC), as it is viewed as part of the lemniscal system mainly responsible for auditory perception. In contrast, the responses of outer cortices (ICO) have largely been unexplored, though they also function in auditory perception tasks. Therefore, we sought to expand on previous work by completing a three-dimensional (3-D) functional mapping study of the whole IC. We analyzed responses to different pure tone and broadband noise stimuli across all IC subregions and correlated those responses with over 2,000 recording locations across the IC. Our study revealed there are well-organized trends for temporal response parameters across the full IC that do not show a clear distinction at the ICC and ICO border. These gradients span from slow, imprecise responses in the caudal-medial IC to fast, precise responses in the rostral-lateral IC, regardless of subregion, including the fastest responses located in the ICO. These trends were consistent at various acoustic stimulation levels. Weaker spatial trends could be found for response duration and spontaneous activity. Apart from tonotopic organization, spatial trends were not apparent for spectral response properties. Overall, these detailed acoustic response maps across the whole IC provide new insights into the organization and function of the IC.NEW & NOTEWORTHY Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.

Ultrasound does not activate but can inhibit in vivo mammalian nerves across a wide range of parameters.

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

Feasibility of Real-Time Conditional Sacral Neuromodulation Using Wireless Bladder Pressure Sensor.

Continuous sacral neuromodulation (SNM) is used to treat overactive bladder, reducing urine leakage and increasing capacity. Conditional SNM applies stimulation in response to changing bladder conditions, and is an opportunity to study neuromodulation effects in various disease states. A key advantage of this approach is saving power consumed by stimulation pulses. This study demonstrated feasibility of automatically applying neuromodulation using a wireless bladder pressure sensor, a real-time control algorithm, and the Medtronic Summit™ RC+S neurostimulation research system. This study tested feasibility of four conditional SNM paradigms over five days in 4 female sheep. Primary outcomes assessed proof of concept of closed-loop system function. While the bladder pressure sensor correlated only weakly to simultaneous catheter-based pressure measurement (correlation 0.26-0.89, median r = 0.52), the sensor and algorithm were accurate enough to automatically trigger SNM appropriately. The neurostimulator executed 98.5% of transmitted stimulation commands with a median latency of 72 ms (n = 1,206), suggesting that rapid decision-making and control is feasible with this platform. On average, bladder capacity increased for continuous SNM and algorithm-controlled paradigms. Some animals responded more strongly to conditional SNM, suggesting that treatment could be individualized. Future research in conditional SNM may elucidate the physiologic underpinnings of differential response and enable clinical translation.

Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis.

Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway.

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

Suppression and facilitation of auditory neurons through coordinated acoustic and midbrain stimulation: investigating a deep brain stimulator for tinnitus.

OBJECTIVE: The inferior colliculus (IC) is the primary processing center of auditory information in the midbrain and is one site of tinnitus-related activity. One potential option for suppressing the tinnitus percept is through deep brain stimulation via the auditory midbrain implant (AMI), which is designed for hearing restoration and is already being implanted in deaf patients who also have tinnitus. However, to assess the feasibility of AMI stimulation for tinnitus treatment we first need to characterize the functional connectivity within the IC. Previous studies have suggested modulatory projections from the dorsal cortex of the IC (ICD) to the central nucleus of the IC (ICC), though the functional properties of these projections need to be determined. APPROACH: In this study, we investigated the effects of electrical stimulation of the ICD on acoustic-driven activity within the ICC in ketamine-anesthetized guinea pigs. MAIN RESULTS: We observed ICD stimulation induces both suppressive and facilitatory changes across ICC that can occur immediately during stimulation and remain after stimulation. Additionally, ICD stimulation paired with broadband noise stimulation at a specific delay can induce greater suppressive than facilitatory effects, especially when stimulating in more rostral and medial ICD locations. SIGNIFICANCE: These findings demonstrate that ICD stimulation can induce specific types of plastic changes in ICC activity, which may be relevant for treating tinnitus. By using the AMI with electrode sites positioned with the ICD and the ICC, the modulatory effects of ICD stimulation can be tested directly in tinnitus patients.