A prospective, multicenter, international study to explore the effect of three different amplitude settings in female subjects with urinary urge incontinence receiving interstim therapy.

AIMS: The aim of this study is to evaluate the effect of sub-sensory amplitude settings of sacral neuromodulation therapy on overactive bladder symptoms in subjects with urinary urge incontinence. METHODS: Subjects who qualified for a neurostimulator device implant were randomized to one of three amplitude settings (50% of sensory threshold [ST], 80% of ST, and ST). Subjects completed urinary voiding diaries (3-day), International consultation on incontinence modular questionnaire-overactive bladder symptoms quality of life questionnaire, and patient global impression of improvement (PGI-I) to assess change in voiding symptoms and quality of life (QoL) from baseline through 12 weeks. RESULTS: Forty-eight subjects had a successful test stimulation, 46 were implanted with a neurostimulator device and 43 completed the 12-week follow-up visit. The change from baseline to 12 weeks is -3.0 urinary incontinence (UI) episodes/day (95% confidence interval [CI]: -4.4 to -1.7) for the 50% of sensory threshold group, -2.9 UI episodes/day (95% CI: -4.7 to -1.2) for 80% of sensory threshold group, and -3.6 UI episodes/day (95% CI: -5.2 to -1.9) for the sensory threshold group. In each randomized group, improvements were observed in health-related QoL, its subscales, and symptom interference. Subjects across all three randomization groups reported on the PGI-I that their bladder condition was better at 12 weeks compared to before they were treated with InterStim therapy. CONCLUSION: These findings provide insights into possible advancements in the postimplantation phase of therapy with potential for improved patient comfort and increased device longevity.

The science behind programming algorithms for sacral neuromodulation.

AIM: Sacral neuromodulation (SNM) is a widely adopted treatment for overactive bladder, non-obstructive urinary retention and faecal incontinence. In the majority, it provides sustained clinical benefit. However, it is recognized that, even for these patients, stimulation parameters (such as amplitude, electrode configuration, frequency and pulse width) may vary at both initial device programming and at reprogramming, the latter often being required to optimize effectiveness. Although some recommendations exist for SNM programming, the scientific data to support them are understood by few clinicians. METHODS: This is a narrative review of the literature covering some of the science behind stimulating a mixed peripheral nerve and available preclinical data in the field of SNM. It covers electrode configuration, amplitude, frequency, pulse width and cycling considerations. The review is targeted at clinicians with an interest in the field and does not seek to provide exhaustive detail on basic neuroscience. RESULTS AND CONCLUSIONS: Knowledge of the science of neuromodulation provides some guiding principles for programming but these are broad. These principles are not refuted by preclinical data but specific parameters in clinical use are not strongly supported by animal data, even after the limitations of small and large animal models are considered. The review presents a shortlist of programming principles on a theoretical basis but acknowledges that current practice is as much derived from evolved experience as science.

Neuroplasticity: an appreciation from synapse to system.

OBJECTIVE: To integrate our functional knowledge in neurorehabilitation with a greater understanding of commonly held theories and current research in neuroplasticity. DESIGN: Literature review. SETTING: Not applicable. PARTICIPANTS: Animal and human research. INTERVENTIONS: Interventions specific to application in humans: constraint-induced movement therapy, transcranial magnetic stimulation, and transcranial direct current stimulation. MAIN OUTCOME MEASURES: Cortical excitability, blood oxygen level-dependent signal, and functional outcomes. RESULTS: There is increasing evidence elucidating the cellular and molecular mechanisms of plasticity of the nervous system including growth, modification, degradation, and even death of neurons. Some of these mechanisms directly correlate with therapy-induced behavioral changes, and all provide an understanding of the response of the nervous system to altered inputs. The understanding of neural correlates of behavior can then form the foundation for more productive, comprehensive interventions. CONCLUSIONS: The focus of recent research surrounds translational projects aimed at enhancing clinical outcomes. Knowledge of mechanisms underlying this adaptability is the foundation for our treatments, diagnoses, and prognoses. The increasing understanding of the mechanisms underlying neuroplasticity can guide, direct, and focus the practice of current and future therapies to greater efficacy and better functional outcomes in clinical rehabilitation.

Closed-loop sacral neuromodulation for bladder function using dorsal root ganglia sensory feedback in an anesthetized feline model.

Overactive bladder patients suffer from a frequent, uncontrollable urge to urinate, which can lead to a poor quality of life. We aim to improve open-loop sacral neuromodulation therapy by developing a conditional stimulation paradigm using neural recordings from dorsal root ganglia (DRG) as sensory feedback. Experiments were performed in 5 anesthetized felines. We implemented a Kalman filter-based algorithm to estimate the bladder pressure in real-time using sacral-level DRG neural recordings and initiated sacral root electrical stimulation when the algorithm detected an increase in bladder pressure. Closed-loop neuromodulation was performed during continuous cystometry and compared to bladder fills with continuous and no stimulation. Overall, closed-loop stimulation increased bladder capacity by 13.8% over no stimulation (p < 0.001) and reduced stimulation time versus continuous stimulation by 57.7%. High-confidence bladder single units had a reduced sensitivity during stimulation, with lower linear trendline fits and higher pressure thresholds for firing observed during stimulation trials. This study demonstrates the utility of decoding bladder pressure from neural activity for closed-loop control of sacral neuromodulation. An underlying mechanism for sacral neuromodulation may be a reduction in bladder sensory neuron activity during stimulation. Real-time validation during behavioral studies is necessary prior to clinical translation of closed-loop sacral neuromodulation.

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.

Deafferentation-induced activation of NFAT (nuclear factor of activated T-cells) in cochlear nucleus neurons during a developmental critical period: a role for NFATc4-dependent apoptosis in the CNS.

During the development and maturation of sensory neurons, afferent activity is required for normal maintenance. There exists a developmental window of time when auditory neurons, including neurons of the anteroventral cochlear nucleus (AVCN), depend on afferent input for survival. This period of time is often referred to as a critical period. The cellular and molecular mechanisms that underlie AVCN neuron susceptibility to deafferentation-induced death remain unknown. Here, we show that only during this critical period deafferentation of mouse AVCN neurons by in vivo cochlea removal results in rapid nuclear translocation and activation of the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4). NFAT activation is abolished by in vivo treatment with the calcineurin inhibitor FK506 and the specific NFAT-inhibitor 11R-VIVIT. Inhibition of NFAT significantly attenuates deafferentation-induced apoptosis of AVCN neurons and abolishes NFAT-mediated expression of FasL, an initiator of apoptotic pathways, in the cochlear nucleus. These data suggest that NFAT-mediated gene expression plays a role in deafferentation-induced apoptosis of cochlear nucleus neurons during a developmental critical period.

Development of the specialized AMPA receptors of auditory neurons.

At maturity, the AMPA receptors of auditory neurons exhibit very rapid desensitization kinetics and high permeability to calcium, reflecting the predominance of GluR3 flop and GluR4 flop subunits and the paucity of GluR2. We used mRNA analysis and immunoblotting to contrast the development of AMPA receptor structure in the chick cochlear nucleus [nucleus magnocellularis (NM)] with that of the slowly desensitizing and calcium-impermeable AMPA receptors of brainstem motor neurons in the nucleus of the glossopharyngeal/vagal nerves. The relative abundance of transcripts for GluRs 1-4 changes substantially in auditory (but not motor) neurons after embryonic day (E)10, with large decreases in GluR2 and increases in GluR3 and GluR4. Relative to the motor neurons, NM neurons show a higher abundance of flop isoforms of GluRs 2-4 at E10, suggesting that auditory neurons are already biased toward expression of flop isoforms before the onset of synaptic function at E11. Immunoreactivities in NM show very distinct developmental patterns from E13 onward: GluR2 declines by >90%, GluR3 increases threefold, and GluR4 remains relatively constant. Our results show that there are a series of critical points during normal development, most occurring after the onset of function, when rapid changes in receptor structure (occurring via both transcriptional and post-transcriptional control mechanisms) produce the specialized AMPA receptor functions that enable auditory neurons to accurately encode acoustic information.