Multimodal assessment of tinnitus using functional near-infrared spectroscopy and psychophysiological measures.

OBJECTIVE: To use a multimodal approach to classify individuals with tinnitus from controls, and individuals with mild versus severe tinnitus. DESIGN: We have previously shown feasibility of a non-invasive imaging technique called functional near-infrared spectroscopy (fNIRS) to detect tinnitus-related changes in cortical activity and classify individuals with tinnitus from controls, as well as individuals with mild versus severe tinnitus. In this study we have used a multimodal approach by recording heart rate, heart rate variability and skin conductance, in addition to fNIRS signals, from individuals with tinnitus and controls. STUDY SAMPLE: Twenty-seven participants with tinnitus and 21 controls were recruited. RESULTS: Our findings show, addition of heart rate measures can improve accuracy of classifying tinnitus severity, in particular loudness as rated subjectively. The f1-score, a measure of classification accuracy, increased from 0.73 to 0.86 when using a support vector machine classifier for differentiating low versus high tinnitus loudness. CONCLUSIONS: Subjective tinnitus is a condition that can only be described by the individual experiencing it, as there are currently no objective measures to determine tinnitus presence and severity, or assess the effectiveness of treatments. Objective measurement of tinnitus is a critical step in developing reliable treatments for this debilitating condition.

Deep brain stimulation for Parkinson's disease modulates high-frequency evoked and spontaneous neural activity.

Deep brain stimulation is an established therapy for Parkinson's disease; however, its effectiveness is hindered by limited understanding of therapeutic mechanisms and the lack of a robust feedback signal for tailoring stimulation. We recently reported that subthalamic nucleus deep brain stimulation evokes a neural response resembling a decaying high-frequency (200-500 Hz) oscillation that typically has a duration of at least 10 ms and is localizable to the dorsal sub-region. As the morphology of this response suggests a propensity for the underlying neural circuitry to oscillate at a particular frequency, we have named it evoked resonant neural activity. Here, we determine whether this evoked activity is modulated by therapeutic stimulation - a critical attribute of a feedback signal. Furthermore, we investigated whether any related changes occurred in spontaneous local field potentials. Evoked and spontaneous neural activity was intraoperatively recorded from 19 subthalamic nuclei in patients with Parkinson's disease. Recordings were obtained before therapeutic stimulation and during 130 Hz stimulation at increasing amplitudes (0.67-3.38 mA), 'washout' of therapeutic effects, and non-therapeutic 20 Hz stimulation. Therapeutic efficacy was assessed using clinical bradykinesia and rigidity scores. The frequency and amplitude of evoked resonant neural activity varied with the level of 130 Hz stimulation (p < .001). This modulation coincided with improvement in bradykinesia and rigidity (p < .001), and correlated with spontaneous beta band suppression (p < .001). Evoked neural activity occupied a similar frequency band to spontaneous high-frequency oscillations (200-400 Hz), both of which decreased to around twice the 130 Hz stimulation rate. Non-therapeutic stimulation at 20 Hz evoked, but did not modulate, resonant activity. These results indicate that therapeutic deep brain stimulation alters the frequency of evoked and spontaneous oscillations recorded in the subthalamic nucleus that are likely generated by loops within the cortico-basal ganglia-thalamo-cortical network. Evoked resonant neural activity therefore has potential as a tool for providing insight into brain network function and has key attributes of a dynamic feedback signal for optimizing therapy.

Subthalamic nucleus deep brain stimulation evokes resonant neural activity.

Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target-specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large-amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes. Ann Neurol 2018;83:1027-1031.

Wireless induction coils embedded in diamond for power transfer in medical implants.

Wireless power and data transfer to medical implants is a research area where improvements in current state-of-the-art technologies are needed owing to the continuing efforts for miniaturization. At present, lithographical patterning of evaporated metals is widely used for miniature coil fabrication. This method produces coils that are limited to low micron or nanometer thicknesses leading to high impedance values and thus limiting their potential quality. In the present work we describe a novel technique, whereby trenches were milled into a diamond substrate and filled with silver active braze alloy, enabling the manufacture of small, high cross-section, low impedance microcoils capable of transferring up to 10 mW of power up to a distance of 6 mm. As a substitute for a metallic braze line used for hermetic sealing, a continuous metal loop when placed parallel and close to the coil surface reduced power transfer efficiency by 43%, but not significantly, when placed perpendicular to the microcoil surface. Encapsulation of the coil by growth of a further layer of diamond reduced the quality factor by an average of 38%, which can be largely avoided by prior oxygen plasma treatment. Furthermore, an accelerated ageing test after encapsulation showed that these coils are long lasting. Our results thus collectively highlight the feasibility of fabricating a high-cross section, biocompatible and long lasting miniaturized microcoil that could be used in either a neural recording or neuromuscular stimulation device.

Effect of current focusing on the sensitivity of inferior colliculus neurons to amplitude-modulated stimulation.

In multichannel cochlear implants (CIs), current is delivered to specific electrodes along the cochlea in the form of amplitude-modulated pulse trains, to convey temporal and spectral cues. Our previous studies have shown that focused multipolar (FMP) and tripolar (TP) stimulation produce more restricted neural activation and reduced channel interactions in the inferior colliculus (IC) compared with traditional monopolar (MP) stimulation, suggesting that focusing of stimulation could produce better transmission of spectral information. The present study explored the capability of IC neurons to detect modulated CI stimulation with FMP and TP stimulation compared with MP stimulation. The study examined multiunit responses of IC neurons in acutely deafened guinea pigs by systematically varying the stimulation configuration, modulation depth, and stimulation level. Stimuli were sinusoidal amplitude-modulated pulse trains (carrier rate of 120 pulses/s). Modulation sensitivity was quantified by measuring modulation detection thresholds (MDTs), defined as the lowest modulation depth required to differentiate the response of a modulated stimulus from an unmodulated one. Whereas MP stimulation showed significantly lower MDTs than FMP and TP stimulation (P values <0.05) at stimulation ≤2 dB above threshold, all stimulation configurations were found to have similar modulation sensitivities at 4 dB above threshold. There was no difference found in modulation sensitivity between FMP and TP stimulation. The present study demonstrates that current focusing techniques such as FMP and TP can adequately convey amplitude modulation and are comparable to MP stimulation, especially at higher stimulation levels, although there may be some trade-off between spectral and temporal fidelity with current focusing stimulation.

LINE1 insertions as a genomic risk factor for schizophrenia: Preliminary evidence from an affected family.

Recent studies show that human-specific LINE1s (L1HS) play a key role in the development of the central nervous system (CNS) and its disorders, and that their transpositions within the human genome are more common than previously thought. Many polymorphic L1HS, that is, present or absent across individuals, are not annotated in the current release of the genome and are customarily termed "non-reference L1s." We developed an analytical workflow to identify L1 polymorphic insertions with next-generation sequencing (NGS) using data from a family in which SZ segregates. Our workflow exploits two independent algorithms to detect non-reference L1 insertions, performs local de novo alignment of the regions harboring predicted L1 insertions and resolves the L1 subfamily designation from the de novo assembled sequence. We found 110 non-reference L1 polymorphic loci exhibiting Mendelian inheritance, the vast majority of which are already reported in dbRIP and/or euL1db, thus, confirming their status as non-reference L1 polymorphic insertions. Four previously undetected L1 polymorphic loci were confirmed by PCR amplification and direct sequencing of the insert. A large fraction of our non-reference L1s is located within the open reading frame of protein-coding genes that belong to pathways already implicated in the pathogenesis of schizophrenia. The finding of these polymorphic variants among SZ offsprings is intriguing and suggestive of putative pathogenic role. Our data show the utility of NGS to uncover L1 polymorphic insertions, a neglected type of genetic variants with the potential to influence the risk to develop schizophrenia like SNVs and CNVs. © 2016 Wiley Periodicals, Inc.

Effects of chronic cochlear electrical stimulation after an extended period of profound deafness on primary auditory cortex organization in cats.

Extended periods of deafness have profound effects on central auditory system function and organization. Neonatal deafening results in loss of the normal cochleotopic organization of the primary auditory cortex (AI), but environmentally-derived intracochlear electrical stimulation, via a cochlear implant, initiated shortly after deafening, can prevent this loss. We investigated whether such stimulation initiated after an extended period of deafness can restore cochleotopy. In two groups of neonatally-deafened cats, a multi-channel intracochlear electrode array was implanted at 8 weeks of age. One group received only minimal stimulation, associated with brief recordings at 4-6-week intervals, over the following 6 months to check the efficacy of the implant. In the other group, this 6-month period was followed by 6 months of near-continuous intracochlear electrical stimulation from a modified clinical cochlear implant system. We recorded multi-unit clusters in the auditory cortex and used two different methods to define the region of interest in the putative AI. There was no evidence of cochleotopy in any of the minimally stimulated animals, confirming our earlier finding. In three of six chronically stimulated cats there was clear evidence of AI cochleotopy, and in a fourth cat in which the majority of penetrations were in the anterior auditory field there was clear evidence of cochleotopy in that field. The finding that chronic intracochlear electrical stimulation after an extended period of deafness is able to restore cochleotopy in some (but not all) cases has implications for the performance of patients implanted after an extended period of deafness.

Feed-forward hierarchical model of the ventral visual stream applied to functional brain image classification.

Functional brain imaging is a common tool in monitoring the progression of neurodegenerative and neurological disorders. Identifying functional brain imaging derived features that can accurately detect neurological disease is of primary importance to the medical community. Research in computer vision techniques to identify objects in photographs have reported high accuracies in that domain, but their direct applicability to identifying disease in functional imaging is still under investigation in the medical community. In particular, Serre et al. (: In: IEEE Conference on Computer Vision and Pattern Recognition (CVPR-05). pp 994-1000) introduced a biophysically inspired filtering method emulating visual processing in striate cortex which they applied to perform object recognition in photographs. In this work, the model described by Serre et al. [2005] is extended to three-dimensional volumetric images to perform signal detection in functional brain imaging (PET, SPECT). The filter outputs are used to train both neural network and logistic regression classifiers and tested on two distinct datasets: ADNI Alzheimer's disease 2-deoxy-D-glucose (FDG) PET and National Football League players Tc99m HMPAO SPECT. The filtering pipeline is analyzed to identify which steps are most important for classification accuracy. Our results compare favorably with other published classification results and outperform those of a blinded expert human rater, suggesting the utility of this approach.

Increased CNV-region deletions in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects in the ADNI sample.

We investigated the genome-wide distribution of CNVs in the Alzheimer's disease (AD) Neuroimaging Initiative (ADNI) sample (146 with AD, 313 with Mild Cognitive Impairment (MCI), and 181 controls). Comparison of single CNVs between cases (MCI and AD) and controls shows overrepresentation of large heterozygous deletions in cases (p-value<0.0001). The analysis of CNV-Regions identifies 44 copy number variable loci of heterozygous deletions, with more CNV-Regions among affected than controls (p=0.005). Seven of the 44 CNV-Regions are nominally significant for association with cognitive impairment. We validated and confirmed our main findings with genome re-sequencing of selected patients and controls. The functional pathway analysis of the genes putatively affected by deletions of CNV-Regions reveals enrichment of genes implicated in axonal guidance, cell-cell adhesion, neuronal morphogenesis and differentiation. Our findings support the role of CNVs in AD, and suggest an association between large deletions and the development of cognitive impairment.

Transposable elements and psychiatric disorders.

Transposable Elements (TEs) or transposons are low-complexity elements (e.g., LINEs, SINEs, SVAs, and HERVs) that make up to two-thirds of the human genome. There is mounting evidence that TEs play an essential role in genomic architecture and regulation related to both normal function and disease states. Recently, the identification of active TEs in several different human brain regions suggests that TEs play a role in normal brain development and adult physiology and quite possibly in psychiatric disorders. TEs have been implicated in hemophilia, neurofibromatosis, and cancer. With the advent of next-generation whole-genome sequencing approaches, our understanding of the relationship between TEs and psychiatric disorders will greatly improve. We will review the biology of TEs and early evidence for TE involvement in psychiatric disorders.

Implantation Surgery for Abdominal Vagus Nerve Stimulation and Recording Studies in Awake Rats.

Abdominal vagus nerve stimulation (VNS) can be applied to the subdiaphragmatic branch of the vagus nerve of rats. Due to its anatomical location, it does not have any respiratory and cardiac off-target effects commonly associated with cervical VNS. The lack of respiratory and cardiac off-target effects means that the intensity of stimulation does not need to be lowered to reduce side effects commonly experienced during cervical VNS. Few recent studies demonstrate the anti-inflammatory effects of abdominal VNS in rat models of inflammatory bowel disease, rheumatoid arthritis, and glycemia reduction in a rat model of type 2 diabetes. Rat is a great model to explore the potential of this technology because of the well-established anatomy of the vagus nerve, the large size of the nerve that allows easy handling, and the availability of many disease models. Here, we describe the methods for cleaning and sterilizing the abdominal VNS electrode array and surgical protocol in rats. We also describe the technology required for confirmation of suprathreshold stimulation by recording evoked compound action potentials. Abdominal VNS has the potential to offer selective, effective treatment for a variety of conditions, including inflammatory diseases, and the application is expected to expand similarly to cervical VNS.

Cochlear implant induced changes in cortical networks associated with tinnitus severity.

Objective.We investigated tinnitus-related cortical networks in cochlear implant users who experience tinnitus and whose perception of tinnitus changes with use of their implant. Tinnitus, the perception of unwanted sounds which are not present externally, can be a debilitating condition. In individuals with cochlear implants, use of the implant is known to modulate tinnitus, often improving symptoms but worsening them in some cases. Little is known about underlying cortical changes with use of the implant, which lead to changes in tinnitus perception. In this study we investigated whether changes in brain networks with the cochlear implant turned on and off, were associated with changes in tinnitus perception, as rated subjectively.Approach.Using functional near-infrared spectroscopy, we recorded cortical activity at rest, from 14 cochlear implant users who experienced tinnitus. Recordings were performed with the cochlear implant turned off and on. For each condition, participants rated the loudness and annoyance of their tinnitus using a visual rating scale. Changes in neural synchrony have been reported in humans and animal models of tinnitus. To assess neural synchrony, functional connectivity networks with the implant turned on and off, were compared using two network features: node strength and diversity coefficient.Main results.Changes in subjective ratings of loudness were significantly correlated with changes in node strength, averaged across occipital channels (r=-0.65, p=0.01). Changes in both loudness and annoyance were significantly correlated with changes in diversity coefficient averaged across all channels (r=-0.79,p<0.001 and r=-0.86,p<0.001). More distributed connectivity with the implant on, compared to implant off, was associated with a reduction in tinnitus loudness and annoyance.Significance.A better understanding of neural mechanisms underlying tinnitus suppression with cochlear implant use, could lead to their application as a tinnitus treatment and pave the way for effective use of other less invasive stimulation-based treatments.

Magnetically coupled percutaneous connector for chronic electrical peripheral nerve stimulation and recording in awake rats.

A fast-growing field of neuroscience and medicine is the treatment of disease via electrical stimulation of the peripheral nervous system. Peripheral nerve stimulation delivers stimulation to nerves of the periphery where the target nerve can and is often located deep within the abdomen. Long-term preclinical animal models that demonstrate the safety and/or efficacy of electrical stimulation have predominantly used a skull mount to connect to neural interfaces. When targeting nerves of the extremities and abdomen, this mount location is less favourable due to its distance to the implant causing complications in surgery and to the longevity of the device in vivo. OBJECTIVE: Here we aimed to develop and validate a chronic magnetic percutaneous connector designed for placement on the dorsal-lumbar aspect of the spine of awake, freely moving rats. METHODS: A pedestal and external connector was developed, bench tested to assess for continuity, durability and disconnection forces, and validated in awake rats chronically implanted with an abdominal vagus nerve electrode array. The implanted pedestal and external connector were designed with custom PCBs, spring-loaded pins, magnets and biocompatible 3D printed housing. RESULTS: The magnetic coupling mechanism allowed disconnection with minimal force, was highly reliable in maintaining electrical connection in awake rats and allowed recording of electrically evoked compound action potentials after chronic implantation. CONCLUSION: In conclusion, this percutaneous connector is a useful research tool for peripheral nerve stimulation studies. SIGNIFICANCE: The connector described will allow investigation into the safety and efficacy of emerging neuromodulation therapies for the treatment of disease.

Teaching, assessment and best practice in undergraduate psychiatry education in the UK: cross-sectional survey.

AIMS AND METHOD: We conducted a cross-sectional survey to examine how undergraduate psychiatry is taught and assessed across medical schools in the UK that have at least one cohort of graduated students. RESULTS: In total, 27 medical schools completed the survey. Curriculum coverage of common mental disorders, assessment skills and mental health law was broadly consistent, although exposure to psychiatric subspecialties varied. Significant variation existed regarding the duration of psychiatry placements and availability of enrichment activities. Small-group teaching, lectures and e-learning were the most frequent teaching modalities and various professionals and lived experience educators (patient and/or carers) contributed to teaching. Objective structured clinical examinations and multiple-choice questions dominated assessments. CLINICAL IMPLICATIONS: Medical schools should consider increasing students' exposure to different psychiatric subspecialties and integrating physical and mental health training to address comorbidity and promote holistic care. Future research should explore whether specific undergraduate experiences promote greater career interest and skills in psychiatry.

Combined-electrical optogenetic stimulation but not channelrhodopsin kinetics improves the fidelity of high rate stimulation in the auditory pathway in mice.

Novel stimulation methods are needed to overcome the limitations of contemporary cochlear implants. Optogenetics is a technique that confers light sensitivity to neurons via the genetic introduction of light-sensitive ion channels. By controlling neural activity with light, auditory neurons can be activated with higher spatial precision. Understanding the behaviour of opsins at high stimulation rates is an important step towards their translation. To elucidate this, we compared the temporal characteristics of auditory nerve and inferior colliculus responses to optogenetic, electrical, and combined optogenetic-electrical stimulation in virally transduced mice expressing one of two channelrhodopsins, ChR2-H134R or ChIEF, at stimulation rates up to 400 pulses per second (pps). At 100 pps, optogenetic responses in ChIEF mice demonstrated higher fidelity, less change in latency, and greater response stability compared to responses in ChR2-H134R mice, but not at higher rates. Combined stimulation improved the response characteristics in both cohorts at 400 pps, although there was no consistent facilitation of electrical responses. Despite these results, day-long stimulation (up to 13 h) led to severe and non-recoverable deterioration of the optogenetic responses. The results of this study have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss.

Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

Empirical derivation of the reference region for computing diagnostic sensitive ¹8fluorodeoxyglucose ratios in Alzheimer's disease based on the ADNI sample.

Careful selection of the reference region for non-quantitative positron emission tomography (PET) analyses is critically important for Region of Interest (ROI) data analyses. We introduce an empirical method of deriving the most suitable reference region for computing neurodegeneration sensitive (18)fluorodeoxyglucose (FDG) PET ratios based on the dataset collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Candidate reference regions are selected based on a heat map of the difference in coefficients of variation (COVs) of FDG ratios over time for each of the Automatic Anatomical Labeling (AAL) atlas regions normalized by all other AAL regions. Visual inspection of the heat map suggests that the portion of the cerebellum and vermis superior to the horizontal fissure is the most sensitive reference region. Analyses of FDG ratio data show increases in significance on the order of ten-fold when using the superior portion of the cerebellum as compared with the traditionally used full cerebellum. The approach to reference region selection in this paper can be generalized to other radiopharmaceuticals and radioligands as well as to other disorders where brain changes over time are hypothesized and longitudinal data is available. Based on the empirical evidence presented in this study, we demonstrate the usefulness of the COV heat map method and conclude that intensity normalization based on the superior portion of the cerebellum may be most sensitive to measuring change when performing longitudinal analyses of FDG-PET ratios as well as group comparisons in Alzheimer's disease. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

A beamformer post-filter for cochlear implant noise reduction.

Cochlear implant users have limited ability to understand speech in noisy conditions. Signal processing methods to address this issue that use multiple microphones typically use beamforming to perform noise reduction. However, the effectiveness of the beamformer is diminished as the number of interfering noises increases and the acoustic environment becomes more diffuse. A multi-microphone noise reduction algorithm that aims to address this issue is presented in this study. The algorithm uses spatial filtering to estimate the signal-to-noise ratio (SNR) and attenuates time-frequency elements that have poor SNR. The algorithm was evaluated by measuring intelligibility of speech embedded in 4-talker babble where the interfering talkers were spatially separated and changed location during the test. Twelve cochlear implant users took part in the evaluation, which demonstrated a significant mean improvement of 4.6 dB (standard error 0.4, P < 0.001) in speech reception threshold compared to an adaptive beamformer. The results suggest that a substantial improvement in performance can be gained for cochlear implant users in noisy environments where the noise is spatially separated from the target speech.

Towards non-invasive peripheral stimulation as a treatment for Parkinson's disease gait.

Non-invasive coordinated reset stimulation (CRS) to the hands has been shown to improve motor ability in Parkinson's patients, but not specific for gait disturbances. The overall aim of the project is the application of vibrotactile CRS to the feet to improve gait impairments in Parkinson's disease. As a first step towards this objective, we showed that vibrotactile stimulation to the feet can elicit a cortical response and have identified differences in younger and older individuals. Our findings suggest the potential for non-invasive peripheral stimulation as a therapeutic technique.Clinical Relevance- This is an important step towards developing a non-invasive stimulation technique for the management of gait disturbances in Parkinson's disease.

Selective recording of physiologically evoked neural activity in a mixed autonomic nerve using a minimally invasive array.

Real-time closed-loop control of neuromodulation devices requires long-term monitoring of neural activity in the peripheral nervous system. Although many signal extraction methods exist, few are both clinically viable and designed for extracting small signals from fragile peripheral visceral nerves. Here, we report that our minimally invasive recording and analysis technology extracts low to negative signal to noise ratio (SNR) neural activity from a visceral nerve with a high degree of specificity for fiber type and class. Complex activity was recorded from the rat pelvic nerve that was physiologically evoked during controlled bladder filling and voiding, in an extensively characterized in vivo model that provided an excellent test bed to validate our technology. Urethane-anesthetized male rats (n = 12) were implanted with a four-electrode planar array and the bladder instrumented for continuous-flow cystometry, which measures urodynamic function by recording bladder pressure changes during constant infusion of saline. We demonstrated that differential bipolar recordings and cross-correlation analyses extracts afferent and efferent activity, and discriminated between subpopulations of fibers based on conduction velocity. Integrated Aδ afferent fiber activity correlated with bladder pressure during voiding (r2: 0.66 ± 0.06) and was not affected by activating nociceptive afferents with intravesical capsaicin (r2: 0.59 ± 0.14, P = 0.54, and n = 3). Collectively, these results demonstrate our minimally invasive recording and analysis technology is selective in extracting mixed neural activity with low/negative SNR. Furthermore, integrated afferent activity reliably correlates with bladder pressure and is a promising first step in developing closed-loop technology for bladder control.