Sensory Restoration Research Articles

Optogenetic stimulation recruits cortical neurons in a morphology-dependent manner.

Single-photon optogenetics enables precise, cell-type-specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bares promise for Brain-Machine Interfaces for sensory and motor function restoration. However, achieving selective activation of functional cortical representations poses a challenge, as studies show that targeted optogenetic stimulation results in activity spread beyond one functional domain. While recurrent network mechanisms contribute to activity spread, here we demonstrate with detailed simulations of isolated pyramidal neurons from cat of unknown sex that already neuron morphology causes a complex spread of optogenetic activity at the scale of one cortical column. Since the shape of a neuron impacts its optogenetic response, we find that a single stimulator at the cortical surface recruits a complex spatial distribution of neurons that can be inhomogeneous and vary with stimulation intensity and neuronal morphology across layers. We explore strategies to enhance stimulation precision, finding that optimizing stimulator optics may offer more significant improvements than preferentially somatic expression of the opsin through genetic targeting. Our results indicate that, with the right optical setup, single-photon optogenetics can precisely activate isolated neurons at the scale of functional cortical domains spanning several hundred micrometers.Significance Statement Sensory features, such as the position or orientation of a visual stimulus, are mapped onto the surface of cortex as functional domains. Their selective activation, that may enable eliciting complex percepts, is intensively pursued for basic science and clinical applications. However, delivery of light into one functional domain in optogenetically transfected cortex results in complex, widespread neuronal activity, spreading beyond the targeted domain. Our computational study reveals that neuron morphology contributes to this diffuse response in a cortical-layer and intensity-dependent manner. We show that enhancing the stimulator optics is more effective than soma-targeting of the opsin in increasing spatial precision of stimulation. Our simulations provide insights for designing optogenetic stimulation protocols and hardware to achieve selective activation of functional domains.

Feasibility of a cross-face reconstruction of the mental nerve—A cadaveric simulation study with histomorphometric analysis

IntroductionThe inevitable sacrifice of the inferior alveolar nerve (IAN) during oncologic resections results in substantial sensory impairment, impacting crucial functions such as speech, saliva retention, and mastication. This study investigates the feasibility of sensory restoration through cross-face reconstruction of the mental nerve via a contralateral mental nerve branch. MethodsThe cross-face reconstruction procedure was simulated in five formalin-fixed cadavers for both sides to evaluate the anatomic fundamentals and the nerve gap between the mental nerve main trunk and the transferred contralateral mental nerve branch. Furthermore, a histomorphometric analysis was performed to assess cross-sectional area and axon counts. ResultsThe mean gap distance between the main mental nerve trunk and the transferred contralateral branch was 15.3mm. End-to-end coaptation was achieved in 9 out of 10 simulations. The mean cross-sectional area was 0.996 mm2 at the main mental nerve trunk and 0.253mm2 at the coaptation site of the nerve branch. The mean donor-to-recipient axon ratio was found to be 0.3:1. ConclusionThe cadaveric simulation demonstrates the feasibility of a cross-face reconstruction of the mental nerve with only minimal gapping. Advantages of the proposed technique include the use of shorter nerve grafts, minimizing donor site morbidity and enabling fast reinnervation. This technique may offer a promising method for enhancing the quality of life for a patient group with increasing survival rates and life expectancy.

Multilevel neurium-mimetic individualized graft via additive manufacturing for efficient tissue repair

Complicated peripheral nerve injuries or defects, especially at branching sites, remain a prominent clinical challenge after the application of different treatment strategies. Current nerve grafts fail to match the expected shape and size for delicate and precise branched nerve repair on a case-by-case basis, and there is a lack of geometrical and microscale regenerative navigation. In this study, we develop a sugar painting-inspired individualized multilevel epi-/peri-/endoneurium-mimetic device (SpinMed) to customize natural cues, featuring a selectively protective outer sheath and an instructive core, to support rapid vascular reconstruction and consequent efficient neurite extension along the defect area. The biomimetic perineurium dictates host-guest crosslinking in which new vessels secrete multimerin 1 binding to the fibroin filler surface as an anchor, contributing to the biological endoneurium that promotes Schwann cell homing and remyelination. SpinMed implantation into rat sciatic nerve defects yields a satisfactory outcome in terms of structural reconstruction, with sensory and locomotive function restoration. We further customize SpinMed grafts based on anatomy and digital imaging, achieving rapid repair of the nerve trunk and branches superior to that achieved by autografts and decellularized grafts in a specific beagle nerve defect model, with reliable biosafety. Overall, this intelligent art-inspired biomimetic design offers a facile way to customize sophisticated high-performance nerve grafts and holds great potential for application in translational regenerative medicine.

Creation of a biological sensorimotor interface for bionic reconstruction

Neuromuscular control of bionic arms has constantly improved over the past years, however, restoration of sensation remains elusive. Previous approaches to reestablish sensory feedback include tactile, electrical, and peripheral nerve stimulation, however, they cannot recreate natural, intuitive sensations. Here, we establish an experimental biological sensorimotor interface and demonstrate its potential use in neuroprosthetics. We transfer a mixed nerve to a skeletal muscle combined with glabrous dermal skin transplantation, thus forming a bi-directional communication unit in a rat model. Morphological analyses indicate reinnervation of the skin, mechanoreceptors, NMJs, and muscle spindles. Furthermore, sequential retrograde labeling reveals specific sensory reinnervation at the level of the dorsal root ganglia. Electrophysiological recordings show reproducible afferent signals upon tactile stimulation and tendon manipulation. The results demonstrate the possibility of surgically creating an interface for both decoding efferent motor control, as well as encoding afferent tactile and proprioceptive feedback, and may indicate the way forward regarding clinical translation of biological communication pathways for neuroprosthetic applications.

Paraffinoma of the hands: a case report

Paraffin injection has been widely used to improve body contouring or to augment various body parts, although it has now been abandoned owing to serious complications. Paraffin injection may lead to complications after a long latency period, ranging from several years to several decades. Here, we present the rare case of a 77-year-old woman who suffered from recurrent wound problems after a bilateral paraffin injection into her hands 40 years ago. Initially, conservative debridement was carried out due to the patient’s reluctance to undergo extensive surgery and cost concerns. However, this resulted in recurrent wound dehiscence and infection. After serial debridement procedures, a skin graft was performed on her right hand. The patient complained of a depressed contour and numbness at the skin graft site, and tightness and discomfort of her right hand during flexion of the metacarpophalangeal joint. Three years later, the patient presented with a highly similar wound on her left hand. Thorough excision of the soft tissue infiltrated by paraffin was performed, followed by reconstruction using a sensate free anterolateral thigh flap. The patient responded well postoperatively without complications, displaying a fair range of motion without discomfort, sensory restoration of the flap, and satisfaction with the contour of the dorsum. This case report highlights the importance of complete excision of soft tissues infiltrated by paraffin for definitive treatment. Among the various reconstruction options, a sensate free flap is a good choice for achieving favorable functional and esthetic outcomes in hand reconstruction after radical excision of a paraffinoma.

The applications of spinal cord stimulation in diseases with motor disorders, pain, and cognitive disturbance

Spinal cord stimulation (SCS), first used for pain relief in 1967, serves as an invasive neuromodulation with the targeted delivery of stimulations and the alertness of neural activities. Based on the gate-controlled theory of pain and multiple research studies, the application of SCS to motor recovery, pain relief, and sensory and cognitive restoration has been shown to be significant. Considering that movement disorders and pain are complications of various diseases, the categories, applications, and technical operation of SCS are coming of age. In terms of its impact on the immune system, SCS alters the trajectory of neurological diseases by modulating local immune responses through immunomodulatory mechanisms that vary depending on the different patterns of SCS. In addition to existing targets, the combinations of SCS and emerging techniques deepen the research at the molecular level, contributing to the exploration of potential targets and novel treatments. However, to secure a place in the future trend of non-invasive and precise treatment, it is necessary to improve SCS in terms of mechanism research, cost reduction, and application to more diseases.

Integrated Microprism and Microelectrode Array for Simultaneous Electrophysiology and Two-Photon Imaging across All Cortical Layers.

Cerebral neural electronics play a crucial role in neuroscience research with increasing translational applications such as brain-computer interfaces for sensory input and motor output restoration. While widely utilized for decades, the understanding of the cellular mechanisms underlying this technology remains limited. Although two-photon microscopy (TPM) has shown great promise in imaging superficial neural electrodes, its application to deep-penetrating electrodes is technically difficult. Here, a novel device integrating transparent microelectrode arrays with glass microprisms, enabling electrophysiology recording and stimulation alongside TPM imaging across all cortical layers in a vertical plane, is introduced. Tested in Thy1-GCaMP6 mice for over 4 months, the integrated device demonstrates the capability for multisite electrophysiological recording/stimulationand simultaneous TPM calcium imaging. As a proof of concept, the impact of microstimulation amplitude, frequency, and depth on neural activation patterns is investigated using the setup. With future improvements in material stability and single unit yield, this multimodal tool greatly expands integrated electrophysiology and optical imaging from the superficial brain to the entire cortical column, opening new avenues for neuroscience research and neurotechnology development.

Multichannel Conduits with Fascicular Complementation: Significance in Long Segmental Peripheral Nerve Injury.

Despite the advances in tissue engineering approaches, reconstruction of long segmental peripheral nerve defects remains unsatisfactory. Although autologous grafts with proper fascicular complementation have shown meaningful functional recovery according to the Medical Research Council Classification (MRCC), the lack of donor nerve for such larger defect sizes (>30 mm) has been a serious clinical issue. Further clinical use of hollow nerve conduits is limited to bridging smaller segmental defects of denuded nerve ends (<30 mm). Recently, bioinspired multichannel nerve guidance conduits (NGCs) gained attention as autograft substitutes as they mimic the fascicular connective tissue microarchitecture in promoting aligned axonal outgrowth with desirable innervation for complete sensory and motor function restoration. This review outlines the hierarchical organization of nerve bundles and their significance in the sensory and motor functions of peripheral nerves. This review also emphasizes the major challenges in addressing the longer nerve defects with the role of fascicular arrangement in the multichannel nerve guidance conduits and the need for fascicular matching to accomplish complete functional restoration, especially in treating long segmental nerve defects. Further, currently available fabrication strategies in developing multichannel nerve conduits and their inconsistency in existing preclinical outcomes captured in this review would seed a new process in designing an ideal larger nerve conduit for peripheral nerve repair.

Functional outcomes of different surgical treatments for common peroneal nerve injuries: a retrospective comparative study

BackgroundThis study aims to assess the recovery patterns and factors influencing outcomes in patients with common peroneal nerve (CPN) injury.MethodsThis retrospective study included 45 patients with CPN injuries treated between 2009 and 2019 in Jing’an District Central Hospital. The surgical interventions were categorized into three groups: neurolysis (group A; n = 34 patients), nerve repair (group B; n = 5 patients) and tendon transfer (group C; n = 6 patients). Preoperative and postoperative sensorimotor functions were evaluated using the British Medical Research Council grading system. The outcome of measures included the numeric rating scale, walking ability, numbness and satisfaction. Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal time interval between injury and surgery for predicting postoperative foot dorsiflexion function, toe dorsiflexion function, and sensory function.ResultsSurgical interventions led to improvements in foot dorsiflexion strength in all patient groups, enabling most to regain independent walking ability. Group A (underwent neurolysis) had significant sensory function restoration (P < 0.001), and three patients in Group B (underwent nerve repair) had sensory improvements. ROC analysis revealed that the optimal time interval for achieving M3 foot dorsiflexion recovery was 9.5 months, with an area under the curve (AUC) of 0.871 (95% CI = 0.661–1.000, P = 0.040). For M4 foot dorsiflexion recovery, the optimal cut-off was 5.5 months, with an AUC of 0.785 (95% CI = 0.575–0.995, P = 0.020). When using M3 toe dorsiflexion recovery or S4 sensory function recovery as the gold standard, the optimal cut-off remained at 5.5 months, with AUCs of 0.768 (95% CI = 0.582–0.953, P = 0.025) and 0.853 (95% CI = 0.693–1.000, P = 0.001), respectively.ConclusionsOur study highlights the importance of early surgical intervention in CPN injury recovery, with optimal outcomes achieved when surgery is performed within 5.5 to 9.5 months post-injury. These findings provide guidance for clinicians in tailoring treatment plans to the specific characteristics and requirements of CPN injury patients.

Lower Lip Reconstruction after Skin Cancer Excision: A Tailored Algorithm for Elderly Patients.

Lower lip reconstruction is crucial to restore oral integrity post-cancer excision. A perfect balance between form and function should be achieved. With an aging demographic, adapting surgical methods to meet the unique needs of the elderly becomes imperative. Our study aims to introduce a specialized algorithm for lower lip reconstruction; it was tailored to geriatric patients and emphasized the use of "simpler flaps". Additionally, "Pearls and Pitfalls" were provided for surgeons approaching lower lip reconstruction. Between January 2018 and June 2021, a retrospective study was carried out. Data collection included patient demographics, defect attributes, reconstructive approaches, flap viability assessment, wound healing, and complications. The follow-up was carried out for a period of a minimum of 6 months. Among 78 patients, squamous cell carcinoma predominated with a mean defect area of 3308 cm2. Postoperative complications were recorded in two patients. All patients reported sensory restoration and overall satisfaction at the 6-month follow-up; secondary procedures were not necessary. Our reconstructive algorithm, focused on elderly patients, prioritizes less invasive reconstructive techniques and introduces innovative modifications to the established methods to achieve both aesthetic and functional outcomes with a low complication rate. In patients undergoing lower lip reconstruction, the subjective microstomia was found to be less relevant than the objective microstomia.

Doping-induced assembly interface for noninvasive in vivo local and systemic immunomodulation.

Peripheral neural interfaces, potent in modulating local and systemic immune responses for disease treatment, face significant challenges due to the peripheral nerves' broad distribution in tissues like the fascia, periosteum, and skin. The incongruity between static electronic components and the dynamic, complex organization of the peripheral nervous system often leads to interface failure, stalling circuit research and clinical applications. To overcome these, we developed a self-assembling, tissue-adaptive electrode composed of a single-component cocktail nanosheet colloid, including dopants, conducting polymers, stabilizers, and an MXene catalyst. Delivered via a jet injector to designated nerve terminals, this assembly utilizes reactive oxygen species to catalytically dope poly (3,4-ethylenedioxythiophene), enhancing π-π interactions between nanosheets, and yielding a conductive, biodegradable interface. This interface effectively regulates local immune activity and promotes sensory and motor nerve functional restoration in nerve-injured mice, while engaging the vagal-adrenal axis in freely moving mice, eliciting catecholamine neurotransmitter release, and suppressing systemic cytokine storms. This innovative strategy specifically targets nerve substructures, bolstering local and systemic immune modulation, and paving the way for the development of self-adaptive dynamic neural interfaces.

Sensory nerve transfers in the upper limb after peripheral nerve injury: a scoping review.

Nerve transfer for motor nerve paralysis is an established technique for treating complex nerve injuries. However, nerve transfer for sensory reconstruction has not been widely used, and published research on this topic is limited compared to motor nerve transfer. The indications and outcomes of nerve transfer for the restoration of sensory function remain unproven. This scoping review examines the indications, outcomes and complications of sensory nerve transfer. In total, 22 studies were included; the major finding is that distal sensory nerve transfers are more successful than proximal ones in succeeding protective sensation. Although the risk of extension of the sensory deficit with donor site loss and morbidity from neuromas remain a barrier to wider adoption, these complications were not reported in the review. Further, the scarcity of studies and small patient series limit the ability to determine sensory nerve transfer success. However, sensory restoration remains an opportunity for surgeons to pursue.Level of evidence: II.

Reconstructing Nerve Structures from Unorganized Points

Realistic sensory feedback is paramount for amputees as it improves prosthetic limb control and boosts functionality, safety, and overall quality of life. This sensory restoration relies on the direct electrostimulation of residual peripheral nerves. Computational models are instrumental in simulating these neurostimulation effects, offering solutions to the complexities tied to extensive animal/human trials and costly materials. Central to these models is the detailed mapping of nerve geometry, necessitating the delineation of internal nerve structures, such as fascicles, across various cross-sections. In our modeling process, we faced the challenge of organizing an originally unstructured set of points into coherent contours. We introduced a parameter-free curve-reconstruction algorithm that combines valley-seeking clustering, an adaptive Kalman filter, and the nearest neighbor classification technique. While intuitively simple for humans, the task of reconstructing multiple open and/or closed lines with pronounced corners from a nonuniform point set is daunting for many algorithms. Additionally, the precise differentiation of adjacent curves, commonly encountered in realistic nerve models, remains a formidable challenge even for top-tier algorithms. Our proposed method adeptly navigates the complexities inherent to nerve structure reconstruction. While our algorithm is chiefly designed for closed curves, as dictated by nerve geometry, we believe it can be reconfigured with appropriate code adjustments to handle open curves. Beyond neuroprosthetics, our proposed model has the potential to be applied and spark innovations in biomedicine and a variety of other fields.

Immediate Inferior Alveolar Nerve Reconstruction With Ablative Mandibular Resection Results in Functional Sensory Recovery

Ablative mandibular resection with sacrifice of the inferior alveolar nerve (IAN) results in loss of sensation and decreased quality of life. The purpose of this study is to evaluate functional sensory recovery (FSR) of immediate IAN allograft reconstruction performed during ablative mandibular resection at 1year following surgery. This is a single-center retrospective cohort study that included consecutive subjects who underwent mandibular resection with IAN discontinuity and used a nerve allograft of ≥40mm. The primary predictor variable is the use of an immediate nerve allograft in mandibular reconstruction. The main outcome variable is FSR at 1year using the Medical Research Council Scale. Covariates include subject age, sex, specific pathology, nerve gap length, and development of neuropathic pain. Statistical analysis of comparison of neurosensory outcomes was measured by bivariate statistics, weighted values, repeated measures, analysis of variance, and McNemar test. The study sample was composed of 164 subjects, of whom 55 (33.5%) underwent nerve allograft reconstruction and 30 (18.3%) did not have nerve reconstruction. Seventy-nine subjects (48.2%) did not meet the inclusion criteria. In the entire nerve allograft group of 55 subjects, FSR was achieved in 80% at 1year; however, in benign disease alone, 31 of 33 (94%) achieved FSR at 1year. In the nonallograft group (all benign disease), only 2 of 30 (7%) achieved FSR at 1year. The significant covariates were age and pathology. Benign pathologic resections were 5.2 times more likely to achieve FSR than malignancies, and all subjects ≤ 18years of age achieved FSR. After adjusting for age, sex, pathology, nerve gap length, nerve allograft was significantly associated with achieving FSR at 1year (adjusted odds ratio=5.52, 95% confidence interval= (1.03, 29.51), P value=.045<.05). Immediate long-span IAN allograft reconstruction is effective in restoration of sensation with an overall 80% of subjects achieving FSR at 1year, while benign disease resulted in 94% FSR at 1year. Immediate IAN reconstruction should be considered with mandibular resection involving the IAN, especially for children and benign disease.

Effective Delivery of Vagus Nerve Stimulation Requires Many Stimulations Per Session and Many Sessions Per Week Over Many Weeks to Improve Recovery of Somatosensation.

Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation. Here, we characterize the amount, intensity, frequency, and duration of VNS therapy paradigms to determine the optimal dosage for VNS-dependent enhancement of recovery in a model of peripheral nerve injury (PNI). Rats underwent transection of the medial and ulnar nerves in the forelimb, resulting in chronic sensory loss in the paw. Eight weeks after injury, rats were implanted with a VNS cuff and received tactile rehabilitation sessions consisting of repeated mechanical stimulation of the previously denervated forepaw paired with short bursts of VNS. Rats received VNS therapy in 1 of 6 systematically varied dosing schedules to identify a paradigm that balanced therapy effectiveness with a shorter regimen. Delivering 200 VNS pairings a day 4 days a week for 4 weeks produced the greatest percent improvement in somatosensory function compared to any of the 6 other groups (One Way analysis of variance at the end of therapy, F[4 70] P = .005). Our findings demonstrate that an effective VNS therapy dosage delivers many stimulations per session, with many sessions per week, over many weeks. These results provide a framework to inform the development of VNS-based therapies for sensory restoration.

Repair of Fingertip Degloving Injuries Using the Extended Reverse Second Dorsal Metacarpal Artery Flap.

This study aimed to introduce modified reverse second dorsal metacarpal artery flap (MRSDMAF) transfer for the treatment of fingertip degloving injuries. From January of 2004 to March of 2020, 31 patients with fingertip degloving injuries underwent MRSDMAF transfer. The mean defect and flap size were 4.5 × 1.6 cm and 4.7 × 1.7 cm, respectively. Nerve repair was performed in 18 fingers. Flap sensation, function restoration of the reconstructed fingers, and donor-site morbidity were assessed. For comparison, we reviewed a cohort of 45 patients undergoing modified cross-finger flap (MCFF) transfer. Complete flap survival was achieved in 28 fingers, and partial distal flap necrosis was noted in 3 fingers. After a mean of 24 months, the static 2-point discrimination was 8.6 ± 1.0 mm and 7.2 ± 0.8 mm in the MRSDMAF and MCFF groups, with a significant difference ( P < 0.0001). Sensory restoration of the MRSDMAF group was inferior to that of the MCFF group. In addition, the MRSDMAF group presented a higher incidence of fingertip pain ( P = 0.019) and suboptimal appearance of the reconstructed finger ( P = 0.036). On the donor site, the MRSDMAF group presented a lower incidence of scar pain ( P = 0.030) and better appearance ( P = 0.025). MRSDMAF transfer is an alternative treatment for fingertip degloving injuries, especially when MCFF transfer is not feasible. Therapeutic, III.

Comparison of sensory fusion recovery in different types programming of liquid crystal glasses

Objective: to compare the effectiveness of new method of sensory fusion recovery in patients with personalized adjustment of the frequency of alternation of liquid crystal glasses (LCG) compared with the empirical selection of the frequency of alternation. Material and methods. The study included 39 patients with concomitant convergent strabismus with orthotropy and no sensory fusion after surgical treatment of strabismus, who were prescribed LCG. The glasses were programmed empirically at 2 Hz in 21 patients (empiric group), in 18 patients — using the developed formula for calculating the frequency of alternation of LCG (calculated group). The compared groups did not differ in gender, age, visual acuity, and other characteristics. Results. Recovery of sensory fusion occurred more often with LCG in calculated group (16 patients, 88.9%) than in empiric group (9 patients, 42.9%), the difference is highly reliable (p=0.001). Conclusions. Anew method for personalized selection of the frequency of alternating LCG using video oculography is more efficient than empirical programming for sensory fusion restoration in children after surgery for concomitant convergent strabismus.

Comparison of sensory fusion recovery in different types programming of liquid crystal glasses

Objective: to compare the effectiveness of new method of sensory fusion recovery in patients with personalized adjustment of the frequency of alternation of liquid crystal glasses (LCG) compared with the empirical selection of the frequency of alternation. Material and methods. The study included 39 patients with concomitant convergent strabismus with orthotropy and no sensory fusion after surgical treatment of strabismus, who were prescribed LCG. The glasses were programmed empirically at 2 Hz in 21 patients (empiric group), in 18 patients — using the developed formula for calculating the frequency of alternation of LCG (calculated group). The compared groups did not differ in gender, age, visual acuity, and other characteristics. Results. Recovery of sensory fusion occurred more often with LCG in calculated group (16 patients, 88.9%) than in empiric group (9 patients, 42.9%), the difference is highly reliable (p=0.001). Conclusions. Anew method for personalized selection of the frequency of alternating LCG using video oculography is more efficient than empirical programming for sensory fusion restoration in children after surgery for concomitant convergent strabismus.

481-P: 10kHz SCS Restores Mechanical and Thermal Neural Processing in a Rodent Model of Painful Diabetic Neuropathy

A recent randomized controlled trial of 10 kHz spinal cord stimulation (SCS) in patients with painful diabetic neuropathy (PDN) has demonstrated significant and durable improvements in neurologic status, particularly sensory restoration of the foot (Petersen et al 2021, Argoff et al 2023). In order to gain further mechanistic insight into the improvements in sensory processing by 10kHz SCS, we analyzed the receptive field (RF) size and responses of spinal dorsal horn (DH) neurons to mechanical and thermal stimuli of the paw in a PDN rat model. For PDN-model, Rats were given a single effective dose of streptozotocin (STZ), while Naïve animals were injected with 0.9% saline. Four groups were studied: Naïve, STZ, STZ+ShamSCS, and STZ+10kHzSCS. Rats were anesthetized with urethane and a laminectomy was performed for DH neurons recording. We analyzed RF size and the response of DH neurons to vibrotactile stimulation and thermal sensation. Both the Naïve and STZ+10kHzSCS groups had significantly smaller RFs than the STZ Control and STZ+ShamSCS groups. In response to a 1 Hz vibration frequency, Naïve and STZ+10kHzSCS groups had higher peak power spectral density (PSD) of DH firing than STZ+ShamSCS, and PSD for the STZ+10kHzSCS group was statistically higher than for the STZ Control group. Response of DH neurons showed no significant differences between groups during the thermal stimulation, but the post-stimulus firing rates for the STZ+10kHzSCS group were significantly higher compared to STZ Control and STZ+ShamSCS. These data suggest that 10 kHz SCS amplified the DH response to large fiber (vibration) and small fiber (warm) signals and normalized the receptive field of the paw (acuity) in PDN rats. In diabetes, where peripheral sensory compromise from chronic hyperglycemia can lead to loss of protective sensation, such ‘tuned amplification’ as provided by 10 kHz SCS in the central nervous system may compensate for the reduced functionality seen in the peripheral sensory systems. Disclosure K.Lee: Employee; Nevro Corp. D.Lee: Employee; Nevro Corp. D.Wang: Employee; Nevro Corp. Z.B.Kagan: Employee; Nevro Corp. K.Bradley: Employee; Nevro Corp.

Multiparametric non-linear TENS modulation to integrate intuitive sensory feedback

Objective. Transcutaneous electrical nerve stimulation (TENS) has been recently introduced in neurorehabilitation and neuroprosthetics as a promising, non-invasive sensory feedback restoration alternative to implantable neurostimulation. Yet, the adopted stimulation paradigms are typically based on single-parameter modulations (e.g. pulse amplitude (PA), pulse-width (PW) or pulse frequency (PF)). They elicit artificial sensations characterized by a low intensity resolution (e.g. few perceived levels), low naturalness and intuitiveness, hindering the acceptance of this technology. To address these issues, we designed novel multiparametric stimulation paradigms, featuring the simultaneous modulation of multiple parameters, and implemented them in real-time tests of performance when exploited as artificial sensory inputs. Approach. We initially investigated the contribution of PW and PF variations to the perceived sensation magnitude through discrimination tests. Then, we designed three multiparametric stimulation paradigms comparing them with a standard PW linear modulation in terms of evoked sensation naturalness and intensity. The most performant paradigms were then implemented in real-time in a Virtual Reality—TENS platform to assess their ability to provide intuitive somatosensory feedback in a functional task. Main results. Our study highlighted a strong negative correlation between perceived naturalness and intensity: less intense sensations are usually deemed as more similar to natural touch. In addition, we observed that PF and PW changes have a different weight on the perceived sensation intensity. As a result, we adapted the activation charge rate (ACR) equation, proposed for implantable neurostimulation to predict the perceived intensity while co-modulating the PF and charge per pulse, to TENS (ACRT). ACRT allowed to design different multiparametric TENS paradigms with the same absolute perceived intensity. Although not reported as more natural, the multiparametric paradigm, based on sinusoidal PF modulation, resulted being more intuitive and subconsciously integrated than the standard linear one. This allowed subjects to achieve a faster and more accurate functional performance. Significance. Our findings suggest that TENS-based, multiparametric neurostimulation, despite not consciously perceived naturally, can provide integrated and more intuitive somatosensory information, as functionally proved. This could be exploited to design novel encoding strategies able to improve the performance of non-invasive sensory feedback technologies.