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Tremor and Other Hyperkinetic Movements... 2022There is growing recognition of peripheral stimulation techniques for controlling arm symptoms in essential tremor (ET). Recently, the FDA gave clearance to the Cala... (Review)
Review
BACKGROUND
There is growing recognition of peripheral stimulation techniques for controlling arm symptoms in essential tremor (ET). Recently, the FDA gave clearance to the Cala system, a device worn around the wrist to treat arm tremors. The Cala system stimulates the sensory afferents of the peripheral nerves with high-frequency pulses. These pulses are delivered to the median and radial nerves alternately at the tremor frequency of the individual patient.
METHODS
The PubMed database was searched using the terms ("Essential Tremor"[Mesh] OR "essential tremor" [Title/Abstract] OR "tremor" [Title/Abstract]) AND ("peripheral arm stimulation" [Title/Abstract] OR "Cala device" [Title/Abstract] OR "sensory afferent stimulation" [Title/Abstract] OR "afferent stimulation" [Title/Abstract] OR "arm stimulation" [Title/Abstract] OR "peripheral nerve stimulation" [Title/Abstract]).
RESULTS
The search yielded 54 articles. Many studies discussed the rationale and various strategies for peripheral modulation of tremor. While the Cala system was found to be safe and well-tolerated in ET, data on efficacy revealed mixed findings. In a large randomized, blinded trial (n = 77), the primary outcome evaluated with spiral drawing task did not improve but the secondary outcomes reflected by the arm tremor severity and the activities of the daily living score revealed 20-25% improvements. A subsequent trial (n = 323) found that the in-home use of the Cala device led to improvements of similar magnitude lasting for at least three months but the clinical assessments were open-labeled.
DISCUSSION
Peripheral stimulation techniques are promising therapeutic modalities for treating ET symptoms. Stimulation of sensory afferent nerve fibers at the wrist can potentially modulate the peripheral and central components of the tremor network. Although the Cala system is user-friendly, safe, and well-tolerated, the current clinical evidence on the efficacy is inconsistent and insufficient. Thus, more data is warranted for implementing peripheral nerve stimulation as a standard of care for ET.
HIGHLIGHTS
The current review discusses the rationale, background, and potential mechanisms for using peripheral arm stimulation devices for treating ET. The Cala system is a wrist-worn peripheral nerve stimulation device that received FDA clearance to treat arm tremors. The current review evaluates the evidence for the safety and efficacy of using the Cala system and similar devices in clinical practice.
Topics: Essential Tremor; Humans; Peripheral Nerves; Radial Nerve; Transcutaneous Electric Nerve Stimulation; Tremor
PubMed: 35949227
DOI: 10.5334/tohm.685 -
Neuron Oct 2020The development of new tools to interface with the nervous system, empowered by advances in electronics and materials science, has transformed neuroscience and is... (Review)
Review
The development of new tools to interface with the nervous system, empowered by advances in electronics and materials science, has transformed neuroscience and is informing therapies for neurological and mental conditions. Although the vast majority of neural engineering research has focused on advancing tools to study the brain, understanding the peripheral nervous system and other organs can similarly benefit from these technologies. To realize this vision, the neural interface technologies need to address the biophysical, mechanical, and chemical challenges posed by the peripheral nerves and organs. In this Perspective, we discuss design considerations and recent technological advances to modulate electrical signaling outside the central nervous system. The innovations in bioelectronics borne out of interdisciplinary collaborations between biologists and physical scientists may not only advance fundamental study of peripheral (neuro)physiology but also empower clinical interventions for conditions including neurological, gastrointestinal, and immune dysfunction.
Topics: Animals; Electric Stimulation; Electrodes, Implanted; Humans; Man-Machine Systems; Nanotechnology; Neurosciences; Optogenetics; Peripheral Nerves; Peripheral Nervous System; Telemetry
PubMed: 33120023
DOI: 10.1016/j.neuron.2020.09.025 -
Ugeskrift For Laeger Sep 2022The use of peripheral nerve blocks carries a small risk of most often temporary direct damage to the peripheral nerves. Due to lack of research and differing opinions... (Review)
Review
The use of peripheral nerve blocks carries a small risk of most often temporary direct damage to the peripheral nerves. Due to lack of research and differing opinions regarding the potential of nerve blocks delaying the diagnosis of acute compartment syndrome, there is currently no consensus between anaesthetic- and orthopaedic associations regarding the use of peripheral nerve blocks in patients at risk of acute compartment syndrome. More interdisciplinary research is needed to inform and promote an evidence-based discussion of the subject, as argued in this review.
Topics: Anesthesia, Conduction; Compartment Syndromes; Humans; Nerve Block; Peripheral Nerves
PubMed: 36205160
DOI: No ID Found -
Plastic and Reconstructive Surgery Sep 2023Nerve transection is the most common form of peripheral nerve injury. Treatment of peripheral nerve injury has primarily focused on stabilization and mechanical cues to...
BACKGROUND
Nerve transection is the most common form of peripheral nerve injury. Treatment of peripheral nerve injury has primarily focused on stabilization and mechanical cues to guide extension of the regenerating growth cone across the site of transection. The authors investigated the effects of a peripheral nerve matrix (PNM) hydrogel on recovery after nerve transection.
METHODS
The authors used rodent models to determine the effect of PNM on axon extension, electrophysiologic nerve conduction, force generation, and neuromuscular junction formation after nerve transection and repair. The authors complemented this work with in vivo and in vitro fluorescence-activated cell sorting and immunohistochemistry approaches to determine the effects of PNM on critical cell populations early after repair.
RESULTS
Extension of axons from the proximal stump and overall green fluorescent protein-positive axon volume within the regenerative bridge were increased in the presence of PNM compared with an empty conduit ( P < 0.005) 21 days after repair. PNM increased electrophysiologic conduction (compound muscle action potential amplitude) across the repair site ( P < 0.05) and neuromuscular junction formation ( P = 0.04) 56 days after repair. PNM produced a shift in macrophage phenotype in vitro and in vivo ( P < 0.05) and promoted regeneration in a murine model used to characterize the early immune response to PNM ( P < 0.05).
CONCLUSION
PNM, delivered by subepineural injection, promoted recovery after nerve transection with immediate repair, supporting a beneficial macrophage response, axon extension, and downstream remodeling using a range of clinically relevant outcome measures.
CLINICAL RELEVANCE STATEMENT
This article describes an approach for subepineural injection at the site of nerve coaptation to modulate the response to injury and improve outcomes.
Topics: Mice; Animals; Peripheral Nerve Injuries; Hydrogels; Peripheral Nerves; Axons; Neural Conduction; Nerve Regeneration
PubMed: 36946873
DOI: 10.1097/PRS.0000000000010261 -
International Journal of Molecular... May 2023In peripheral nerve injuries (PNI) with substance loss, where tensionless end-to-end suture is not achievable, the positioning of a graft is required. Available options... (Review)
Review
In peripheral nerve injuries (PNI) with substance loss, where tensionless end-to-end suture is not achievable, the positioning of a graft is required. Available options include autografts (e.g., sural nerve, medial and lateral antebrachial cutaneous nerves, superficial branch of the radial nerve), allografts (Avance; human origin), and hollow nerve conduits. There are eleven commercial hollow conduits approved for clinical, and they consist of devices made of a non-biodegradable synthetic polymer (polyvinyl alcohol), biodegradable synthetic polymers (poly(DL-lactide-ε-caprolactone); polyglycolic acid), and biodegradable natural polymers (collagen type I with/without glycosaminoglycan; chitosan; porcine small intestinal submucosa); different resorption times are available for resorbable guides, ranging from three months to four years. Unfortunately, anatomical/functional nerve regeneration requirements are not satisfied by any of the possible alternatives; to date, focusing on wall and/or inner lumen organization/functionalization seems to be the most promising strategy for next-generation device fabrication. Porous or grooved walls as well as multichannel lumens and luminal fillers are the most intriguing options, eventually also including the addition of cells (Schwann cells, bone marrow-derived, and adipose tissue derived stem cells) to support nerve regeneration. This review aims to describe common alternatives for severe PNI recovery with a highlight of future conduits.
Topics: Animals; Humans; Swine; Sciatic Nerve; Polyesters; Peripheral Nerves; Prostheses and Implants; Peripheral Nerve Injuries; Polyglycolic Acid; Nerve Regeneration
PubMed: 37298122
DOI: 10.3390/ijms24119170 -
Scientific Reports Jul 2022Traditional histopathologic evaluation of peripheral nerve employs brightfield microscopy with diffraction limited resolution of ~ 250 nm. Though electron...
Traditional histopathologic evaluation of peripheral nerve employs brightfield microscopy with diffraction limited resolution of ~ 250 nm. Though electron microscopy yields nanoscale resolution of the nervous system, sample preparation is costly and the technique is incompatible with living samples. Super-resolution microscopy (SRM) comprises a set of imaging techniques that permit nanoscale resolution of fluorescent objects using visible light. The advent of SRM has transformed biomedical science in establishing non-toxic means for investigation of nanoscale cellular structures. Herein, sciatic nerve sections from GFP-variant expressing mice, and regenerating human nerve from cross-facial autografts labelled with a myelin-specific fluorescent dye were imaged by super-resolution radial fluctuation microscopy, stimulated emission depletion microscopy, and structured illumination microscopy. Super-resolution imaging of axial cryosections of murine sciatic nerves yielded robust visualization myelinated and unmyelinated axons. Super-resolution imaging of axial cryosections of human cross-facial nerve grafts demonstrated enhanced resolution of small-caliber thinly-myelinated regenerating motor axons. Resolution and contrast enhancement afforded by super-resolution imaging techniques enables visualization of unmyelinated axons, regenerating axons, cytoskeleton ultrastructure, and neuronal appendages of mammalian peripheral nerves using light microscopes.
Topics: Animals; Axons; Humans; Mammals; Mice; Microscopy, Electron; Myelin Sheath; Optical Imaging; Sciatic Nerve
PubMed: 35864187
DOI: 10.1038/s41598-022-16769-0 -
Journal of Neuroinflammation Nov 2023Although peripheral nerves have an intrinsic self-repair capacity following damage, functional recovery is limited in patients. It is a well-established fact that...
BACKGROUND
Although peripheral nerves have an intrinsic self-repair capacity following damage, functional recovery is limited in patients. It is a well-established fact that macrophages accumulate at the site of injury. Numerous studies indicate that the phenotypic shift from M1 macrophage to M2 macrophage plays a crucial role in the process of axon regeneration. This polarity change is observed exclusively in peripheral macrophages but not in microglia and CNS macrophages. However, the molecular basis of axonal regeneration by M2 macrophage is not yet fully understood. Herein, we aimed to identify the M2 macrophage-derived axon regeneration factor.
METHODS
We established a peripheral nerve injury model by transection of the inferior alveolar nerve (IANX) in Sprague-Dawley rats. Transcriptome analysis was performed on the injured nerve. Recovery from sensory deficits in the mandibular region and histological reconnection of IAN after IANX were assessed in rats with macrophage depletion by clodronate. We investigated the effects of adoptive transfer of M2 macrophages or M2-derived cathepsin S (CTSS) on the sensory deficit. CTSS initiating signaling was explored by western blot analysis in IANX rats and immunohistochemistry in co-culture of primary fibroblasts and Schwann cells (SCs).
RESULTS
Transcriptome analysis revealed that CTSS, a macrophage-selective lysosomal protease, was upregulated in the IAN after its injury. Spontaneous but partial recovery from a sensory deficit in the mandibular region after IANX was abrogated by macrophage ablation at the injured site. In addition, a robust induction of c-Jun, a marker of the repair-supportive phenotype of SCs, after IANX was abolished by macrophage ablation. As in transcriptome analysis, CTSS was upregulated at the injured IAN than in the intact IAN. Endogenous recovery from hypoesthesia was facilitated by supplementation of CTSS but delayed by pharmacological inhibition or genetic silencing of CTSS at the injured site. Adoptive transfer of M2-polarized macrophages at this site facilitated sensory recovery dependent on CTSS in macrophages. Post-IANX, CTSS caused the cleavage of Ephrin-B2 in fibroblasts, which, in turn, bound EphB2 in SCs. CTSS-induced Ephrin-B2 cleavage was also observed in human sensory nerves. Inhibition of CTSS-induced Ephrin-B2 signaling suppressed c-Jun induction in SCs and sensory recovery.
CONCLUSIONS
These results suggest that M2 macrophage-derived CTSS contributes to axon regeneration by activating SCs via Ephrin-B2 shedding from fibroblasts.
Topics: Animals; Humans; Rats; Axons; Cathepsins; Ephrin-B2; Fibroblasts; Macrophages; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Rats, Sprague-Dawley; Schwann Cells
PubMed: 37946211
DOI: 10.1186/s12974-023-02943-2 -
Proceedings of the National Academy of... Apr 2022SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from...
SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease.
Topics: Animals; Axons; Diabetes Mellitus; Diabetic Neuropathies; Humans; Mice; Myelin Sheath; Peripheral Nerves; Protein Kinases; Schwann Cells
PubMed: 35344427
DOI: 10.1073/pnas.2121552119 -
International Journal of Molecular... Feb 2023The use of stimulation of peripheral nerves to test or treat various medical disorders has been prevalent for a long time. Over the last few years, there has been... (Review)
Review
The use of stimulation of peripheral nerves to test or treat various medical disorders has been prevalent for a long time. Over the last few years, there has been growing evidence for the use of peripheral nerve stimulation (PNS) for treating a myriad of chronic pain conditions such as limb mononeuropathies, nerve entrapments, peripheral nerve injuries, phantom limb pain, complex regional pain syndrome, back pain, and even fibromyalgia. The ease of placement of a minimally invasive electrode via percutaneous approach in the close vicinity of the nerve and the ability to target various nerves have led to its widespread use and compliance. While most of the mechanism behind its role in neuromodulation is largely unknown, the gate control theory proposed by Melzack and Wall in the 1960s has been the mainstay for understanding its mechanism of action. In this review article, the authors performed a literature review to discuss the mechanism of action of PNS and discuss its safety and usefulness in treating chronic pain. The authors also discuss current PNS devices available in the market today.
Topics: Humans; Chronic Pain; Transcutaneous Electric Nerve Stimulation; Electric Stimulation Therapy; Peripheral Nerves; Pain Management; Chronic Disease
PubMed: 36901970
DOI: 10.3390/ijms24054540 -
Journal of Visualized Experiments : JoVE Oct 2021Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be...
Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.
Topics: Animals; Electric Power Supplies; Electric Stimulation Therapy; Peripheral Nerves; Phrenic Nerve; Prostheses and Implants; Rats; Wireless Technology
PubMed: 34747395
DOI: 10.3791/63085