Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury

Hellman, Abigail; Maietta, Teresa; Byraju, Kanakaharini; Park, Yunseo Linda; Liss, Andrea; Prabhala, Tarun; Neubauer, Paul; Williams, Emery; Burdette, Clif; Shin, Damian S.; Ghoshal, Goutam; Nalwalk, Julia W.; Agrawal, Aira; Jiang, Qian; Pilitsis, Julie G.

doi:10.1016/j.neuroscience.2020.01.016

Neuroscience

2020

DOI: 10.1016/j.neuroscience.2020.01.016

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Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury

Abigail Hellman

Teresa Maietta

Kanakaharini Byraju

et al.

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Cited by 14 publications

(12 citation statements)

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“…3 Recently, our laboratory demonstrated that a single treatment with external low intensity focused ultrasound (liFUS) to the DRG produced significant improvements in mechanical, thermal, and noxious pain for 3-5 days in rodent models of chronic pain. [4][5][6][7] Specifically, we have shown that liFUS treatment of the L5 DRG induces antinociceptive effects, in a dose-dependent manner, without causing histological damage. 4,5,7,8 Repeated treatments showed no evidence of tachyphylaxis.…”

mentioning

confidence: 94%

“…[4][5][6][7] Specifically, we have shown that liFUS treatment of the L5 DRG induces antinociceptive effects, in a dose-dependent manner, without causing histological damage. 4,5,7,8 Repeated treatments showed no evidence of tachyphylaxis. 8 While the therapeutic use of electrical stimulation is commonplace, thermal energy at lower doses has been used sparingly in the modulation of chronic pain.…”

mentioning

confidence: 94%

“…Our existing device was adequate for use in rodents but necessitated modification to target deeper structures. 5,6 In this study, we employed our new liFUS array to reduce allodynia and pain behavior in a common peroneal nerve injury (CPNI) model in swine.…”

mentioning

confidence: 99%

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Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain

Hellman

Maietta

Clum

et al. 2021

Journal of Neurosurgery

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OBJECTIVE The authors’ laboratory has previously demonstrated beneficial effects of noninvasive low intensity focused ultrasound (liFUS), targeted at the dorsal root ganglion (DRG), for reducing allodynia in rodent neuropathic pain models. However, in rats the DRG is 5 mm below the skin when approached laterally, while in humans the DRG is typically 5–8 cm deep. Here, using a modified liFUS probe, the authors demonstrated the feasibility of using external liFUS for modulation of antinociceptive responses in neuropathic swine. METHODS Two cohorts of swine underwent a common peroneal nerve injury (CPNI) to induce neuropathic pain. In the first cohort, pigs (14 kg) were iteratively tested to determine treatment parameters. liFUS penetration to the L5 DRG was verified by using a thermocouple to monitor tissue temperature changes and by measuring nerve conduction velocity (NCV) at the corresponding common peroneal nerve (CPN). Pain behaviors were monitored before and after treatment. DRG was evaluated for tissue damage postmortem. Based on data from the first cohort, a treatment algorithm was developed, parameter predictions were verified, and neuropathic pain was significantly modified in a second cohort of larger swine (20 kg). RESULTS The authors performed a dose-response curve analysis in 14-kg CPNI swine. Specifically, after confirming that the liFUS probe could reach 5 cm in ex vivo tissue experiments, the authors tested liFUS in 14-kg CPNI swine. The mean ± SEM DRG depth was 3.79 ± 0.09 cm in this initial cohort. The parameters were determined and then extrapolated to larger animals (20 kg), and predictions were verified. Tissue temperature elevations at the treatment site did not exceed 2°C, and the expected increases in the CPN NCV were observed. liFUS treatment eliminated pain guarding in all animals for the duration of follow-up (up to 1 month) and improved allodynia for 5 days postprocedure. No evidence of histological damage was seen using Fluoro-Jade and H&E staining. CONCLUSIONS The results demonstrate that a 5-cm depth can be reached with external liFUS and alters pain behavior and allodynia in a large-animal model of neuropathic pain.

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confidence: 94%

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confidence: 94%

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Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain

Hellman

Maietta

Clum

et al. 2021

Journal of Neurosurgery

Self Cite

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“…[10][11][12] We have demonstrated that low intensity focused ultrasound (liFUS) treatment at the DRG has similar efficacy for neuropathic pain in a rodent model of common peroneal nerve injury (CPNI). 13,14 A positive correlation has been identified between swine models and the subsequent translation of treatments ABBREVIATIONS CPN = common peroneal nerve; CPNI = CPN injury; DRG = dorsal root ganglion; liFUS = low intensity focused ultrasound; P0 = myelin protein zero; s.c. = subcutaneously; VFF = von Frey filament.…”

mentioning

confidence: 99%

“…This is a modification of the well-validated sciatic nerve injury model used in rodents and involves ligation of a branch of the sciatic nerve, specifically, the common peroneal nerve (CPN). 13,14,20,21 In order to help move neuropathic pain treatments toward clinical implementation, we have translated our CPNI model from rodents 13,14 to domestic swine. The domestic swine CPNI pain model allows positioning of the incision and nerve ligation site near the patella, thus minimizing damage during surgery at targeted upstream treatment sites such as the nerve roots and the DRG.…”

mentioning

confidence: 99%

Development of a common peroneal nerve injury model in domestic swine for the study of translational neuropathic pain treatments

Hellman

Maietta

Clum

et al. 2021

Journal of Neurosurgery

Self Cite

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OBJECTIVE To date, muscular and bone pain have been studied in domestic swine models, but the only neuropathic pain model described in swine is a mixed neuritis model. Common peroneal nerve injury (CPNI) neuropathic pain models have been utilized in both mice and rats. METHODS The authors developed a swine surgical CPNI model of neuropathic pain. Behavioral outcomes were validated with von Frey filament testing, thermal sensitivity assessments, and social and motor scoring. Demyelination of the nerve was confirmed through standard histological assessment. The contralateral nerve served as the control. RESULTS CPNI induced mechanical and thermal allodynia (p < 0.001 [n = 10] and p < 0.05 [n = 4], respectively) and increased pain behavior, i.e., guarding of the painful leg (n = 12). Myelin protein zero (P0) staining revealed demyelination of the ligated nerve upstream of the ligation site. CONCLUSIONS In a neuropathic pain model in domestic swine, the authors demonstrated that CPNI induces demyelination of the common peroneal nerve, which the authors hypothesize is responsible for the resulting allodynic pain behavior. As the anatomical features of domestic swine resemble those of humans more closely than previously used rat and mouse models, utilizing this swine model, which is to the authors’ knowledge the first of its kind, will aid in the translation of experimental treatments to clinical trials.

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Motor Neuron‐Specific Membrane Depolarization of Transected Peripheral Nerves by Upconversion Nanoparticle‐Mediated Optogenetics

Yan,

Wan,

et al. 2023

Adv Funct Materials

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It remains a fundamental challenge to administer guided regeneration and functional recovery of peripheral nerves after the complete transection. Herein, a new concept to specifically depolarize the membranes of the target acetylcholinergic motor neurons by near infrared (NIR) laser‐triggered optogenetics for promoted functional reconnection of transected peripheral nerves is reported. The approach features the anchoring of acetylcholine‐modified upconversion nanoparticles (UCNP) onto the acetylcholine receptors on the postsynaptic membrane and selective infection of the motor neural cells with adeno‐associated virus loading channelrhodopsin 2 (ChR2). The upconversion fluorescence mediated by UCNP can activate ChR2 protein for membrane depolarization of the acetylcholinergic motor neurons. It induces a cascade of events, including axonal regeneration, Schwann cells remyelination, brain‐derived neurotrophic factor expression enhancement, and the remodeling of neuromuscular junctions (NMJ) from muscle denervation, which leads to promoted functional reconnection of the injured peripheral nerves. The results of behavioral and electrophysiological experiments further verify the functional recovery of transected peripheral nerves by the approach. The UCNP‐mediated optogenetic strategy of minimally invasive, precisely guided, and functional reconnection of injured nerves shall bring great benefits to both fundamental research and translational development in neural regenerative medicine.

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Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury

Cited by 14 publications

References 31 publications

Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain

Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain

Development of a common peroneal nerve injury model in domestic swine for the study of translational neuropathic pain treatments

Motor Neuron‐Specific Membrane Depolarization of Transected Peripheral Nerves by Upconversion Nanoparticle‐Mediated Optogenetics

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