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

Abstract

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.

Low-Intensity Focused Ultrasound Alleviates Chronic Neuropathic Pain-Induced Allodynia by Inhibiting Neuroplasticity in the Anterior Cingulate Cortex

“…FUS is a noninvasive targeting therapy that uses a novel concave head to concentrate ultrasound energy into a range of millimeter diameters [ 31 ]. Unlike the thermal effects of high-intensity focused ultrasound (HIFU) [ 32 ], the biological effects of LIFU with regard to neuromodulation are primarily mechanical and can activate or inhibit neuronal activity by altering the state of mechanically sensitive ion channels embedded in cell membranes [ 33 , 34 ]. Over the past decade, ultrasound stimulation of neurons has shown numerous advantages over electrical stimulation.…”

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

“…This novel treatment represents a noninvasive alternative to current neuromodulatory treatments that involve the surgical placement of electric stimulators. 38 In the present study, we chose to measure neuropathic allodynia 7 days after CPNI induction. Rodent CPNI models based on VFF responses have shown that nerve ligation results in 180 days of neuropathic allodynia.…”

“…This swine model worked well for our liFUS treatment, because the treatment alleviated neuropathic pain symptoms over a 1-month period. 38 However, measuring long-term change (such as during a 1-year period) would be difficult in this model, as animals weigh more than 300 kg at full size. 43 The novel swine CPNI model of neuropathic pain presented here is a modified version of the sciatic nerve injury surgery commonly used in rats.…”

The Emergence of Functional Ultrasound for Noninvasive Brain–Computer Interface

“…[ 139 ] showed that ultrasound stimulation of the rat dorsal root ganglia increased mechanical and thermal sensory thresholds, and this improvement was more substantial in female rats [ 140 ]. They also demonstrated that ultrasound can alter pain behavior and allodynia in a porcine peroneal nerve-injury model [ 141 ]. This may be related to the improvement in the inflammatory response of the dorsal root ganglia via ultrasound stimulation [ 142 ].…”