Novel Pulsed Ultrahigh-frequency Spinal Cord Stimulation Inhibits Mechanical Hypersensitivity and Brain Neuronal Activity in Rats after Nerve Injury

Chin-Tsang Yang; Yun Guan; Chih-Cheng Chen; Wei-Tso Lin; Kuo-Hsiang Lu; Chung-Ren Lin; Bai-Chuang Shyu; Yeong-Ray Wen

doi:10.1097/ALN.0000000000004680

Novel Pulsed Ultrahigh-frequency Spinal Cord Stimulation Inhibits Mechanical Hypersensitivity and Brain Neuronal Activity in Rats after Nerve Injury

Anesthesiology. 2023 Nov 1;139(5):646-663. doi: 10.1097/ALN.0000000000004680.

Authors

Chin-Tsang Yang¹, Yun Guan², Chih-Cheng Chen³, Wei-Tso Lin⁴, Kuo-Hsiang Lu⁵, Chung-Ren Lin⁶, Bai-Chuang Shyu⁷, Yeong-Ray Wen⁸

Affiliations

¹ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; and Department of Leisure Industry and Health Promotion, National Ilan University, Yilan, Taiwan.
² Department of Anesthesiology and Critical Care Medicine, Department of Neurological Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
³ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan; and Taiwan Mouse Clinic, Biomedical Translational Research Center, Academia Sinica, Taipei, Taiwan.
⁴ Gimer Medical Co., New Taipei City, Taiwan.
⁵ Kuo-Hsiang Lu, M.S.; Gimer Medical Co., New Taipei City, Taiwan.
⁶ Department of Anesthesiology, National Cheng Kung University Hospital, Tainan, Taiwan.
⁷ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁸ Pain Management and Research Center, Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan; and College of Medicine, China Medical University, Taichung, Taiwan.

PMID: 37428715
DOI: 10.1097/ALN.0000000000004680

Abstract

Background: Spinal cord stimulation (SCS) is an important pain treatment modality. This study hypothesized that a novel pulsed ultrahigh-frequency spinal cord stimulation (pUHF-SCS) could safely and effectively inhibit spared nerve injury-induced neuropathic pain in rats.

Methods: Epidural pUHF-SCS (± 3V, 2-Hz pulses comprising 500-kHz biphasic sinewaves) was implanted at the thoracic vertebrae (T9 to T11). Local field brain potentials after hind paw stimulation were recorded. Analgesia was evaluated by von Frey-evoked allodynia and acetone-induced cold allodynia.

Results: The mechanical withdrawal threshold of the injured paw was 0.91 ± 0.28 g lower than that of the sham surgery (24.9 ± 1.2 g). Applying 5-, 10-, or 20-min pUHF-SCS five times every 2 days significantly increased the paw withdrawal threshold to 13.3 ± 6.5, 18.5 ± 3.6, and 21.0 ± 2.8 g at 5 h post-SCS, respectively (P = 0.0002, < 0.0001, and < 0.0001; n = 6 per group) and to 6.1 ± 2.5, 8.2 ± 2.7, and 14.3 ± 5.9 g on the second day, respectively (P = 0.123, 0.013, and < 0.0001). Acetone-induced paw response numbers decreased from pre-SCS (41 ± 12) to 24 ± 12 and 28 ± 10 (P = 0.006 and 0.027; n = 9) at 1 and 5 h after three rounds of 20-min pUHF-SCS, respectively. The areas under the curve from the C component of the evoked potentials at the left primary somatosensory and anterior cingulate cortices were significantly decreased from pre-SCS (101.3 ± 58.3 and 86.9 ± 25.5, respectively) to 39.7 ± 40.3 and 36.3 ± 20.7 (P = 0.021, and 0.003; n = 5) at 60 min post-SCS, respectively. The intensity thresholds for pUHF-SCS to induce brain and sciatic nerve activations were much higher than the therapeutic intensities and thresholds of conventional low-frequency SCS.

Conclusions: Pulsed ultrahigh-frequency spinal cord stimulation inhibited neuropathic pain-related behavior and paw stimulation evoked brain activation through mechanisms distinct from low-frequency SCS.