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. 2021 Dec 31:2021:6510383.
doi: 10.1155/2021/6510383. eCollection 2021.

Transcranial Ultrasound Stimulation of the Anterior Cingulate Cortex Reduces Neuropathic Pain in Mice

Xiangjun Feng  1   2   3 , Lili Niu  3   4   5 , Meng Long  3   4   5 , Kaixuan Luo  1   3 , Xiaowei Huang  3 , Moxian Chen  1 , Zhengrong Lin  3 , Wei Zhou  3 , Shasha Yi  1   3 , Lijuan Ao  1
Affiliations

Transcranial Ultrasound Stimulation of the Anterior Cingulate Cortex Reduces Neuropathic Pain in Mice

Xiangjun Feng et al. Evid Based Complement Alternat Med. .

Abstract

Focused ultrasound (FUS) is a potential tool for treating chronic pain by modulating the central nervous system. Herein, we aimed to determine whether transcranial FUS stimulation of the anterior cingulate cortex (ACC) effectively improved chronic pain in the chronic compress injury mice model at different stages of neuropathic pain. The mechanical threshold of pain was recorded in the nociceptive tests. We found FUS stimulation elevated the mechanical threshold of pain in both short-term (p < 0.01) and long-term (p < 0.05) experiments. Furthermore, we determined protein expression differences in ACC between the control group, the intervention group, and the Sham group to analyze the underlying mechanism of FUS stimulation in improving neuropathic pain. Additionally, the results showed FUS stimulation led to alterations in differential proteins in long-term experiments, including cellular processes, cellular signaling, and information storage and processing. Our findings indicate FUS may effectively alleviate mechanical neuropathic pain via the ACC's stimulation, especially in the chronic state.

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Conflict of interest statement

The authors declare that there are no conflicts of interest regarding the publication of this study.

Figures

Figure 1
Figure 1
Experimental schematics. Experimental schematic diagram (a). Acoustic field distributions with or without a fresh mouse skull (b).
Figure 2
Figure 2
Transcranial FUS stimulation slowly improved the mechanical withdraw threshold in the short-term experiment. Timeline of the short-term experiment (n = 6) (a). Ultrasound stimulation increased the mechanical withdrawal thresholds of the surgical side (##p=0.003) (b). The increase in the mechanical and thermal withdrawal thresholds of the contralateral side (c, e). The variation of sciatic nerve index and body weight (f, g). # represents a statistically significant difference between the FUS2 group and the other two groups. ∗ indicates a statistically significant difference between the FUS2 group and the Sham group.  + indicates a statistically significant difference between the FUS1 group and the Sham group.
Figure 3
Figure 3
FUS stimulation promptly improved the mechanical withdraw threshold in the long-term experiment. Timeline of the long-term experiment (n = 12) (a). Ultrasound stimulation increased the mechanical withdraw threshold of the surgical side (p < 0.05) (b). There were no significant changes in the mechanical withdraw threshold of the contralateral side. The bilateral thermal withdraw threshold, body weight, and sciatic nerve index between the FUS2 group and the Sham group (c–f). ∗ indicates statistical significance between the FUS2 group and the Sham group.
Figure 4
Figure 4
Ultrasound-induced inhibition of neuronal discharges from the ACC slices. Experimental schematics (a). Representative traces randomly selected of the neuronal discharges from the ACC slices obtained using MEA recording (b). Ultrasound stimulation substantially decreased the spike frequency of neuronal discharges (c) (∗∗∗p < 0.001 (prior to during: p ≤ 0.001, prior to following: p=0.002)).
Figure 5
Figure 5
FUS-induced differences in protein expression indicated alterations in pathways in the ACC. EggNOG entry statistics (a). Subcellular location analysis (b). Visualized functional enrichment (c). Pathway analysis (d).
Figure 6
Figure 6
FUS2-induced changes in the expression of Hnrnph1, Hnrnpd, Snrpb, and Dhx16. The expression of Hnrnph1, Hnrnpd, Snrpb, and Dhx16 in tissue was measured by western blotting. ∗ indicates statistical significance between the Sham group and the Control group, the FUS2 group and the Control group. # indicates statistical significance between the FUS2 group and the Sham group.
Figure 7
Figure 7
Safety and temperature evaluation. HE staining of the ACC brain tissue and the CCI surgery local site (×400).
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