The different analgesic effects of alpha high-definition transcranial alternating current stimulation over the primary sensorimotor cortex and the left dorsolateral prefrontal cortex during sustained experimental pain

Pain is an unpleasant combination of sensations and emotions that is intricately controlled by neural oscillations and interconnections across different brain regions and waves [[1]Kim J.A. Davis K.D. Neural oscillations: understanding a neural code of pain.Neuroscientist. 2021; 27: 544-570https://doi.org/10.1177/1073858420958629Crossref PubMed Scopus (34) Google Scholar]. Within pain-induced neural symphony, brain oscillations within the alpha frequency band (8–13 HZ) exert regulatory control over the processing of incoming sensory information, utilizing inhibitory pathways to promote pain relief. Studies have consistently identified alpha oscillation as a promising target for potential analgesic interventions [[2]Ahn S. Prim J.H. Alexander M.L. McCulloch K.L. Fröhlich F. Identifying and engaging neuronal oscillations by transcranial alternating current stimulation in patients with chronic low back pain: a randomized, crossover, double-blind, sham-controlled pilot study.J Pain. 2019; 20 (e11): 277.e1https://doi.org/10.1016/j.jpain.2018.09.004Abstract Full Text Full Text PDF Scopus (61) Google Scholar,[3]Peng W. Zhan Y. Jin R. Lou W. Li X. Aftereffects of alpha transcranial alternating current stimulation over the primary sensorimotor cortex on cortical processing of pain.Pain. 2023; 164: 1280-1290https://doi.org/10.1097/j.pain.0000000000002814Crossref Scopus (0) Google Scholar]. High-definition transcranial alternating current stimulation (HD-tACS) is a non-invasive brain stimulation technique that has been shown to enhance focus and more effectively modulate alpha oscillations within pain-related brain region [[4]Takeuchi N. Pain control based on oscillatory brain activity using transcranial alternating current stimulation: an integrative review.Front Hum Neurosci. 2023; 17941979https://doi.org/10.3389/fnhum.2023.941979Crossref Scopus (1) Google Scholar]. The primary sensorimotor cortex (SM1) and the left dorsolateral prefrontal cortex (DLPFC) are classic targets in non-invasive brain stimulation analgesia research [[5]Brighina F. De Tommaso M. Giglia F. Scalia S. Cosentino G. Puma A. et al.Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex.J Headache Pain. 2011; 12: 185-191https://doi.org/10.1007/s10194-011-0322-8Crossref PubMed Scopus (90) Google Scholar,[6]Yao J. Li X. Zhang W. Lin X. Lyu X. Lou W. et al.Analgesia induced by anodal tDCS and high-frequency tRNS over the motor cortex: immediate and sustained effects on pain perception.Brain Stimul. 2021; 14: 1174-1183https://doi.org/10.1016/j.brs.2021.07.011Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. However, the different analgesic effects of alpha HD-tACS on these two regions remain largely unclear. Elucidating these differences could potentially augment our understanding of targeted pain treatment methodologies. Additionally, existing analgesic research mainly evaluates the analgesic effect of the tACS post-stimulation period, overlooking evaluation of the stimulation period analgesic effect and failing to capture the dynamic evolution of the analgesic effect over time. Here, we performed a double-blind, within-subject design, sham-controlled experimental study to evaluate the specific "online effects" (stimulation period) and "aftereffects" (post-stimulation period) analgesics of alpha HD-tACS between the right SM1 and left DLPFC by using the capsaicin sensitization experimental tonic pain model [[7]Reinhart R.M.G. Nguyen J.A. Working memory revived in older adults by synchronizing rhythmic brain circuits.Nat Neurosci. 2019; 22: 820-827https://doi.org/10.1038/s41593-019-0371-xCrossref PubMed Scopus (295) Google Scholar]. Participants attended four lab sessions (Fig. 1A), each separated by 10 days. Before the first session, participants undergo a pain-calibration procedure (See supplementary material). In each session, they received one of the following: active HD-tACS on SM1, active HD-tACS on DLPFC, combined active HD-tACS (simultaneous stimulation of SM1 and DLPFC), or sham HD-tACS. The 0.5 mL Capzasin-HP cream (containing 0.1% capsaicin) was evenly applied on a 4 × 3.5 cm sterile wound dressing on the inner side of the left forearm of the participant to induce a tonic pain state [[8]Qiu S. Lyu X. Zheng Q. He H. Jin R. Peng W. Temporal dynamics of electroencephalographic microstates during sustained pain.Cerebr Cortex. 2023; 33: 8594-8604https://doi.org/10.1093/cercor/bhad143Crossref Scopus (1) Google Scholar]. The HD-tACS (NeuStim) has five Ag–AgCl sintered ring electrodes arranged in a 4 (0.375 mA) ×1 (1.5 mA) montage. The central electrode was placed at C4 for right SM1 stimulation or at F3 for left DLPFC stimulation, following the 10–20 system of electrode placement (Fig. 1B) [[3]Peng W. Zhan Y. Jin R. Lou W. Li X. Aftereffects of alpha transcranial alternating current stimulation over the primary sensorimotor cortex on cortical processing of pain.Pain. 2023; 164: 1280-1290https://doi.org/10.1097/j.pain.0000000000002814Crossref Scopus (0) Google Scholar,[9]Tremblay S. Lepage J.F. Latulipe-Loiselle A. Fregni F. Pascual-Leone A. Théoret H. The uncertain outcome of prefrontal tDCS.Brain Stimul. 2014; 7: 773-783https://doi.org/10.1016/j.brs.2014.10.003Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. This same electrode placement was used for simultaneous stimulation of SM1 and DLPFC in combined stimulation (See supplementary material for electrode placement and combined stimulation electric field modeling). Active HD-tACS applied alternating current with a frequency of 10 Hz for a duration of 30 minutes [[3]Peng W. Zhan Y. Jin R. Lou W. Li X. Aftereffects of alpha transcranial alternating current stimulation over the primary sensorimotor cortex on cortical processing of pain.Pain. 2023; 164: 1280-1290https://doi.org/10.1097/j.pain.0000000000002814Crossref Scopus (0) Google Scholar]. Sham HD-tACS provides one minute (30 seconds of acceleration and 30 seconds of deceleration) of active HD-tACS at the beginning and end of the phase, applied randomly to either SM1 or DLPFC [[3]Peng W. Zhan Y. Jin R. Lou W. Li X. Aftereffects of alpha transcranial alternating current stimulation over the primary sensorimotor cortex on cortical processing of pain.Pain. 2023; 164: 1280-1290https://doi.org/10.1097/j.pain.0000000000002814Crossref Scopus (0) Google Scholar]. The study followed the Declaration of Helsinki principles with written informed consent from all participants and obtained approval from the Institutional Review Board of the Affiliated Hospital of North Sichuan Medical College. A total of 34 healthy participants (age: 18–26 years, mean ± SD: 23.26 ± 1.48, 15 females) were recruited for the study. Our experiment comprised two periods (Fig. 1A): a 30-minute HD-tACS stimulation period after applying 0.5 mL of Capzasin-HP cream, and a 30-minute post-stimulation period. Participants rated pain intensity every 2 minutes using a 0–10 numeric rating scale (NRS), with 10 denoting extreme pain [[6]Yao J. Li X. Zhang W. Lin X. Lyu X. Lou W. et al.Analgesia induced by anodal tDCS and high-frequency tRNS over the motor cortex: immediate and sustained effects on pain perception.Brain Stimul. 2021; 14: 1174-1183https://doi.org/10.1016/j.brs.2021.07.011Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. The mean NRS score within each 6-minute interval was employed as a dynamic indicator for a comprehensive examination of the 60-minute temporal analgesic effects (See supplementary material for the statistical results of each 2-minute interval). The primary outcome was centered on the comparison of the NRS scores between active and sham stimulation. Secondary results utilize the area under the curve (AUC) method to compare comprehensive analgesic effects at different periods. The Dunnett and Tukey's post hoc tests were employed to correct for multiple comparisons. In our results, there was no difference in whether participants thought they had received active or sham stimulation, and no adverse effects were observed across the four sessions (Table S1). ANOVA analysis revealed significant main effects of stimulation type (F3,1485 = 16.29, p < 0.0001) and time interval (F10,1485 = 219.2, p < 0.0001) on the 6-minute NRS scores. No statistically significant interaction effects were observed. Post hoc test showed statistically significant reductions in NRS scores at specific intervals for active HD-tACS applied on DLPFC (36–60 minutes), SM1 (48–60 minutes), and combined stimulation (48–60 minutes), compared to sham (Fig. 1C). Both the AUC and NRS curve peak were significantly lower for active HD-tACS compared to sham (Fig. 1D). During stimulation, only active HD-tACS on DLPFC yielded a significantly lower NRS AUC of online effects than sham (p = 0.042, Tukey's post hoc test) (Fig. 1E). In the post-stimulation period, all active HD-tACS demonstrated significantly lower NRS AUC of aftereffects than sham (Fig. 1F). Our results showed that active HD-tACS to both SM1 and DLPFC demonstrated analgesic effects. Notably, active HD-tACS on DLPFC demonstrated a quicker onset of analgesia. Pain is a complex phenomenon that involves various aspects, including sensory, emotional, cognitive, and motivational components. The SM1 is important for sensory discrimination and precise localization of pain signals. In contrast, the DLPFC serves a crucial function in pain management by modulating both cortico-subcortical and cortico-cortical pathways, involving the engagement of both somatosensory regions and regions responsible for processing emotionally significant stimuli [[5]Brighina F. De Tommaso M. Giglia F. Scalia S. Cosentino G. Puma A. et al.Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex.J Headache Pain. 2011; 12: 185-191https://doi.org/10.1007/s10194-011-0322-8Crossref PubMed Scopus (90) Google Scholar]. Furthermore, several studies showed the involvement of the DLPFC in the suppression of pain and the maintenance of pain inhibition [[10]Che X. Cash R.F.H. Luo X. Luo H. Lu X. Xu F. et al.High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: a systematic review and meta-analysis.Brain Stimul. 2021; 14: 1135-1146https://doi.org/10.1016/j.brs.2021.07.004Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. Therefore, manipulating the neural oscillations of the DLPFC may result in pain relief, consistent with its function in regulating cognitive and emotional processes. This may be one of the factors explaining why the application of HD-tACS on DLPFC resulted in a more rapid initiation of pain relief than on SM1. Additionally, our findings did not show superior analgesic effects with combined active HD-tACS. It suggests that optimizing the interplay of neural oscillations across both brain regions and calibrating the stimulation frequency and intensity may be requisite for maximizing the combined analgesic effect. This work was supported by the National Natural Science Foundation of China (No. 81973962, 81901821, 82071879, 32071061), Sichuan Provincial Natural Science Foundation Youth Fund Project (24NSFSC7688), and Sichuan Provincial Health Commission Clinical Research Special Project (23LCYJ019).