Analgesic Effects Of High-Definition Transcranial Direct Current Stimulation Targeting The Anterior Cingulate Cortex

BackgroundPain remains a major medical challenge that affects more than 30%of the world’s population.High-definition transcranial direct current stimulation（HD-tDCS）,a non-invasive brain stimulation technique,is considered a promising treatment for pain as it modulates specific neural networks in the brain associated with pain processing and facilitates downstream pain inhibitory regulatory mechanisms for pain relief.Most of the existing clinical studies have used HD-tDCS over the superficial areas of the pain matrix to modulate pain.However,the current evidence for HD-tDCS-driven pain relief and hyperalgesia remains controversial.Recent evidence suggests that neuromodulation techniques that affect the activity of certain deeper brain structures may result in better analgesia.ObjectiveThe aim of this study was to examine whether HD-tDCS targeting the anterior cingulate cortex（ACC）would selectively reduce pain-related symptoms in healthy individuals and in experimental pain model.ACC is a brain region that is always activated by pain and plays an important role in nociceptive control,as well as being central to the integration of the emotional component of pain.MethodsStudy 1:In this parallel randomized controlled trial,66 female healthy subjects were randomly assigned to three experimental groups（anodal HD-tDCS group,cathodal HD-tDCS group,sham stimulation group）and received a single 20-minute HD-tDCS intervention.The primary outcome was pain sensitivity,including pressure pain thresholds（PPT）,heat pain thresholds（HPT）and cold pain thresholds（CPT）.Quantitative sensory testing of pain sensitivity and positive and negative affective schedule（PANAS）were conducted before and after the HD-tDCS intervention.Paired samples t-tests were used to examine within-group differences,and non-parametric tests were used to examine between-group differences in change before and after the intervention.Study 2:In this parallel randomized controlled trial,84 female healthy subjects were randomly assigned to three experimental groups（anodal HD-tDCS group,cathodal HD-tDCS group,sham stimulation group）.Topical capsaicin-induced experimental pain was maintained throughout the experiment;self-reported pain intensity and pain unpleasantness were assessed using the Numerical Rating Scale（NRS）.Baseline assessments（pain intensity,pain unpleasantness and pain sensitivity）were performed one hour after capsaicin application.Subsequently,all subjects were given a single20-minute HD-tDCS intervention;and outcome indicators were measured and collected from subjects immediately after and 60 minutes after the end of the intervention.Paired samples t-tests were used to examine within-group differences,and non-parametric tests were used to examine between-group differences in change before and after the intervention.ResultsStudy 1:Dynamic and static pain sensitivity associated with HPT and PPT was significantly reduced in subjects after cathodal HD-tDCS intervention compared to baseline（p<0.01）.Cathodal HD-tDCS induced a significant increase in HPT（p<0.05）and PPT（p<0.01）compared to sham stimulation.Compared to baseline,PANAS scores tended to decrease in all three groups after the HD-tDCS intervention,but the difference between groups was not significant（positive affect,p=0.924;negative affective,p=0.349）.Study 2:Capsaicin application induced a moderate pain(NRS-_{pain intensity}>5).Immediately after the HD-tDCS intervention,cathodal HD-tDCS induced a reduction in current NRS-_{pain intensity}and current NRS-_{pain unpleasantness}.At 60 minutes after the end of the HD-tDCS intervention,cathodal HD-tDCS induced a significant reduction in current NRS-_{pain intensity}（p=0.009）,current NRS-_{pain unpleasantness}（p=0.003）and mean NRS-_{pain intensity}over the past 1 hour（p=0.029）.After HD-tDCS intervention,cathodal HD-tDCS induced increases in HPT and PPT at all measured sites,but only showing statistically significant difference at the clCAPSITE（HPT,p=0.033;PPT,p=0.014）and the right rectus femoris muscle（PPT,p=0.017）compared to the sham stimulation group.Additionally,compared to baseline,PANAS scores tended to decrease in all three groups after the HD-tDCS intervention,but the difference between groups was not significant（positive affect,p=0.054;negative affective:p=0.837）.ConclusionsStudy 1:Our findings suggest that cathodal HD-tDCS protocol targeting ACC can provide a strong anti-nociceptive effect in healthy individuals,resulting in significant increases in HPT and PPT,demonstrating the positive biological effects of HD-tDCS.Study 2:To our knowledge,this was the first time that the analgesic effect of HD-tDCS targeting ACC was validated in capsaicin-induced experimental pain models.Our findings suggested that cathodal HD-tDCS targeting ACC induced significant analgesic effects in capsaicin-induced experimental pain.Future work combining neuroimaging techniques and consideration of different stimulation parameters is needed to further refine this innovative neural circuit-based pain treatment tool.