Does transcranial direct current stimulation enhance the hypoalgesic effect of exercise?

Abstract

Exercise produces a decrease in pain sensitivity via an effect called exercise-induced hypoalgesia (EIH). Transcranial direct current stimulation (tDCS), acting on similar analgesic mechanisms as EIH, represents a potential complementary intervention that may amplify the effects of exercise on pain. This study aimed to explore if anodal tDCS could enhance the effect of exercise on pain compared to exercise alone. A total of 35 healthy participants aged 19-37 years completed a familiarisation session followed by two separate sessions where active and sham tDCS was applied in a randomised cross-over design. The familiarisation session involved familiarisation to the pain assessment and exercise tasks, while the subsequent tDCS sessions involved pain sensitivity assessment, exercise and either anodal tDCS or sham tDCS. tDCS doses were applied at 2 ​mA over the primary motor cortex for 10 ​min, with the reference electrode placed over the contralateral supraorbital area. The exercise task involved a sustained isometric grip strength contraction at 35% of maximal voluntary contraction (MVC) until volitional exhaustion. Pain sensitivity was evaluated as pressure pain threshold before tDCS, after tDCS, and after exercise. Across both tDCS conditions, pain threshold was higher after exercise when compared to pre- and post-tDCS measurement. This increase in pain threshold did not differ between active and sham tDCS conditions. Our findings suggest that the hypoalgesic effects of active anodal tDCS over the motor cortex prior to exercise are no greater than the effects of sham tDCS prior to exercise.

Keywords

Transcranial direct current stimulation / Grip strength / Pain sensitivity / Time to exhaustion / Pain pressure threshold / tDCS

CRediT authorship contribution statement

Aidan Lewis: Writing - review & editing, Writing - original draft, Methodology, Formal analysis, Data curation, Conceptualization. Ben Rattray: Writing - review & editing, Supervision, Methodology, Conceptualization. Constantino Toufexis: Writing - review & editing, Writing - original draft. Andrew Flood: Writing - review & editing, Validation, Supervision, Project administration, Conceptualization.

Data availability

The datasets generated and analysed during the current study are available in the Digital Commons Data repository: https://doi.org/10.17632/g94823v5vw.1.

Ethical approval statement

All participants signed an informed consent document before starting the study. All experimental procedures were approved by the University of Canberra's Human Research Ethics Committee (Project ID: 11882) and conformed to the principles outlined in the Declaration of Helsinki.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Koltyn KF, Umeda M. Contralateral attenuation of pain after short-duration submaximal isometric exercise. J Pain. 2007; 8(11):887-892. https://doi.org/10.1016/j.jpain.2007.06.003.

[2] Gomolka S, Vaegter HB, Nijs J, et al. Assessing endogenous pain inhibition: test-retest reliability of exercise-induced hypoalgesia in local and remote body parts after aerobic cycling. Pain Med. 2019; 20(11):2272-2282. https://doi.org/10.1093/pm/pnz131.

[3] Koltyn KF, Brellenthin AG, Cook DB, Sehgal N, Hillard C. Mechanisms of exercise-induced hypoalgesia. J Pain. 2014; 15(12):1294-1304. https://doi.org/10.1016/j.jpain.2014.09.006.

[4] Cuesta-Vargas AI, Gonzalez-Sanchez M, Casuso-Holgado MJ. Effect on health-related quality of life of a multimodal physiotherapy program in patients with chronic musculoskeletal disorders. Health Qual Life Outcome. 2013; 11(1):19. https://doi.org/10.1186/1477-7525-11-19.

[5] Jansen MJ, Viechtbauer W, Lenssen AF, Hendriks EJM, de Bie RA. Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review. J Physiother. 2011; 57(1):11-20. https://doi.org/10.1016/S1836-9553(11)70002-9.

[6] Kosek E, Ekholm J, Hansson P. Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls. Pain. 1996; 64(3):415-423. https://doi.org/10.1016/0304-3959(95)00112-3.

[7] Stolzman S, Danduran M, Hunter SK, Bement MH. Pain response after maximal aerobic exercise in adolescents across weight status. Med Sci Sports Exerc. 2015; 47(11):2431-2440. https://doi.org/10.1249/mss.0000000000000678.

[8] Vaegter HB, Dørge DB, Schmidt KS, Jensen AH, Graven-Nielsen T.Test-retest reliabilty of exercise-induced hypoalgesia after aerobic exercise. Pain Med. 2018; 19(11):2212-2222. https://doi.org/10.1093/pm/pny009.

[9] Vaegter HB, Lyng KD, Yttereng FW, Christensen MH, Sørensen MB, Graven-Nielsen T. Exercise-induced hypoalgesia after isometric wall squat exercise: a test-retest reliabilty study. Pain Med. 2019; 20(1):129-137. https://doi.org/10.1093/pm/pny087.

[10] Rice D, Nijs J, Kosek E, et al. Exercise-induced hypoalgesia in pain-free and chronic pain populations: state of the art and future directions. J Pain. 2019; 20(11): 1249-1266. https://doi.org/10.1016/j.jpain.2019.03.005.

[11] Crombie KM, Brellenthin AG, Hillard CJ, Koltyn KF. Endocannabinoid and opioid system interactions in exercise-induced hypoalgesia. Pain Med. 2018; 19(1):118-123. https://doi.org/10.1093/pm/pnx058.

[12] Terman GW, Morgan MJ, Liebeskind JC. Opioid and non-opioid stress analgesia from cold water swim: importance of stress severity. Brain Res. 1986; 372(1):167-171. https://doi.org/10.1016/0006-8993(86)91472-1.

[13] Ye Y, Yan X, Wang L, Xu J, Li T. Transcranial direct current stimulation attenuates chronic pain in knee osteoarthritis by modulating bdnf/trkb signaling in the descending pain modulation system. Neurosci Lett. 2023; 810:137320. https://doi.org/10.1016/j.neulet.2023.137320.

[14] Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000; 527(3):633-639. https://doi.org/10.1111/j.1469-7793.2000.t01-1-00633.x.

[15] Garcia-Larrea L, Peyron R. Motor cortex stimulation for neuropathic pain: from phenomenology to mechanisms. Neuroimage. 2007; 37:S71-S79. https://doi.org/10.1016/j.neuroimage.2007.05.062.

[16] Hughes SW, Ward G, Strutton PH. Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin-induced dynamic mechanical allodynia and mechanical pain sensitivity in humans. Eur J Pain. 2020; 24(6): 1130-1137. https://doi.org/10.1002/ejp.1557.

[17] Soler MD, Kumru H, Pelayo R, et al. Effectiveness of transcranial direct current stimulation and visual illusion on neuropathic pain in spinal cord injury. Brain. 2010; 133(9):2565-2577. https://doi.org/10.1093/brain/awq184.

[18] Mendonca ME, Simis M, Grecco LC, Battistella LR, Baptista AF, Fregni F. Transcranial direct current stimulation combined with aerobic exercise to optimize analgesic responses in fibromyalgia: a randomized placebo-controlled clinical trial. Front Hum Neurosci. 2016; 10:68. https://doi.org/10.3389/fnhum.2016.00068.

[19] Pinto CB, Teixeira Costa B, Duarte D, Fregni F. Transcranial direct current stimulation as a therapeutic tool for chronic pain. J ECT. 2018; 34(3):e36-e50. https://doi.org/10.1097/yct.0000000000000518.

[20] Flood A, Waddington G, Cathcart S. High-definition transcranial direct current stimulation enhances conditioned pain modulation in healthy volunteers: a randomized trial. J Pain. 2016; 17(5):600-605. https://doi.org/10.1016/j.jpain.2016.01.472.

[21] Borovskis J, Cavaleri R, Blackstock F, Summers SJ. Transcranial direct current stimulation accelerates the onset of exercise-induced hypoalgesia: a randomized controlled study. J Pain. 2021; 22(3):263-274. https://doi.org/10.1016/j.jpain.2020.08.004.

[22] Yezierski RP. The effects of age on pain sensitivity: preclinical studies. Pain Med. 2012; 13(2):27-36. https://doi.org/10.1111/j.1526-4637.2011.01311.x.

[23] Norton K. New australian standard for adult pre-exercise screening. Sport Health. 2012; 30(2):14-16.

[24] Flood A, Waddington G, Thompson K, Cathcart S. Increased conditioned pain modulation in athletes. J Sports Sci. 2017; 35(11):1066-1072. https://doi.org/10.1080/02640414.2016.1210196.

[25] Bailey DM, Evans KA, McEneny J, et al. Exercise-induced oxidative-nitrosative stress is associated with impaired dynamic cerebral autoregulation and blood-brain barrier leakage. Exp Physiol. 2011; 96(11):1196-1207. https://doi.org/10.1113/expphysiol.2011.060178.

[26] Taylor R, Galvez V, Loo C. Transcranial magnetic stimulation (tms) safety: a practical guide for psychiatrists. Australas Psychiatr. 2018; 26(2):189-192. https://doi.org/10.1177/1039856217748249.

[27] Villamar MF, Volz MS, Bikson M, Datta A, DaSilva AF, Fregni F. Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (hd-tdcs). JoVE. 2013; 77:e50309. https://doi.org/10.3791/50309.

[28] Faul F, Erdfelder E, Buchner A, Lang A-G. Statistical power analyses using g* power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009; 41(4): 1149-1160. https://doi.org/10.3758/BRM.41.4.1149.

[29] Faul F, Erdfelder E, Lang A, Buchner A. A flexible statistical power analysis program for the social, behavioral and biomedical sciences. Behav Res Methods. 2007; 39: 175-191. https://doi.org/10.3758/BF03193146.

[30] Katsavelis D, Threlkeld J. Quantifying thigh muscle co-activation during isometric knee extension contractions: within- and between-session reliability. J Electromyogr Kinesiol. 2014; 24(4):502-507. https://doi.org/10.1016/j.jelekin.2014.04.004.

[31] Giboin L-S, Gruber M. Anodal and cathodal transcranial direct current stimulation can decrease force output of knee extensors during an intermittent mvc fatiguing task in young healthy male participants. J Neurosci Res. 2018; 96(9):1600-1609. https://doi.org/10.1002/jnr.24254.

[32] Veale JF. Edinburgh handedness inventory - short form: a revised version based on confirmatory factor analysis. Laterality. 2014; 19(2):164-177. https://doi.org/10.1080/1357650X.2013.783045.

[33] Aspinall SL, Jacques A, Leboeuf-Yde C, Etherington SJ, Walker BF. Pressure pain threshold and temporal summation in adults with episodic and persistent low back pain trajectories: a secondary analysis at baseline and after lumbar manipulation or sham. Chiropr Man Ther. 2020; 28(1):36. https://doi.org/10.1186/s12998-020-00326-5.

[34] Hermens HJ, Freriks B, Disselhorst-Klug C, Rau G. Development of recommendations for semg sensors and sensor placement procedures. J Electromyogr Kinesiol. 2000; 10(5):361-374. https://doi.org/10.1016/S1050-6411(00)00027-4.

[35] Rossini PM, Burke D, Chen R, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an i.F.C.N. Committee. Clin Neurophysiol. 2015; 126(6):1071-1107. https://doi.org/10.1016/j.clinph.2015.02.001.

[36] Antal A, Terney D, Kühnl S, Paulus W. Anodal transcranial direct current stimulation of the motor cortex ameliorates chronic pain and reduces short intracortical inhibition. J Pain Symptom Manag. 2010; 39(5):890-903. https://doi.org/10.1016/j.jpainsymman.2009.09.023.

[37] Mordillo-Mateos L, Dileone M, Soto-Leon V, et al. Effects of transcranial direct current stimulation on temperature and pain perception. Sci Rep. 2017; 7(1):2946. https://doi.org/10.1038/s41598-017-03173-2.

[38] Li X, Yao J, Zhang W, Chen S, Peng W. Effects of transcranial direct current stimulation on experimental pain perception: a systematic review and meta-analysis. Clin Neurophysiol. 2021; 132(9):2163-2175. https://doi.org/10.1016/j.clinph.2021.05.020.

[39] Pacheco-Barrios K, Cardenas-Rojas A, Thibaut A, et al. Methods and strategies of tdcs for the treatment of pain: current status and future directions. Expet Rev Med Dev. 2020; 17(9):879-898. https://doi.org/10.1080/17434440.2020.1816168.

[40] Angius L, Hopker JG, Marcora SM, Mauger AR. The effect of transcranial direct current stimulation of the motor cortex on exercise-induced pain. Eur J Appl Physiol. 2015; 115(11):2311-2319. https://doi.org/10.1007/s00421-015-3212-y.

[41] Kuo H, Bikson M, Datta A, et al. Comparing cortical plasticity induced by conventional and high-definition 4 x 1 ring tdcs: a neurophysiological study. Brain Stimul. 2013; 6(4):644-648. https://doi.org/10.1016/j.brs.2012.09.010.

[42] Buchanan DM, Amare S, Gaumond G, D'Angiulli A, Robaey P. Safety and tolerability of tdcs across different ages, sexes, diagnoses, and amperages: a randomized double-blind controlled study. J Clin Med. 2023; 12(13):4346. https://doi.org/10.3390/jcm12134346.

[43] El Jamal C, Harrie A, Rahman-Filipiak A, et al. Tolerability and blinding of high-definition transcranial direct current stimulation among older adults at intensities of up to 4 ma per electrode. Brain Stimul. 2023; 16(5):1328-1335. https://doi.org/10.1016/j.brs.2023.08.025.

[44] Saturnino GB, Puonti O, Nielsen JD, Antonenko D, Madsen KH, Thielscher A.Simnibs 2.1:A Comprehensive Pipeline for Individualized Electric Field Modelling for Transcranial Brain Stimulation. Cham (CH): Springer; 2019.

[45] Alghamdi KS, Al-Sheikh MH. Effect of stress on pain perception in young women. Saudi Med J. 2009; 30(4):478-484.

[46] Black CD, Huber JK, Ellingson LD, et al. Exercise-induced hypoalgesia is not influenced by physical activity type and amount. Med Sci Sports Exerc. 2017; 49(5): 975-982. https://doi.org/10.1249/mss.0000000000001186.

[47] Peterson JA, Schubert DJ, Campbell J, Bemben MG, Black CD. Endogenous pain inhibitory function: endurance-trained athletes vs active controls. Pain Med. 2019; 20(9):1822-1830. https://doi.org/10.1093/pm/pnz014.

[48] Team RC.R: A Language and Environment for Statistical Computing. 2013.

[49] Cardenas-Rojas A, Pacheco-Barrios K, Giannoni-Luza S, Rivera-Torrejon O, Fregni F. Noninvasive brain stimulation combined with exercise in chronic pain: a systematic review and meta-analysis. Expert Rev Neurother. 2020; 20(4):401-412. https://doi.org/10.1080/14737175.2020.1738927.

[50] Alsouhibani A, Vaegter HB, Hoeger Bement M. Systemic exercise-induced hypoalgesia following isometric exercise reduces conditioned pain modulation. Pain Med. 2019; 20(1):180-190. https://doi.org/10.1093/pm/pny057.

[51] Giannoni-Luza S, Pacheco-Barrios K, Cardenas-Rojas A, et al. Noninvasive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis. Pain. 2020; 161(9):1955-1975. https://doi.org/10.1097/j.pain.0000000000001893.

[52] Cooper K, Carmody J. The characteristics of the opioid-related analgesia induced by the stress of swimming in the mouse. Neurosci Lett. 1982; 31(2):165-170. https://doi.org/10.1016/0304-3940(82)90110-0.