Motor cortex stimulation for neuropathic pain: From phenomenology to mechanisms
Abstract
Motor cortex stimulation (MCS) is relatively recent neurosurgical technique for pain control, the use of which is growing steadily since its description in the last decade. While clinical series show that at least 50% of patients with chronic, pharmacoresistant neuropathic pain may benefit from this technique, the mechanisms of action of MCS remain elusive. In this review, we synthesise a number of studies that, combining electrophysiology and functional imaging, have permitted to proceed from phenomenology to models that may account for part of such mechanisms. MCS appears to trigger rapid and phasic activation in the lateral thalamus, which leads to a cascade of events of longer time-course in medial thalamus, anterior cingulate/orbitofrontal cortices and periaqueductal grey matter. Activity in these latter structures is delayed relative to actual cortical neurostimulation and becomes maximal during the hours that follow MCS arrest. Current hypotheses suggest that MCS may act through at least two mechanisms: activation of perigenual cingulate and orbitofrontal areas may modulate the emotional appraisal of pain, rather than its intensity, while top down activation of brainstem PAG may lead to descending inhibition toward the spinal cord. Recent evidence also points to a possible secretion of endogenous opioids triggered by chronic MCS. This, along with the delayed and long-lasting activation of several brain structures, is consistent with the clinical effects of MCS, which m…
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Several viral infections, including HIV, HCV, and HSV, increase activation of the kynurenine pathway, which is implicated in the neurological and cognitive impairments of patients with HIV, HCV, and HSV.
“Several viral infections, including HIV [19], HCV [20], and HSV [21] increase activation of the KP, which interestingly is implicated in the neurological and cognitive impairments of patients with HIV, HCV, and HSV [21,22].”
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“It should be noted that in clinical studies, pain alleviation by M1 stimulation may be based not only on spinal but also on supraspinal actions that influence higher processing of nociceptive signals such as emotional appraisal of pain ( Garcia-Larrea and Peyron 2007; Ohara et al. 2005).”
BackgroundEffects of Exercise-induced Hypoalgesia and Its Neural Mechanisms
Wu, B., Zhou, L.-L., Chen, C.-C., Wang, J., Hu, L., & Wang, X.-Q. (2021) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002781 · Cited by 39 · see citing works
de Assis, E. B., Martins, W. K. N., de Carvalho, C. D., Ferreira, C. M., Gomes, R., Rodrigues, E. T. D. A., Meira, U., de Holanda, L. J., Lindquist, A. R. R., Morya, E., et al. (2021) · Scientific Reports · doi:10.1038/s41598-022-05254-3 · Cited by 39 · see citing works
Lopes, P. S. S., Campos, A. C. P., Fonoff, E. T., de Britto, L. R. G., & Pagano, R. L. (2019) · Behavioral and Brain Functions · doi:10.1186/s12993-019-0156-0 · Cited by 44 · see citing works
Validation of Computational Studies for Electrical Brain Stimulation With Phantom Head Experiments.
Kim, D., Jeong, J., Jeong, S., Kim, S., Jun, S., & Chung, E. (2015) · Brain Stimulation · doi:10.1016/j.brs.2015.06.009 · Cited by 39 · see citing works
“However, despite these animal [11–13] and human studies [14,15], a thorough understanding of the fundamental mechanisms of EBS is still lacking; thus, the stimulation parameters for the best medical practices (electrode position, amplitude, waveform, and duration) remain unclear.”
Deep Brain Stimulation and Motor Cortical Stimulation for Neuropathic Pain
Stadler, J. A. I., Ellens, D. J., & Rosenow, J. (2011) · Current pain and headache reports · doi:10.1007/s11916-010-0161-3 · Cited by 39
“PET and electrophysiological studies demonstrate regional activity differences during stimulation [ 28 ].”
BackgroundInfluentialEffects of transcranial theta-burst stimulation on acute pain perception
Antal, A., & Paulus, W. (2010) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-2010-0555 · Cited by 39 · see citing works
“…of M1 appears to trigger activation in the lateral thalamus, which leads to a flow of events in the medial thalamus, anterior cingulate and orbitofrontal cortices and periaqueductal grey matter (for a review with regard the possible mechanisms of M1 stimulation see Garcia-Larrea and Peyron, 2007).”
Mutual interaction between motor cortex activation and pain in fibromyalgia: EEG-fNIRS study
Gentile, E., Brunetti, A., Ricci, K., Delussi, M. D., Bevilacqua, V., & de Tommaso, M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0228158 · Cited by 39 · see citing works
Mo, J.-J., Hu, W.-H., Zhang, C., Wang, X., Liu, C., Zhao, B.-T., Zhou, J., & Zhang, K. (2019) · BMC Neurology · doi:10.1186/s12883-019-1273-y · Cited by 36
Bolognini, N., Spandri, V., Olgiati, E., Fregni, F., Ferraro, F., & Maravita, A. (2013) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2013.06.014 · Cited by 36 · see citing works
Motor corticospinal excitability: a novel facet of pain modulation?
Granovsky, Y., Sprecher, E., & Sinai, A. (2019) · PAIN Reports · doi:10.1097/pr9.0000000000000725 · Cited by 33 · see citing works
“synaptic events influencing activity in the medial thalamus and in the brain structures involved in descending pain inhibition such as perigenual anterior cingulate cortex, orbitofrontal cortex, and periaqueductal gray.(21,22,46) In addition to the established in-”
BackgroundO'Brien, A. T., Amorim, R., Rushmore, R., Eden, U., Afifi, L., Pietro, L. D., Wagner, T., & Valero-Cabré, A. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00545 · Cited by 33
Epoxy fatty acids mediate analgesia in murine diabetic neuropathy
Wagner, K. M., Lee, K. S. S., Yang, J., & Hammock, B. D. (2016) · European Journal of Pain · doi:10.1002/ejp.939 · Cited by 37 · see citing works
“GABA interneurons in the PAG or raphe magnus modulate the enkephalin sensitive neurons in these areas which may be subject to opioid receptor antagonism (Garcia-Larrea and Peyron, 2007).”
BackgroundSpatial and Temporal Brain Responses to Noxious Heat Thermal Stimuli in Burning Mouth Syndrome
Shinozaki, T., Imamura, Y., Kohashi, R., Dezawa, K., Nakaya, Y., Sato, Y., Watanabe, K., Morimoto, Y., Shizukuishi, T., Abe, O., et al. (2016) · Journal of dentistry research · doi:10.1177/0022034516653580 · Cited by 33 · see citing works
“ACC and PCC are reported to be the key structures in pain processing and modulation (Garcia-Larrea and Peyron 2007; Staud et al. 2007; Bogdanov et al. 2014).”
BackgroundHouzé, B., Bradley, C., Magnin, M., & Garcı́a-Larrea, L. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs255 · Cited by 33 · see citing works
“…induces greater metabolic and BOLD changes in the lateral thalamus than in sensorimotor cortex, and this whether the stimulation is epidural (Garcia-Larrea and Peyron 2007) or transcranial (Bestmann et al. 2004), lending support to the hypothesis of significant cortico-thalamo-cortical…”
BackgroundResultInfluentialSelf-citationPeyron, R. (2016) · Pain · doi:10.1097/j.pain.0000000000000387 · Cited by 31 · see citing works
Self-citationZheng, Y., Liu, C. W., Chan, D. X. H., Ong, D., Ker, J., Ng, W. H., & Wan, K. R. (2023) · Neuromodulation Technology at the Neural Interface · doi:10.1016/j.neurom.2023.05.003 · Cited by 37 · see citing works
Brietzke, A., Rozisky, J. R., Dussán-Sarria, J., Deitos, A., Laste, G., Hoppe, P., Muller, S., Torres, I., Álvares-da-Silva, M., de Amorim, R. F. D., et al. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00498 · Cited by 29 · see citing works
Bai, Y., Pacheco‐Barrios, K., Pacheco-Barrios, N. V., Liang, G., & Fregni, F. (2024) · Nature Mental Health · doi:10.1038/s44220-024-00235-z · Cited by 31 · see citing works
“There is a wealth of imaging literature underscoring functional activation of PAG in patients with NP during EMCS 22,23,47 , which was corroborated by preclinical data showing enhanced neuronal firing rates and FOS expression in ipsilateral PAG induced by EMCS 29,48,49 .”
InfluentialCortical Regulation of Nociception of the Trigeminal Nucleus Caudalis
Castro, A., Raver, C., Li, Y., Uddin, O., Rubin, D. C., Ji, Y., Masri, R. M., & Keller, A. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3897-16.2017 · Cited by 34 · see citing works
“Although motor cortex stimulation provides relief to some patients, the efficacy of this approach remains relatively low and inconsistent (Canavero and Bonicalzi, 2002; Garcia-Larrea and Peyron, 2007; Lima and Fregni, 2008).”
BackgroundHuman primary somatosensory cortex is differentially involved in vibrotaction and nociception.
Lenoir, C., Huang, G., Vandermeeren, Y., Hatem, S., & Mouraux, A. (2017) · Journal of Neurophysiology · doi:10.1152/jn.00615.2016 · Cited by 28 · see citing works
“This has led some authors to propose that the rTMS or tDCS delivered over the sensorimotor cortex may activate descending inhibitory control mechanisms acting on the spinal transmission of ascending nociceptive inputs (Garcia-Larrea and Peyron 2007).”
Devoize, L., Alvarezl, P., Monconduit, L., & Dallel, R. (2011) · European Journal of Pain · doi:10.1016/j.ejpain.2010.11.017 · Cited by 29 · see citing works
“However, the ventral mPFC may also be more directly involved in the perception of pain, notably through the modulation of diencephalon and/or brainstem structures modulating pain (Lorenz et al., 2003; Garcia-Larrea and Peyron, 2007).”
BackgroundMeeker, T. J., Schmid, A., Keaser, M. L., Khan, S. A., Gullapalli, R. P., Dorsey, S. G., Greenspan, J. D., & Seminowicz, D. A. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.119278 · Cited by 30 · see citing works
“Demonstrating the potential clinical importance of the DPMN, enhanced FC within the DPMN during placebo analgesia and motor cortex stimulation is positively related to magnitude of analgesia experienced (Bingel et al., 2006; Eippert et al., 2009; Garcia-Larrea and Peyron, 2007; Meeker et al., 2019); additionally, ther…”
Zhao, C.-G., Sun, W., Ju, F., Jiang, S., Wang, H., Sun, X.-L., Mou, X., & Yuan, H. (2021) · Pain and Therapy · doi:10.1007/s40122-021-00261-0 · Cited by 27 · see citing works
“First, rTMS may improve the excitability of the cerebral cortex, leading to top-down activation of the brainstem and descending inhibition [38].”
BackgroundJiang, L., Ji, Y., Voulalas, P., Keaser, M., Xu, S., Gullapalli, R., Greenspan, J., & Masri, R. (2013) · Brain Stimulation · doi:10.1016/j.brs.2013.12.013 · Cited by 27
“Previous studies investigating brain activation using PET showed no significant changes in S1 after MCS (17, 28).”
BackgroundPain influences hedonic assessment of visual inputs
Godinho, F. L. F., Frot, M., Perchet, C., Magnin, M., & Garcı́a-Larrea, L. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06196.x · Cited by 26 · see citing works
“Similar conclusions have been recently reached in the context of pain and analgesia, where increased activity in perigenual ACC was associated with the relief of neuropathic pain (Willoch et al., 2003; Garcia-Larrea & Peyron, 2007).”
ResultSelf-citationGarcı́a-Larrea, L., & Magnin, M. (2008) · La Presse Médicale · doi:10.1016/j.lpm.2007.07.025 · Cited by 32 · see citing works
Waris, A., Siraj, M., Khan, A. A., Lin, J., Asim, M., & Alhumaydhi, F. A. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00494 · Cited by 29 · see citing works
Cho, Y., Kim, K., Dutta, A., Park, S. H., Lee, J. Y., Kim, H. W., Park, J., Kim, J., Min, W. K., Won, C., et al. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202310908 · Cited by 26 · see citing works
Li, L.-L., Huang, H.-L., Yu, Y., Jia, Y.-Q., Liu, Z.-Y., Shi, X., Wang, F., & Zhang, T. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.800560 · Cited by 25 · see citing works
Martucci, K. T., & Mackey, S. (2016) · Anesthesiology Clinics · doi:10.1016/j.anclin.2016.01.001 · Cited by 35 · see citing works
“Current techniques use adaptive models(97) and target brain regions that have the potential to activate multiple downstream effects.(98)”
Background
- Authors
- Garcia-Larrea, L., & Peyron, R.
- Affiliations
- Inserm (FR)
- ORCID
- Peyron, Roland
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2007
- Volume
- 37
- Pages
- S71-S79
- ISSN
- 1053-8119 (ISSN-L)
- OpenAlex
- W2029045410
- Cited by
- 259
- References
- 75
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 12 · 2023: 13 · 2022: 15 · 2021: 20 · 2020: 14 · 2019: 18 · 2018: 11 · 2017: 11 · 2016: 17 · 2015: 21 · 2014: 16 · 2013: 13 · 2012: 15
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- motor cortex stimulation, neuropathic pain, chronic pain, mechanism of action, lateral thalamus, medial thalamus, periaqueductal gray, anterior cingulate cortex, orbitofrontal cortex, descending pain inhibition, endogenous opioids, pain management
- MeSH terms
- Animals, Cerebrovascular Circulation, Chronic Disease, Endorphins, Humans, Magnetic Resonance Imaging, Motor Cortex, Pain, Peripheral Nervous System Diseases, Neurosurgical Procedures, Positron-Emission Tomography, Pain Management
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