699: Neuromodulation of Peak Alpha Frequency and Its Relationship with Conditioned Pain Modulation

Topic: Experimental (Non-clinical) Human Studies
Subtopic: Non -specific to any diagnosis, Electrophysiology/Clinical neurophysiology (e.g. microneurography, EEG, MEG, OPMs, TMS), Neuromodulation (e.g. rTMS, tDCS, FUS, DBS, biofeedback), Quantitative Sensory testing (static and dynamic, e.g., HPT, PPT, CPM, TSP, offset analgesia)

Background and Aims: Persistent pain has been associated with alterations in brain oscillations, particularly peak alpha frequency (PAF), where slower PAF in some individuals is linked to chronic pain and increased pain sensitivity during experimental tonic pain [1, 2, 3]. This may involve individual degrees of brain neuroadaptability to pain (NAP), defined as the brain’s ability to adjust to acute pain exposure [4]. Individual differences in NAP are here exemplified by alterations in the pain regulatory system such as variable pain sensitivity and efficacy of conditioned pain modulation (CPM). Further, preliminary studies show that entrainment of PAF is possible through transcranial alternating current stimulation (tACS) [5]. Whether the entrainment effects of tACS can be increased when combined with sensory entrainment (SE) is unknown. Therefore, this study aims to investigate tACS, SE, and a combination of the two, for increasing PAF, and whether such modulation positively affects the CPM-effect.

Methods: The experiment is a randomized crossover study (N=30) with four sessions comparing tACS, SE, tACS+SE, and sham stimulation for entrainment of PAF. The four sessions are randomly allocated on four different days and participants will be blinded to the order of the sessions. Each session starts with resting state electroencephalography (rs-EEG) to determine PAF and cuff algometry to assess pain sensitivity and CPM-effect, followed by 20 minutes of either tACS, SE, tACS+SE, or sham stimulation, and concluding with rs-EEG, pain sensitivity and CPM assessments. tACS is delivered at C3 and O2 based on the 10-10 system [6] and SE is delivered as binaural beats and blinks [7, 8]. All stimulations are done with 1 Hz above the individual’s PAF based on earlier evidence regarding entrainment for increasing PAF [5]. The sham stimulations will be carried out by 30 seconds of tACS [9] and non-rhythmic SE [9].

Results: Primary outcomes will include within‑subject changes in PAF following tACS, SE, tACS+SE, and sham stimulation. Secondary outcomes will include the association between changes in PAF and changes in pain sensitivity and CPM efficacy. Linear mixed models will be used to compare stimulation conditions for entrainment of PAF, accounting for interindividual variability. Correlation analysis will assess the relationship between changes in PAF and CPM across conditions. It is hypothesized that combining tACS and SE will induce the largest increase in PAF compared with tACS or SE alone, and that larger increases in PAF will be associated with enhanced CPM effect.

Conclusions: This study aims to examine the potential for modulating PAF using tACS and SE in healthy participants and its relationship with pain sensitivity and CPM efficacy. The results may provide insights into the effectiveness of different neuromodulation approaches for entrainment of brain oscillations and subsequent effects on pain regulatory systems. Furthermore, interindividual variability in responsiveness to PAF modulation and its association with CPM efficiency may offer insight into individual brain neuroadaptability to pain.

References: [1] A. J. Furman, M. Prokhorenko, M. L. Keaser, J. Zhang, S. Chen, A. Mazaheri and S. D. A, "Sensorimotor Peak Alpha Frequency Is a Reliable Biomarker of Prolonged Pain Sensitivity," Cerebral Cortex, vol. 30, no. 12, pp. 6069-6082, 2020.
[2] A. J. Furman, T. Thapa, S. J. Summers, R. Cavaleri, J. S. Fogarty, G. Z. Steiner, S. M. Schabrun and D. A. Seminowicz, "Cerebral peak alpha frequency reflects average pain severity in a human model of sustained, musculoskeletal pain," Jornal of Neurophysiology, vol. 122, no. 4, pp. 1784-1793, Oct 2019.
[3] S. K. Millard, A. K. Chiang, N. Chowdhury, W.-J. Chang, A. J. Furman, E. De Martino, T. Graven-Nielsen and S. M. S. D. A. Schabrun, "Peak Alpha Frequency Is Not Significantly Altered by Five Days of Experimental Pain and Repetitive Transcranial Stimulation of the Left Dorsolateral Prefrontal Cortex," European Journal of Neuroscience, vol. 62, no. 4, 2025.
[4] T. Graven-Nielsen, "Mechanisms and manifestations in musculoskeletal pain: from experimental to clinical pain settings," PAIN, vol. 163, no. 1, pp. 29-45, 2022.
[5] A. Pahor and N. Jausovec, "Making Brains run Faster: are they Becoming Smarter?," The Spanish Journal of Psychology , vol. 19, p. E88, 2016.
[6] B. P. De Koninck, D. Brazeau, S. Guay, A. H. Babiloni and L. De Beaumont, "Transcranial Alternating Current Stimulation to Modulate Alpha Activity: A Systematic Review," Neuromodulation: Technology at the Neural Interface, vol. 26, no. 8, pp. 1549-1584, 2023.
[7] K. Ecsy, A. Jones and C. Brown, "Alpha-range visual and auditory stimulation reduces the perception of pain," European Journal of Pain, vol. 21, no. 3, pp. 562-572, 2016.
[8] L. Ronconi and D. Melcher, "The Role of Oscillatory Phase in Determining the Temporal Organization of Perception: Evidence from Sensory Entrainment," The Journal of Neuroscience, vol. 37, no. 44, pp. 10636-10644, 2017.
[9] L. Xing, S. Halpin and A. J. Casson, "A smartphone-based platform for portable, non-invasive, audio and visual neurostimulation with a non-rhythmic sham stimulation mode," IEEE, 2023.

Presenting Author: Katrine Aagaard Gregersen
Submitting Author: Katrine Aagaard Gregersen

Senior Author: Thomas Graven-Nielsen

IASP 2026 Global Year theme of Neuropathic Pain: No

• Katrine Aagaard Gregersen: MSc - Center For Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University
• Dennis Boye Larsen: PhD - Center For Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University
• Thomas Graven-Nielsen: DMSc. PhD. - Center For Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University