703: Neurotransmitter and oscillatory changes in the motor cortex induced by tonic experimental pain

Topic: Experimental (Non-clinical) Human Studies
Subtopic: Non -specific to any diagnosis, Electrophysiology/Clinical neurophysiology (e.g. microneurography, EEG, MEG, OPMs, TMS), Pain models (e.g. saline injection, capsaicin, UVB, HFS, incision, exercise, itch), Imaging (e.g. fMRI, PET, MRS)

Background and Aims: The transition from acute to chronic pain may depend on an individual’s brain response to acute pain [1], herein referred to as brain neuro-adaptability to pain. One region known to exhibit such neuro-adaptability is the primary motor cortex (M1), which undergoes a net inhibitory excitability shift during tonic experimental pain [2,3,4]. However, how M1 neuro-adaptability relates to individual pain sensitivity and risk factors for chronic pain development remains unclear. This study combines measures of cortical excitability and local neurotransmitter levels, specifically glutamatergic and γ-aminobutyric acid (GABA)ergic, assessed via transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) and magnetic resonance spectroscopy (MRS), before and during tonic capsaicin-induced pain. The aim is to characterize M1 neuro-adaptability to pain by means of cortical excitatory and neurotransmitter changes occurring during tonic experimental pain and how they relate to an individual’s pain sensitivity.

Methods: Fifty pain-free participants partake in two experimental sessions within one week (currently acquired: N=35). In the first session, participants complete a questionnaire battery and undergo MRS targeting the left M1 on a 3T GE MR scanner (voxel size: 25mm isotropic). Glutamate + Glutamine (Glx) and GABA levels are quantified using semi-LASER and MEGA-PRESS sequences, respectively. In the second session, participants undergo manual and cuff algometry followed by TMS-EEG over M1. Neuronavigation assured measures from TMS-EEG on M1 were collected on the precise MRS voxel location used in session 1. Both MRS and TMS-EEG are acquired before and during tonic experimental pain induced by a capsaicin patch on the right volar forearm. Pain intensity is rated on a numerical rating scale (NRS; 0-10). Linear mixed models and correlation analyses will be used to examine pain-induced changes in MRS and TMS-EEG measures, their inter-relationship, and their associations with an individual’s pain sensitivity.

Results: For the available dataset, capsaicin induced comparable pain ratings across both sessions, with 3.6 (1.8) and 3.5 (2.3) (values as mean (SD); p=0.6) at the start of the MRS and TMS-EEG acquisition. MRS quality was high and comparable before and during pain for both sequences, as assessed by shim quality through water peak linewidths (semi-LASER: before: 7.5Hz (0.6); during: 7.6Hz (0.6); p=0.2; MEGA-PRESS: before: 6.6Hz (0.7); during: 6.5Hz (0.8); p=0.4) and by creatine signal-to-noise-ratios (SNR) for semi-LASER (before: 93.2 (14.1); during: 95.6 (13.4); p=0.2) and GABA SNR for MEGA-PRESS (before: 9.3 (1.5); during: 9.5 (2.1); p=0.6). For TMS–EEG, of a minimum of 200 acquired epochs, 162.5 (15.1) were retained before pain and 172.0 (17.1) during pain, providing sufficient data for analysis. No other preliminary analyses have been performed due to pending preregistration. Results of the complete dataset will be presented at the congress.

Conclusions: The data acquired to date demonstrate the study's feasibility. Combining cortical excitability and neurotransmitter measures may offer a more comprehensive characterization of M1 neuro-adaptability to pain and its inter-individual variability than either measure alone. This improved understanding has the potential to advance the identification of neural markers predictive of the transition from acute to chronic pain.

References: 1. Fillingim RB. Individual differences in pain: understanding the mosaic that makes pain personal. Pain. 2017.
2. Burns E, Chipchase LS, Schabrun SM. Primary sensory and motor cortex function in response to acute muscle pain: A systematic review and meta-analysis. Eur J Pain. 2016.
3. De Martino E, Casali A, Casarotto S, Hassan G, Rosanova M, Graven-Nielsen T, Ciampi de Andrade D. Acute pain drives different effects on local and global cortical excitability in motor and prefrontal areas: insights into interregional and interpersonal differences in pain processing. Cereb Cortex. 2023.

Presenting Author: Thomas Graven-Nielsen
Submitting Author: Laura Sirucek

Senior Author: Thomas Graven-Nielsen

IASP 2026 Global Year theme of Neuropathic Pain: No

• Laura Sirucek - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Jacob Sørensen - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Carolina Queiroz - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Bruno Andry Nascimento Couto - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Anne Jakobsen - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Matilde Bredal Christensen - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Jakob Blicher - Aalborg University Hospital
• Daniel Ciampi de Andrade - Center for Neuroplasticity and Pain (CNAP), Aalborg University
• Niklaus Zölch - University of Zurich
• Jens Brøndum Frøkjær - Aalborg University Hospital
• Thomas Graven-Nielsen - Center for Neuroplasticity and Pain (CNAP), Aalborg University