Background & Aims
The intensity of pain following activation of the nociceptive pathway can be modulated centrally [1]. The key role in this process has been attributed to the dorsolateral prefrontal cortex (DLPFC), a region implicated e.g., in placebo analgesia [2, 3]. Therefore, the functional state of the DLPFC likely determines the character of the brain’s response to a painful stimulus. The level of activation and functional integration of a cortical network is governed by its ratio of neuronal excitation (E) and inhibition (I) [4]. It has been proposed that the E/I in the human brain can be estimated from the power spectrum density (PSD) of an electroencephalogram (EEG) [5], and more specifically, from the slope of its aperiodic component [6, 7]. This study aimed to investigate, whether the E/I within the DLPFC (approximated by the aperiodic exponent ?) can predict the magnitude of cortical activity evoked by a painful stimulus (laser-evoked potentials; LEP) and/or the intensity of elicited pain.
Methods
25 healthy volunteers (18–55 y.o.) participated in the study. Resting-state brain activity (3 mins) and 2 blocks of laser-evoked potentials (left/right hand, 30 trials/block) were recorded with a 63-channel EEG system with active electrodes. Pain intensity ratings were taken after each stimulus using a visual analog scale. LEP amplitudes were extracted from the global field power of single-trial responses. To assess the relationship between the overall DLPFC E/I and the response to painful stimuli, the power law exponent ? (= aperiodic component slope) was estimated from resting-state EEG. The signal was projected to the source space and ? was calculated from the PSD of the signal attributed to generators within the DLPFC. The sign from generators in the visual cortex was used as control. To explore the influence of the immediate DLPFC E/I, ? was also estimated at single-trial level using 2s epochs preceding each laser stimulus. Linear mixed models were used for statistical evaluation.
Results
Results of a preliminary analysis performed in the original sensor space data suggest that there is indeed a relationship between the E/I within prefrontal cortices and the magnitude of laser-evoked cortical activity. More negative ? (corresponding to steeper slopes of the aperiodic PSD component) represent smaller E/I and thus more prominent local inhibitory neurotransmission. Therefore, we expect smaller E/I in the DLPFC to be associated with larger LEPs and more intense pain.
Conclusions
The presented study combines EEG source localization, analysis of EEG frequency spectra, and experimental painful laser stimulation to investigate the role of the DLPFC in the modulation of pain. It links the E/I within this brain area to the cortical response evoked by laser stimuli and to the intensity of the associated pain. This way, it potentially provides the explanation for the analgesic effect of non-invasive DLPFC stimulation [8] and the grounds for further development of neuro-modulatory approaches targeting this area.
References
1.Tan, L.L. and R. Kuner, Neocortical circuits in pain and pain relief. Nature Reviews Neuroscience, 2021. 22(8): p. 458-471.
2.Tracey, I. and P.W. Mantyh, The cerebral signature for pain perception and its modulation. Neuron, 2007. 55(3): p. 377-391.
3.Benedetti, F., No prefrontal control, no placebo response. Pain, 2010. 148(3): p. 357-358.
4.Dehghani, N., et al., Dynamic balance of excitation and inhibition in human and monkey neocortex. Scientific reports, 2016. 6(1): p. 23176.
5.Ahmad, J., et al., From mechanisms to markers: novel noninvasive EEG proxy markers of the neural excitation and inhibition system in humans. Translational Psychiatry, 2022. 12(1): p. 467.
6.Gao, R., E.J. Peterson, and B. Voytek, Inferring synaptic excitation/inhibition balance from field potentials. Neuroimage, 2017. 158: p. 70-78.
7.Ostlund, B., et al., Spectral parameterization for studying neurodevelopment: How and why. Developmental Cognitive Neuroscience, 2022. 54: p. 101073.
8.Che, X., et al., High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: a systematic review and meta-analysis. Brain Stimulation, 2021. 14(5): p. 1135-1146.