“Characterization of spatiotemporal dynamics of binary and graded tonic pain in humans using intracranial recordings”

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks’ relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded “yes” or “no” to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus. Significance Statement We investigated the neural encoding of pain psychophysics across 16 brain regions during a continuous thermal stimulus in humans. Mixed-effects models were used to analyze trends across 20 human subjects. Using intracranial electrodes, we show a parametric relationship between behavioral responses and HFA during ongoing pain. We found that HFA in cognitive and emotional pain processing regions was closely associated with pain evaluation at the stimulus onset, end, or both. The neural encoding of subjective pain intensity, measured by a visual analog scale, differed from that of binary pain intensity. Perception and psychophysical correlates to pain depend on how patients are asked to evaluate it. Our findings provide evidence that HFA can serve as a neural marker within specific brain regions of behavioral pain responses, as measured by sEEG. ### Competing Interest Statement JDR has received consulting fees from Medtronic, NeuroPace, and Corlieve Therapeutics.