Background & Aims

Pain leads to learning and motivated action, including escape and avoidance. When expected and observed sensory information diverge, a prediction error (PE) message is generated in the brain. Pain results in an aversive PE that fosters reinforcement learning of cue-pain associations. In contrast, convergence of expected and observed pain-related sensory information, as observed in chronic pain conditions, results in impaired learning. While human fMRI data support the involvement of periaqueductal grey (PAG) in encoding aversive PE (1), the temporal and spectral properties of aversive PEs are not yet completely understood. Here, we present preliminary data from an ongoing project using Magnetoencephalography (MEG) that aims to localize spatial-spectral-temporal correlates of aversive PEs in complex regional pain syndrome (CRPS) cohort.

Methods

22 CRPS patients (age: 45 ± 12 yrs, 15F) with unilateral lower extremity pain and 27 healthy controls (age: 31 ± 7 yrs, 13F) performed an instrumental pain avoidance task (1) while continuous MEG signals were acquired. The task entailed choosing between 2 options, while learning to avoid the choice with high probability of receiving a pressure pain outcome on the thumb (controls) and affected extremity hallux (CRPS) nailbed. Subjects’ task behavior (choices) were investigated as a function of pain outcome using a temporal difference reinforcement learning model to estimate PEs. Preprocessed MEG signals time-locked to outcome onset were subjected to source estimation and time-frequency (TF) maps computed at each source. Normalized TF power estimates (alpha and beta bands) were entered into a GLM to identify significant source clusters, that satisfy axiomatic conditions (activity for pain > no-pain outcome, higher activity for low expected pain regardless of outcome) to define a PE (2).

Results

In healthy controls, PE correlates were observed in the alpha frequency band localized to the right lateral orbitofrontal cortex (lOFC) (120 – 445ms post-outcome onset), right ventrolateral (300 – 450ms)/ventromedial (225 – 350ms) prefrontal cortex and right ventral diencephalon (vDC) (170 – 295ms), irrespective of the laterality of the thumb receiving the outcome. In CRPS patients, PE correlates were found in the beta band localized to bilateral ventral anterior insular cortex (vaI) (840 – 1015ms), right lOFC (945 – 1015ms) and right vDC (980 – 1015ms), irrespective of the laterality of the hallux receiving the outcome. In both controls and patients, unexpected pain resulted in greater synchronization compared to expected pain, and unexpected absence of pain resulted in greater desynchronization compared to expected absence.

Conclusions

These finding provide preliminary evidence into the altered spatial–temporal–spectral patterns of brain activity associated with pain-related aversive PEs in the chronic pain condition. Our data suggests lOFC could act as a cortical hub for aversive PE, as it receives sensory information through the ventral cortical streams and projects to striatal area (vDC) to guide decision making and reinforcement learning (3). In CRPS patients, however, the involvement of vaI provides evidence for dysregulation of cognitive-affective processes (4) resulting from pain chronification. Further, in CRPS patients the PE signal was temporally delayed and encoded in a higher frequency band providing preliminary neurophysiological evidence of learning deficits. Greater desynchronization during expected pain and unexpected pain absence could indicate mobilization of neural resources associated with coping and learning strategies involving the cortico-striatal circuits through the OFC.

References

1.Roy M, Shohamy D, Daw N, Jepma M, Wimmer GE, Wager TD. Representation of aversive prediction errors in the human periaqueductal gray. Nature neuroscience. 2014;17(11):1607-1612.PMC4213247
2.Rutledge RB, Dean M, Caplin A, Glimcher PW. Testing the reward prediction error hypothesis with an axiomatic model. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010;30(40):13525-13536.PMC2957369
3.Rolls ET, Cheng W, Feng J. The orbitofrontal cortex: reward, emotion and depression. Brain Commun. 2020;2(2):fcaa196.PMC7749795
4.Labrakakis C. The Role of the Insular Cortex in Pain. Int J Mol Sci. 2023;24(6).PMC10056254

Presenting Author

Raghavan Gopalakrishnan

Poster Authors

Raghavan Gopalakrishnan

PhD

Cleveland Clinic

Lead Author

Sylvain Baillet PhD

Montreal Neurological Institute, McGill University, Montreal, Qc., Can., H3A 1G1

Lead Author

Andre Machado MD PhD

Department of Neurosurgery, Cleveland Clinic, Cleveland, OH 44195, USA

Lead Author

Tor Wager

Dartmouth College

Lead Author

Mathieu Roy

Dept. of Psychology, McGill University, Montreal, Qc., Can., H3A 1G1

Lead Author

Topics

  • Pain Imaging