5: Brain-Wide Activity Patterns Underlying Individual Differences in Chronic Pain Expression

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Assessment and Measurement of Pain/Nociception, Neuroanatomical circuit analysis, Behavioral studies

Background and Aims: Chronic pain emerges in only a subset of individuals following comparable injury, yet the neural basis of this divergence remains unclear. Most preclinical studies emphasize group means and reflexive sensory assays, overlooking multidimensional behavioural outcomes and inter-individual variability. We hypothesized that chronic pain vulnerability represents a multidimensional phenotype encompassing sensory hypersensitivity, naturalistic behavioural disruption, and social dysfunction, supported by distributed supraspinal circuits. Using a neuropathic pain model, we combined whole-brain activity mapping with high-resolution behavioural phenotyping to identify brain-wide predictors of pain susceptibility and to determine how sensory and affective-social dimensions of chronic pain are correlated.

Methods: Outbred CD1 mice (n = 52F, 10M) underwent unilateral chronic constriction injury (CCI) of the sciatic nerve. Sensory sensitivity was quantified twice daily for five days using a 0°C cold plate assay. Naturalistic behaviour was analysed using DeepLabCut-based pose estimation and unsupervised clustering with Keypoint-MoSeq, identifying behavioural motifs. Social interactions were assessed in 10-minute dyads with a younger, same-sex conspecific, with ultrasonic vocalisations quantified. Whole-brain c-Fos expression was mapped in a subset (n = 20) across 1,277 regions using ABBA, QuPath, and BraiAn. Linear regressions related behavioural variability to supraspinal and spinal neural activity.

Results: Cold plate testing revealed marked inter-individual variability, with females exhibiting significantly longer and more variable injured hind paw withdrawals than males (p < 0.01). Withdrawal behaviour correlated strongly with activity in canonical pain-related regions including periaqueductal gray (R² = 0.42), basomedial amygdala (R² = 0.49), orbital cortex (R² = 0.55), and anterior cingulate cortex (R² = 0.35), as well as nucleus of Darkschewitsch (R² = 0.49) and supramammillary nucleus (R² = 0.34). Eight of 37 behavioural motifs were significantly altered following CCI. Social engagement decreased post-injury, yet social disruption showed weak association with cold hypersensitivity. Spinal c-Fos activity did not significantly predict sensory variability.

Conclusions: These findings support a model in which chronic pain vulnerability reflects a multidimensional phenotype rather than a unitary sensory state. Individual differences in pain expression were predicted by distributed supraspinal activity patterns, while affective-social disruption was only partially coupled to sensory hypersensitivity. The absence of strong spinal predictors underscores the dominant contribution of brain-wide circuits in shaping long-term pain outcomes. By integrating sensory, ethological, and social dimensions, this work advances a translational framework for stratifying pain susceptibility and identifying mechanistically defined targets for intervention.

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Presenting Author: Damien Boorman
Submitting Author: Damien Boorman

Senior Author: Loren Martin

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Farhada Khaled: NA - University of Toronto
• Andrew Boyce: NA - University of Toronto
• Gurleen Hans: NA - University of Toronto
• Loren Martin: PhD - University of Toronto