Patients with different putative chronic pain mechanisms have different cortical complexity and synchrony

Mechanism-based classification of chronic pain includes nociceptive, neuropathic, and nociplastic descriptors, which are believed to relate to three different clinical phenotypes. It remains unknown whether such classification translates into measurable differences in inter-regional cortical connectivity. Here, we hypothesized that cortical oscillatory responses measured at cortical areas implicated in different dimensions of pain processing: cognitive-evaluative (dorsolateral prefrontal cortex), affective-motivational (anterior cingulate cortex), discriminative-evaluative (postero-superior insula), and modulatory/allostatic control (primary motor cortex-M1), would differ in patients with chronic pain classified according to mechanistic descriptors. Transcranial magnetic stimulation (TMS) combined with electroencephalography was used to evoke cortical responses in 90 patients with chronic pain (30: neuropathic, 29: nociceptive, and 31: nociplastic). Participants received single-pulse TMS to each of the 4 cortical targets, and TMS-evoked responses were quantified by global and local mean field power, perturbational complexity index (PCIst), intertrial coherence (ITC), and event-related spectral perturbation. Clinical measures included pain intensity, interference, pain location and spread, mood, fatigue/sleep quality, and quality of life. People with nociplastic pain had more widespread body pain and higher depression levels compared with the other groups (all P < 0.05). Relative to nociplastic pain, neuropathic pain showed lower PCIst at M1 stimulation ( P < 0.05), reduced ITC during dorsolateral prefrontal cortex stimulation ( P < 0.05), and decreased event-related spectral perturbation during anterior cingulate cortex stimulation ( P < 0.05). Across all phenotypes, lower PCIst and ITC correlated with higher pain intensity ( P < 0.05). These findings indicate that mechanism-based clinical classification categorizes patients into significantly different phase-based oscillatory connectivity patterns, despite having similar pain intensities, and that shared reductions in these measures consistently relate to greater symptom burden.