Altered Functional Connectivity within the Pain Connectome in Type 2 Diabetic Patients with Painful Peripheral Neuropathy: Evidence from Pain Matrix Hubs

Brain Res Bull. 2026 Mar 19:111833. doi: 10.1016/j.brainresbull.2026.111833. Online ahead of print.

ABSTRACT

OBJECTIVE: We investigated the pain connectome in patients with diabetic peripheral neuropathy (DPN), particularly those with neuropathic pain, by characterizing functional interactions within the traditional pain matrix and across large-scale brain networks.

METHODS: Sixty-two patients with type 2 diabetes mellitus (25 without DPN, 20 with painless DPN, and 17 with painful DPN) and 33 healthy controls were enrolled in this study. All participants underwent resting-state functional MRI, and region of interest (ROI)-to-ROI functional connectivity (FC) analysis was performed within predefined core regions of the pain matrix, supplemented by group independent component analysis to evaluate interactions between pain related networks. Partial correlation analyses were conducted to assess associations between connectivity strength and pain-related measures, peripheral nerve function, and neuropsychological outcomes.

RESULTS: Compared with HCs, patients with painful DPN showed presented decreased FC between the amygdala and the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), thalamus, and periaqueductal gray (PAG), as well as between the thalamus and PAG. Higher peak pain scores and lower Douleur Neuropathique 4 questionnaire (DN4) questionnaire scores were associated with lower FC in these pathways (all P < 0.05). Lower FC in these pathways (except FC between the amygdala and the PAG) was also associated with poorer peripheral nerve functions (all P < 0.05). Higher anxiety levels were associated with increased FC between the right amygdala and the right ACC (r = 0.600, P = 0.023).

CONCLUSIONS: Patients with painful DPN exhibit distinct FC alterations, and the amygdala may play a key role in pain perception and emotional regulation in the neuropathic pathophysiology of DPN.

PMID:41864513 | DOI:10.1016/j.brainresbull.2026.111833