# Neuroimaging-Guided Insights into the Molecular and Network Mechanisms of Chronic Pain and Neuromodulation

## TL;DR

This review explores how neuroimaging helps understand chronic pain's molecular and brain network changes and how neuromodulation can target these for treatment.

## Contribution

The paper integrates neuroimaging and neuromodulation to link molecular and network mechanisms of chronic pain for precision treatment strategies.

## Key findings

- PET and MR spectroscopy show dysregulated glutamate/GABA and neuroimmune activation in chronic pain regions.
- Multimodal imaging reveals altered brain network activity and structural changes in chronic pain patients.
- Neuromodulation techniques can target maladaptive circuits and test chronic pain mechanisms in vivo.

## Abstract

Chronic pain is a pervasive and debilitating condition that affects millions of individuals worldwide. Unlike acute pain, which serves a protective physiological role, chronic pain persists beyond routine tissue healing and often arises without a discernible peripheral cause. Accumulating evidence indicates that chronic pain is not merely a symptom but a disorder of the central nervous system, underpinned by interacting molecular, neurochemical, and network-level alterations. Molecular neuroimaging using PET and MR spectroscopy has revealed dysregulated excitatory–inhibitory balance (glutamate/GABA), altered monoaminergic and opioidergic signaling, and neuroimmune activation (e.g., TSPO-indexed glial activation) in key pain-related regions such as the insula, anterior cingulate cortex, thalamus, and prefrontal cortex. Converging multimodal imaging—including functional MRI, diffusion MRI, and EEG/MEG—demonstrates aberrant activity and connectivity across the default mode, salience, and sensorimotor networks, alongside structural remodeling in cortical and subcortical circuits. Parallel advances in neuromodulation, including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), deep brain stimulation (DBS), and emerging biomarker-guided closed-loop approaches, provide tools to perturb these maladaptive circuits and to test mechanistic hypotheses in vivo. This review integrates neuroimaging findings with molecular and systems-level mechanistic insights into chronic pain and its modulation, highlighting how imaging markers can link biochemical signatures to neural dynamics and guide precision pain management and individualized therapeutic strategies.