Thalamic remodeling underlying below-level neuropathic pain following spinal cord injury: neuroimmune, neurochemical, and circuit-level mechanisms

Below-level neuropathic pain (BLNP) is a common and refractory complication of spinal cord injury (SCI). Its persistence and significant clinical heterogeneity are difficult to explain solely through mechanisms within the injured spinal cord. The thalamus receives ascending sensory input from the spinal cord and has extensive connections with the somatosensory cortex, insula, and cingulate cortex; sustained thalamic remodeling may serve as a critical mechanism by which abnormal spinal activity drives central pain processing. Existing evidence indicates that partial sensory deafferentation and abnormal neural activity transmitted via spared pathways can alter thalamic afferent input, while signaling involving C-C motif chemokine ligand 21 (CCL21) may influence the local neuroimmune environment of the thalamus. Microglial responses, altered excitatory-inhibitory synaptic regulation, changes in ion-channel expression, and synaptic structural modifications are all associated with hyperexcitability and aberrant firing patterns in thalamic neurons. These local changes may also be accompanied by the reorganization of corticothalamic feedback and alterations in thalamocortical functional connectivity. Human imaging studies suggest that pain phenotypes are associated with thalamic metabolism, related white-matter microstructure, and functional connectivity. This review examines thalamic afferent status, neuroimmune signaling, neurochemical and electrophysiological changes, and the reorganization of related circuits to enhance understanding of supraspinal mechanisms, systematically consolidate existing evidence, and provide a basis for investigating thalamus-related candidate clinical measures and mechanism-based interventions.