Human brain imaging has revealed that acute pain results from activation of a network of brain regions, including the somatosensory,insula, prefrontal, and cingulate cortices. In contrast, many investigations report little or no alteration in brain activity associated withchronic pain, particularly neuropathic pain. It has been hypothesized that neuropathic pain results from misinterpretation of thalamocorticalactivity, and recent evidence has revealed altered thalamocortical rhythm in individuals with neuropathic pain. Indeed, it wassuggested nearly four decades ago that neuropathic painmaybe maintained by a discrete central generator, possibly within the thalamus.In this investigation, we used multiple brain imaging techniques to explore central changes in subjects with neuropathic pain of thetrigeminal nerve resulting in most cases (20 of 23) from a surgical event. Individuals with chronic neuropathic pain displayed significantsomatosensory thalamus volume loss (voxel-based morphometry) which was associated with decreased thalamic reticular nucleus andprimary somatosensory cortex activity (quantitative arterial spin labeling). Furthermore, thalamic inhibitory neurotransmitter contentwas significantly reduced (magnetic resonance spectroscopy), which was significantly correlated to the degree of functional connectivitybetween the somatosensory thalamus and cortical regions including the primary and secondary somatosensory cortices, anterior insula,and cerebellar cortex. These data suggest that chronic neuropathic pain is associated with altered thalamic anatomy and activity, whichmay result in disturbed thalamocortical circuits. This disturbed thalamocortical activity may result in the constant perception of pain.