Human brain imaging has revealed that acute pain results from activation of a network of brain regions, including the somatosensory, insular, prefrontal, and cingulate cortices. In contrast, many investigations report little or no alteration in brain activity associated with chronic pain, particularly neuropathic pain. It has been hypothesized that neuropathic pain results from misinterpretation of thalamocortical activity, and recent evidence has revealed altered thalamocortical rhythm in individuals with neuropathic pain. Indeed, it was suggested nearly four decades ago that neuropathic pain may be 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 the trigeminal nerve resulting in most cases (20 of 23) from a surgical event. Individuals with chronic neuropathic pain displayed significant somatosensory thalamus volume loss (voxel-based morphometry) which was associated with decreased thalamic reticular nucleus and primary somatosensory cortex activity (quantitative arterial spin labeling). Furthermore, thalamic inhibitory neurotransmitter content was significantly reduced (magnetic resonance spectroscopy), which was significantly correlated to the degree of functional connectivity between 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, which may result in disturbed thalamocortical circuits. This disturbed thalamocortical activity may result in the constant perception of pain.

The neural mechanisms underlying the development and maintenance of chronic neuropathic pain remain unclear. Evidence from human investigations suggests that neuropathic pain is associated with altered thalamic burst firing and thalamocortical dysrhythmia. Additionally, experimental animal investigations show that neuropathic pain is associated with altered infra-slow (Ͻ0.1 Hz) frequency oscillations within the dorsal horn and somatosensory thalamus. The aim of this investigation was to determine whether, in humans, neuropathic pain was also associated with altered infra-slow oscillations within the ascending "pain" pathway. Using resting-state functional magnetic resonance imaging, we found that individuals with orofacial neuropathic pain have increased infra-slow oscillatory activity throughout the ascending pain pathway, including within the spinal trigeminal nucleus, somatosensory thalamus, thalamic reticular nucleus, and primary somatosensory cortex. Furthermore, these infra-slow oscillations were temporally coupled across these multiple sites and occurred at frequencies similar to calcium waves in activated astrocytes. The region encompassing the spinal trigeminal nucleus also displayed increased regional homogeneity, consistent with a local spread of neural activity by astrocyte activation. In contrast, no increase in oscillatory behavior within the ascending pain pathway occurred during acute noxious stimuli in healthy individuals. These data reveal increased oscillatory activity within the ascending pain pathway that likely underpins increased thalamocortical oscillatory activity, a self-sustaining thalamocortical dysrhythmia, and the constant perception of pain.

Human brain imaging investigations have revealed that acute pain is associated with coactivation of numerous brain regions, including the thalamus, somatosensory, insular, and cingulate cortices. Surprisingly, a similar set of brain structures is not activated in all chronic pain conditions, particularly chronic neuropathic pain, which is associated with almost exclusively decreased thalamic activity. These inconsistencies may reflect technical issues or fundamental differences in the processing of acute compared with chronic pain. The appreciation of any differences is important because better treatment development will depend on understanding the underlying mechanisms of different forms of pain. In this investigation, we used quantitative arterial spin labeling to compare and contrast regional cerebral blood flow (CBF) patterns in individuals with chronic neuropathic orofacial pain (painful trigeminal neuropathy) and chronic nonneuropathic orofacial pain (painful temporomandibular disorder). Neuropathic pain was associated with CBF decreases in a number of regions, including the thalamus and primary somatosensory and cerebellar cortices. In contrast, chronic nonneuropathic pain was associated with significant CBF increases in regions commonly associated with higher-order cognitive and emotional functions, such as the anterior cingulate and dorsolateral prefrontal cortices and the precuneus. Furthermore, in subjects with nonneuropathic pain, blood flow increased in motor-related regions as well as within the spinal trigeminal nucleus.

These data show that during pain, catastrophic thinking has a significant impact on activity in motor and sensory integrative regions. Reducing negative coping strategies may be an effective means in reducing fear avoidance behaviours and the intensity of ongoing pain.

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