Chronic Neuropathic Pain: It's about the Rhythm

Abstract

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.

Thalamic Bursts and the Epic Pain Model

“…This scenario is thought to lead to hyper-excitability, sensitization, and enhanced bursting of thalamic neurons. Imaging and biochemical studies in humans further support the notion that TRN neurons are inhibited during chronic pain (Henderson et al, 2013; Gustin et al, 2014; Alshelh et al, 2016; Henderson and Di Pietro, 2016). However, there is latent contradiction in the assumption that thalamic bursts are increased while TRN activity is simultaneously suppressed.…”

The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain

“…Informed written consent was obtained for all procedures according to the Declaration of Helsinki and the study was approved by our local Institutional Human Research Ethics Committees. A subset of the neuroimaging data (not spectroscopy or EEG data) from 11 of the 20 chronic pain subjects was used in a previous investigation (Alshelh et al, ).…”

“…While these previous studies used both electroencephalography and magnetoencephalography techniques to explore resting brain rhythms in individuals with neuropathic pain in different body locations, they consistently found increases in resting low‐frequency cortical power in individuals with neuropathic pain. Similarly, we used resting‐state functional magnetic resonance imaging to demonstrate significantly increased infra‐slow oscillation power (0.03–0.06 Hz) within the ascending pain pathway, including the thalamus, in individuals with chronic orofacial neuropathic pain (Alshelh et al, ). We demonstrated that increased infra‐slow oscillations were temporally coupled across specific regions in the ascending pain pathway, including the ventroposterior medial thalamus, the thalamic reticular nucleus (TRN), and the orofacial representation in the primary somatosensory cortex.…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…Recently, Alshelh et al used resting-state fMRI in orofacial neuropathic pain patients to identify increased infra-slow oscillatory activity in the ascending pain pathway, including the spinal trigeminal nucleus, somatosensory thalamus, thalamic reticular nucleus, and primary somatosensory cortex; this increased oscillatory activity was not seen in control patients without orofacial pain [127]. This rhythm showed increased regional homogeneity in the spinal trigeminal nucleus region, consistent with a local spread of neural activity by astrocytes, and was suggestive of a self-sustaining thalamocortical dysrhythmia.…”