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 (<0.1 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. Significance statement: Chronic neuropathic pain is associated with altered thalamic firing and thalamocortical dysrhythmia. The mechanisms responsible for these changes remain unknown. In this study, we report in individuals with neuropathic pain increased oscillatory neural activity within the ascending pain pathway with evidence that these changes result from altered neural-astrocyte coupling. We propose a series of neural and glial events after nerve injury that result in the generation of altered thalamocortical activity and a persistent neuropathic pain state. Defining the underlying mechanisms responsible for neuropathic pain is critical if we are to develop more effective treatment regimens.

Keywords: astrocytes; infra-slow oscillations; orofacial pain; regional homogeneity; spinal trigeminal nucleus; thalamocortical rhythm.

Figure 1.

Infra-slow oscillations within the thalamus. a, A cuboid 18 × 24 × 15 mm consisting of 240 individual VOIs was placed over the left (contralateral to highest pain) thalamus in 44 controls and 16 subjects with orofacial NP. Slice locations are indicated by the horizontal lines on the coronal section and the numbers to the top right of each axial slice in MNI space. At each rostrocaudal level of the thalamus, 48 VOIs were assessed for significant power differences. b, Each gray band beside an axial image consists of a row for each VOI in that slice, with spectral power differences between control and NP subjects (controls > NP or controls < NP) at frequencies between 0.006 and 0.25 Hz color coded for significance (p value). Gray represents no significant difference. c, A plot of the percentage of significantly different voxels over the entire frequency spectrum revealed that the frequency band 0.03–0.06 Hz had the highest percentage of significantly different VOIs. This frequency band was used for all subsequent analysis.

Figure 2.

NP is associated with increased infra-slow oscillation power in the ascending pain pathway. Brain regions in which NP subjects had significantly increased (hot color) or decreased (cool color) ALFFs (a) and fALFFs (b; random effects, p < 0.05, false discovery rate corrected, minimum cluster size of 10 voxels). Location of each axial slice in MNI space is indicated at the top right. The green shading indicates the thalamic region activated during innocuous brushing of the right lip, i.e., the orofacial somatosensory thalamus. NP is associated with increased infra-slow oscillations in the region of the primary afferent synapse (spinal trigeminal nucleus), as well as other parts of the ascending pain pathway. dlPFC, Dorsolateral prefrontal cortex. c, Power spectrum plots of four clusters in which power in the 0.03–0.06 Hz range was significantly increased in NP subjects (red) compared with controls (black). Plots of the mean ± SEM power between 0.03 and 0.06 Hz are shown for controls and NP subjects. Note that, at frequencies above 0.06 Hz, power was remarkably similar in both control and NP subjects. cont, Controls; ipsi, ipsilateral.

Figure 3.

Signal intensity fluctuations in the ascending pain pathway are coupled temporally. Graph shows cross-correlations of resting signal intensity changes within the ascending pain pathway in controls and NP subjects. Tight temporal coupling with zero time lag occurred between the spinal trigeminal nucleus, somatosensory thalamus, and TRN. A lag of ∼4 s occurred between the somatosensory thalamus and cortex. Also note the, in only NP subjects, correlation peaks (indicated by red asterisks) occurred at ∼30 s apart, i.e., indicating ongoing increased infra-slow oscillations in the 0.03 Hz range.

Figure 4.

NP is associated with increased degree centrality in the ascending pain pathway and increased regional homogeneity at the primary afferent synapse. a, Brain regions in which NP subjects displayed the highest (hot color) degree centrality (p < 0.05, false discovery rate corrected, minimum cluster size of 10 voxels). Increased degree centrality implies a greater influence of the pain pathway in the overall flow of information through the brain. The location of each axial slice in MNI space is indicated at the top right (z-direction in millimeters). The green shading indicates the thalamic region activated during innocuous brushing of the right lip, i.e., the orofacial somatosensory thalamus. b, Plots of mean ± SEM degree centrality in controls (black) and NP subjects (red) in four regions of the ascending pain pathway. These plots show there is a significant increase in degree centrality in the ascending pain pathway in NP subjects compared with controls. c, NP subjects also displayed greater regional homogeneity than controls, although this increase was restricted to the region of the ipsilateral spinal trigeminal nucleus, cerebellar cortex, and mid-cingulate cortex (p < 0.05, false discovery rate corrected, minimum cluster size of 10 voxels). Regional homogeneity evaluates the similarity of the time series within each voxel and its nearest neighbors and could result from local astrocyte activation. dlPFC, Dorsolateral prefrontal cortex; ipsi, ipsilateral; MCC, mid-cingulate cortex.

Figure 5.

Significant changes in infra-slow oscillation power during acute pain compared with pain-free condition in controls. Acute pain did not evoke increased infra-slow oscillation power in any brain region, but did evoke decreased power (cool color scale) in the contralateral ventral striatum, bilateral posterior cingulate cortex (PCC) and precuneus. Power spectrum plots of four clusters within the ascending pain pathway derived from the analysis between controls and NP subjects are shown in the lower panel. The four clusters chosen were those which in NP subjects displayed increased infra-slow oscillations (red shading). The power spectrum plots as well as plots of mean (±SEM) power between 0.03–0.06Hz in controls during acute pain (black) and in controls during no pain (green) show that power was not significantly increased in the ascending pain pathway during acute pain (two-tailed, two-sample t test, p < 0.05). Location of each axial slice in MNI space is indicated at the top right. cont, Controls; ipsi, ipsilateral.

Figure 6.

Proposed series of events that result in the maintenance of chronic NP. After nerve injury, excess activity within primary afferent neurons results in excessive neurotransmitter release at the primary afferent synapse. This release results in neural death and elicits astrocyte activation, which results in more regular and increased magnitude calcium waves resulting in increased regional homogeneity (RH). This in turn results in oscillatory gliotransmitter release and increased infra-slow neural oscillations, which are subsequently transferred to the somatosensory thalamus. Additional neural loss in the somatosensory thalamus results in reduced blood flow in the TRN and a subsequent reduction in GABAergic release back onto the somatosensory thalamus. This reduced inhibition combined with increased infra-slow oscillations and the recurrent nature of thalamocortical circuits results in altered thalamocortical connectivity, increased dominance of the ascending pain pathway in overall brain function represented by increased degree centrality (DC), altered thalamocortical loop dynamics, a self-sustaining thalamocortical dysrhythmia, and the constant perception of pain.