Chronic pain: lost inhibition?

Abstract

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.

Figure 1.

A, Gray-matter volume decreases (cool color scale) in the thalamus of subjects with PTN compared with pain-free controls overlaid onto an individual's axial T1-weighted anatomical image. Thalamic region activated during innocuous lip brushing in 20 control subjects is indicated by the red shading and its overlap with gray-matter loss by the green shading. This green shading encompasses the somatosensory thalamus, i.e., ventroposterior nucleus. The slice location in MNI space is indicated at the bottom-left of the image. B, Plots of mean (±SEM) gray-matter volumes in the somatosensory thalamus in PTN subjects and pain-free controls.

Figure 2.

A, Thalamic activation during innocuous brushing of the lip in 20 control and 12 subjects with PTN displayed on an individual's axial T1-weighted anatomical image. B, Plots of mean (±SEM) x, y, and z coordinates in MNI space during lip brushing in controls (blue) and PTN subjects (red). C, plots of mean (±SEM) percentage signal intensity (SI) change during lip brushing in controls and PTN subjects. The vertical gray bars represent the brushing periods. The bar graph shows the mean (±SEM) percentage change during all lip brushing periods in controls and PTN subjects. Note that neither the location nor magnitude of signal intensity change differed between controls and PTN subjects.

Figure 3.

A, Cerebral blood flow (CBF) decreases (cool color scale) in the contralateral (to pain) thalamus of subjects with PTN compared with pain-free controls and overlaid onto an individual's axial and coronal T1-weighted anatomical images. The CBF decrease encompasses the region of the TRN. Slice locations in Montreal Neurological Institute space are indicated at the lower left of each image. To the right are two graphs: the left graph is a plot of mean (±SEM) CBF in the TRN of PTN subjects and pain-free controls; the right graph is a plot of CBF in the TRN against ongoing scan pain intensity measured on a VAS. Note that as TRN blood flow decreases, pain intensity increases. B, CBF decreases in the contralateral primary somatosensory cortex (SI) in PTN subjects compared with pain-free controls are overlaid onto an individual's coronal T1-weighted anatomical image. The slice location is indicated at the lower left of the image. A plot of mean (±SEM) CBF in the SI of PTN subjects and pain-free controls is shown to the right. C, A plot of mean (±SEM) CBF in the medial VPM of PTN subjects and pain-free controls. The location of the VPM area used to extract CBF values is indicated on the coronal slice by the green shading.

Figure 4.

A, Axial slice showing location from which proton spectroscopy was performed in the contralateral thalamus of subjects with PTN and pain-free controls. Slice location in MNI space is indicated at the bottom-left of the image. B, Typical MEGA-PRESS spectrum obtained from the thalamus. Glx, Glutamine; NAA, N-acetyl aspartate. C, A plot of mean (±SEM) GABA/Cr ratio in the thalamus of PTN subjects and pain-free controls.

Figure 5.

A, Brain regions in PTN subjects, in which the strength of the correlation between baseline signal fluctuations and signal within the somatosensory (ventroposterior thalamus) was significantly correlated with thalamic content. The ventroposterior thalamus “seed” region is indicated by the green shading. Significant clusters are overlaid onto an individual subject's T1-weighted image set. The hot color scale indicates that as thalamic GABA content decreases, signal intensity fluctuates more closely with that of the ventroposterior thalamus. Slice locations in MNI space are indicated at the top-right of each image. MI, Primary motor cortex; PCC, posterior cingulate cortex; SI, primary somatosensory cortex. B, Plots of thalamic GABA/Cr values against connectivity strength in a number of brain regions in PTN subjects (red) and controls (black). Note that although in PTN subjects, thalamic GABA was significantly correlated to VP connectivity in a number of brain regions; it was not significantly correlated in controls. *Indicates significant differences between correlation strength in PTN and controls.

Figure 6.

Proposed central events which result in the development and/or maintenance of chronic neuropathic pain. An initial loss of neurons in the VP results in a loss of excitatory inputs to the TRN which in turn results in altered inhibitory GABA input in VP thalamus. This disturbed thalamocortical activity may result in the constant perception of pain.