Altered resting activity patterns and connectivity in individuals with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder that typically occurs in the limbs, usually the upper limb. CRPS usually develops from a peripheral event but its maintenance relies on changes within the central nervous system. While functional abnormalities in the thalamus and primary somatosensory cortex (S1) of the brain are some of the most consistently reported brain findings in CRPS, the mechanisms are yet to be explored in full, not least of all how these two regions interact and how they might relate to clinical deficits, such as the commonly reported poor tactile acuity in this condition. This study recruited 15 upper-limb CRPS subjects and 30 healthy controls and used functional magnetic resonance imaging (fMRI) to investigate infra-slow oscillations (ISOs) in critical pain regions of the brain in CRPS. As hypothesised, we found CRPS was associated with increases in resting signal intensity ISOs (0.03-0.06 Hz) in the thalamus contralateral to the painful limb in CRPS subjects. Interestingly, there was no such difference between groups in S1, however CRPS subjects displayed stronger thalamo-S1 functional connectivity than controls, and this was related to pain. As predicted, CRPS subjects displayed poor tactile acuity on the painful limb which, interestingly, was also related to thalamo-S1 functional connectivity strength. Our findings provide novel evidence of altered patterns of resting activity and connectivity in CRPS which may underlie altered thalamocortical loop dynamics and the constant perception of pain.

Altered regional cerebral blood flow and hypothalamic connectivity immediately prior to a migraine headache.

BACKGROUND: There is evidence of altered resting hypothalamic activity patterns and connectivity prior to a migraine, however it remains unknown if these changes are driven by changes in overall hypothalamic activity levels. If they are, it would corroborate the idea that changes in hypothalamic function result in alteration in brainstem pain processing sensitivity, which either triggers a migraine headache itself or allows an external trigger to initiate a migraine headache. We hypothesise that hypothalamic activity increases immediately prior to a migraine headache and this is accompanied by altered functional connectivity to pain processing sites in the brainstem. METHODS: In 34 migraineurs and 26 healthy controls, we collected a series comprising 108 pseudo-continuous arterial spin labelling images and 180 gradient-echo echo planar resting-state functional magnetic resonance volumes to measure resting regional cerebral blood flow and functional connectivity respectively. Images were pre-processed and analysed using custom SPM12 and Matlab software. RESULTS: Our results reflect that immediately prior to a migraine headache, resting regional cerebral blood flow decreases in the lateral hypothalamus. In addition, resting functional connectivity strength decreased between the lateral hypothalamus and important regions of the pain processing pathway, such as the midbrain periaqueductal gray, dorsal pons, rostral ventromedial medulla and cingulate cortex, only during this critical period before a migraine headache. CONCLUSION: These data suggest altered hypothalamic function and connectivity in the period immediately prior to a migraine headache and supports the hypothesis that the hypothalamus is involved in migraine initiation.

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

Recurrent thalamocortical connections are integral to the generation of brain rhythms and it is thought that the inhibitory action of the thalamic reticular nucleus is critical in setting these rhythms. Our work and others' has suggested that chronic pain that develops following nerve injury, that is, neuropathic pain, results from altered thalamocortical rhythm, although whether this dysrhythmia is associated with thalamic inhibitory function remains unknown. In this investigation, we used electroencephalography and magnetic resonance spectroscopy to investigate cortical power and thalamic GABAergic concentration in 20 patients with neuropathic pain and 20 pain-free controls. First, we found thalamocortical dysrhythmia in chronic orofacial neuropathic pain; patients displayed greater power than controls over the 4-25 Hz frequency range, most marked in the theta and low alpha bands. Furthermore, sensorimotor cortex displayed a strong positive correlation between cortical power and pain intensity. Interestingly, we found no difference in thalamic GABA concentration between pain subjects and control subjects. However, we demonstrated significant linear relationships between thalamic GABA concentration and enhanced cortical power in pain subjects but not controls. Whilst the difference in relationship between thalamic GABA concentration and resting brain rhythm between chronic pain and control subjects does not prove a cause and effect link, it is consistent with a role for thalamic inhibitory neurotransmitter release, possibly from the thalamic reticular nucleus, in altered brain rhythms in individuals with chronic neuropathic pain.

Limb-specific autonomic dysfunction in complex regional pain syndrome modulated by wearing prism glasses.

In unilateral upper-limb complex regional pain syndrome (CRPS), the temperature of the hands is modulated by where the arms are located relative to the body midline. We hypothesized that this effect depends on the perceived location of the hands, not on their actual location, nor on their anatomical alignment. In 2 separate cross-sectional randomized experiments, 10 (6 female) unilateral CRPS patients wore prism glasses that laterally shifted the visual field by 20°. Skin temperature was measured before and after 9-minute periods in which the position of one hand was changed. Placing the affected hand on the healthy side of the body midline increased its temperature (Δ°C=+0.47 ± 0.14°C), but not if prism glasses made the hand appear to be on the body midline (Δ°C=+0.07 ± 0.06°C). Similarly, when prism glasses made the affected hand appear to be on the healthy side of the body midline, even though it was not, the affected hand warmed up (Δ°C=+0.28 ± 0.14°C). When prism glasses made the healthy hand appear to be on the affected side of the body midline, even though it was not, the healthy hand cooled down (Δ°C=-0.30 ± 0.15°C). Friedman's analysis of variance and Wilcoxon pairs tests upheld the results (P<0.01 for all). We conclude that, in CRPS, cortical mechanisms responsible for encoding the perceived location of the limbs in space modulate the temperature of the hands.