The Role of the Brain in Complex Regional Pain Syndrome (CRPS) Pain and Motor Dysfunction

Background: Complex regional pain syndrome (CRPS) is the most painful disorder known to man and presents with altered sensory perceptions and motor dysfunction. Past neuroimaging studies demonstrate that CRPS is associated with brain changes. The overall aim of this thesis was to investigate the role of the brain in CRPS pain and motor dysfunction. The sensorimotor cortex is important in pain and motor function. Sensorimotor cortical reorganisation and disinhibition have been identified in CRPS and many have postulated that such changes involve altered gamma-aminobutyric acid (GABA) mechanisms. These sensorimotor changes are thought to be so significant that treatments of CRPS aim to restore sensorimotor cortical reorganisation and disinhibition. And yet despite the postulated GABAergic mechanisms for sensorimotor disinhibition, sensorimotor cortex concentrations of inhibitory and excitatory neurotransmitters have never been evaluated in CRPS. In addition to the sensorimotor cortex, the basal ganglia also regulates pain. The basal ganglia has separate functional loops involved in motor and non-motor functions. In CRPS, it has been shown that there are changes to basal nuclei such as the putamen and caudate nucleus and such changes have been linked to CRPS pain and motor dysfunction. Further, neuroinflammation by infiltration of activated astrocytes has been found in the basal ganglia of CRPS patients. However, the basal ganglia functional loops have not been systematically evaluated in CRPS. Finally, the transmission and modulation of pain involves multiple brainstem nuclei such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM). In other chronic pain conditions, the PAG, LC, and RVM have been found to facilitate pain. Interestingly, many CRPS studies have postulated that pain processing is altered at the brainstem, yet the brainstem has not yet been directly investigated in CRPS. Methods: A series of three experiments were conducted comparing upper limb CRPS patients with pain-free controls to investigate various brain regions important in pain and motor function. i) In Chapter 2, magnetic resonance spectroscopy (MRS) was used to determine GABA and glutamate concentrations in the sensorimotor cortex of 14 CRPS and 30 pain-free controls. The relationship between GABA and glutamate concentrations and tactile acuity in CRPS was determined using Pearson’s correlation. ii) In Chapter 3, resting-state functional magnetic resonance imaging (fMRI) was used to determine infraslow oscillations (ISO) and functional connectivity of the motor and non-motor basal ganglia loops in 15 CRPS and 45 age- and sex-matched pain-free controls. Pearson’s correlation was used to determine the relationship between basal ganglia ISO and pain and motor function in CRPS. iii) Finally, in Chapter 4 resting-state fMRI was used to determine the functional connectivity between the PAG, LC, and RVM, and the functional connectivity of the PAG and LC to higher brain areas in 15 CRPS and 30 age and sex-matched pain-free controls. Using Pearson’s correlations, the relationship between CRPS functional connectivity changes of brainstem nuclei and pain intensity was determined. Results: Contrary to our original hypothesis, sensorimotor cortex GABA and glutamate concentrations did not differ between CRPS and controls or between CRPS brain hemispheres and neither concentration was correlated to tactile acuity in CRPS. Investigations of the basal ganglia circuitry revealed the motor putamen of CRPS patients had increased ISO power and both the putamen and caudate body had increased functional connectivity to the basal ganglia cortical input areas such as the primary motor cortex (M1), cingulate motor area, and orbitofrontal cortex. Increased ISO and functional connectivity of the putamen were correlated to increased perceived pain and motor dysfunction in CRPS. Additionally, functional connectivity between the PAG, LC, and RVM was not different between CRPS and controls. However, compared to controls, the PAG and LC had altered functional connectivity to higher brain areas in CRPS, with decreased PAG to S1 and posterior parietal cortex connectivity and increased LC to the caudate nucleus, anterior cingulate cortex, and hippocampus connectivity. Decreased PAG to S1 functional connectivity correlated to decreased pain in CRPS. Conclusions: Overall these findings demonstrate that CRPS involves changes to the basal ganglia motor and non-motor loops and brainstem pathways to the higher brain areas but does not involve changes to sensorimotor cortex GABA or glutamate concentration. Increased ISOs in the motor putamen may indicate neuroinflammation via astrogliosis and increased astrocytic calcium wave propagation in CRPS. It is postulated that noradrenaline released by the LC may induce the basal ganglia ISO increases of CRPS by activation of astrocytic α1 receptors. This in turn can potentially decrease GABAA receptor activity which may explain CRPS sensorimotor reorganisation and disinhibition. Additionally, altered functional connectivity of the PAG and LC to higher brain areas but not the RVM suggests that there are altered ascending brainstem pain pathways but not descending pain modulatory pathways in CRPS. Together with the correlations of brain changes to pain and motor dysfunction, this thesis suggests that basal ganglia and ascending brainstem pain pathways may underpin pain and motor dysfunction in CRPS. Future CRPS studies could aim to investigate the role of GABAA and α1 receptors