In complex regional pain syndrome (CRPS), hyperalgesia typically extends beyond the CRPS-affected limb to encompass other sites on the ipsilateral side of the body. In addition, discomfort evoked by noise and light is greater on the ipsilateral than contralateral side and may exacerbate pain in the affected limb. These observations suggest that a disturbance within the central nervous system disrupts nociceptive processing in CRPS. We believe that this disturbance involves cortical and spinal projections from the ipsilateral locus coeruleus.To explore this concept, we will test three hypotheses:
- A proxy measure of noradrenaline production – neuromelanin-sensitive magnetic resonance imaging (NM-MRI) – will be lower in the locus coeruleus of CRPS patients than controls, and will be lower on the ipsilateral than contralateral side in patients with CRPS.
- Pupillary dilatation to painless and painful stimuli (indirect measures of locus coeruleus activity), and inhibitory pain modulation evoked by painful stimuli, will be lower and will fatigue more rapidly in CRPS patients than controls, and will be lower on the ipsilateral than contralateral side in patients with CRPS.
- Pupillary responses will be weakest in patients with clear signs of adrenergic deficit in the locus coeruleus on NM-MRI.
To investigate these hypotheses, we will use NM-MRI to measure signal intensity in the locus coeruleus (which reflects the structural integrity of noradrenergic neurons at this site) and contrast this with signal intensity at a reference site (the rostral pontine tegmentum). We will also use voxel-based morphometry to carry out a volumetric assessment of the brainstem; and a multi- shell diffusion MRI scan to assess microstructural features such as neurite density and neuronal organisation. In the second part of the study, we will assess locus coeruleus function by measuring pain, inhibitory pain modulation and autonomic (pupillary, cardiac and electrodermal) responses to a painful stimulus (applying ice to the temple); and we will also assess autonomic responses to a painless stimulus (an acoustic startle stimulus). We will then assess the link between the intensity of the NM-MRI signal and functional signs of locus coeruleus activity.
Despite recent major advances in clarifying the pathophysiology of CRPS, the mechanisms that generate symptoms and that maintain chronic pain remain unclear. Unfortunately, this has hampered the development of effective treatment regimens for this debilitating disorder. We believe that identifying the source of sensory disturbances in CRPS is crucial because, once mechanisms are better understood, these mechanisms can be targeted to manage pain more effectively. The studies outlined will be the first to use NM-MRI to examine the structural integrity of the locus coeruleus in CRPS, and to examine links between structural and functional signs of deficit in locus coeruleus activity. Thus, we expect to clarify the source of sensory disturbances and pain in CRPS.
Dr Philip Finch, Professor Peter Drummond, Murdoch University, Western Australia;
Dr Sjoerd Vos, Harry Perkins Institute of Medical Research, University of Western Australia.
The project was awarded A$69,416 funding through the ANZCA research grants program for 2024.