Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition that develops after minor limb trauma in 1 in 10 people. The pathophysiology of CRPS is poorly understood and consequently current treatments are vastly inadequate with many patients suffering pain for years. Whilst persistent pain is a defining characteristic of CRPS, another major feature is dysfunction of the autonomic nervous system. The manifestations of this include fluctuating temperature, swelling and sweating of the affected limb and increased heart rate. Our previous work has shown that autonomic dysfunction critically contributes to the presence of on-going pain in CRPS. For example, pain increases during sympathetic arousal, whilst blocking peripheral α1-adrenoceptors and sympathetic nerve block reduce pain. Inflammation is also a key component in CRPS, contributing to changes in the autonomic nervous system within the injured limb and consequently the presence of pain. Circulating inflammatory mediators can act on key autonomic regulatory nuclei in the hypothalamus and brainstem to alter sympathetic outflow via the ‘immune-to-brain’ transmission route, contributing to autonomic dysfunction centrally. The inflammatory response is strongest at the time of injury, and consequently early treatment with anti-inflammatory corticosteroids has shown promise. However, activated central memory T lymphocytes are increased in chronic (>6mths) CRPS, and skin biopsy samples from the affected limb of CRPS patients have increased mast and dendritic cell activation. Thus, long-term inflammatory activation may be critical for the maintenance of ongoing CRPS symptoms.
This study brings together experts in brain imaging, autonomic function and peripheral immune assessment with the use of cutting-edge technology and innovative techniques to clarify the pathophysiology of CRPS. The team has significant expertise in the use of the ‘Hyperion’ imaging mass cytometry system which can assess up to 40 markers in human skin. Using our established 39 antibody mass cytometry panel we aim to determine the activation status of all major immune cell populations in the blood of acute and chronic CRPS patients, combined with analysis of serum cytokine expression. The Hyperion system and unsupervised spatial analyses will be used to examine resident and infiltrating immune cell activation, and α1-adrenoceptors expression and nerve terminal density in the skin.
Our team will also be the first to use the latest 7T ultrahigh resolution MRI brain imaging in CRPS to assess changes in brain activation at rest and during painful stimuli. We expect to identify dramatic differences in CRPS patients, in particular we aim to assess the function of discrete hypothalamic and brainstem nuclei that underpin the various autonomic disturbances that occur in CRPS. We will use the latest machine learning analyses to assess the relationship of blood and skin inflammatory markers with changes in brain activation patterns in CRPS.
An increased understanding of autonomic dysfunction and the intersection of neuro-immune mechanisms in CRPS is clearly warranted, and is critical to identifying diagnostic markers, pathological sub-types of CRPS, and developing more specific treatment approaches. The current proposal aims to address this gap in knowledge using the latest high-dimensional suspension and tissue mass cytometry combined with high-resolution neural imaging.
Associate Professor Marc Russo, Hunter Pain Specialists, University of Newcastle and University of Sydney NSW, Associate Professor Paul Austin, Professor Luke Henderson, Brain and Mind Centre, University of Sydney, NSW, Professor Peter Drummond, Adjunct Professor Philip Finch, Murdoch University, WA, Dr Peter Georgius, Sunshine Coast Clinical Research, QLD, Professor Andrew Harman, Westmead Institute for Medical Research, University of Sydney NSW.
The project was awarded $A70,000 through the ANZCA research grants program for 2022.
This Chronic Regional Pain Syndrome (CPRS) study has found for the first time that specific immune cells (Langerhans cells and CXCR3+ lymphocyte cells) were closer to nerves in the affected skin of CRPS patients, which may contribute to persistent pain.
It also found that the sensory cortex, thalamus and hypothalamus - brain regions responsible for pain and autonomic responses - respond differently to heat pain in patients with CRPS, suggesting these brain changes are responsible for propagating ongoing pain and autonomic symptoms in CRPS patients.
The study, Immune-to-brain signalling in CRPS: unravelling the detrimental relationship between inflammation and autonomic dysfunction, led by the University of Sydney’s Associate Professors Marc Russo and Paul Austin, was completed this year. It also included two technical world-firsts: the first ever ultra-high resolution functional MRI study in CRPS, and the first high-parameter assessment of neuroimmune interactions in CRPS affected tissues.
These insights may lead to changes in clinical practice in treating CRPS. Understanding the pathogenic immune cell-nerve interactions could lead to targeted anti-inflammatory pain treatment strategies, and appreciating the pain pathway changes in specific brain regions could help to develop therapies to alter aberrant activity. Finally, identification of predictive immune biomarkers could enhance earlier diagnosis and treatment before long standing changes occur in the brain.
This grant has supported 7 conference presentations: five at the Australian Pain Society meetings (2023 and 2024, 4 talks, 1 poster), a poster 1 at the Australian Neuroscience Society, and an invited talk at IASP CRPS Special Interest Group in Bath, UK in August 2024. It is anticipated it will form the basis of at least high-impact 3-4 research articles.