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Cottam, William (2018) Assessing the neural mechanisms of chronic knee osteoarthritis pain using functional magnetic resonance imaging. PhD thesis, University of Nottingham.

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Abstract

Chronic pain is a multifactorial experience combining sensory, affective and cognitive components and the underlying neural activity related to pain is subsequently diverse and encompasses widespread regions of the brain. Functional neuroimaging studies have suggested altered patterns of brain activity relating to chronic pain and in response to acute experimental pain but these findings have been inconsistent. Furthermore, research into chronic knee osteoarthritis pain (one of the most commonly presenting chronic pain states) has to date been lacking. The research here seeks to first assess the consistency of findings within the present literature and subsequently use these findings to motivate investigation into the neural correlates of chronic pain and its impact on brain state using advanced functional magnetic resonance imaging techniques alongside questionnaire-based participant report in a chronic knee osteoarthritis pain cohort.

The consistency of previously published functional neuroimaging findings of acute experimental pain in healthy and chronic pain cohorts was first established using coordinate based meta-analysis. A large-scale dataset was collated from the literature including over 200 published articles whilst a new coordinate based meta-analytic algorithm was applied that was shown to improve on the multiple-test correction of those previously available. Pain-related brain activity from healthy controls and chronic pain patient displayed no differences when assessed. Subsequent analysis found that application of a painful stimulus to the clinically affected site in a chronic pain patient displayed significant differences compared to that seen in healthy volunteers in the left lentiform nucleus, middle frontal gyrus and right posterior insula. Investigation into other pain-related brain activity such as pain-anticipatory and intensity related displayed overlapping regional activity within the bilateral anterior insula and anterior cingulate (core regions of the salience network). Pain-related deactivation in healthy controls was significant within the subgenual cingulate and the paracentral lobule.

Subsequently, as over 200 studies collated did not prove the sensitivity of evoking experimental pain to elucidate alterations in brain activity related to chronic pain, the next study was motivated to directly study the neural correlates of chronic pain itself. Arterial spin labelling (a functional MRI technique that displays increased sensitivity to tonic stimuli such as chronic pain) was used to study 26 chronic knee osteoarthritis patients and 27 matched healthy controls. Reported pain perception was found to correlate significantly with cerebral blood flow (controlled for age, sex and mean whole-brain cerebral blood flow) in limbic regions in OA patients not consistently seen within acute experimental pain such as the bilateral amygdala and subgenual cingulate. Additionally controlling for reported trait anxiety markedly reduced this relationship but was not found to mediate it when tested. Comparisons between knee osteoarthritis pain patients and matched controls displayed no significant differences.

Lastly, as chronic osteoarthritis knee pain patients had been found to show an altered state of pain-related brain activity (as assessed via arterial spin labelling) and that networks such as the salience network had been observed in response to pain anticipation and intensity encoding (as assessed via coordinate based meta-analysis), the final study was motivated to study the effect of chronic knee osteoarthritis pain on the state of the brain. Specifically, using resting-state blood oxygenation level dependent functional MRI that is sensitive to the detection of oscillations and correlations. Via these correlations, brain networks such as the salience, default mode and central executive brain networks are observable at rest. An in depth characterisation of connectivity between- and within-networks was carried out using functional, effective and dynamic connectivity analysis. Functional connectivity was assessed via seed-based correlations and found evidence of altered connectivity (increased anticorrelation) of the salience and default mode networks. Additional altered connectivity was found between the central executive network and the salience network. Effective connectivity analysis (via Granger causality analysis) displayed significantly increased negative outflow also from the salience to the default mode network in line with the functional connectivity finding. Lastly, dynamic functional connectivity analysis (as assessed via a ‘sliding window’ approach in which correlations between brain regions were calculated for subsequent 100-second windows along the functional MRI timeseries) analysis was carried out within each network. Dynamic functional connectivity was found to be significantly reduced within the default mode network of chronic pain patients.

The functional differences observed provide evidence to stress the role of negative affect on neural activity underlying perceived chronic knee osteoarthritis pain and the effect of chronic pain on the resting brain. These functional neuroimaging findings have potential implications for understanding the brain in chronic pain and may provide framework for future studies.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Auer, D. Tanasescu, R.
Keywords:	Osteoarthritis; Chronic pain; Functional MRI; Coordinate based meta-analysis
Subjects:	W Medicine and related subjects (NLM Classification) > WE Muscoskeletal system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	51405
Depositing User:	Cottam, William
Date Deposited:	31 Aug 2018 12:19
Last Modified:	08 Feb 2019 08:15
URI:	https://eprints.nottingham.ac.uk/id/eprint/51405

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