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Pelvic Organ Prolapse (POP) is a dysfunction of pelvic floor support and have an ad-verse effect on the quality of life (QOL). The predominant symptom is the feeling of a vaginal bulge. However, a considerable proportion of women report a sensation of dragging, or pelvic pressure vaginally without a bulge or large objective prolapse being present. A mechanism suggested to explain this anomaly describes the augmentation of pain transmission secondary to central sensitization (CS). This explanation is like the pathophysiological changes postulated for central sensitivity syndromes (CSS) (a term collectively used for a group of pain disorders like fibromyalgia, chronic fatigue syn-drome, temporomandibular disorder, chronic pelvic pain, and interstitial cystitis). The purpose of this thesis is to determine whether patients with central sensitivity syn-dromes have different outcomes from the surgical treatment of prolapse, compared to those without CSS. The survey explored the level of awareness about CSS amongst healthcare profession-als managing pelvic organ prolapse and identified that there is gap in knowledge about CSS in this specific group. The second part explored the proportion of women with central sensitivity syndrome attending the gynaecology outpatient clinic and revealed that around 32% of women with pelvic organ prolapse, and 40% with other gynaeco-logical problems had evidence of CSS. The third part of the thesis reviewed the litera-ture around the impact of CSS on post-surgical outcomes. This demonstrated that there is limited evidence currently available on the role of CSS on surgical outcomes. The fourth part of the thesis compared the outcomes of pelvic organ prolapse surgery be-tween the two groups (i.e. those with and without CSS) and found that women with CSS had a lower level of satisfaction and impression of improvement with persistence of symptoms compared to women without CSS. The qualitative study explored wom-en’s views on reasons for poor outcome from surgery amongst women with CSS. Poor surgical technique and /or underlying unidentified bowel or bladder pathology was the perceived reason for poor outcome, rather than CSS. The above findings suggest that there is suboptimal awareness about this condition, amongst healthcare professionals and patients. The findings of the study also suggest that the presence of underlying CSSs could be one of the contributing factors responsible for poor outcomes. These findings will enable clinicians to adequately counsel women with CSS for the possible outcomes of the surgery, while also enabling those patients to have more realistic expectations from the surgery.

Chronic neuropathic pain affects up to 8% of the United Kingdom population and is a difficult condition to manage. It is established and maintained through many mechanisms, including central sensitisation (CS) in the spinal cord and brainstem. Neuropathic pain manifests as spontaneous pain, sensory loss and evoked hypersensitivity. The development of novel treatments for neuropathic pain is challenging, in part due to inadequate experimental models of clinically relevant pain. The use of functional magnetic resonance imaging (fMRI) techniques for imaging acute and increasingly tonic states enables the assessment of the neural correlates of evoked hypersensitivity and persistent pain, with the goal of developing appropriate biomarkers to test new therapies. This thesis develops novel techniques for the assessment of ongoing pain states and their modulation by therapies. We first identified a suitable human experimental model of CS using topical capsaicin, and an fMRI pipeline for the investigation of supraspinal involvement in pain hypersensitivity. In a placebo-controlled study, we then demonstrated the improved sensitivity of fMRI above subjective reports in detecting the efficacy of a known analgesic as compared to an ineffective active compound in a small cohort. To translate this to the more clinically relevant symptom of spontaneous pain, we developed and validated the use of a multi-inversion time pseudo-continuous arterial spin labelling (ASL) imaging and analysis pipeline for the neural assessment of tonic states and the absolute quantification of cerebral blood flow (CBF). Current evidence from structural and functional studies suggests a direct role for the posterior insula cortex in the encoding of nociception and pain. Using the ASL pipeline, we found that only a CBF change in the posterior insula region was correlated with the changing perception of persistent capsaicin-induced pain, and in a separate experiment showed that suppression of CBF in this region by gabapentin was related to the drug's suppression of subjective pain perception. We also demonstrated in a cohort of phantom limb patients that pain relief resulting from transcranial direct current stimulation of the deprived sensorimotor cortex is neurally represented by a decrease in posterior insula CBF. In a separate study, we showed that baseline CBF in the periaqueductal grey can predict individuals who are most vulnerable to pain and hypersensitivity following the induction of capsaicin-related CS. Taken together, these findings suggest that fMRI can be used as a tool to assess the efficacy of established and novel analgesics, with the midbrain reticular formation and posterior insula cortex being prime candidates as biomarkers of CS mechanisms and persistent pain respectively. Relatedly, ASL-fMRI may also be an effective technique for evaluating individuals' susceptibility to pain following inflammation or injury.

Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown pathogenesis, characterised by fatigue which is not relieved by rest, accompanied by assorted symptoms including cognitive difficulties, pain, and unrefreshing sleep. One hallmark of the symptom complex in CFS is a transient exacerbation of the fatigue state after relatively minor physical activity or cognitive activity often termed a post-exertional exacerbation . By applying challenge paradigms, the studies presented in this thesis aimed to analyse the biological underpinnings of the disorder during periods of worsened fatigue and symptoms following the imposition of environmental challenges a physical exercise protocol and a simulated-driving protocol (representing a cognitively-demanding task). These paradigms allowed analysis of a working conceptual model that CFS is a result of central sensitisation , representing augmented responsiveness of the central nervous system (CNS) to signals either from the periphery or from within the brain - resulting in altered sensory processing within the brain and ultimately the excessive conscious sensation of fatigue. Across the two challenge studies, patients with CFS reported high levels of fatigue in their baseline state (consistent with the diagnostic criteria for the disorder). This was measured using a new fatigue scale specifically designed for these studies to allow real-time measurement of the phenomenon. In comparison to matched healthy participants, at baseline, the patients had impairments in cognitive function, longer night-time sleep, less day-time physical activity and movement, and less heart rate variability - an index of vagal activity, around the time of night-time sleep, but no alterations in gene expression for biomarkers previously linked with the sensation of fatigue, or in indices of interoception. These findings are generally consistent with previous evidence for autonomic nervous system and cognitive disturbances in patients with CFS. However, while both the physical and cognitive challenges induced an exacerbation of fatigue lasting hours-to-days in patients with CFS (with little or no change in healthy participants), there were no corresponding changes in gene expression, cognitive performance, indices of interoception, indices of vagal activity, or sleep and activity patterns. As such, the inability to detect meaningful changes in biological parameters indirectly reflecting central sensitisation post-challenge did not allow for confirmation or denial of the hypothesis that the post-exertional exacerbation of fatigue and related symptoms is due to central sensitisation . Further studies are warranted using these challenge protocols in conjunction with more direct measures of central sensitisation such as functional neuro-imaging.