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Summary In the general introduction in chapter 1, we describe the background of the research and the research questions we have studied. Persistent physical symptoms (PPS) are one or more physical symptoms that last at least weeks and cause dysfunction or significant distress. The physical symptoms may occur in the context of an (adequately treated) medical condition or in the absence of a medical condition. Central sensitization (CS) is a hypersensitivity of the central nervous system to sensory stimuli. In CS, these stimuli are amplified due to an increase in receptors and neurotransmitters in the dorsal horn of the spinal cord. We investigated whether CS can serve as a useful explanatory model for GPs and patients with PPS, and whether the addition of a test makes the explanation more acceptable and clear. In Chapter 2 we report on our systematic review of the literature regarding definitions, operationalisations and mechanisms of CS in chronic pain and persistent physical symptoms research. The most mentioned theme in the definitions of CS was the hyperexcitability of the central nervous system. We found eight different operationalisations. CS is most frequently measured with various forms of quantitative sensory testing (QST), (f)MRI, laboratory evaluation of neurotransmitters and questionnaires. In chapter 3 we report the results of our Delphi study for tests for CS in general practice. In this study we aimed to assess which tests might have added value compared with providing only an explanation and which might be feasible and thus be suitable for use in general practice. In two rounds, the panellists reached a consensus on 14 of the 15 tests: 3 were included, and 11 were excluded. In the first round we included the Central Sensitisation Inventory (CSI) and in the second round the algometer to measure pressure pain thresholds (PPTs). In the second round we also selected the monofilament to measure temporal summation, because the score of the panellists of 69%

Background and Aims: Spinal manipulation (SM) is currently recommended for the management of back pain. Experimental studies indicate that the hypoalgesic mechanisms of SM may rely on inhibition of segmental processes related to temporal summation of pain and, possibly, on central sensitization, although this remains unclear. The aim of this study was to determine whether experimental back pain, secondary hyperalgesia, and pain-related brain activity induced by capsaicin are decreased by segmental SM. Methods: Seventy-three healthy volunteers were randomly allocated to one of four experimental groups: SM at T5 vertebral level (segmental), SM at T9 vertebral level (heterosegmental), placebo intervention at T5 vertebral level, or no intervention. Topical capsaicin was applied to the area of T5 vertebra for 40 min. After 20 min, the interventions were administered. Pressure pain thresholds (PPTs) were assessed outside the area of capsaicin application at 0 and 40 min to examine secondary hyperalgesia. Capsaicin pain intensity and unpleasantness were reported every 4 min. Frontal high-gamma oscillations were also measured with electroencephalography. Results: Pain ratings and brain activity were not significantly different between groups over time (p > 0.5). However, PPTs were significantly decreased in the placebo and control groups (p < 0.01), indicative of secondary hyperalgesia, while no hyperalgesia was observed for groups receiving SM (p = 1.0). This effect was independent of expectations and greater than placebo for segmental (p < 0.01) but not heterosegmental SM (p = 1.0). Conclusions: These results indicate that segmental SM can prevent secondary hyperalgesia, independently of expectations. This has implications for the management of back pain, particularly when central sensitization is involved.

Objective: To investigate if calcitonin gene-related peptide infusion induces migraine-like attacks in chronic migraine patients. Methods: Fifty-eight patients with chronic migraine, either with or without headache on the experimental day, were assessed for the incidence of migraine-like attacks after an intravenous infusion with calcitonin gene-related peptide 1.5 µg/min over 20 min. The primary endpoint was the incidence of migraine-like attacks after calcitonin gene-related peptide. Exploratory endpoints were the association between the incidence of migraine-like attacks and presence of headache on the experimental day, and headache frequency in the past month. Migraine-like attack data was compared to a historic cohort of 91 episodic migraine patients without headache on the experimental day. Total tenderness score, pressure-pain threshold and supra-threshold pressure pain at baseline were investigated in relation to incidence of migraine-like attacks and presence of headache on the experimental day. Results: In total, 83% of the 58 chronic migraine patients developed migraine-like attacks after calcitonin gene-related peptide infusion. Migraine-like attacks were found in 92% of chronic migraine patients with headache on the experimental day compared to 65% of chronic migraine patients without headache on the experimental day (p = 0.035). No differences were observed in total tenderness score and pressure-pain threshold between chronic migraine patients with and without headache on the experimental day. The incidence of migraine-like attacks following calcitonin gene-related peptide in chronic migraine patients without headache (65%) was equal to the historic cohort of 91 episodic migraine patients without headache (67%) on the experimental day. Conclusions: Chronic migraine patients are hypersensitive to calcitonin gene-related peptide. The potency of calcitonin gene-related peptide as a migraine inductor is increased in chronic migraine patients with ongoin

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 wi

Introduction: To understand the function of the genes and their products in the pain system, studies will have to deal with complex issues related to intercellular communication, e.g. plasticity in neuronal networks. To provide a basis for such studies, the present thesis compares basic features of the nociceptive spinal systems including the organization of nociceptive withdrawal reflexes (NWR), laminar organization of the nociceptive C-fibre input to the spinal cord and plastic mechanisms in the mouse and rat. On this basis, the role of adhesion molecules, in particular L1 adhesion molecules, in the nociceptive system is analyzed for the first time by using mutated mice. Results: It is confirmed that sensorimotor transformations performed by the NWR circuits abide the same principles as in the rat, at least for two of the wild-type mouse strains tested. This finding indicates that mice NWR has a modular organization as previously demonstrated in the rat. Interestingly, mouse strains with a deficit in LTP mechanisms also exhibit a deficient sensorimotor transformation, suggesting that LTP mechanisms are involved in the developmental mechanisms that fine-tune the NWR. Furthermore, basic features such as nociceptive C-fibre evoked field potentials and response characteristics like short term potentiation in deep dorsal horn neurones appear to be very similar in mouse and rat. By contrast, marked differences were found in the properties of nociceptive transmission in the superficial laminae. In particular, apparently normal wild type mice seem to lack both short and long term potentiation in the first order synapses, mechanisms that are powerful in the rat. These findings suggest that the current view on the locus of the central sensitization mechanisms needs to be reconsidered. In the second part of the thesis, the role of the cell adhesion molecule L1 in the pain system was studied in mutated mice. Interestingly, these animals were found to be almost analgesic. This

This study compares the effect of experimental muscle pain on deep tissue sensitivity and force attenuation in the wrist extensors of patients with lateral epicondylalgia (n=20), and healthy controls (n=20) with experimentally induced sensori-motor characteristics simulating lateral epicondylalgia. Delayed onset muscle soreness (DOMS) in wrist extensors of healthy controls was induced by eccentric exercise in one arm 24 h prior to injection (Day 0). Saline-induced pain intensity (visual analogue scale, VAS), distribution, and quality were assessed quantitatively in both arms for both groups. Pressure pain thresholds (PPT) were assessed at three different sites in the wrist extensors. Maximal grip force and wrist extension force were recorded. In response to saline-induced pain in the extensor carpi radialis brevis, regardless of arm, the patient group demonstrated a significantly quicker pain onset (P<0.01), mapped larger pain areas and more referred pain areas, compared to healthy controls (P<0.03). Pain persisted significantly longer in the sore arm of the patient group, compared with all other arms (P<0.02). Patients demonstrated significant bilateral hyperalgesia at extensor carpi radialis brevis during and post saline-induced pain compared to pre-injection and healthy controls (P<0.04). The sore arm in patients and the DOMS arms in healthy subjects showed significantly reduced maximal force (P<0.0001), at all Day 1 times compared with the control arms. In patients, the bilateral increase in deep tissue sensitivity and enlarged referred pain areas during saline-induced pain might suggest involvement of central sensitisation.

Background: Chronic low back pain (CLBP) is one of the most prevalent reasons people seek healthcare assistance worldwide. Guidelines for managing CLBP prioritise the development of self-management strategies. Levels of central sensitisation (CS) may contribute to the relatively poor efficacy of treatments aiming to facilitate self-management. CS might be a dominant factor predicting worse self-management in people with CLBP following interventions aiming to improve such outcomes. Quantitative sensory testing (QST) may provide reliable and valid indices of CS and it may predict musculoskeletal pain and disability. CS might be associated with increasing psychological distress, pain, fatigue and catastrophisation which might also be predictors of ineffective self-management. CS has also been associated in people with knee pain with self-report measures of widespread pain distribution (reported by shading a pain manikin) or a self-report Central Mechanisms Trait score, comprising of items addressing depression, anxiety, neuropathic-like symptoms, pain distribution, catastrophising, sleep, fatigue and cognitive difficulties. Objectives: [1] to systematically review the literature in order to determine the ability of QST to predict musculoskeletal outcomes; [2] to establish the reliability and validity of distinct QST modalities as classification and measurement tools of CS; [3] to establish a cut off for number of body sites shaded on a self-reported pain manikin that best identifies those with widespread pain and explore whether certain self-reported items taken to indicate central mechanisms involvement contribute to a single latent trait in individuals with CLBP; [4] to determine whether different CS indices are associated specifically with self-management/self-care outcomes at a single time-point; [5] to test whether any cross-sectional associations between baseline CS indices and self-management/self-care outcomes are also present longitudinally, after participants