The contemporary model of vertebral column joint dysfunction and impact of high-velocity, low-amplitude controlled vertebral thrusts on neuromuscular function

Peer reviewedPublisher PD

Non-invasive approaches to identify the cause of premature fatigue in Inflammatory Bowel Disease patients

Inflammatory bowel disease (IBD) fatigue is a pervasive secondary disease symptom. The aetiology is poorly understood, meaning that treatment options are sparse. This is of particular concern for the relatively large proportion of patients with quiescent disease, who continue to report an increased perception of fatigue and demonstrate premature exercise fatigue, relative to healthy individuals. Fatigue is multidimensional and can manifest as a disproportionate perception of tiredness, perturbed cognitive functioning and an inability to sustain a required work output during exercise. In contrast to other chronic disease, to date there has been no mechanistic assessment of IBD fatigue reported in the literature. This is congruent with the essential absence of any effective treatment strategies convincingly shown to reduce IBD fatigue burden, independent of targeting known clinical causes. The application of Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) techniques during exercise represents a unique opportunity to non-invasively probe in-vivo metabolism across multiple organs. This thesis seeks to characterise IBD fatigue aetiology by combining laboratory-based assessment of peripheral muscle function and cardiorespiratory fitness, with proton (1H) MRI and phosphorus (31P) MRS during within-bore exercise. This thesis represents the first attempt to comprehensively interrogate IBD physiology with the aim of identifying potential treatment targets for fatigue. Following an introduction to IBD in Chapter one, a detailed review of IBD fatigue aetiology follows in Chapter 2. Chapters 3 and 4 outline the methodology and developmental experiments undertaken to facilitate the MRI and 31P MRS experiments. Chapter 5 details the assessment of peripheral muscle function and body composition in quiescent Crohn’s disease patients relative to a healthy age and BMI matched control group. This is followed by the assessment of cardiovascular, brain and peripheral muscle deconditioning in Chapter 6 and 7. A final discussion chapter is dedicated to a review of the collective findings of this thesis in the context of existing data within the literature base. Suggestions are then made for future research priorities in the field of IBD fatigue

The urothelium and lamina propria as an alternative target for clinical antimuscarinics

Introduction: Overactive bladder is the most common type of bladder dysfunction and involves spontaneous contractions of the urinary bladder during the filling phase. The first-line pharmaceutical therapies for managing this disorder are antimuscarinics (Moro et al., 2011), which have a primary action of blocking the action of acetylcholine in the urothelium and lamina propria (Nardulli et al., 2012). However, more than 70% of patients who are administered these drugs cease their treatment regimen due to lower than expected treatment benefits or adverse side effects (Vouri et al., 2019). The reason for this is unclear, although this does suggest a varied effectiveness or selectivity of antimuscarinics on urinary bladder tissue. Aim: This study aims to find the differences in the abilities to inhibit contractions of the U&LP for commonly prescribed clinical antimuscarinics. Methods: Strips of porcine U&LP were mounted in carbogen-gassed Krebs-bicarbonate solution at 37°C. The tissues were paired with carbachol concentration-response curves performed in the absence or presence of clinically used antimuscarinics. The concentration for each antagonist was chosen at which the inhibited contractions reached a significant, but sub-maximal, extent. pEC50 values for each curve were analysed and estimated affinities calculated. Ethical approval was not required for this study as tissues were sourced from the local abattoir after slaughter for the routine commercial provision of food. Results: The clinical antimuscarinics producing right parallel shifts from the control in the U&LP (concentration; n value; estimated affinity or pkD; paired Student’s two-tailed t-test) included oxybutynin (1µM; 18; 7.08; p<0.001), solifenacin (1µM; 11; 6.88; p<0.001), darifenacin (100nM; 10; 6.48; p<0.001), tolterodine (1µM; 10; 8.00; p<0.001), trospium (100nM; 10; 7.63; p<0.001) and fesoterodine (100nM; 11; 7.40; p<0.001). Propiverine (concentration; n value; paired Student’s two-tailed t-test) did not produce a shift (1µM; 11; p=0.50). Conclusion: The data highlights a variance in the effectiveness of each clinically used antimuscarinic to antagonise the response to muscarinic receptor activation of the U&LP

Non-invasive approaches to identify the cause of premature fatigue in Inflammatory Bowel Disease patients

Inflammatory bowel disease (IBD) fatigue is a pervasive secondary disease symptom. The aetiology is poorly understood, meaning that treatment options are sparse. This is of particular concern for the relatively large proportion of patients with quiescent disease, who continue to report an increased perception of fatigue and demonstrate premature exercise fatigue, relative to healthy individuals. Fatigue is multidimensional and can manifest as a disproportionate perception of tiredness, perturbed cognitive functioning and an inability to sustain a required work output during exercise. In contrast to other chronic disease, to date there has been no mechanistic assessment of IBD fatigue reported in the literature. This is congruent with the essential absence of any effective treatment strategies convincingly shown to reduce IBD fatigue burden, independent of targeting known clinical causes. The application of Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) techniques during exercise represents a unique opportunity to non-invasively probe in-vivo metabolism across multiple organs. This thesis seeks to characterise IBD fatigue aetiology by combining laboratory-based assessment of peripheral muscle function and cardiorespiratory fitness, with proton (1H) MRI and phosphorus (31P) MRS during within-bore exercise. This thesis represents the first attempt to comprehensively interrogate IBD physiology with the aim of identifying potential treatment targets for fatigue. Following an introduction to IBD in Chapter one, a detailed review of IBD fatigue aetiology follows in Chapter 2. Chapters 3 and 4 outline the methodology and developmental experiments undertaken to facilitate the MRI and 31P MRS experiments. Chapter 5 details the assessment of peripheral muscle function and body composition in quiescent Crohn’s disease patients relative to a healthy age and BMI matched control group. This is followed by the assessment of cardiovascular, brain and peripheral muscle deconditioning in Chapter 6 and 7. A final discussion chapter is dedicated to a review of the collective findings of this thesis in the context of existing data within the literature base. Suggestions are then made for future research priorities in the field of IBD fatigue

Oncology Section EDGE Task Force on Prostate Cancer Outcomes: A Systematic Review of Clinical Measures of Strength and Muscular Endurance

Background: Strength deficits are a common morbidity following treatment for prostate cancer. Accurate assessment of strength and muscular endurance following prostate cancer treatments is essential to identify deficits and plan rehabilitation. Purpose: To identify strength and muscular endurance outcome measures that possess strong psychometric properties and are clinically useful for examination of men treated for prostate cancer. Methods: Multiple electronic databases were searched for articles published after 1995. Studies of tools used to assess strength and muscular endurance were included if they reported psychometric properties, were clinically feasible methods, performed on adults, and published in the English language. Each outcome measure was independently reviewed and rated by two reviewers. A single Cancer EDGE Task Force Outcome Measure Rating Form was completed for each category of strength or endurance assessment, and a recommendation was made using the 4-point Cancer EDGE Task Force Rating Scale. Results: Of the original 683 articles found, 30 were included in this review. Hand-grip strength and hand-held dynamometry were rated 3, recommended for clinical use. One repetition maximum was rated 2A, unable to recommend at this time but the measure has been used in research on individuals with prostate cancer. Manual muscle testing was rated 2B, unable to recommend at this time due to lack of psychometric support, and muscular endurance testing was not recommended (1). Conclusions: Utilizing objective dynamometry for hand grip and muscle strength testing provides precise measurement to assess baseline status and monitor change among men treated for prostate cancer

Multiple sclerosis: Physiological, perceptive and neural responses to exercise intensity

The aim of this work was to investigate physiological, perceptive and neurological responses to exercise intensity in people with multiple sclerosis (PwMS). The thesis begins with reviews of Multiple Sclerosis (MS) and exercise followed by three main studies. The first study explores the within session and test-retest reliability of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) from the resting tibialis anterior (TA) muscle of people with multiple sclerosis (PwMS). MEPs were recorded from 10 PwMS (2male, 8female) in 5 blocks of 5 trials using stimulators configured to fire a single pulse. MEP peak amplitudes (mV) and MEP areas (mV.mS) were measured at 2 durations MEPshort (30ms) and MEPlong (mean 50ms). The size of the first MEP (T1) from each block (mean 5.1) was significantly different to subsequent trials (T2 -T5) for MEPlong (mean 4.5 p 0.05). The testretest intraclass coefficients of correlation (ICC) and their 95% confidence intervals indicated high (>0.80) reliability for both MEParea and MEPpeak. The results showed that consistent, repeatable TMS measures were obtained from the resting TA of PwMS. The second study compared physiological and perceptive measures of PwMS to a group of healthy individuals while performing a symptom-limited graded exercise test (GXT), and through the post-exercise time-course to recovery. 54 PwMS (MSG, mean age 52.8years ± 9.0) and 17 healthy, age-matched controls (CG,mean age 48.9 years ± 5.7) performed a symptom-limited graded exercise test (GXT). Expired air (VO2), heart rate (HR), and differential ratings of perceived exertion (RPE breathing and RPE legs) were recorded during exercise, and HR and RPE (breathing and legs) during the recovery period. There were no significant differences in any baseline measure except RPEleg (MSG mean1.1±1.2; CG 0.2 ±0.4 p <0.05). During the GXT MS group means (±SD) failed to reach any criterion measure considered to represent peak performance. The control group mean exercise measures reached recognised criteria for peak testing on two measures; mean heart rate of within ± 10 beats of age predicted HRmax, mean RER value greater than 1.10. Significant differences existed between groups in all peak measures (mean MSG VO2 peak 20.1±6.4, mean CG VO2 peak 27.8 ±6.8; mean MSG HRpeak 140.1±24.8, mean CG HRpeak 167.7± 9.4; mean MSG RPE breathing 5.1±1.7, mean CG RPE breathing 6.8± 2.3; mean MS watts 97.4±35.2, mean CG watts 161.8 ± 43.4 p 0.05). There were no significant effects on the peak measures of variables when weighted by MS classification (RR-MS, SP-MS and PP- MS). There were differences between group recovery values for RPEleg at 10 mins (mean MSG 1.8 ±1.2, mean CG 1.0±1.1 p<0.05) and Temp°C at 3mins (mean MSG 36.5± 0.5, mean CG 36.9± 0.6 p<0.05) and 10mins (mean MSG 36.4±0.4, mean CG 37.0±0.3p<0.05) post-exercise. MS HR remained marginally above preexercise HR values at 10 minutes post-exercise. Differential measures of RPE for both groups recovered to pre-exercise values at 5 mins (±SD). During maximal exertion, it was observed that PwMS irrespective of disease classification, or years from onset were neither limited by their heart rate, nor their breathing, but that leg fatigue or lack of central drive to the lower limb was the reason for their inability to continue. In the third study, the physiological perceptive and central responses of PwMS were explored during exercise at low and high intensity, and through the timecourse to recovery. Participants performed 2 exercise training (ET) sessions where they performed 20 minutes of exercise on a cycle ergometer at 45% (ET45) and 60% (ET60) relative to peak watts determined during a GXT. 12 MSG and 9 CG completed the 2 exercise sessions. Repeated measures ANOVA revealed no significant differences in groups’baseline measures of HR, Temp°C, RPEbr, RPEleg or TMS measures between-groups or between-sessions. When comparing groups during ET45, measures of all variables were similar, except for RPE leg at 14mins,(mean MSG 3.3 ±1.1, CG 2.1±1.2 p<0.05). During ET60 MSG HR was higher from 14mins (mean 107.8bpm ±12.6 bpm, CG 136.8 bpm ±13.8 p<0.05). When comparing the results of MSG ET45 and ET60, during the 35 minute postexercise phase MSG HR recovered to pre-exercise values at 10 mins (mean HR 71.4bpm ±12.7, baseline 63.8 bpm ±9.8 p>0.05) after ET45, while post-ET60 HR failed to recover before session-end (mean HR 83 bpm ±11.3, baseline 64.6 bpm ±8.2, p<0.05). TMS measures were significantly depressed after both training sessions. Mean MEP size were 71% ±38% of pre-exercise levels at 30 secs post-ET45 (p<0.05) and 52% ±17.8% post ET60 at 2 minutes (p<0.05). Post-ET45 MEPs recovered to pre-exercise values at 10mins while post-ET-60 MEPs recovered at 20 mins. MEP latency and MEPρeriph were unchanged. Following ET60 we observed a strong negative relationship between Temp°C and MEPs (r=-.65, p=0.023). The investigation revealed significant, intensity-dependent, physiological and perceptive differences, during exercise and through the time-course to recovery. Analysis of responses to post-exercise TMS revealed a significant depression in corticospinal excitability, with a clear intensity-dependent difference in the depth and duration of MEP depression. In addition, an inverse relationship was found between internal body temperature and corticospinal excitability. The results may offer further guidance to clinicians for the provision of safe, appropriate and effective exercise prescription to PwMS

Neuroplasticity following pallidal stimulation for dystonia.

Dystonia is a disabling condition characterised by involuntary muscle spasms and abnormal postures. Its pathophysiology is incompletely understood but most lines of evidence point to an underlying defect of basal ganglia function leading to abnormal corticomotor output. Various abnormalities have been shown, including abnormal neuronal activity in basal ganglia output nuclei, defective neural inhibition at the spinal, brainstem, cortical level and sensorimotor misprocessing. More recently, increased neural plasticity has been found in dystonia patients in response to transcranial magnetic stimulation (TMS) protocols which induce motor cortex plasticity. Excessive plasticity might contribute to dystonia by promoting or reinforcing abnormal patterns of connectivity. The most significant advance in the treatment of generalised dystonia has been the development of globus pallidus internus (GPi) deep brain stimulation (DBS). Interestingly its beneficial effects are progressive over weeks to months rather than immediate. A plasticity effect has been implicated but physiological evidence has been lacking. Furthermore it is unknown what impact GPi DBS has on the underlying pathophysiology such as defective inhibition or excessive plasticity. The aim of the present work was to examine the impact of GPi DBS on underlying pathophysiological features such as disinhibition and abnormal motor cortical plasticity. In this thesis, studies in a consecutive series of dystonia patients, mainly those with primary generalised dystonia, who underwent bilateral GPi DBS, are presented. Patients were studied in a prospective, longitudinal manner with both clinical assessment of dystonia using a validated rating scale and electrophysiological studies including blink reflex excitability and forearm H-reflex reciprocal inhibition. In addition, once stable improvement had been achieved, the impact of GPi DBS on motor cortex plasticity was studied using TMS paired associative stimulation (PAS). The clinical study of these patients confirmed the therapeutic efficacy of GPi DBS and provided direct evidence of the superiority of the posteroventral globus pallidus as the optimal target. The longitudinal studies of blink and H-reflex, showed progressive normalisation of brainstem and spinal excitability, which correlated with the time-course of clinical improvement. These data provide the first evidence of reversal of underlying dystonia pathophysiology by GPi DBS and are compatible with progressive long-term neural reorganisation (plasticity) playing a role in the mechanism of action of GPi DBS. Furthermore, the result of TMS PAS experiments demonstrated that GPi DBS reduces the short-term plasticity of the motor cortex, the magnitude of this effect also correlated with therapeutic effect. This result is compatible with the concept that excessive plasticity promotes dystonia and reversal of these abnormalities may be another mechanism by which GPi DBS acts. In conclusion, work presented in this thesis provides the first electrophysiological correlates of clinical improvement in dystonia after GPi DBS, which collectively supports the notion that both long and short-term plasticity within the central nervous system are involved in the mechanism of GPi DBS action

Muscle activation patterns in shoulder impingement patients

Introduction: Shoulder impingement is one of the most common presentations of shoulder joint problems 1. It appears to be caused by a reduction in the sub-acromial space as the humerus abducts between 60o -120o – the 'painful arc'. Structures between the humeral head and the acromion are thus pinched causing pain and further pathology 2. Shoulder muscle activity can influence this joint space but it is unclear whether this is a cause or effect in impingement patients. This study aimed to observe muscle activation patterns in normal and impingement shoulder patients and determine if there were any significant differences. Method: 19 adult subjects were asked to perform shoulder abduction in their symptomatic arm and non-symptomatic. 10 of these subjects (age 47.9 ± 11.2) were screened for shoulder impingement, and 9 subjects (age 38.9 ± 14.3) had no history of shoulder pathology. Surface EMG was used to collect data for 6 shoulder muscles (Upper, middle and lower trapezius, serratus anterior, infraspinatus, middle deltoids) which was then filtered and fully rectified. Subjects performed 3 smooth unilateral abduction movements at a cadence of 16 beats of a metronome set at 60bpm, and the mean of their results was recorded. T-tests were used to indicate any statistical significance in the data sets. Significance was set at P<0.05. Results: There was a significant difference in muscle activation with serratus anterior in particular showing a very low level of activation throughout the range when compared to normal shoulder activation patterns (<30%). Middle deltoid recruitment was significantly reduced between 60-90o in the impingement group (30:58%).Trends were noted in other muscles with upper trapezius and infraspinatus activating more rapidly and erratically (63:25%; 60:27% respectively), and lower trapezius with less recruitment (13:30%) in the patient group, although these did not quite reach significance. Conclusion: There appears to be some interesting alterations in muscle recruitment patterns in impingement shoulder patients when compared against their own unaffected shoulders and the control group. In particular changes in scapula control (serratus anterior and trapezius) and lateral rotation (infraspinatus), which have direct influence on the sub-acromial space, should be noted. It is still not clear whether these alterations are causative or reactionary, but this finding gives a clear indication to the importance of addressing muscle reeducation as part of a rehabilitation programme in shoulder impingement patients