The Role of Scapular Dyskinesis in Rotator Cuff and Biceps Tendon Pathology

Shoulder tendon injuries including impingement, rotator cuff disease, and biceps tendon pathology are common clinical conditions and are a significant source of joint pain, instability, and dysfunction. These injuries may progress into partial tears then to complete tendon ruptures, which have limited healing capacity even when surgically repaired. These injuries are frequently seen in the presence of abnormal scapulothoracic joint kinematics (termed scapular dyskinesis). However, the cause and effect relationship between scapular dyskinesis and shoulder injury has not been directly defined. Additionally, while the incidence of shoulder injuries and recurrent failure of repairs is well-documented, the mechanisms behind them are not well-established, making optimal clinical management difficult. Therefore, the objectives of this study were to examine the effect of scapular dyskinesis on the initiation and progression of pathological changes in the rotator cuff and biceps tendon and to define the mechanical processes that lead to these changes. Unfortunately, clinical and cadaveric studies are unable to address the underlying causes of injury and cannot evaluate the injury process over time. Therefore, a rat model of scapular dyskinesis (created by denervating the trapezius and serratus anterior) was developed and used, both alone and in combination with overuse, to investigate the cause and effect relationships between changes in joint loading and alterations in tendon mechanical, histological, organizational, and biological properties. We hypothesized that scapular dyskinesis would result in altered joint loading conditions that would lead to degeneration of the rotator cuff and long head of the biceps. We found that scapular dyskinesis diminished joint function and passive joint mechanics and significantly reduced tendon properties. We also investigated the effect of overuse on tendon properties and found that overuse activity in the presence of scapular dyskinesis resulted in significantly more structural and biological adaptations than scapular dyskinesis alone. We also investigated the effect of scapular dyskinesis on supraspinatus tendon healing and found that scapular dyskinesis was detrimental to tendon properties. These results indicate that scapular dyskinesis is a causative mechanical mechanism of shoulder tendon injury. Identification of scapular dyskinesis as a mechanism of pathological changes will help inform and guide clinicians in developing optimal prevention and long-term rehabilitation strategies

An Investigation into Noxious Mechanosensation, and the Role of Peripheral Neuron Subpopulations in Pain

This thesis uses transgenic mice to explore the role of candidate and known mechanotransducers in acute mechanical pain. It also utilises transgenics to ablate whole populations of sensory neurons in mice to establish what role these also have in pain, both under normal and inflammatory conditions. The water and ion channel Aquaporin 1 (Aqp1) is preferentially expressed in the small diameter neurons of the peripheral nervous system (PNS). These are responsible for nociception, and Aqp1 has previously been implicated in pain sensation. Its role in acute mechanical pain has not fully been explored. By using global Aqp1 knockout (Aqp1KO) mice and mechano-clamp electrophysiology I am the first to demonstrate that Aqp1 contributes to the mechanically activated (MA) currents associated with pain sensing in nociceptors. However, it does not produce MA currents when expressed in naïve cells. Aqp1 is necessary for normal mechanical pain in vivo as Aqp1KO animals have an increased mechanical pain threshold. Thus, it is unlikely that Aqp1 is a pore-forming component of a noxious mechanotransducer but may form part of a membrane complex essential to mechanical pain sensation. Piezo2 is a known mammalian mechanotransducer and is responsible for light touch sensation and proprioception. It’s contribution to mechanical pain under pathological conditions is established but it’s role in acute mechanical pain remains controversial. I generate mice with a nociceptor-specific Piezo2 deletion and again use a combination of electrophysiological and behavioural assays to demonstrate that Piezo2 is not required for acute noxious mechanosensation. Thus, my data confirms that the mechanotransducer responsible for mechanical pain remains ambiguous. Finally I study the role of the cutaneous population of Parvalbumin-positive (PV+) sensory neurons in pain. This population is required for innocuous mechanical sensation including vibration sensing. By genetically ablating PV+ neurons to generate ‘PVDTA’ mice, I provide evidence that these neurons are necessary for negatively regulating the thermal, mechanical, and inflammatory pain response, as behaving animals are hypersensitive to these insults. I am the first to propose that cutaneous PV+ neurons are responsible for closing the so-called ‘pain gate’ in the dorsal horn of the spinal cord. Further evidence for this comes from an in vivo electrophysiological study of dorsal horn neurons in PVDTA mice, which exhibit increased excitability as a consequence of noxious stimulation. In vivo DRG neuron imaging in animals expressing a reporter protein in PV+ sensory neurons show that these neurons are capable of responding to noxious stimuli, thus solidifying this hypothesis

Bihemispheric reorganization of neuronal activity during hand movements after unilateral inactivation of the primary motor cortex

Le cortex moteur primaire (M1) est souvent endommagé lors des lésions cérébrales telles que les accidents vasculaires cérébraux. Ceci entraîne des déficits moteurs tels qu'une perte de contrôle des membres controlatéraux. La récupération des lésions M1 s'accompagne d'une réorganisation hémodynamique dans les zones motrices intactes des deux hémisphères. Cette réorganisation est plus prononcée dans les premiers jours et semaines qui suivent la lésion. Toutefois, nous avons une compréhension limitée de la réorganisation neuronale rapide qui se produit dans ce réseau moteur cortical complexe. Ces changements neuronaux nous informent sur l’évolution possible de la plasticité subaiguë impliquée dans la récupération motrice. Par conséquent il était grand temps qu’une caractérisation de la réorganisation rapide de l'activité neuronale dans les régions motrices des deux hémisphères soit entreprise. Dans cette thèse nous avons exploré l'impact d'une lésion corticale localisée, unilatérale et réversible dans M1 sur l'activité neuronale des zones motrices des hémisphères ipsi et contralésionnel lorsque des primates non humains ont effectués des mouvements d’atteinte et de saisie. Notre modèle d'inactivation nous a permis d'enregistrer en continu des neurones isolés avant et après l'apparition des déficits moteurs. Dans une première étude, la réorganisation rapide qui se produit dans le cortex prémoteur ventral (PMv) des deux hémisphères a été étudiée (Chapitre 2). Le PMv est une zone connue pour être impliquée dans le contrôle moteur de la main et la récupération des lésions M1. Dans une seconde étude, la réorganisation rapide du M1 contralésionnel (cM1) a été étudiée et comparée à celles se produisant dans les PMv bilatérales (Chapitre 3). Le cM1 joue un rôle complexe dans la récupération des mouvements de précision de la main suite à une blessure à son homologue. Nous révélons une réorganisation neuronale importante et beaucoup plus complexe que prévu dans les deux hémisphères lors de l’apparition initiale des déficiences motrices. Nos données démontrent que les changements neuronaux survenant quelques minutes après une lésion cérébrale sont hétérogènes à la fois dans et entre les zones du réseau moteur cortical. Ils se produisent dans les deux hémisphères lors des mouvements des bras parétiques et non parétiques, et ils varient au cours des différentes phases du mouvement. Ces découvertes constituent une première étape nécessaire pour démêler les corrélats neuronaux complexes de la réorganisation au travers du réseau moteur des deux hémisphères à la suite d’une lésion cérébrale.After brain injuries such as stroke, the primary motor cortex (M1) is often damaged leading to motor deficits that include a loss of fine motor skills of the contralateral limbs. Recovery from M1 lesions is accompanied by hemodynamic reorganization in motor areas distal to the site of injury in both hemispheres that are most pronounced early after injury. However, we have limited understanding of the rapid neuronal reorganization that occurs in this complex and distributed cortical motor network. As these neural changes reflect the landscape on which subacute plasticity involved in motor recovery will take place, an exploration of the rapid reorganization in neural activity that occurs in motor regions of both hemispheres is long overdue. In the current thesis, we set out to explore the impact of a localized, unilateral and reversible cortical injury to the M1 hand area on neuronal activity in motor-related areas of both the ipsi and contralesional hemispheres as non-human primates performed a reach and grasp task. Our inactivation model allowed us to continuously record isolated neurons before and after the onset of motor deficits. In a first study, the rapid reorganization taking place in the ventral premotor cortex (PMv) of both hemispheres was investigated (Chapter 2). The PMv is an area well-known to be critically involved in hand motor control and recovery from M1 lesions. In a second study, the rapid reorganization taking place in the contralesional M1 (cM1) was studied and compared to those occurring in bilateral PMv (Chapter 3). The cM1 has a complex role in recovery of dexterous hand movements following injury to its homologue. We reveal extensive, and much more complex than expected, neuronal reorganization in both hemispheres at the very onset of motor impairments. Our data demonstrate that neuronal changes occurring within minutes after brain injury are heterogenous both within and across areas of the cortical motor network. They occur in the two hemispheres during movements of both the paretic and non-paretic arms, and they vary during different phases of movement. These findings constitute a first step in a much needed and timely effort to unravel the complex neuronal correlates of the reorganization that takes place across the distributed motor network after brain injury

Exploration of the relationship between hypoxia and measures of clinical status and inflammation in children with cystic fibrosis

Hypoxia in cystic fibrosis (CF) may occur during sleep, and also during exercise, chest exacerbations and air travel. No standardised definition of nocturnal hypoxia in CF exists. Theoretical evidence suggests hypoxia may have a deleterious impact on clinical status in CF, due to effects on upregulation of pro-inflammatory cytokines, changes in Pseudomonas aeruginosa growth patterns, and causation of pulmonary hypertension. It was hypothesised that hypoxia, and resultant inflammation would adversely affect clinical phenotype in CF. Forty-one children with CF were studied, each undergoing home oximetry before attending for a day of clinical testing (exercise testing, lung function, respiratory and skeletal muscle testing, echocardiography, and quality of life assessment). In vitro work was undertaken to assess the effects of hypoxia on cell growth and interleukin-8 (IL-8) secretion in wild-type and CF airway epithelial cells. The effects of hypoxia were compared to a known proinflammatory stimulus - lipopolysaccharide (LPS) from Pseudomonas aeruginosa. ROC statistics were used to derive the most sensitive and specific definition of sleep hypoxia in the detection of elevated levels of inflammation (WBC, CRP, neutrophil counts and IL-8 levels). This definition (SpO2 10% sleep) was used to dichotomise the study population. Hypoxic CF subjects (n=9) had, when compared to normoxic controls (n=32): lower exercise capacity, lower BMI, lower FEV1 and FVC, elevated RV/TLC ratio, and higher Chrispin-Norman scores. Hypoxic subjects also had reduced quality of life, bone density, and increased RV thickness on echocardiogram. Hypoxic cell culture was suggested to be pro-inflammatory, with increased IL-8 production, and synergistically increased IL-8 secretion when cells were co-incubated with LPS under hypoxic conditions. Hypoxia is associated with reduced clinical well-being and increased inflammation in childhood CF. The paradigm exists of whether hypoxia is merely an endpoint of severe CF lung disease; or whether hypoxia may be a causative factor (as suggested by the in vitro work), as well as an effect of CF lung inflammation. A trial of restoration of normoxia in children with CF, with careful re-evaluation of clinically-relevant outcomes is suggested from this preliminary work

Exploring the role of interhemispheric inhibition in musculoskeletal pain

The overarching aim of this thesis was to determine whether: i) interhemispheric inhibition (IHI) is altered in response to unilateral musculoskeletal pain; and ii) a relationship exists between altered IHI (if any) and the development of bilateral sensorimotor dysfunction. To achieve this, three studies were conducted. These studies provided novel insight into IHI in experimentally induced acute muscle pain and chronic lateral elbow pain. The body of work in this thesis provides an original contribution to the field of musculoskeletal pain that deepens our understanding of IHI, and its potential association with changes in sensorimotor function in the unaffected limb, in unilateral conditions. Study 1 demonstrated a reduction in IHI from the affected to unaffected M1 but no change in IHI from the affected to unaffected S1 was observed in Study 2. In both studies, increased sensitivity to pressure was observed on the affected and unaffected sides. No change in IHI between M1s, and no differences in sensorimotor function were observed between individuals with chronic LE and healthy controls in Study 3. Taken together, the findings presented in this thesis suggest that IHI between M1s is reduced in response to acute muscle pain and altered IHI could contribute to the development of bilateral sensorimotor symptoms soon after pain onset. Conversely, IHI between S1s is preserved in response to acute muscle pain. In a clinical chronic musculoskeletal pain population, IHI is also preserved. However, further research is needed to determine whether the degree of change in IHI is related to various features of clinical pain such as pain severity, or the severity of bilateral sensorimotor dysfunction. The studies in this thesis are amongst the first to investigate: i) IHI in response to musculoskeletal pain of varying durations; and ii) the relationship between altered IHI and the development of bilateral sensorimotor dysfunction. Longitudinal studies that follow individuals from an initial episode of acute musculoskeletal pain to recovery, or to the development of chronic musculoskeletal pain, are required to further explore the relationship between IHI and the development of bilateral sensorimotor symptoms in unilateral musculoskeletal pain conditions

The influence of estrogen on skeletal muscle myosin regulatory light chain phosphorylation, post-tetanic potentiation, work, and power in C57BL/6 mice

Estrogen hormones are implicated in influencing skeletal muscle contractile function and specifically, the interactions between myosin and actin that facilitate contraction. Myosin regulatory light chain (RLC) phosphorylation (RLC-p) is highly associated with an increase in the percentage of myosin proteins strongly bound to actin during contractile activity. Myosin RLC-p is also highly associated with post-tetanic potentiation (PTP) i.e. the short-term increase in force observed following tetanic stimulation characteristic of fast-twitch skeletal muscle. The purpose of this study was to examine the influence of ovarian hormone deficiency and 17β-Estradiol (E2) replacement, on the PTP of concentric twitch force and myosin RLC-p of mouse fast twitch skeletal muscle. To this end, 4-month-old wildtype C57BL/6 mice were allocated to the ovariectomized (OVX), ovariectomized with E2 replacement (OVX+E), or sham-ovariectomized (SHAM) condition (n=8 mice). Extensor digitorum longus (EDL) muscles were surgically extracted and mounted for in vitro contractile experiments at 25° C involving the use of a brief potentiating stimulus (PS) to induce PTP. The PS, consisting of four equally spaced tetani (400Hz, 100ms) over 10.5s, significantly increased concentric twitch force and myosin RLC-p levels across condition groups. However, no significant differences in PTP, myosin RLC-p, or rates of force development and relaxation were observed between muscles of the OVX, OVX+E and SHAM conditions. A significant drop in relative tetanic force amongst the first and second tetanus within the PS was observed of muscles from OVX mice compared to that of OVX+E and SHAM mice. Specific force, calculated as the ratio of force to muscle PCSA, total work, peak work, and power production, were significantly increased following the PS across conditions, and were significantly less of muscles from OVX mice compared to OVX+E and SHAM, both prior to and following the PS. Data are contrary to the primary hypothesis that E2 influences myosin RLC-p and PTP in fast twitch skeletal muscle, though are suggestive of an influence of OVX and E2 on skeletal muscle quality

Reward and punishment: the neural correlates of reinforcement feedback during motor learning

‘By the carrot or the stick’ reward or punishment has been contemplated by instructors to motivate their pupils to learn a new motor skill. The reinforcements of reward and punishment have demonstrated dissociable effects on motor learning with punishment enhancing the learning rate and reward increasing retention of the motor task. However it is still unclear how the brain processes reward and punishment during motor learning. This study sought to investigate the role of reinforcement feedback in cortical neural activity associated with motor learning. A novel visuomotor rotation task was employed with reward punishment or null feedback as the participants adapted their movement to a 30-degree counter-clockwise rotation. We measured movement time and task accuracy throughout the task. Surface electroencephalography was utilized to record cortical neural activity throughout the learning and retention of the motor task. Event-related potentials (ERPs) were calculated to assess how the brain processes the reinforcement feedback and prepares for movement. Repeated measures ANOVAs were utilized to detect differences in the movement parameters and ERP amplitudes. This study found that reward and punishment feedback did not produce different effects on the rate of task learning. However punishment feedback impaired the retention (memory) of the motor task. These behavioral effects were accompanied by changes in the amplitude of ERPs during feedback presentation and movement preparation. These results suggest that punishment feedback alters brain processes involved in memory formation during motor learning

Physiological and whole-body correlates of contest behaviour in the hermit crab Pagurus bernhardus

The series of experiments that comprise this thesis used shell fights in the hermit crab Pagurus hernhardus as a model system to address the proximate physiological and whole-organism correlates of contest behaviour. These correlates of fighting ability rangec from the metal ions magnesium (Mg ) and calcium (Ca ), through respiratory pigments and muscular proteins to whole-organism performance capacities and behavioural syndromes. The work presented here thus demonstrates that a suite of physiological and whole organism variables influence contest behaviour in hermit crabs, and that both aerobic and performance capacities are very important in determining agonistic success.EThOS - Electronic Theses Online ServiceGBUnited Kingdo