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Prevalence rates, mechanisms and consequences of sleep disorders in people with MS are unclear. Accordingly, in Study 1, I investigated rates of sleep disorders and poor sleep quality in a consecutively recruited cohort (n=111) of people with mild to moderately-severe MS. I used a comprehensive sleep assessment battery that included a home-based sleep study, validated sleep questionnaires and actigraphy. >50% had a sleep disorder (sleep apnoea 31%, insomnia 29% and restless legs syndrome 25%). 66% reported poor sleep. Poor sleep and insomnia were significant predictors of fatigue and depression. Actigraphy showed prolonged periods lying down. Increased time spent lying over a 24-hour period was associated with poorer subjective sleep quality. Common sleep apnoea screening questionnaires had similar performance characteristics to those reported in non-MS populations. In Study 2, the Study 1 cohort was reassessed six months after a home-based step-training exercise intervention. The intervention group (n=53) was encouraged to perform 2h training per/week, while controls (n=58) continued usual physical activity. Step-training exercise did not change perceived or objective sleep quality or sleep apnoea. However, the odds of having excessive daytime sleepiness at reassessment were lower in the intervention group. Changes in sleep quality correlated with changes in fatigue, depression and sleepiness. While there was individual variability in certain sleep parameters, on average, sleep parameters were stable at 6-month follow-up. In Study 3, I investigated mechanisms of sleep apnoea in MS. The reflex responses to brief pulses of negative pharyngeal pressure of the largest upper-airway dilator muscle, genioglossus, were compared in people with sleep apnoea with versus without MS (n=11/10). There was no systematic difference in reflex responses between groups. However, ~30% of the MS group had an absent or abnormal response which was not seen in the controls. The two MS participants without a reflex response had multiple brainstem demyelinating lesions with an extensive lesion affecting the hypoglossal nucleus bilaterally. In summary, these findings highlight the major impact that sleep disorders and sleep disruption have on important comorbidities in people with MS and provide novel insight into a potential unique cause of sleep apnoea in certain people with MS.

Obstructive sleep apnoea (OSA) results from a combination of anatomical and neuromuscular defects. The mechanical properties of the airway and muscular activity in response to neural drive are poorly characterized. Objectives: To quantify the movement and strain of the upper airway tissues using dynamic MRI techniques and to improve understanding of airway mechanics. Methods: Spatial Modulation of Magnetization (SPAMM) and Magnetic Resonance Elastography (MRE) were used to investigate the mechanics of the tissues surrounding the airway in OSA patients. EMG was performed to quantify any respiratory related geniohyoid activity in quiet breathing and in the genioglossus with 90Hz vibration to ensure the vibration stimulus used during MRE was not activating the muscle as a potential confounder. SPAMM allows a grid of saturated magnetization to be superimposed on tissues using MRI and tissue motion to be followed with ultra-fast imaging as the grid deforms. SPAMM was used to image the movement of the tongue and lateral walls of the airway associated with quiet breathing in OSA patients compared to controls matched for age, sex and BMI. It was also used to image the movement of the tissues surrounding the airway associated with mandibular advancement across a spectrum of OSA (AHI range 0 75) and the effect of increasing airway pressure from 5 to 10cmH2O in subjects with moderate or severe OSA. MRE is a method of quantifying the shear storage modulus of tissue by imaging the propagation speed of a shear wave produced by vibrating the tissue. Oscillating motion sensitive field gradients are synchronized with the propagating waves in order to image the wave and a quantitative map of tissue mechanical properties is produced by mathematically reconstructing the wave in three dimensions. The shear modulus of the tissue is related to the wavelength of the wave in the tissue. Viscosity can be measured from the attenuation of the amplitude of the wave. MRE was used to measure the shear modulus and viscosity of the tongue and soft palate in OSA patients compared to matched controls and to compare the stiffness of the tissues in patients with OSA with and without 10cmH2O CPAP. Diffusion tensor imaging (DTI) mapped the fibre direction of the tongue so that anisotropic analysis of the MRE data could be performed. EMG of the geniohyoid was performed in normal subjects to correlate geniohyoid EMG activation with previous imaging studies using SPAMM (Cheng, Butler et al. 2008) which showed the genioglossus sliding over a stationary geniohyoid in normal subjects. Results: EMG of the geniohyoid showed minimal respiratory related activity. EMG with 90Hz vibration showed no change in activity from baseline. The SPAMM study of quiet breathing in OSA patients compared to matched controls showed that all subjects had airway opening in the sagittal plane associated with inspiration. AHI correlated negatively with the amount of movement of the nasopharyngeal lateral walls at inspiration (R = - 0.542, p = 0.006). In the sagittal plane, four movement patterns of the tongue were associated with inspiration: en bloc movement of the whole posterior tongue; movement of only the oropharyngeal tongue; rotational movement; or minimal movement. The minimal movement pattern was significantly associated with high AHI (p = 0.009). Shear modulus of the tongue in OSA patients was reduced compared to matched controls (2.68 ± 0.35 kPa compared to 2.98 ± 0.44 kPa, mean ± standard deviation, p < 0.001) and AHI was significantly negatively associated with isotropic tongue shear modulus (R = -0.496, p = 0.043). Anisotropic analysis revealed that parallel to the muscle fibres, the shear moduli of the tongue and soft palate were significantly less in OSA patients (p = 0.028, 0.041). During dynamic imaging, the mandible was advanced a mean 5.6 ± 1.8 mm. This produced lateral movement of the lateral walls through a connection from the ramus of the mandible to the pharyngeal lateral walls in all subjects. In the sagittal plane, 3 patterns of posterior tongue deformation were seen with mandibular advancement - A) en bloc anterior movement, B) anterior movement of the oropharyngeal region and C) minimal anterior movement. Subjects with lower AHI were more likely to have en bloc movement (p = 0.04) than minimal movement. Antero-posterior elongation of the tongue increased with AHI (R= 0.461, p = 0.01). Application of 10cmH20 CPAP increased the shear modulus of the soft palate from mean 1.8 ± 0.3 to 2.3 ± 0.5 kPa (p = 0.02) but there was no significant effect on the stiffness of the tongue. SPAMM sequences with increasing CPAP revealed no movement in 48/111 (43%) sequences, with 27/111 (24%) showing expansion and 36/111 (32%) showing narrowing. In the expansion sequences, the oropharynx moved more on average (2.2 ± 1.3mm) than the nasopharynx (1.3 ±1.5 mm, p = 0.007). Conclusions: In the most severe OSA patients the tongue moves little and is less stiff than matched controls. Increased multiunit EMG activity (Mezzanotte, Tangel et al. 1992) previously found in OSA patients do not seem to translate into movement or increased stiffness of the muscle, which may suggest that neural drive is ineffective. There was no change in tongue stiffness with CPAP application which suggests that decreased drive to the tongue associated with CPAP (Lo, Jordan et al. 2006) did not change the stiffness of the tongue, which is also evidence for ineffective neural drive. In subjects with intermediate severity there is heterogeneous movement which may represent intermediate progression of disease or inter-subject anatomical differences which result in regional regulation of the airway patency. Imaging of mandibular advancement suggested two mechanisms by which mandibular advancement improves airway collapsibility in some OSA patients; firstly subjects with lower AHI had movement of the entire tongue forward during mandibular advancement and secondly by increasing lateral airway dimensions via a direct connection from the lateral ramus of the mandible, which is a novel target of future investigation. It was likely the underlying structure in this region was the pterygomandibular raphe.

This thesis addresses the organisation of drive to human upper airway and inspiratory pump muscles. The characterisation of single motor unit activity is important as the discharge frequency or timing of discharge of each motor unit directly reflects the output of single motoneurones. Thus, the firing properties of a population of motor units is indicative of the neural drive to the motoneurone pool. The experiments presented in Chapter 2 measured the recruitment time of five inspiratory pump muscles (diaphragm, scalene, second parasternal intercostal, and third and fifth dorsal external intercostal muscles) during normal quiet breathing and quantified the timing and magnitude of drive reaching each muscle. Chapter 3 examined the EMG activity of a major upper airway muscle (the genioglossus). The single motor units of the genioglossus display activity that can be grouped into six types based on its association or lack of association with respiration. The types of activity are termed: Inspiratory Phasic, Inspiratory Tonic, Expiratory Phasic, Expiratory Tonic, Tonic, and Tonic Other. A new method is presented in Chapter 4 to illustrate large amounts of data from single motor units recorded from respiratory muscles in a concise manner. This single figure displays for each motor unit, the recruitment time and firing frequency, the peak discharge frequency and its time, and the derecruitment time and its frequency. This method, termed the time-and-frequency plot, is used to demonstrate differences in behaviour between populations of diaphragm (Chapter 2) and genioglossus (Chapter 3) motoneurones. In Chapter 5, genioglossus activity during quiet breathing is compared between a group of patients with severe OSA and healthy control subjects. The distribution of central drive is identical between the OSA and control subjects with the same proportion of the six types of motor unit activity in both groups. However, there are alterations in the onset time of Inspiratory Phasic and Inspiratory Tonic motor units in OSA subjects and their peak discharge rates are also altered. Single motor unit action potentials in OSA subjects showed an increased area. This suggests the presence of neurogenic changes and may provide a pathophysiological explanation for the increased multiunit electromyographic activity reported in OSA subjects during wakefulness.