Measurement of Upper Motor Neuron Abnormalities with Diffusion Tensor Imaging and Transcranial Magnetic Stimulation in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that produces weakness and ultimately death from respiratory failure. ALS results in the death of nearly 400 Australians per year, with a median survival of only 2-3 years from diagnosis. While respiratory failure in ALS patients is generally a direct consequence of muscle weakness during disease end stage, a proportion of patients develop early and severe respiratory difficulties during sleep termed, Nocturnal Hypoventilation (NH). Hypoventilation produces nocturnal hypoxia, increasingly recognized as a predictor of survival, independent of respiratory muscle weakness. Intervention with Non Invasive Ventilation (NIV) in ALS patients with symptomatic respiratory failure improves survival. It is therefore critical to identify patients with NH, so that NIV can be offered. NH is increasingly recognized as a predictor of survival, independent of respiratory weakness. A mean nocturnal arterial oxygen saturation of less than 93% is predictive of a dramatically shortened mean survival time of less than 6 months. Although hypoxia is a consequence of muscle weakness, the mechanisms involved in NH - early in ALS - are largely unknown. The initial aim for this research was to develop a technique that could determine the level of Upper Motor Neuron (UMN) involvement in ALS patients who suffered from NH in comparison with ALS patients who did not. After extensive data collection had already begun, there was a lack of ALS patients suffering from NH during data collecting so the focus remained on developing a better technique for determining UMN involvement in ALS. ALS targets the Corticospinal Tract (CST), brain stem and Lower Motor Neurons (LMNs), resulting in progressive weakness in the limb, thoracic, bulbar and abdominal musculature. The UMNs in the motor cortex and LMNs in the brainstem and spinal cord can either be affected together or in isolation. The determination of UMN involvement is more of a challenge and no objective technique exists. The sensitivity of neurological assessment is limited due to LMN signs, such as testing reflexes in weak muscles. A marker to monitor UMN involvement in ALS is necessary to monitor disease progression, as well as to provide more pertinent insights into the pathological conditions of the neuronal tissues. Denervation and fasciculation in LMNs is examined by electromyography studies but there is no definitive diagnostic test for central nervous system injury. Transcranial Magnetic Stimulation (TMS) is a method for neurophysiological assessment of UMN function and cortical abnormalities in ALS. Diffusion Tensor Imaging (DTI) indirectly investigates CST pathology in ALS. The technique studies the water diffusion characteristics — with a higher diffusion indicating tract abnormalities. The TMS findings in this thesis back up previous studies and show that there is an increase in excitability of corticomotoneurons and a decrease in intracortical inhibition, contributing to motor cortex excitability in ALS. The DTI studies in this thesis have identified considerable differences between ALS patients and controls in diffiisivity along the CST between the internal capsule and midbrain in patients with ALS. There is a clear difference between the ALS patients and control group in both the DTI and TMS studies. There were many correlations between the TMS and DTI parameters. The most promising TMS parameter is Short-Interval Intracortical Inhibition (SICI). When SICI was divided by any DTI parameter there was a significant difference between the ALS and control group. This simple algorithm could potentially be used as a marker of UMN involvement in ALS.