Exploring function and effective connectivity of the motor cortex and its role in Tourette syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by vocal and motor tics. It is associated with cortical–striatal–thalamic–cortical (CSTC) circuit dysfunction and hyper-excitability of cortical motor regions. TS follows a developmental time course, in which tics often become increasingly more controlled during adolescence. Importantly, however, a substantial minority of patients continue to have debilitating tics into adulthood. This indicates that there may be important differences between adult TS patients and children and adolescents with the disorder.\ud \ud The first aim of my thesis was to explore the excitability of the primary motor cortex (PMC) at rest, during motor preparation, motor execution and the inhibition of action. In Chapters 3 and 4 I demonstrate that, in contrast to studies of adult patients, resting motor threshold (RMT) and the variability of motor-evoked potential (MEP) responses are increased in young people with TS, while the gain of motor excitability in reduced. Furthermore, these differences normalise with age over adolescence. I conclude that these effects are likely due to a developmental delay in the maturation of key brain networks in TS, consistent with recent brain imaging studies of structural and functional brain connectivity. Importantly, these findings suggest that the alterations in brain network structure and function associated with TS may be quite different in children and adult patients with the condition.\ud \ud In Chapter 4, I demonstrate that whilst there is evidence of reduced gain during motor execution in young people with TS relative to controls (Chapter 3), the reduction is likely driven by baseline differences and when corrected to baseline patients with TS show an increased ramping of motor excitability during motor execution. In fact, patients’ tic severity was inversely related to the modulation of motor excitability whereby those with the most severe tics were least able to increase excitability. Patients showed largely the same patterns of change in excitability during motor preparation and response inhibition. However, the extent to which patients could modulate excitability during motor preparation was related to phonic tic severity whereby those with the least severe tics had higher excitability change from baseline. In addition, those that were able to suppress motor excitability to a greater extent whilst inhibiting action had the least severe tics, likely engaging inhibitory mechanisms to a greater extent with the consequence of slower response times during the task. I conclude that the ability to modulate motor excitability is both related to pathology and adaptive compensatory mechanisms that may help in tic suppression.\ud \ud The second aim of this thesis was to explore effective connectivity, excitatory and inhibitory physiological mechanisms and the neurochemistry of PMC in young healthy adults. Subsequent experiments in Chapters 5 and 6 used various transcranial magnetic stimulation (TMS) techniques and proton magnetic resonance spectroscopy (1H-MRS) to investigate these issues. Chapter 5 explored interhemispheric facilitation and inhibition (IHI and IHF) in two directions between bilateral PMC. The results provided evidence for an asymmetry of interhemispheric interactions using dual site TMS (ds-TMS) whereby the left-to-right direction is more inhibitory than right-to-left. Furthermore, females appeared to show greater interhemispheric modulation than males and whilst there was robust evidence for IHI (in the left-to-right direction) IHF appeared to not be robust.\ud \ud Finally, Chapter 6 explored how TMS-induced measures of excitation and inhibition related to 1H-MRS measures of neurochemicals γ-aminobutyric acid (GABA), glutamate (Glu) and glutamine (Gln). GABA is the primary inhibitory neurotransmitter in the human brain and is critical for the regulation of neuronal excitability and the orchestration of neuronal networks and is critically important in neurodevelopmental disorders such as TS. GABA was not found to be related to measures of synaptic neurotransmission as assessed by TMS and neither was Gln. In contrast, Glu was found to be related to a hub of TMS measures, in particular, Glu was positively related to both intracortical facilitation (ICF) and long intracortical inhibition (LICI). Chapters 5 and 6 further uncovered relationships between ds-TMS, pp-TMS and 1H-MRS showing that these various measures likely have overlapping mechanisms.\ud \ud The final chapters extend our knowledge about the PMC and the methodologies used to assess its state. Chapter 5 extends our understanding of the communication between right and left PMC and highlights a normal asymmetry in communication. This is important for understanding neurodevelopmental disorders such as TS of which asymmetry in effective connectivity and brain volume have been implicated. Chapter 6 importantly shows that 1H-MRS measured GABA is likely irrelevant for assessing synaptic neurotransmission and thus its interpretations should be limited to non-synaptic levels of GABA. This is particularly important for TS research in which both changes in GABAA receptor activity is present in the PMC and abnormalities in GABA concentration have been shown