Musculoskeletal disorders are a leading cause of disease burden worldwide. Alarmingly, the prevalence and socioeconomic impact of these conditions is rising. Pain is a common and disabling feature of many musculoskeletal disorders. While significant individual burden is evident at all stages of pain, socioeconomic costs increase dramatically when pain becomes chronic (> 3 months). Therapies that reduce the duration and severity of chronic pain are needed to lessen the individual and socioeconomic burden of these conditions. However, current interventions achieve limited success. The lack of effective therapies is hypothesised to be caused, in part, by a limited understanding of the neurophysiology of chronic musculoskeletal pain and the mechanisms driving the transition to chronicity. Recent advances in technology provide evidence of structural and functional changes in brain regions, including the primary motor cortex (M1), in response to musculoskeletal pain. Lasting changes in the excitability, topography and organisation of M1 have been hypothesized to underpin symptom chronicity in musculoskeletal disorders, however the mechanisms underlying these changes remain unclear. Inhibitory intracortical networks modulate the excitability, organisation and output of extrinsically projecting M1 neurons, and are well positioned to influence the cortical response to pain. Yet, the effect of acute and chronic muscle pain on inhibitory intracortical networks has not been fully elucidated. Thus, the overall aim of this thesis was to contribute to the body of knowledge on the intracortical response to musculoskeletal pain using i) acute experimental pain models in healthy individuals and ii) clinical populations living with chronic pain. The findings from the four studies conducted in this thesis provide novel insight into the intracortical response to acute and chronic musculoskeletal pain. As each of the mechanisms investigated are thought to be mediated by distinct neuronal populations, these findings suggest that the intracortical response to musculoskeletal pain is extensive and diverse. Observations of opposing changes in short- and long interval intracortical inhibition in the acute (increased inhibition) and chronic (decreased inhibition) stages of pain suggest that these forms of inhibition could play a role in the transition to chronicity. However, study 3 and 4 did not detect a correlation between intracortical inhibition and measures of pain and disability in LE and LBP, respectively. While this suggest that changes in intracortical activity may not contribute directly to symptoms of chronic pain and motor dysfunction, there is the possibility of a non-linear relationship between these variables. When the findings are taken together, changes in intracortical inhibition in pain suggest the enactment of a cortically driven motor strategy to protect painful tissues from further insult. While beneficial in the short term when the need to protect the tissues is high, failure to return to normal intracortical function in the long-term could lead to pain persistence through altered tissue loading. Large, longitudinal trials examining the transition from acute to chronic pain are necessary to confirm these hypotheses. If confirmed, future therapies which target maladaptive intracortical change could lead to greater improvements in pain and function for individuals experiencing chronic musculoskeletal pain
