Investigation of the neural correlates of ongoing pain states using quantitative perfusion arterial spin labelling

At present, there are few clinically effective pain therapies available to treat chronic pain. One reason is due to a lack of understanding about how pain emerges in the brain. Excitingly, an emerging body of work suggests that the perfusion imaging technique, arterial spin labelling (ASL), is particularly well-suited to investigate this issue. The primary aim of this thesis is to develop and optimise a quantitative perfusion imaging approach to investigate the neural correlates of both experimental and pathological tonic pain. In Chapter 2, we explore different methods of inducing ongoing pain in healthy subjects. Results from this study show that mechanically induced pain is well suited for use in ASL FMRI experiments. In Chapter 3, we compare currently available ASL FMRI approaches for investigating tonic states, using a range of sensory paradigms. Results from these experiments support the use of an optimised version of Continuous ASL (CASL) FMRI to obtain whole-brain perfusion. Additionally, we discuss our decision to proceed with the newly acquired pseudo-continuous ASL (pCASL); a novel ASL technique that benefits from maximal signal-to-noise (SNR) across a whole-brain volume. In Chapter 4 we implement the pCASL FMRI approach to image the neural correlates of ongoing experimental pain. Results from the investigation of parametrically modulated ongoing mechanical pain show robust pain-related activation of key pain related regions that are monotonically active with an increase in stimulus intensity. Additionally, data from this experiment shows the presence of complex perfusion dynamics relative to pain worthy of further study. In Chapter 5, we optimised the pCASL sequence to obtain absolute perfusion changes across the whole-brain volume, using multi-inversion times, so that we could investigate the perfusion dynamics observed in Chapter 4. Results show that absolute perfusion changes during tonic pain are considerably less than for regions recruited during a non- pain task. Additionally, dynamic perfusion changes show complex stimulus responses across all active regions regardless of stimulus type. We conclude that while the technique is well suited to quantify absolute perfusion, the mechanisms underlying the dynamic changes in CBF (neuronal signal, neurovascular coupling) need further study. Finally, in Chapter 6, we implement the absolute perfusion approach developed in Chaper 5 to interrogate the neural correlates of the genetic pain disease, Erythromelalgia, and pleasurable relief. The results of this study show pain-related activation (and relief-induced reduction) of key pain-related regions. We conclude from these results that the ASL technique developed over the course of this thesis can be used to study a range of pain pathologies.
Taken together, the results of this thesis document the development of a powerful perfusion imaging technique capable of quantifying absolute perfusion changes across a whole-brain volume. The data presented here from investigations of both experimental and pathological pain states supports the use of this technique in future tonic pain studies, as well as other neuroscience applications. We are confident that implementation of this imaging approach will provide integral insight into the mechanisms of ongoing pain states; and further the development of novel efficacious pain treatment options.

Keywords: functional magnetic resonance imaging
pain neuroscience
chronic pain imaging
pain imaging
arterial spin labelling
Advisor: Tracey, I