Developing and characterising imaging biomarkers for pain and analgesia

There is a need to improve translation of novel pain treatments from pre-clinical to clinical research, and the development of objective standardised biomarkers to verify target engagement is a vital step towards this goal. Features of chronic pain conditions, such as central sensitisation, can be experimentally induced in healthy humans. Functional magnetic resonance imaging (fMRI) is a highly valuable method to explore the neural basis for pain and also analgesic activity. This thesis combines these two research tools to develop and characterise neuroimaging biomarkers for pain and analgesia.
The first chapter consists of a systematic literature review, evidencing that this combination of techniques has provided a wealth of information about brain activity during pain states and analgesia. Co-ordinate based meta-analysis conducted to summarise results for a simple comparison between the neural responses during experimental hyperalgesia compared to control showed activation clusters in the insula cortex and thalamus.
Next, exploratory analysis of early 7 Tesla MRI data was conducted to investigate the neural changes that occur during the onset of central sensitisation. Conclusions were limited due to a low sample size, but there were interesting results showing increased blood oxygen-level dependent (BOLD) response in the insula and in the nucleus cuneiformis, a brainstem region shown to be specific to maintenance of central sensitisation.
The remaining three chapters comprise primary results and exploratory analysis from the IMI- PainCare BioPain RCT4 trial. The trial utilises the high frequency stimulation (HFS) model to induce central sensitisation, the neural basis for which had not previously been studied using fMRI. Comparison between pre-HFS and post-HFS data showed that the neural basis for HFS-induced central sensitisation was aligned to that seen with the well-characterised capsaicin model in imaging studies.
Subsequently, analysis of the main trial endpoints was conducted, to investigate the effects of lacosamide, pregabalin and tapentadol on biomarkers of pain processing observed by fMRI. Pregabalin reduced the punctate-evoked BOLD response in the posterior insula cortex. Lacosamide modulated resting state functional connectivity between the thalamus and secondary somatosensory cortex. In whole-brain analyses, tapentadol modulated responses in areas relevant to pain processing such as the anterior insula cortex.
Finally, exploratory analysis was conducted to characterise the placebo effect in the trial, showing that during placebo analgesia changes in brain activity were observed in regions associated with pain perception, including the insula and anterior cingulate cortices, and regions involved in affective and cognitive aspects of pain processing, such as the amygdala and dorsolateral prefrontal cortex.
Overall, this work comprises a valuable contribution to increase the utility and standardisation of applying experimental models in conjunction with fMRI in the assessment of novel analgesics prior to large scale clinical trials. As evidenced in the systematic review, individual fMRI studies are highly informative, but lack of standardisation makes comparison between studies difficult. The BioPain work addresses this challenge, providing a standardised assessment of multiple drugs across many pain biomarkers, demonstrating how these biomarkers can be valuably employed in drug development.

Keywords: neuroscience
fMRI
imaging
biomarkers
pain
Advisor: Tracey, I
Wanigasekera, V