Brainstem’s Role in Placebo and Pain Perception Highlighted Interview with:
Lewis Crawford, B.Sci (Hons), PhD Candidate 
Neural Imaging Laboratory | Faculty of Medicine and Health
University of Sydney  What is the background for this study?  What are the main findings?

Response: This study was performed as a means to accurately and robustly define the areas of the brainstem responsible for alleviating and enhancing pain via conditioning and expectation alone, that is, the phenomena of placebo analgesia and nocebo hyperalgesia. The reason we were able to do this was by being able to access a 7-tesla ultra-high field MRI, one of only two in Australia, that allowed us to resolve the small nuclei in the brainstem which make up descending analgesic circuitry (they carry signals from your brain to your spinal cord).

We found that a central pathway, comprised of the midbrain Periaqueductal Gray (PAG) and Rostral Ventromedial Medulla (RVM), acted during both phenomena, however in opposite ways. We also identified several other nuclei as playing a role in the modulation of pain which, prior to this study, had not been explored or suggested to play a role in this context. We believe that the brainstem circuitry we defined here enables further research into mechanisms responsible for analgesia and hyperalgesia and will promote further investigation into brainstem function in humans. What should readers take away from your report?

Response: Readers should take away from our study that there are unique pathways within the brainstem which are responsible for modulating your perception of pain, going beyond simply “tricking” someone into reporting their pain as higher or lower than they are experiencing, there are indeed neural mechanisms which can act to modulate your perception of pain, and they can be called upon to do so via expectation and conditioning cues for pain relief and enhancement, respectively. What recommendations do you have for future research as a result of this work?

Response: I would recommend that future research continues to investigate how the brainstem is acting in both an ascending (sending information up to the cortex) and descending (sending information down to the spinal cord), way. We know that unique brainstem nuclei hold crucial roles in both the supply and transmission of some pretty important neurotransmitters around you brain and body (dopamine, opioids, cannabinoids, and norepinephrine), however, due to its small size and complex organization, the brainstem goes largely unexplored in most neuroimaging research.

In the future I personally would now like to explore which regions of the cortex are responsible for calling upon the nuclei which we observed as playing a role in the modulation of pain, as well as if different conditioning cues (for example we used a false placebo and nocebo cream, but you could also use lights, sounds, and social cues), activate a similar or different circuitry to facilitate pain modulation. Is there anything else you would like to add?

Response: The placebo effect has been around since its original induction as a means to return injured soldiers from the front line in world war 2. The fact that it is still being investigated today tells us that we still don’t fully understand how to reliably trigger this phenomena, nor exactly how it is acting within the brain to enact the desired effect of pain relief. It is an exciting field to be working in and i look forward to seeing how far the field grows as 7-tesla MRI’s become more readily available for research. 


Brainstem Mechanisms of Pain Modulation: a Within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses



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