How neuroimaging of pain pathways can decode chronic pain

Javeria Ali Hashmi¹
¹Anesthesia, Pain Management & Perioperative Medicine, Dalhousie University, Halifax, NS, Canada

Synopsis

Towards understanding the role of the brain in chronic pain aetiology, we investigate how threat predictions modulate pain perception through PAG circuitry. The central nervous system has an inbuilt capacity to modify pain intensity adaptively in relation to perceived threat (3). Processes in the brain that integrate noxious inputs with top-down threat signals play a key role in pain perception. These systems also have the capacity to bias the experience of pain away from the sensory evidence and towards expectations and beliefs. This talk discusses neurobiological pathways and mechanisms that are affected in chronic pain.

Chronic pain is one of the least understood clinical problems of our time and is widespread, affecting every 1 in 5 people. Recent decade of research has made it clear that nociceptive pathophysiology tells us only a part of the story, and that the central nervous system, especially the brain, actively contributes to the aetiology of chronic pain (1).Due to repeated treatment failures and long medical histories of unaddressed medical needs, people with chronic pain have altered expectations towards pain (2). Suffering from intense pains over long periods of times results in altered schemas about pain, and maladaptive schemas can further exacerbate pain. Note that pain serves as a stressor: it signals the threat of tissue damage and reinforces the aversive value of associated events. It is hence important to understand how schemas influence pain perception and how they contribute to chronic pain.

One area of interest is top-down pain modulation. This concept is based on the idea that the central nervous system has an inbuilt capacity to adaptively modify pain intensity with perceived threat (3). Processes in the brain that integrate noxious inputs with top-down threat signals play a key role in pain perception. Several regions and their connections in the brain stem ensure our survival by detecting threats and generating both fast and slow responses to escapable vs inescapable pain (4). These systems also have the capacity to find the threshold between threat and safety to make explore/withdraw decisions and the experience of pain is a necessary enforcer for such decisions (5). These systems can however, also detect false alarms: our brain can adaptively learn about situations that are unsafe and require immediate action and when it is safe and okay to carry on and explore. Interestingly, pain is not only a signal used as a sensory evidence for actual or potential threat of tissue damage; in uncertain situations, the pain intensity is weighted more towards top-down processes and less by sensory details transmitted by bottom-up pathways (3). Thus, prior states of anxiety towards pain can have a strong influence on the perceived threat and can result in magnification of pain response (6). This is especially true for persistent pain which acts as an intermittent and unreliable signal and such pain is thus more prone to be exacerbated in situations of unabated stressor of an impending threat to the body. Pain intensity in given conditions is often easily modifiable and can be cranked up when the perceived threat is high and cranked down when threat is low.

The PAG (periaqueductal gray area) is a key region, centrally involved in pain modulation. It consists of several columns located in the midbrain regions. These columns are an important hub where pain inputs interface with other survival functions such as threat and defense processing. Our lab is investigating whether multiband imaging of the entire brain with a 3T magnet can give insights into PAG activity and connectivity in relation with expectation and pain. Findings triangulated from several analyses have shown that the dorsal lateral PAG may be involved in detecting salient threats and the ventrolateral PAG in contextualization and semantic appraisal of threats (4). In addition, the PAG response to noxious stimuli can be altered by threat cues in healthy controls and in people who suffer from chronic pain. Aberrant ventrolateral periaqueductal gray response to noxious heat and high connectivity with dorsolateral prefrontal cortex predicts poor working memory and high intensity of chronic back pain (7). Thus, studying these neurobiological systems with a combination of neuroimaging and experimental paradigms are essential for understanding sensory disorders such as chronic pain. Such exposition opens up new ways of tackling mental health disorders and could even lead us to a better understanding of what goes awry in chronic pain states.

This new approach makes allowances for pivoting away from representational models and towards a functional role of pain that explains pain disorders. They also present an epistemological challenge on how we have traditionally viewed sense perception in general and it may even lead us to demarcate the boundaries of what real and what is illusory about pain and can reveal the limitation of perception such as placebo effects, cognitive biases and chronic pain disorders. Thus, we may be able to locate lacunae in brain function that lead to aberrant processing and use these to strategize therapeutics.

Acknowledgements

The authors thank all participants who took part in the experiments. We would like to acknowledge our funding sources: the Natural Sciences and Research Engineering Council of Canada (NSERC) Discovery Grant, the Canada Research Chairs Program, the John R. Evans Leaders and Canada Innovation Funds (CFI-JELF), the Canadian Institute of Health Research (CIHR) Project Grant, the Nova Scotia Health Authority (NSHA) Establishment Grant, and the NSHA Fibromyalgia Research Grant. The authors declare no conflicts of interest.

References

1. Hashmi, J.A., Baliki, M.N., Huang, L., Torbey, S., Herman, K., Schnitzer, T.J., Apkarian, A.V. (2013). Shape shifting pain: Chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain, 136, 2751–2768.

2. Hashmi, J.A. (2018). Placebo response: Theory, mechanisms and teleological roots. Neurobiology of the Placebo Effect. Editor Luana Colloca. ELSEVIER- Serial International Review of Neurobiology, volume 1383.

3. Lim, M., O’Grady, C., Cane., D, Goyal, A, Lynch, M., Beyea, S., Hashmi, J.A. (2020). Schemas induce enduring perceptual bias in pain perception. Journal of Neuroscience.

4. Wang S, Veinot J, Goyal A, Khatibi A, Lazar SW, Hashmi JA. (Accepted 2022). Distinct networks of periaqueductal gray columns in pain and threat processing. Neuroimage

5. LeDoux, J., & Daw, N. D. (2018). Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour. Nat Rev Neurosci, 19(5), 269-282. doi:10.1038/nrn.2018.22

6. Aristi, G., O’Grady C, Goyal, A, Lynch, M, Bowen, C, Beyea, S, Lazar, S, Hashmi, J.A. (in review, 2022) Top-down bias in pain perception is predicted by intrinsic structural and functional connections of the brain. Neuroimage

7. Veinot, J, Hashmi J.A. (2021). Brain Networks Underlying Working Memory are Linked to Subjective Experience of Chronic Pain. In review

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)