Emotional contributions to the pain experience: The role of Cerebellar-Periaqueductal Gray communication

Acute pain is short lasting and is a necessary sensory function that signals tissue damaging stimuli vital for survival. In comparison, chronic pain can persist beyond the period of tissue repair or have no known cause lasting months to years. Treatment strategies effective for acute pain often fail in chronic pain, which is notoriously challenging to manage. Therefore, new research is essential to identify novel targets for developing chronic pain treatments. For acute and chronic pain, the experience is dynamic, and can change depending on psychosocial factors related to an individual’s emotional, social and cognitive state. Emotions, such as fear and anxiety can directly contribute to the impact of chronic pain in a patient. For example, an immediately fearful or aversive event can cause a reduction in pain, while anxiety from a potential threat can enhance it. These emotionally driven changes in the pain experience can impact a patients’ day-to-day functioning, and quality of life. Furthermore, mental health disorders such as depression and anxiety are risk factors for the development of chronic pain, while patients with chronic pain have increased risk for developing depression and anxiety. These comorbidities suggest common underlying mechanisms linking emotions and pain. A major unanswered question is what are the neurobiological mechanisms connecting emotions and the pain experience? Targeting neurobiological mechanisms could help patients with their quality of life by modifying the impact of emotional contributions to pain. One such mechanism might involve the suppression or enhancement of pain transmission by pathways travelling from the brain to the spinal cord through the so-called descending pain modulatory system (DPMS). In some individuals the DPMS becomes abnormal and amplifies the pain signal leading to chronic pain. Survival networks, made up of networks of neurons across many brain regions, drive protective behavioural responses to aversive events and contribute towards the emotional experience and expression of fear and anxiety. These networks make predictions about the world around us which are then compared with actual outcomes. If the predictions are wrong, an error signal is created and the outcome is modified. We hypothesise that chronic pain is due to a change in the ability of survival networks to correctly predict the appropriate pain response to injury, and that this causes amplification of the pain signal by the DPMS. The periaqueductal grey (PAG) is a region of the brain known to co-ordinate fear and anxiety related behaviours, while playing a key role in modulating the DPMS. The cerebellum also contributes to survival circuits and emotional behaviour, in part through its connections with the PAG. Both regions are able to detect predictable and unpredictable pain information making them strong candidates in driving emotional contributions to the pain experience. This project will test, using a rat model of pain, how the cerebellum and PAG contributes to chronic pain and if emotionally driven contributions to the pain experience are dependent on cerebellar interactions with the PAG. The results from this project will provide essential foundational knowledge for developing treatment strategies that benefit chronic pain patients. For example, future research could explore the use of non-invasive brain stimulation targeting the cerebellum to reduce psychological factors affecting pain. Additionally, it may help patients with comorbid mental health issues better understand the mechanisms underlying their chronic pain.