Chronic pain continues to be a significant problem affecting over 100 million Americans. One key feature to understanding chronic pain is the nature of its evolution and devolution (i.e., disease or treatment resilience). Neuropathic pain most frequently involves the peripheral nervous that sets up a cascade that produces functional, morphological and chemical changes in the brain. These changes may underlie chronification and the emergence of comorbidity such as depression. Here we propose to measure alterations in peripheral nerve and brain and correlate these with psychological measures for fear and self-efficacy that may predict outcome. We will evaluate these measures in (1) responders and non-responders in a model of neuropathic pain following ankle injury in a longitudinal study over 12 months or (2) treatment resistant subjects who have had their pain for greater than 12 months. In doing so we will define those brain changes that remain resistant to recovery and those that are implicated in recovery and we will correlate nerve alterations with brain changes. In order to carry out the project we propose the following specific aims:
Aim 1 : Nerve and Brain Measures of the Evolution and Devolution of Neuropathic Pain.
Aim 2 : Psychological Processes of Pain- Related Vulnerability (Fear) and Resilience (Self-Efficacy) Predict Recovery from Neuropathic Pain.
Aim 3 : Plastic vs. Non-Plastic Changes in Treatment Resistant Patients. We hypothesize that recovery from neuropathic pain is associated with resolution of peripheral nerve damage as well as normalization of specific brain networks and that chronification is related to the ongoing presence of maladaptive brain networks that contribute to the ongoing recruitment of emotional circuitry and treatment resistance. We will carry out the study in teenage subjects for a number of reasons including: (a) the peak incidence of ankle sprain occurs between fifteen and nineteen years of age and equal incidence occurs in males and females; (b) the recovery profile is usually rapid and even in the chronic state children are not as resistant to treatment as adults, thus allowing for data to be collected over a shorter time. We are well positioned to execute the Aims of the study based on: (1) our ability to evaluate brain changes in pediatric patients with chronic pain; (2) a highly skilled and experienced multidisciplinary research team; and (3) preliminary results obtained from our group that demonstrate our ability to carry out the proposed experiments. The successful outcome of this research proposal will provide insights into brain mechanisms of pain relief and pain chronification, novel rapid non- invasive processes for evaluating nerve damage in children and predictors of ongoing pain. These approaches could be rapidly and easily integrated into the clinic or clinical trials.

Public Health Relevance

The research proposed in this grant will study children with ankle sprains, a very common injury in teenage years that result in chronic pain from nerve injuries. Brain, nerve and psychological measures will be made in responders and non-responders. The measures will provide future guidance for targets for specific therapies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Marden, Susan F
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Boston Children's Hospital
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Borsook, David; Youssef, Andrew M; Simons, Laura et al. (2018) When pain gets stuck: the evolution of pain chronification and treatment resistance. Pain 159:2421-2436
Borsook, David; Youssef, Andrew M; Barakat, Nadia et al. (2018) Subliminal (latent) processing of pain and its evolution to conscious awareness. Neurosci Biobehav Rev 88:1-15