A Multidisciplinary Translational Approach to Investigate the Mechanisms, Predictors, and Prevention of Persistent Post-Traumatic Headache

Topic Area: Post-Traumatic Headaches (PTHs)

Importance of Problem Addressed by this Proposed Research: In the US there are >2 million individuals diagnosed with mild traumatic brain injury (mTBI) each year. TBIs are common in the civilian population during participation in sports, due to falls, due to vehicular accidents, and other mechanisms. TBIs are also very common in the military. Between 2000 and 2018, 380,000 US Armed Service members were diagnosed with TBIs, of which >80% were mTBIs. In fact, mTBI has become known as the 'signature wound' of the recent conflicts in the Middle East. The personal and societal costs from TBI are enormous. In the military, the cost of care increased from $21 million in 2003 to $646 million in 2010, and the typical healthcare cost for Veterans with TBI is three times higher than for Veterans without TBI. PTH is the most common symptom following mTBI. Some PTHs resolve within the first few days of onset, without any specific treatment. However, in a large proportion of individuals, the PTHs do not resolve, and they last for many months to years. These persistent PTHs cause substantial pain and disability. There are no approved treatments for PTH, and treatments commonly used for other headache disorders typically provide little benefit for those with persistent PTH. Optimally, individuals who are at high risk for PTH persistence would be identified and treated, with the intent of preventing headache persistence. Currently, methods to prevent PTH persistence have not been found since the mechanisms responsible for PTH persistence are largely unknown, predictors for PTH persistence have not been identified, and treatments for PTH have not been adequately studied.

How the Proposed Research Addresses this Critical Problem: This Focused Program research will help to address a critical area of need by investigating underlying mechanisms responsible for the persistence of PTH, identifying factors that predict which people are at highest risk for having PTH persistence, and determining methods of treating PTH and preventing its persistence. Clinical, translational, animal model, imaging, molecular, and genetic data will be used to develop models that describe mechanisms and predictors for PTH persistence. This research includes a clinical trial that will test a newly developed medication that targets a mechanism of persistent headache pain. This treatment, a calcitonin gene-related peptide (CGRP) receptor monoclonal antibody, has just recently shown to be very effective for treating migraine and has received Food and Drug Administration approval for treating migraine. In this Focused Program, the CGRP monoclonal antibody treatment will be studied in a clinical trial for PTH.

This Focused Program consists of individual research projects that include: (1) animal studies utilizing state-of-the-art models of mTBI and PTH to investigate the mechanisms of and biomarkers for PTH persistence; (2) human studies that will collect very detailed descriptions of symptoms in patients with PTH; (3) human and animal neurophysiology studies investigating cutaneous and light-induced pain thresholds; (4) human brain imaging studies to investigate functional and structural measurements that predict PTH persistence, response to PTH treatment, and brain changes that occur as individuals have PTH persistence or resolution; (5) human and animal molecular and genetic biomarker investigations looking for substances in the blood that predict PTH persistence and response to PTH treatment; (6) a clinical trial of a CGRP receptor monoclonal antibody for treatment of PTH; and (7) advanced statistics and machine learning methods to identify the optimal combination of data from the individual projects for predicting who will develop persistent PTH and for predicting who will respond to treatment.

Impact/Applicability of Research: The short-term impact from this research includes identifying mechanisms underlying the persistence of PTH, potential methods to prevent PTH persistence, identification of clinical, imaging, molecular and genetic predictors for PTH persistence, and a randomized controlled treatment trial in PTH. The long-term impact from this research includes the identification of who is likely to develop persistent PTH and a personalized medicine approach to the prevention of persistent PTH. This approach would substantially reduce the burden from PTH amongst civilian and military populations.