Project: Research project

Project Details


Overarching Challenge: The overarching goal of this Focused Program is to identify mechanisms and predictors for the persistence of post-traumatic headache (PTH) and methods to treat PTH and prevent its persistence. Clinical, translational, animal model, imaging, neurophysiologic, molecular, and genetics data that will be collected during this Focused Program will allow for development of multivariate models that describe mechanisms and predictors for the persistence of PTH due to mild traumatic brain injury (mTBI). This Focused Program will also include a Phase II clinical trial investigating a calcitonin gene-related peptide (CGRP) receptor monoclonal antibody for the treatment of PTH.Background and Rationale: Annually in the US there are ~2.8 million TBI-related emergency department (ED) visits, hospitalizations, and deaths, and over 2 million individuals are diagnosed with mTBI. Between 2000 and 2018, 380,000 US Armed Service members were diagnosed with TBIs, of which over 80% were mTBIs. The personal and societal costs from TBI are substantial. In the military, the cost of care increased from $21 million in 2003 to $646 million in 2010 and the median healthcare cost for Veterans with TBI is three times higher than for those without TBI. PTH is the most common symptom following mTBI. Although some PTHs resolve within the first few days, a large proportion of individuals with PTH do not have headache resolution and thus have persistence of PTH. Persistent PTH results in substantial pain, disability, and medical expense. There are no approved treatments for PTH, and treatments currently 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 receive effective treatment, thereby preventing the persistence of PTH. This Focused Program will address this area of need by investigating mechanisms for PTH persistence, biomarkers that predict PTH persistence, and methods of preventing PTH persistence.Research Plan: This Focused Program consists of six synergistic, non-interdependent, individual projects that address the overarching goal via use of animal models of PTH due to mTBI, human investigations of individuals with PTH via in-depth phenotyping, neurophysiology testing, imaging brain structure and function, and via human and animal molecular and genetic biomarker identification. Finally, this Focused Program includes a Phase II clinical trial of a CGRP receptor monoclonal antibody for the treatment of PTH. Advanced multivariate modeling methods with machine-learning techniques will be utilized to identify the optimal combination of data from the individual projects for predicting PTH persistence and for predicting treatment response to the CGRP receptor monoclonal antibody. Individuals with PTH will be enrolled from the Mayo Clinic, the Phoenix VA Healthcare System, and Luke Air Force Base.Impact: The short-term impact from this research includes identification of mechanisms underlying PTH persistence; potential methods to prevent PTH persistence; identification of clinical, imaging, molecular and genetic predictors for PTH persistence; and a Phase II randomized placebo-controlled clinical trial in PTH testing a CGRP monoclonal antibody. The long-term impact from this research includes the ability to identify who is likely to have PTH persistence and a personalized medicine approach for preventing PTH persistence by intervening with treatment early after onset of PTH in those individuals who are in need of such therapy (i.e., those likely to have PTH persistence and those likely to respond to the treatment). This approach would substantially reduce the burden from PTH among civilian and military populations.Military Relevance: PTH is the most common and one of the most persistent symptoms following mTBI. Given the high rates of mTBI among Service members during combat and among Service members, Veterans, and beneficiaries off the battlefield, PTH exerts a substantial personal, economic, and societal burden on the military. Identifying mechanisms and predictors of PTH persistence, an effective treatment for PTH, and predictors of responding to PTH treatments, will allow for optimization of PTH treatment, i.e., those individuals who are most in need of treatment would receive such treatment.

Effective start/end date9/1/198/31/23


  • Congressionally Directed Medical Research Programs: $9,999,820.00


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