An Investigation of the Biological and Neuronal Mechanisms of Post Traumatic Stress Disorder, Depression and Post-Concussive Syndrome Onset Following a Traumatic Brain Injury
Condition: Traumatic Brain Injury; PTSD; Depression
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Post-Concussion Syndrome; Wounds and Injuries; Depression; Depressive Disorder; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Observational

Summary: 
      Background: A traumatic brain injury (TBI) could mean a person is at high risk for other
      long-lasting problems. These problems could include post-traumatic stress disorder (PTSD),
      depression, and post-concussive syndrome (PCS). For example, about 700,000 Americans each
      year who have a TBI later go on to have PTSD also. Depression and PCS are also common in
      people who had a TBI. Some people will have these problems later. These problems can
      seriously interfere with a person s life. Some people will not have these problems at all.
      There are many reasons for this difference. Researchers think the main reason is that people
      have different genetic and environmental influences. Right now, we only have few kinds of
      treatments to prevent or treat these problems after a TBI. The few treatments we have often
      do not work well. It is important to understand what factors make a person at high risk for
      these problems after a TBI. This could allow researchers and doctors to help address these
      problems early. Addressing these problems earlier may help a person have better health in the
      long run.

      Objectives:

        -  To study the biological changes that happen after mild to moderate TBI which could be
           linked to the onset of PTSD, depression, and post-concussive syndrome

        -  To study brain mechanisms that could explain risks for getting a psychiatric disorder
           after mild to moderate TBI. This will be done using a test called functional MRI (fMRI).
           This test takes images of the brain while a person is doing a simple task.

      Eligibility:

        -  Men and women who are 18 to 65 years old.

        -  Had a mild to moderate TBI (including concussion) in the last month.

      Design:

        -  5 outpatient visits to the NIH Clinical Center over one year.

        -  The first visit is a screening visit to see if you can join the study. This visit must
           happen within 30 days of the TBI. The visit includes lab work (blood and urine), a
           history and physical exam done by a physician or nurse practitioner, and a psychiatric
           interview with a behavioral health nurse.

        -  Visits 2, 3, 4 and 5 happen at one, three, six and twelve months post-injury. At these
           visits participants may have some or all of the following tests: blood and saliva
           collection, urine collection, questionnaires and interviews to assess symptoms, a test
           to see your response to stress (called hydrocortisone challenge), and fMRI brain
           imaging.

        -  This study does not provide treatment.

        -  This study is not a substitute for seeing a primary care provider.

        -  This study should not replace any therapies you may be taking.
    

Detailed description: 
      Objective: A traumatic brain injury (TBI) places individuals at high risk for developing
      posttraumatic stress disorder (PTSD). TBIs account for the onset of PTSD in approximately
      700,000 Americans each year. Depression and post-concussive syndrome (PCS) are also common
      and often comorbid with PTSD. However, even in this group, there is a high-level of
      inter-individual response to traumatic brain injuries, suggesting that a better understanding
      of the mechanisms underlying this risk would be of great value in directing preventive
      interventions. The reasons for this heterogeneity are undoubtedly multi-factorial, and
      involve a complex interplay between genetic and environmental factors, that we may be able to
      understand through peripheral biomarkers and central examination of neuronal functioning. We
      suggest that DNA methylation may be a putative biomarker of psychiatric risk, as it reflects
      long-term changes in the function of the gene and may shape the recovery ability of the TBI
      patient through changes in cell function. In addition, differential proteomic response,
      including the function of the neuroendocrine system, likely relates to changes from
      epigenetic modification in both neurons and immune cells, which may contribute to the risk
      for the onset of PTSD as well as depression and PCS. We have previously shown that both PTSD
      and depression are associated with endocrine alterations, leading us to question if this
      biological change may underlie vulnerability for the onset of PTSD as well as depression and
      PCS following a TBI. In support of the idea of shared vulnerability, patients with a TBI also
      often display endocrine function alterations. In addition, sleep disturbance is common
      following TBI and is a core symptom of PTSD depression and PCS, suggesting that sleep may
      contribute to psychiatric and neurological recovery from a TBI. This line of research is
      essential, as current treatments to prevent or treat psychiatric risk following TBI are often
      ineffective, and even treatment of PCS is limited. This poor understanding results in our
      limited ability to reduce the risk for compromises in the health and well-being of patients
      who sustain a TBI.

      Study population: Participants with a moderate or mild TBI (n=100) will be followed for a
      period of one year.

      Design: This is a natural history study that will recruit patients within 30 days of a
      mild/moderate TBI, and will follow them over a one year period, with follow-up at 1, 3, 6 and
      12 months following the TBI. Biological profiles including the concentration of inflammatory
      proteins and neuropeptides, and DNA methylation will be examined. An optional structural and
      functional magnetic resonance imaging (fMRI), and a hydrocortisone stimulation test will be
      used to evaluate the role of neuronal and neuroendocrine functioning following TBI.

      Outcome measures: The primary outcomes of interest are the biological changes that occur
      following TBI which are associated with the onset of psychiatric disorders of PTSD, and
      depression, as well as the onset of PCS. The secondary aim is to examine neuronal mechanisms
      that underlie the risks for these disorders through the use of fMRI. Additional aims will
      determine the role of psychological resilience traits in recovery and also how sleep relates
      to recovery and psychiatric risk.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        This study will follow patients who sustained a mild or moderate TBI. Up to 120
        participants (target n of completers = 100) will be enrolled into the study within 30 days
        of the TBI and will be followed over one year. Two groups will emerge: (1) those who
        develop PTSD, PCS, or depression and (2) those who are resistant to developing these
        disorders. Participants must be enrolled in CNRM recruiting protocol (11-N-0084), evaluated
        for a TBI at the George Washington University Hospital, or referred from the NIH/CC Office
        of Patient Recruitment. NIH employees may participate.
      
Keywords: Post-Traumatic Stress Disorder (PTSD); Traumatic Brain Injury; Neuroendocrine; Epigenetics; Natural History