An Investigation of the Biological and Neuronal Mechanisms of Post Traumatic Stress Disorder, Depression and Post-Concussive Syndrome Onset Following a Traumatic Brain Injury

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Nursing Research (NINR) )
ClinicalTrials.gov Identifier:
NCT02019654
First received: December 20, 2013
Last updated: September 18, 2014
Last verified: April 2014
  Purpose

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.


Condition
Depression
Traumatic Brain Injury
PTSD

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: An Investigation of the Biological and Neuronal Mechanisms of Post-Traumatic Stress Disorder, Depression and Post-Concussive Syndrome Onset Following a Traumatic Brain Injury

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Examine proteomic concentrations of inflammatory proteins and neuropeptides following TBI and determine if these biomarkers relate to a greater risk for PTSD, depression or PCS. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • We will investigate the activation and effective connectivity between the amygdala and other target regions regulating emotions by analyzing fMRI data to determine neuronal mechanisms related to PTSD, PCS, and depression onset. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Examine epigenetic modifications (i.e. DNA methylation) and genetic predisposition using blood and saliva that may relate to the risk for PTSD, depression and PCS onset following a TBI. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 120
Study Start Date: December 2013
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Participants must be enrolled in the recruiting protocol (11-N-0084), through the CNRM under the PI Dr. Latour.
  • Participants will have had a mild to moderate TBI in the previous 30 days.
  • Participants will be between the age of 18 and 65 years
  • Ability to give own consent
  • Demonstrate understanding of the protocol by passing a short consent quiz with a score of 6.

EXCLUSION CRITERIA:

  • Psychiatric Risks: Actively suicidal or at risk for suicide
  • Previous or current diagnosis of schizophrenia, bipolar disorder, other psychoses.
  • Current diagnosis of depression
  • Previous or current PTSD
  • Current diagnosis of PCS
  • Alcohol or drug abuse or dependence.
  • Pregnancy
  • Under treatment for major illness or injury that may put the participant at higher risk during participation (such as: IV therapy for severe infections, chemotherapy for cancer, multiple necessary surgical interventions for injuries, unstable cardiac disease, severe immune dysfunction, etc.)
  • History of any endocrine disorder or dysfunction, unless cleared via an endocrinology consult (including thyroid, adrenal and pituitary disorders)
  • Abnormal lab values that may indicate endocrine disorder or dysfunction (unless cleared by endocrine consult) or that may suggest major illness as described above as determined by the screening clinician.
  • Diabetes Mellitus

Participant may be able to participate in the study but will not be able to have an MRI if they have any of the following:

  • Aneurysm clip; implanted neural stimulator; implanted cardiac pacemaker or auto-defibrillator; cochlear implant; ocular foreign body, e.g. metal shavings; insulin pump; or irremovable body piercing
  • Claustrophobia
  • Cannot lie comfortably flat on their back for up to 90 minutes in the MRI scanner
  • Weigh over 250 lbs.

Participant may be able to participate in the MRI but not the Affective Stroop portion of the procedure if they are: Unable to see images close up without the aid of glasses (plastic goggles and contacts are permissible)

-Are unable to use their index and pointer fingers on both hands for the task

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02019654

Contacts
Contact: Amber K Cabrejos (301) 496-4061 priceak@mail.nih.gov
Contact: Jessica Gill, Ph.D. (301) 451-6960 gillj@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Jessica Gill, Ph.D. National Institute of Nursing Research (NINR)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Nursing Research (NINR) )
ClinicalTrials.gov Identifier: NCT02019654     History of Changes
Other Study ID Numbers: 140032, 14-NR-0032
Study First Received: December 20, 2013
Last Updated: September 18, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Post -Traumatic Stress Disorder (PTSD)
Traumatic Brain Injury
Neuroendocrine
Epigenetics

Additional relevant MeSH terms:
Depression
Depressive Disorder
Brain Injuries
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Post-Concussion Syndrome
Behavioral Symptoms
Mood Disorders
Mental Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Anxiety Disorders
Brain Concussion
Head Injuries, Closed
Wounds, Nonpenetrating

ClinicalTrials.gov processed this record on September 30, 2014