Neural Markers and Rehabilitation of Executive Functioning in Veterans With Traumatic Brain Injury and Posttraumatic Stress Disorder

Background: It is estimated that up to half of all military service members with
combat-related traumatic brain injury (TBI) also meet criteria for Posttraumatic Stress
Disorder (PTSD). TBI and PTSD are both characterized by deficits in multiple cognitive
domains, including attention, executive function, and affective and cognitive control.
However, cognitive and affective sequelae associated with TBI are compounded by the presence
of PTSD symptoms in returning veterans. Specifically, it has been shown that significant
frontal lobe dysfunction, particularly disinhibition, occurs more often among veterans with
both TBI and PTSD than among veterans diagnosed with only one of these conditions. The
combination of TBI and PTSD in veterans has also been linked to problems with anger and
violence, which are common complaints of veterans seeking mental health services
post-deployment and have been shown to predict poor treatment outcomes in Iraq and
Afghanistan veterans. Executive dysfunction, especially difficulty with attentional
processing, is strongly related to hostility and aggressiveness in Iraq and Afghanistan
veterans; increasingly so in the presence of TBI and PTSD.

Objective/Hypothesis: Although the relationship between combined TBI/PTSD diagnoses and
post-deployment adjustment problems has been clearly demonstrated, there has been little
empirical research into clinical interventions designed to reduce the severity of cognitive
and affective symptoms in veterans with both TBI and PTSD. Therefore, the investigators
propose to conduct a randomized trial of theoretically based cognitive rehabilitation to
improve executive function and affective control among Iraq and Afghanistan veterans with
both TBI and PTSD, and to measure clinical outcomes using a comprehensive array of functional
and structural methods. The investigators hypothesize that improved executive function among
those in the experimental group as well as reduced irritability/impulsivity and improved
social/occupational functioning. The investigators further hypothesize that, as a group,
veterans participating in the cognitive rehabilitation program will show significant changes
in neural activity associated with executive functions when comparing pre- and post-treatment
EEG and fMRI responses.

Specific Aims: Better understanding of the neural circuitry and neurocognitive function
underlying executive function and associated affective control deficits in veterans with both
TBI and PTSD, and how they relate to treatment outcome, will allow us to better identify
therapeutic targets for cognitive rehabilitation. The current proposal aims to explore the
relationship between brain function and connectivity in selective pathways/circuits,
neuropsychological functioning, and cognitive rehabilitation response in veterans with both
TBI and PTSD.

Study Design: Toward this end, the investigators propose a randomized clinical trial
involving a cognitive rehabilitation intervention that targets improved executive
functioning, with the participation of N=100 veterans diagnosed with both TBI and PTSD (n=50
in experimental group and n=50 receiving usual care). As part of the study, all participants
will receive an iPod touch. Participants will be placed into one of the two study groups
randomly. Based on which group participants are placed in, they will receive one of two
different sets of iPod touch apps and programs that address and aim to improve different
facets of cognitive functioning. Regardless of which group, Veterans will be instructed to
daily practice iPod touch applications on cognitive functioning. Also, family members will be
trained as "mentors" to reinforce use of the applications in everyday living environments.
Trained facilitators will also travel to participants' homes to meet with veterans and family
to review their respective applications and mentoring processes. The investigators will
examine both cognitive and behavioral changes, as well as neural changes associated with
cognitive rehabilitation using EEG and fMRI at baseline and six months.

Military Benefit: This study of the neurobiology and neuropsychology associated with
intervention efficacy will allow us to identify veterans with both TBI and PTSD who are
predisposed to positive treatment outcomes. To our knowledge, this will be the first attempt
to integrate neurobiological and neurocognitive techniques with information about the
efficacy of a theoretically and empirically driven cognitive rehabilitation intervention in
veterans with combined TBI/PTSD diagnoses. This research may suggest additional avenues for
assessment of clinical intervention efficacy and the identification of therapeutic targets
(e.g. alteration of function in fronto-limbic circuits) relevant to the military population.
Given links between TBI/PTSD, executive dysfunction, and anger, impulsivity, and aggression,
efforts to rehabilitate cognitive function will be particularly important to ensure that
current and future veterans adjust successfully when they return home to their families,
workplaces, and communities.

Inclusion Criteria:

OIF/OEF Veteran inclusion criteria include:

1. has served in one of the military branches (Army, Navy, Marines, Air Force, National
Guard);

2. is between the ages of 18 and 65;

3. has served in Iraq or Afghanistan War since October 2001;

4. has screened positive for TBI and PTSD prior to baseline interview. Definition of TBI:
The American Congress of Rehabilitation Medicine (ACRM) (Kay et al., 1993), Center for
Disease Control (CDC, 2003), and Military TBI Task Force
(http://www.div40.org/pdf/Military_TBI.pdf) have sought to define criteria for
different types of head injuries. In the current DoD application, for both the
research registry and pre-screening, criteria for TBI should be defined as a veteran
who: 1. reports that during military service, head was hurt/injured in a way that
caused problems; AND 2. endorses at least one of the following:

- loss of consciousness or getting "knocked out."

- immediately after the injury or upon regaining consciousness, being dazed or
"seeing stars."

- immediately after the injury or upon regaining consciousness, being unable to
recall the event.

- being over one hour after the injury was it before veteran started remembering
new things again.

- needing brain surgery after the injury.

Definition of PTSD: For the purposes of the current research, we use the Diagnostic
Statistical Manual-IV-TD (DSM-IV-TR) definition of PTSD for the purposes of the current
research. Specifically, subjects must report a traumatic event according to DSM criteria
and report experiencing re-experiencing, avoidance, and hyperarousal symptoms to qualify
for the diagnosis. Study registries define PTSD as having a score above the cut-off of 60
on the Clinical Assessment of PTSD (CAPS). We will re-screen potential participants before
enrollment by administering the PTSD Checklist, scores above 50 indicative of PTSD among
OIF/OEF veterans. Please note below that the CAPS will be administered as part of the main
clinical interview after veterans have signed informed consent.

Family member inclusion criteria include: (1) has family member/friend who served in one of
the military branches (Army, Navy, Marines, Air Force, National Guard); (2) age 18-65; and
(3) has family member who served at least one tour in Iraq or Afghanistan since October
2001 and meets above criteria Inclusion of Women and Minorities in Study: It is anticipated
that the distribution of our sample by gender and race/ethnicity will reflect the client
population served by the North Carolina healthcare system. No one will be excluded from the
study because of gender or racial/ethnic group.

Exclusion Criteria:

Since MRI sessions are a part of the study, subjects should not participant if:

1. They have any foreign metal objects or implants in their body as determined by the
safety questionnaires.

2. Veteran is a woman and is pregnant or unwilling to take a pregnancy test.