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The Rehabilitation Research and Development (RR&D) Service is encouraging VA investigators to conduct research on the chronic effects of neurotrauma. The purpose of this funding announcement is twofold:  1) to provide an alternate funding mechanism for the conduct of chronic studies and 2) to encourage researchers to work on chronic models of injury to the central nervous system, specifically, traumatic brain and spinal cord injuries.  As the  standard Merit Review provides funding for up to four years, long-term, chronic studies employing survival periods of one year or longer may not be feasible within a four-year project and  this RFA is therefore specifically directed at five-year projects. 

Background:  A role of RR&D in improving the health of Veterans is to translate bench science into clinically proven treatments.  The current conflicts have resulted in the exposure of a significant number of service personnel to the direct effects of active combat duty, including improvised explosive devices, vehicular crashes, and sniper fire, often resulting in injuries to the central nervous system (CNS).  While much of the focus of research on neurotrauma has been on the acute time period following injury, this RFA focuses on the chronic, long-term time period, consistent with Veteran-centric health issues.  In particular, this RFA targets the effects of long-term injury and the means to repair these injuries after they have been chronically established.

Traumatic Brain Injury (TBI):  TBI can lead to immediate, long-lasting and debilitating impairments in cognition, psychological health, and sensorimotor abilities.  Recent post-mortem studies on athletes suggest that repeated concussive or mild TBIs are  a risk factor for the long-term development of chronic traumatic encephalopathy (CTE; Gavett et al., 2010, Alzheimer's Research and Therapy,  and Omalu et al., 2005, Neurosurgery) and possibly other neurodegenerative pathologies and conditions as well.  Oftentimes the affected individual presents with clinical indications reminiscent of neurodegenerative diseases (Gavett et al., 2010), or epileptic seizures (Vespa et al., 2010, Neurology). Although there appears to be a correlation between repeated mild TBI and development of CTE, little is known about the mechanisms underlying this conversion from acute injury to chronic pathology and symptomatology.  Less is known about the effects of a single exposure to TBI and its chronic consequences.  With approximately 196,000 cases of TBI reported in OIF/OEF between 2000 and 2010 (150,000 being mild and 33,000 moderate TBI), the study of the long-term effects of TBI as it relates to the sequelae of neurological events following single or multiple exposures to trauma warrants investigation.

Spinal Cord Injury (SCI):  The effects of SCI are also debilitating, with approximately 46% of active duty-related injuries resulting in tetraplegia and 54% in paraplegia.  Almost all affected individuals from OIF/OEF are young men in their 20's.  Unlike TBI, however, an active research program exists on the long-term consequences of SCI.  As a result, health care continues to improve, and many Veterans with SCI survive the initial trauma and live longer life spans comparable to ambulatory individuals.   Yet, with all of these health care advancements, there is much to learn about how to best approach repair of the chronically injured cord, and the role that endogenous repair and plasticity plays in recovery of function. 

Scope of the Program:  This RFA is directed at the study of chronic injury to the brain and spinal cord, with emphasis on the long-term effects of injury on the development of secondary neurodegenerative disorders and the repair of the injury. Multi-site collaborative research proposals that utilize VA and non-VA resources to increase efficiency and to reduce duplication are strongly encouraged.

• TBI:  Human studies.  This RFA focuses on the long-term consequences of either single or multiple exposures to TBI.  Emphasis will be placed on the development of and transition to a neurodegenerative state along with symptomatology reminiscent of dementia, Parkinson's, or motor neuron disease.  Non-exempt human studies are within the scope of the RFA and will be included.  RR&D recognizes that humans represent the most relevant physiological model of TBI and encourages investigators to consider conducting longitudinal studies on these populations.  Examples of possible studies include, but are not limited to use of imaging modalities conducted in parallel with neurocognitive testing (can also include performance on specific tasks assessing executive function and/or memory).  Due to the lack of knowledge concerning the long-term evolution of the effects of TBI, studies employing interventional designs will not be considered in this initial announcement, as this current RFA is directed at the collection of data as it pertains to the development of secondary pathology, biomarkers, and functional consequences following TBI. The proposed research must include safety monitoring of study participants. 

• TBI:  Animal studies.  Studies employing animals should examine the effects of long-term survival post-TBI, mimicking the human condition employing a single moderate injury or multiple mild, traumatic injuries.  Use of larger non-rodent mammals must be discussed with the Scientific Program Manager prior to application.  Emphasis will be placed on validated models that employ closed head injury, e.g., linear impact, coronal rotational acceleration, or blast tube models.  The key to using animal models is to determine whether they can adequately predict long-term consequences of TBI.   For example, chronic time points in rodent models should exceed 4 months and time points up to 1 year are preferable.  Use of novel genetic backgrounds such as APP, presenilin, tau, ubiquitin, etc. backgrounds is encouraged.  RR&D recognizes that mice with these backgrounds may not be available at all institutions and encourages collaboration with investigators who can provide mice with the appropriate backgrounds.  Possible outcome measures could include acceleration of neurodegenerative pathology in transgenic mice, decline of function (e.g. cognitive function on an appropriate task), and any change in the general physical appearance (e.g. weight gain or loss, presence of seizures) of the animal. 

• SCI:  Human studies.  Studies conducted on human subjects should focus on the effects of activity dependent exercise/rehabilitation to train spinal circuits.  Emphasis will be placed on the degree of functional recovery achieved by activity alone.  Specific questions that should be addressed include the duration and frequency of activity, types of activity (e.g. weight training, yoga/stretching, aerobic, etc.), and for specific tasks (i.e. walking, grasping, etc.)  As this RFA is examining the effects of activity-dependent plasticity on recovery of function in individuals with SCI, studies involving interventions other than activity/exercise will not be considered responsive to this solicitation.  A caveat that investigators should consider is whether extensive training of a particular circuit may regain function in that circuit but at the expense of another.  Investigators are encouraged to examine plasticity at both the spinal and cortical levels using non-invasive imaging techniques as anatomical correlates of recovery.  Additional outcomes may include recovery of sensation, ease of bowel and bladder function, a decrease in spasticity, etc. that may increase the quality of life.  

• Animal studies.  Studies on animals should focus on the repair of the chronically injured spinal cord.  Although the chronically injured spinal cord shows extensive spontaneous recovery (non-human primates; Rosenzweig et al., Nature Neuroscience 2010), and also demonstrates sprouting/regeneration with combination therapy (rats; Kadoya et al., Neuron 2009), it is unclear whether reparative strategies produce functional recovery beyond what is observed with standard rehabilitative strategies alone.  Studies using chronic models should thus emphasize use of reparative and rehabilitative strategies to determine whether these strategies produce clinically meaningful improvement (sensory and/or motor) over that achieved by endogenous repair and rehabilitation alone.  Chronic time points in the rodent should exceed 4 months post-injury and up to one year post-injury.  Use of larger mammals must be discussed with the Scientific Program Manager prior to application.  The use of novel combination therapies include but are not limited to, cell and growth factor therapies, non-invasive imaging, bioengineering, rehabilitative, and comparative-effectiveness methodologies. 

This RFA is intended to encourage projects that will examine the consequences of chronic injury as well as its repair. 

Possible project goals should include, but are not limited to:

• Development of databases (i.e. imaging scans, neurocognitive tests, general physical status, psychological status) of human subjects with TBI.
• Identifying the mechanism(s) underlying the transition from acute to chronic pathology following TBI. 
• Identification of functional outcomes "trainable" by activity dependent exercise in human subjects with SCI, both sensory and motor.
• Identification of anatomical correlates (cortical and spinal) of plasticity following activity dependent exercise in subjects with SCI.
• Development and/or employment of novel interventions in chronic animal models for both TBI and SCI. 
• Use of imaging (MRI, DTI, etc.) modalities to view endogenous repair and ensuing sprouting/regeneration following repair in animal models of TBI and SCI.
• Identifying mechanisms underlying the diminished capacity of the chronically injured CNS toward reparative strategies in animal models (i.e. is this simply a result of age?)
• Examining the role of endogenous repair and whether it hinders or enhances new axonal growth following chronic SCI in animal models (i.e. the self-repaired cord is being re-injured during the repair process; does this affect new growth, result in a loss of function, etc.)
• Identifying possible adverse side effect(s) of therapies (e.g. pain) following chronic injury and repair in both TBI and SCI animal models.
• Determining whether co-morbid psychological conditions that negatively impact repair and recovery of function after TBI and SCI.
• Determining when the window of opportunity for repair closes (e.g. at what point in time is the risk: benefit of repair reached) in both chronic TBI and SCI animal models.
• Examining the effects of genetic polymorphisms known to affect rehabilitation and plasticity on reparative strategies (e.g. BDNF). 

Investigators are strongly encouraged to consult with VA RR&D program staff to determine if the proposed research is within the goals of the RFA.  This early contact will also provide an opportunity to clarify the applicant's understanding of program goals and guidelines, including the scope of projects within the program.  The proposed research must adhere to an overall budget of 1.1 million dollars in a period not to exceed 5-years.