The National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, is looking for individuals to participate in clinical studies. Participating in clinical trials allows you to play an active role in research on the nature and causes of many disorders of the brain and nervous system, and to possibly help physician-scientists develop future treatments. The information below is designed to help you quickly learn about actively recruiting research studies for which you or someone you know may be eligible.


Background and significance: Currently, more that 5.3 million Americans (or 2% of the population) live with disabilities resulting from TBI. Among OEF/OIF Veterans, TBI incidence estimates as high as 23% have been reported, with mild TBI (mTBI) being the most common.1 This proposal addresses the recommendations of the consensus of scientific conferences by aiming to develop a biomarker of traumatic cerebrovascular injury (TCVI) which can be useful in clinical trials of therapies. Substantial data point to traumatic cerebrovascular injury (TCVI) underlying a significant portion of TBI-related disability. 2 The cerebral vasculature is a highly plastic tissue making TCVI an attractive target for therapeutic intervention after TBI. Preliminary studies indicate that PDE5 inhibitors such as sildenafil (Viagra®) show promise as treatment for cerebrovascular dysfunction after TBI. 3,4 We adapted MRI-Blood Oxygenation Level Dependent (BOLD) with hypercapnia challenge, to the portable, less expensive, office-based Near InfraRed Spectroscopy (NIRS) technology and incorporated hypercapnia challenge as the functional challenge with NIRS. MRI- BOLD BOLD (with 5% carbon dioxide (CO2) hypercapnia challenge via the Douglas Bag method) and fNIRS (also with 5% CO2 hypercapnia challenge via the Douglas Bag method) in traumatic brain injury (TBI) and healthy controls. The complementary methods give similar results with a high degree of correlation in TBI patients compared to healthy controls. 5 Nitric Oxide (NO), the primary endogenous vasodilator in the brain, plays a prominent role. Specific PDE5 inhibitors have come into widespread use, the first is Sildenafil (Viagra®) for the treatment of erectile dysfunction and primary pulmonary hypertension. The beneficial effect of sildenafil is related to increased local CBF and enhanced neurogenesis, vasculogenesis, and axonal remodeling in the peri-infarct zone. 6-9 To date, there have been no longitudinal studies of CVR using functional NIRS from the acute to the subacute/chronic stages of TBI in humans. Objectives of this study: 1. To measure over time brain blood flow using fNIRS (using lights on the scalp) with hypercapnia challenge (like breath holding for about a minute at a time) in 30 people who have had a brain injury, moderate and severe patients, and compare it to that of 10 age-matched uninjured controls, starting as early as within 29 days of injury with the goal of within 7 days and measuring each time at approximately 1, 3 and 6 months after injury to better understand the extent and timing of cerebrovascular reactivity (CVR) in the first 6 months after TBI. 2. To compare brain injury-related brain blood flow changes with clinical magnetic resonance imaging (MRI) and post-concussive symptoms measured by survey questionnaires, a neurologist's examination, testing to measure thinking ability, and learn about blood markers associated with traumatic brain injury. 3. To measure changes in CVR longitudinally before and after a single dose administration of a phosphodiesterase 5 inhibitor, sildenafil citrate, up to 4 study time points (first 29 days days and approximately 1, 3 and 6 months after TBI). 4. To compare CVR measurements by fNIRS versus BOLD MRI with hypercapnia challenge. 5. In conjunction with primary measurement of cerebrovascular reactivity using BOLD MRI, secondary measurement of cerebrovascular permeability will also be collected using DCE MRI. Study Design The proposal is a 24-month project in which we will conduct a prospective, longitudinal, observational study of up to 40 acute TBI patients and 10 healthy controls. 1. WRNMMC male and female military health care beneficiaries (active duty, veterans or DEERS eligible) aged 18 to 55 years, presenting with a diagnosis of moderate or severe (DoD criteria) traumatic brain injury (TBI) and healthy volunteers aged 18 to 55 years. 2. Study participants at WRNMMC will be recruited from eligible military healthcare beneficiaries presenting to the WRNMMC ED or admitted to WRNMMC for TBI within 1 week of their injury (most through TBI inpatient consult service and likely on trauma surgery, neurosurgery, orthopedics, neurology, PMR and/or internal medicine inpatient services). Procedures: Participants will sign a consent form, attend scheduled visits, and be paid $50 for each blood sample collected from them at each of the up to 4 visits over a 6 month period. Participants will have an inverview about their injury and medical history and examination by a study physician, have a urine pregnancy test (if applicable), complete some questionnaires, have some memory and thinking tests, give a blood sample, and do some imaging. Imaging Magnetic Resonance Imaging (MRI). One MRI before and after about 45 minutes of one dose of sildenafil 50mg. Each imaging session will use hypercapnia using a Douglas bag, equipped with a switch to allow rapid shifting every minute from room air to 5% CO2 mixed with room air over 7 minutes. This kind of imaging will be done at 2 or 3 of the visits. The 29-day visit is optional, so if the participant's first visit is at the 30-day visit they will have imaging at that visit and then again at the 6-month visit. No imaging at the 90-day visit. - Also common TBI MRI techniques will be performed (e.g. high-resolution 3D T1-weighted, T2, T2*, diffusion tensor imaging, arterial spin labeling), as well as the following sequences: - Dynamic contrast-enhanced (DCE) MRI with intravenous gadolinium-based contrast agents (GBCAs) Participant goes to Radiology and gets heplock, etc. (pregnancy test if female) Structural MRI Participant comes out of scanner to place oral piece/noseclip for MRI-BOLD c hypercapnia. Quick T1 for co-registration, then MRI-BOLD c hypercapnia challenge (10-15 min) Participant comes out of the scanner and takes mouthpiece/nose clip off. Next,DCE sequence, the participant is injected with the contrast agent through a heplock/iv in the scanner and the sequence takes about 15 min. TOTAL scanner time is approximately 75-90 min. Functional near infrared spectroscopy (fNIRS) will be be performed twice at each study visit, once before and once about 45 minutes after single dose administration of sildenafil 50 mg. Study Medication The study medication is used to activate a change in brain blood flow during the observation and measurement of cerebrovascular reactivity. The study drug will be sildenafil citrate (Viagra®, Pfizer. Inc.). For this study, we will use 50 mg tablets for the single dose administration at each visit. Collection of Human Biological Specimens Serum and plasma (5 ml each) will be collected at at each study visit (10 ml per visit or up to 40 ml over the 180 day course of the study). Length of participation in the study: Participants enrolled in the TBI Group will have up to four study visits over a period of approximately 6 months and be enrolled for that length of time. Non-TBI Control participants require only a single visit and will be discharged from the study after their study visit is complete and results have been recorded. Risks and Discomforts fNIRS with hypercapnia challenge We anticipate the following non-serious adverse events (likely, with event rate

Eligibility Criteria:

Inclusion Criteria (See Table 2 for more details) 1. Age 18 to 55 years, inclusive 2. Either gender 3. TBI subjects ONLY: Meets DoD criteria for moderate or severe TBI and TBI occurred less than 30 days prior to study enrollment (Sustained a traumatically induced physiological disruption of brain function, as manifested by at least one of the following: 1. . Period of loss of consciousness > 30 minutes 2. . Loss of memory for events lasting> 24 hours after the accident 3. . Alteration of mental state lasting> 24 hours after the accident (e.g., feeling dazed, disoriented, and confused) 4. . Clinical neuroimaging intracranial abnormality. - Traumatically induced includes the head being struck, the head striking an object, or the brain undergoing an acceleration/deceleration movement (i.e. whiplash) without direct external trauma to the head. 4. Ability to undergo fNIRS testing with hypercapnia challenge serially 5. Ability to provide informed consent. Exclusion Criteria: 1. Unstable respiratory or hemodynamic status 2. Evidence of penetrating brain injury 3. TBI requiring craniotomy or craniectomy 4. History of disabling pre-existing neurologic disorder, e.g. dementia, uncontrolled epilepsy, multiple sclerosis, strokes, brain tumors, prior severe TBI, or other disorder that confounds interpretation of NIRS testing or neuropsychological results 5. History of pre-existing disabling mental illness, e.g. major depression or schizophrenia 6. Exclusion criteria for sildenafil: History of melanoma; Current use of organic nitrate vasodilators; Use of ritonavir (HIV-protease inhibitor); Current use of erythromycin, ketoconazole, or itraconazole; Current use of cimetidine; Current use of Alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipress); Resting hypotension (systolic BP

Study Design:

Study Location: