Cerebrovascular Reactivity Assessed With fNIRS as a Biomarker of TCVI After Acute Traumatic Brain Injury in Military
Cerebrovascular Reactivity Assessed With fNIRS as a Biomarker of TCVI After Acute Traumatic Brain Injury in Military
The study includes people who have recently had a traumatic brain injury (TBI) and healthy
 controls who have not had a TBI and is designed to measure brain blood flow serially after a
 TBI. Studies have shown that small blood vessels in the brain may be injured during a TBI.
 The goal is to learn about brain blood vessel function from as early as the first week to 6
 months after a TBI . The study uses Near Infrared Spectroscopy (NIRS) which uses small lights
 that detect oxygen levels in the blood, measuring blood flow in the brain. This is compared
 with magnetic resonance imaging (MRI). When blood flow increases in the brain in response to
 a stimulus, this is called cerebral vascular reactivity (CVR).

 The study aims to learn about CVR using a few minutes of special breathing similar to breath
 holding while in an MRI (magnetic resonance imaging), and CVR measures after one dose of a
 common drug called sildenafil (generic Viagra) 50 mg taken once during CVR measurements at
 each of up to 4 visits. The investigators will measure CVR at different times during a
 6-month period in participants who have had a TBI to see how CVR measures and blood vessels
 function during the first 6 months after a brain injury.
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

 The investigators 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 the investigators 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
 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 participants 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, the
 investigators 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

 The investigators anticipate the following non-serious adverse events (likely, with event
 rate < 5%):

 1. Slight discomfort from the NIRS band on the head

 2. Minor warmth under the band from the light emitters after ~ 30 minutes of testing

 3. Anxiety and/or panic attack during hypercapnia challenge

 4. Headache during/after hypercapnia challenge.

 However, there are well recognized adverse effects. The following lists the adverse events
 reported by at least 2% of patients taking sildenafil in flexible dose Phase 2/3 studies, and
 were more common at the 100 mg dose than at lower dose than this study will be using.

 Adverse events attributed to sildenafil in placebo-controlled randomized trials Adverse Event
 % of patients on sildenafil reporting AE (n = 734) % of patients on placebo reporting AE (n =
 725) Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Urinary Tract
 Infection 3% 2% Abnormal vision* 3% 0% Diarrhea 3% 1% Dizziness 2% 1% Rash 2% 1%

 *Abnormal Vision: Mild and transient, predominantly color tinge to vision, but increased
 sensitivity to light or blurred vision. In these studies, only one patient discontinued due
 to abnormal vision.

 Orthostatic hypotension is an infrequent adverse effect of sildenafil therapy. VIAGRA doses
 above 25 mg should not be taken within 4 hours of taking an alpha-blocker.

 Study participants will also be given the contact information for one of the study
 investigator physicians.

 Neurocognitive tests Testing is critical for studying the effect of TBI on memory, behavior
 and functioning. All testing will be performed by a trained research assistant or
 psychometrist. No serious adverse events are anticipated.

 Boredom Fatigue Frustration

 Phlebotomy

 Trained study personnel will draw 10 ml (2 teaspoons) at each study visit. Possible
 non-serious adverse events:

 Bleeding Bruising Infection

 Magnetic Resonance Imaging:

 MRI has been safely performed in millions of persons; research subjects will be screened for
 metallic foreign bodies or other contraindications, similar to all clinical patients.
 Pregnant females will also be excluded from participating in these research MRIs.

 Subjects may experience discomfort or anxiety while lying in the magnet and may communicate
 with the MRI technologist. Participants will have hearing protection.

 Gadolinium-Based Contrast Agents:

 Risks include local side effects from IV placement and contrast injection, systemic reaction
 to the MR contrast agents (less common than with CT contrast agents), and a rare but serious
 disease called nephrogenic systemic fibrosis (NSF).

 There have been more recent descriptions of gadolinium deposition in the brain after exposure
 to MR contrast agents. The clinical significance (if any) of this discovery is currently
 unknown.

 Subject Withdrawal

 As stated in the consents, and as will be explained to the subjects, subjects may withdraw
 their participation from the study, at any time, without explanation. The procedure for
 withdrawal is stated in the consent document.

 Privacy

 All screening and enrollment procedures will be conducted in the study site clinics. All
 recruitment and subsequent study-related activities involving face-to-face interactions with
 subjects will be conducted in a private, closed-door office setting. All telephone contacts
 will be carried out in a closed room.

 Confidentiality Protection

 Each subject will be assigned a numerical code for identification purposes pertaining to data
 and biospecimens. The numberical code will contain no identifiers (numerical code only). A
 computer file linking subjects to their assigned numerical code will be safely stored as an
 encrypted file on a password protected computer. Paper records will be stored in locked
 cabinets in locked office space. Linking files will be kept for the life of the study and
 then destroyed. No subject will be identified in future publications as having taken part in
 this study.
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 <90); Severe renal insufficiency; Hepatic cirrhosis; Cardiac failure or
 coronary artery disease causing unstable angina; Retinitis pigmentosa; Pregnant or
 breastfeeding female; Known hypersensitivity or allergy to sildenafil.

 7. Inability to read and communicate in English

 8. Exclusion criterion for healthy subjects only: History of TBI.

 9. Current use of a PDE5 inhibitor (a drug such as Sildenafil, Tadalafil, Vardenafil,
 Avanafil, Udenafil,Dipyridamole, Vardenafil hydrochloride)