Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Inclusion Criteria:

Inclusion Criteria applied to all participants

In order to be included in this study, all participants must meet the following minimum criteria:

1. Age 18 - 55 years, inclusive
2. Ability to undergo MRI scanning.
3. Ability to read, write, and speak English.
4. Stable doses of concomitant medications for at least 2 weeks prior to enrollment.
5. Likelihood of completing 18 weeks of study procedures. Likelihood of ability to complete the study procedures means that the person has 1) a low probability of being deployed during the 18-week period 2) verbalizes intent to complete the study.

Inclusion Criteria for Group 1 (symptomatic TBI)

In order to be included in the symptomatic TBI Group, study participants must meet the following criteria:

1. A history of having sustained a TBI > 6 months and \< 10 years prior to enrollment. Evidence will be any one of the following 3 criteria:

   1. GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)
   2. Post-traumatic amnesia > 24 hours
   3. TBI-related abnormality on neuroimaging (either CT or MRI). (Some missing information about the initial injury (i.e. documentation of initial GCS) is not necessarily exclusionary if the bulk of the available history is indicative that the patient suffered a TBI and meets the inclusion criteria)

2. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including:

   1. Evidence from neuropsychological testing of difficulty in attention or memory. (refers to neuropsychological testing done as a part of the patient's hospital or rehabilitation care not as a part of screening for this study)
   2. Three or more of the following symptoms, which started shortly after the trauma and persist for at least three months:

   i) Fatigability ii) Disordered sleep iii) Headache iv) Vertigo or dizziness v) Irritability or aggression vi) Anxiety, depression, or affective instability vii) Changes in personality (e.g. social or sexual inappropriateness) viii) Apathy or lack of spontaneity c) Symptoms in criteria (a) and (b) must have their onset after trauma, or there was a significant worsening of pre-existing symptoms after trauma.

   d) Disturbance from these symptoms causes significant impairment of social or occupational functioning and represents a significant decline from previous level of functioning.

   Inclusion Criteria Group 2-Healthy controls In order to be included in this study, participants must meet the inclusion criteria for all participants listed in 4.2.

   3.2.3 Inclusion Criteria Group 3-Recovered TBI

1. History of having sustained a TBI > 6 months and \< 10 years prior to enrollment. This evidence will be any one of the following:

a) GCS 3 - 12 (GCS obtained in Emergency Room after injury and noted in medical record) b) Post-traumatic amnesia > 24 hours c) TBI-related abnormality on neuroimaging (either CT or MRI) 2. Does not meet criteria for persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-concussional Disorder defined by the following:

1. No evidence from neuropsychological testing of difficulty in attention or memory.
2. No more than 1 of the following symptoms, which started shortly after the trauma and persists for at least three months:

i) Fatigability ii) Disordered sleep iii) Headache iv) Vertigo or dizziness v) Irritability or aggression vi) Anxiety, depression, or affective instability vii) Changes in personality (e.g. social or sexual inappropriateness) viii) Apathy or lack of spontaneity c) No impairment of social or occupational functioning or a significant decline from previous level of functioning.

Exclusion Criteria:

Exclusion Criteria for all Groups:

1. Contraindication to sildenafil which includes the following:

   1. Current use of organic nitrate vasodilators
   2. use of ritonavir (HIV-protease inhibitor)
   3. Current use of erythromycin, ketoconazole, or itraconazole
   4. Current use of cimetidine
   5. Alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipres). These medications are usually used for the treatment of enlarged prostate.
   6. Current resting hypotension (BP \< 90/50 mm Hg)
   7. Current severe renal insufficiency (Creatinine Clearance \< 30 mL/min)
   8. Current hepatic cirrhosis
   9. Current cardiac failure or coronary artery disease causing unstable angina
   10. Retinitis pigmentosa
   11. Known hypersensitivity or allergy to sildenafil or any component of the tablet
2. Evidence of penetrating injury
3. Daily therapy with a PDE5 inhibitor within the past 2 months

4. History or evidence of pre-existing neurological or psychiatric disorder not related to TBI, such as:

   1. Multiple sclerosis, pre- or co-existing
   2. Stroke (other than stroke at the time of TBI)
   3. Pre-existing developmental disorder
   4. Pre-existing epilepsy
   5. Pre-existing major depressive disorder
   6. Pre-existing schizophrenia
5. Women who are pregnant or breast-feeding.

Exclusion for Healthy Control Group Any evidence or history of a TBI or concussion is exclusionary for the Control Group.