Neurobiology of Sleep and Sleep Treatment Response in Returning Veterans

The overarching objectives of this study are: 1) To investigate the neurobiology of posttraumatic stress disorder (PTSD) during Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep relative to wakefulness; 2) To identify the neurobiological underpinnings of sleep treatment response to prazosin or placebo during wakefulness, REM sleep, and NREM sleep in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) ( veterans with PTSD; and 3) To explore pre-treatment brain activity patterns during wakefulness, REM sleep, and NREM sleep that predict sleep treatment response. We will also explore the stability of the Positron Emission Tomography (PET) signal by comparing pre- and post-placebo changes in brain glucose metabolism in non-responders. For non-PTSD veterans, the stability of the PET signal will be evaluated in a subsample of 6 veterans without PTSD who will repeat the PET imaging procedures 8 weeks after the initial PET series.

The overarching hypothesis is that PTSD is characterized by neurobiological alterations in the amygdala, medial prefrontal cortex (mPFC), and brain centers involved in the regulation of NREM and REM sleep, and that these neurobiological changes are normalized with effective sleep treatment.

PTSD affects both daytime functioning and sleep. Complaints of poor sleep, objective disruption of sleep, and heightened sympathovagal tone during sleep occurring early after trauma exposure increase the risk of developing PTSD up to one year later. (1-4). Insomnia is one the most common reasons for referral to mental health services in active duty personnel (5). In military personnel returning from Iraq and Afghanistan, more than 70 percent of those with PTSD report sleep problems and fatigue, whereas more than 25% percent of those without PTSD endorse these symptoms (6). Other disruptive nocturnal behaviors and sleep disorders including sleep terrors, nocturnal anxiety attacks, simple and complex motor behaviors and vocalizations, acting out dreams, sleep apnea, and periodic leg movement disorders are also frequently reported by PTSD patients (7-12). In PTSD, sleep disturbances independently contribute to poor clinical outcomes such as increased severity of daytime PTSD symptoms (8), depression (13), suicidality (13), general psychiatric distress (14), poorer quality of life and functioning (14), poorer perceived physical health (14), and increased substance use (15;16).

Eligibility Criteria:
Inclusion Criteria:

* OIF/OEF veteran
* Between the ages of 18 and 50 years old
* Not taking medications known to affect sleep or wake function for 2 weeks

Additional selection criteria for PTSD subjects are:

* Trauma occurred three months or more before study entry
* Meeting diagnostic criteria for current PTSD according to the Clinician Administered PTSD Scale (CAPS)
* Participants will remain in ongoing counseling services

Additional selection criterion for non-PTSD healthy subjects:

* Not meet DSM-IV diagnostic criteria for current PTSD
* Have a total score \< 13 on the Beck Depression Inventory
* Participants who are active-duty military personnel will be required to obtain permission from their commander to participate in this study.

Exclusion Criteria:

* Current diagnosis of untreated, severe depression as determined by the Structured Clinical Interview for Diagnostic and Statistical Manual- IV Edition (DSM-IV), non-patient version
* Beck Depression Inventory \> 30
* History of psychotic or bipolar disorder
* Current history (within 3 months) of substance or alcohol abuse
* Significant or unstable acute or chronic medical conditions
* Other current sleep disorders
* Presence of implanted devices or metal in body such as cardiac pacemaker, aneurysm clip, ear implant, shrapnel, neurostimulators or other metal devices
* Fear of closed spaces
* Previous radiation exposure (past year) that exceeds recommended safety limits
* Pregnancy or breast feeding
* Resting blood pressure \< 90/60 at the screening physical examination
* Heart rate \> 100 beats/minutes
* Current use of a beta-blocker
* Use of an alpha-1 antagonist agent in the previous 3 weeks
* Refusal to follow the safety measures in the case of use of a phosphodiesterase 5 inhibitor (Cialis, Viagra, Levitra)
* Unexpected, untreated, or serious EKG findings