Brain GABA and Glutamate in Acute PTSD
Long-lasting dysfunction in glutamatergic and GABA-ergic neurotransmission and related cytotoxic cell death are postulated to explain the clinical symptomatology of stress-related anxiety disorders, such as panic disorder and posttraumatic stress disorder (PTSD). GABA and glutamate (Glu) are critical for memory registration and for encoding emotional and fear memory. Individuals with low GABA levels in plasma are more vulnerable to acute PTSD, but the relationship between plasma and brain GABA levels is unknown. In-vivo proton magnetic resonance spectroscopy (1H MRS) at high static magnetic fields can measure regional brain concentrations of GABA in addition to those of Glu, glutamine, and N-acetylaspartate (NAA), a neuronal marker. Cortical GABA concentration measured by high-field 1H MRS is reduced in panic disorder. NAA is reduced in the hippocampus of PTSD patients. The medial prefrontal is likely also affected in acute and chronic stress disorders.
We propose to measure cortical GABA, Glu, and NAA at high magnetic field (4 Tesla) in hippocampus and medial prefrontal cortex of 20 returning Iraqi veterans with PTSD related to combat and of 20 returning Iraqi veterans without PTSD. Participants, recruited from Mental Health at the SFVA and related centers in Northern California, will have been fully characterized regarding PTSD and depressive symptomatology, alcohol and tobacco use. PTSD patients will also participate in a CBT/D-Cycloserine clinical treatment trial proposed at the SFVA (PI: Dr. Marmar). Potential reversibility of metabolite abnormalities associated with CBT/D-Cycloserine treatment will be tested in 10 of these patients by obtaining repeat 1H MRS after treatment completion.
The central hypotheses to be tested are: 1) GABA concentrations are low and Glu concentrations are high in the mesial temporal lobe (including the hippocampus) and in the medial prefrontal cortex of veterans with PTSD relative to veterans without PTSD; low GABA and high Glu concentrations correlate with greater PTSD symptomatology. 2) NAA concentration in the mesial temporal lobe is low in PTSD and associated with low GABA and high Glu concentrations. 3) CBT/D-Cycloserine treatment is associated with normalization of GABA and Glu levels and a corresponding reduction of PTSD symptomatology. These studies will start to illuminate the roles of GABA and Glu neurotransmission and neuronal compromise in PTSD and will identify potential objective surrogate markers of PTSD-related brain injury and possibly of treatment response.