Cerebral GABA and Fear Conditioning in PTSD
Condition: Stress Disorders, Post-Traumatic
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Observational

Summary: 
      Posttraumatic stress disorder (PTSD) is a common and debilitating neuropsychiatric disorder
      in which an acute fear response to a traumatic event does not abate. This failure to recover
      from trauma is thought to be due at least in part to a deficit in learning not to fear
      situations and stimuli previously associated with the trauma (i.e., specifically due to a
      failure of extinction recall). Pavlovian fear conditioning can be simulated and measured
      experimentally in humans using a 2-day fear conditioning paradigm developed by our group,
      wherein conditioning and extinction learning phases are conducted on Day 1, and extinction
      recall is tested on Day 2.

      Recent functional magnetic resonance imaging (fMRI) evidence indicates that PTSD is
      associated with hyper-responsivity of the insular cortex and hyporesponsivity of the
      ventromedial prefrontal cortex (VMPFC) during exposure to fear-inducing stimuli, consistent
      with altered excitability of brain regions mediating fear conditioning and extinction. As the
      brain's principal inhibitory neurotransmitter, GABA exerts a prominent role in modulating
      neuronal excitability. Interestingly, there are reports that adjunctive treatment with
      GABA-enhancing antiepileptics is efficacious in PTSD. There is also evidence, albeit
      inconsistent, that lower serum GABA levels predict a more chronic course of the illness.
      However, it is unclear whether serum levels accurately reflect brain GABA, which may
      contribute to inconsistency of serum findings. Moreover, it is possible that GABA alterations
      may vary in their presence, nature and significance across brain regions implicated in PTSD.
      The proposed study will examine the relationship of PTSD symptoms and behavioral fear
      conditioning deficits with regional brain gamma-aminobutyric acid (GABA) using proton
      magnetic resonance spectroscopy (1H-MRS).

      We have the following aims and hypotheses:

        1. To determine whether GABA alterations are associated with the categorical diagnosis of
           PTSD and not merely exposure to trauma. It is hypothesized that PTSD will be associated
           with higher GABA in VMPFC and lower GABA in the right insula.

        2. To determine whether GABA levels are significantly associated with dimensional measures
           of PTSD symptom severity and individual symptom dimensions. It is predicted that higher
           GABA in the VMPFC and lower GABA in the right anterior insula will be associated with
           greater total symptom severity.

        3. To determine whether GABA in VMPFC and right anterior insula are significantly
           associated with measures of extinction recall failure and anxiety sensitivity in PTSD.
           It is hypothesized that VMPFC GABA will be positively correlated with skin conductance
           response to a conditioned stimulus that had previously been extinguished and insula GABA
           will be negatively correlated with anxiety sensitivity.
    


Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Subjects will be between the ages of 20 and 50 years. These will include 31 subjects
        meeting DSM-IV criteria for PTSD, 31 trauma-exposed healthy subjects, and 31 healthy
        comparison (HC) subjects without any trauma exposure.
      
Keywords: posttraumatic stress disorder; fear conditioning; proton magnetic resonance spectroscopy; GABA