Cerebral GABA and Fear Conditioning in PTSD

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Mclean Hospital
Sponsor:
Collaborator:
Mclean Hospital
Information provided by (Responsible Party):
Isabelle Rosso, McLean Hospital
ClinicalTrials.gov Identifier:
NCT01800383
First received: February 14, 2013
Last updated: June 2, 2014
Last verified: June 2014
  Purpose

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.

Condition
Stress Disorders, Post-Traumatic

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional

Resource links provided by NLM:


Further study details as provided by Mclean Hospital:

Primary Outcome Measures:
  • Regional brain gamma-aminobutyric acid (GABA) levels in the ventromedial prefrontal cortex (VMPFC), right anterior insula, and right posterior temporal cortex [ Time Frame: Measured on the day of the MRI scan ] [ Designated as safety issue: No ]
    Single voxel high-field H-MRS in the VMPFC, right insular cortex, and posterior temporal cortex using a MEGAPRESS sequence at 3 Tesla will be used to detect and quantify GABA in these brain regions.


Estimated Enrollment: 93
Study Start Date: February 2013
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Groups/Cohorts
Control
No Axis I psychiatric disorder and no trauma exposure
Trauma-Exposed Normal Control
History of trauma exposure and subthreshold PTSD symptoms.
PTSD
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of PTSD as determined by the Structured Clinical Interview for DSM-IV-TR

  Eligibility

Ages Eligible for Study:   20 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.

Criteria

Inclusion Criteria:

  • 20-50 years of age
  • right-handed
  • DSM-IV diagnosis consistent with group assignment
  • groups to be matched for age, sex, education, race/ethnicity
  • ability to provide written informed consent
  • groups to be matched on proportion of female subjects in follicular/luteal menstrual phases.

Exclusion Criteria:

  • Medical condition that would confound results
  • history of seizures or head trauma with loss of consciousness
  • exposure to psychotropic medications within 4 weeks of study (8 weeks for fluoxetine)
  • metal implants, claustrophobia or other Magnetic Resonance Imaging (MRI) exclusions
  • positive urine toxicology or human chorionic gonadotropin (HCG) status on scan day
  • history of psychotic disorder, bipolar disorder, eating disorder, mental retardation, or pervasive developmental disorder; history of meeting full criteria for non-PTSD anxiety disorder.
  • PTSD and trauma subjects will be matched in terms of comorbid depressive disorder, not to exceed 50%. Trauma-exposed subjects will have a history of trauma exposure and will not meet criteria for PTSD. Non-traumatized healthy subjects will have no history of Axis I psychiatric disorder and no trauma exposure.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01800383

Contacts
Contact: Lauren Demers 617-855-2268 ldemers@mclean.harvard.edu

Locations
United States, Massachusetts
McLean Hospital Recruiting
Belmont, Massachusetts, United States, 02478
Sponsors and Collaborators
Isabelle Rosso
Mclean Hospital
Investigators
Principal Investigator: Isabelle Rosso, PhD Mclean Hospital
  More Information

No publications provided

Responsible Party: Isabelle Rosso, Director, Anxiety and Traumatic Stress Disorders Laboratory, McLean Hospital
ClinicalTrials.gov Identifier: NCT01800383     History of Changes
Other Study ID Numbers: MH096987-01A1
Study First Received: February 14, 2013
Last Updated: June 2, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Mclean Hospital:
posttraumatic stress disorder
fear conditioning
proton magnetic resonance spectroscopy
GABA

Additional relevant MeSH terms:
Stress Disorders, Post-Traumatic
Stress Disorders, Traumatic
Anxiety Disorders
Mental Disorders

ClinicalTrials.gov processed this record on July 20, 2014