Cerebral GABA and Fear Conditioning in PTSD
| Status: | Recruiting |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 20 - 50 |
| Updated: | 4/21/2016 |
| Start Date: | February 2013 |
| End Date: | February 2018 |
| Contact: | Lauren Demers |
| Email: | adlab@mclean.harvard.edu |
| Phone: | 617-855-2268 |
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.
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.
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.
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