Computational Assessment of GABA Receptor Modulation in PTSD

A substantial majority of Veterans with posttraumatic stress disorder (PTSD) continue to suffer even with the best current medications. Progress in developing more effective medications is hampered by the substantial variability within Veterans with PTSD, meaning the most effective medication likely varies from individual to individual. New scientific tools to help identify distinct subgroups of Veterans with PTSD who are likely to respond to specific medications could help improve treatment in this population. Research has indicated that a specific subgroup of Veterans with PTSD with a high level of anxious arousal may benefit from medications which boost signaling of the neurotransmitter gamma-aminobutyric acid (GABA). This project aims to validate a clinical test to identify these individuals using new computational and neuroimaging methods combined with the medication lorazepam, a positive GABA modulator. The ultimate goal is to use these methods in future clinical trials of new medications to target the best treatments to individual Veterans with PTSD.

Heterogeneity in Veterans with PTSD has been identified as a major obstacle in developing effective treatments for this population. Research suggests that a PTSD subgroup characterized by elevated arousal, relative to general negative affect, may benefit from novel medications that positively modulate inhibitory gamma aminobutyric acid (GABA) signaling. An objective, functional phenotypic marker for this subgroup could therefore enable targeted treatment and improve clinical outcomes. The investigators propose a computational goal-directed control paradigm as a novel clinical assessment based on the premise that a reduction in dynamic inhibition, regulated by GABA signaling, can serve as a specific, objective phenotypic target in a high arousal PTSD (HA-PTSD) subgroup. This study will leverage: 1) a single dose of a benzodiazepine as an acute GABA receptor modulator for phenotypic target validation rather than treatment purposes; 2) a novel computational control modeling strategy to precisely measure the effect of GABA receptor modulation on dynamic inhibition; 3) functional neuroimaging to assess specific neural mechanisms of GABAergic influence on dynamic inhibition.

The investigators have developed the rapid assessment of motor processing (RAMP) paradigm, a computational goal-directed control task which enables precise estimation of a dynamic inhibition parameter. Compared to other behavioral measures, dynamic inhibition exhibits excellent measurement reliability. Dynamic inhibition is negatively associated with subjective fear, and this relationship persists after controlling for general negative affect. Critically, dynamic inhibition is lower in an HA-PTSD subgroup (with high residual fear, controlling for negative affect) compared to both a low arousal PTSD (LA-PTSD) subgroup and healthy controls (HC). Dynamic inhibition is also associated with structure and function in arousal-related regions such as dorsal anterior cingulate cortex (dACC) and insula.

Benzodiazepines are robust positive GABA receptor modulators which acutely reduce anxious arousal but result in tolerance and side effects when used chronically. Several novel pharmacotherapies (either FDA-approved for other indications or currently in development) may chronically normalize deficient GABA signaling without the downsides of chronic benzodiazepines. Given heterogeneity in PTSD, precision phenotyping will be critical for assigning these treatments to Veterans most likely to benefit, i.e. to an HA-PTSD group with deficient GABA signaling. The investigators propose that RAMP dynamic inhibition can serve as a specific, objective phenotypic target for positive GABA modulation in HA-PTSD. While preliminary data from the investigators has established a specific relationship between dynamic inhibition and fear (relative to negative affect), a crucial step prior to clinical use is validation of the relationship between dynamic inhibition and GABA receptor modulation. The investigators propose to test this causal relationship using the benzodiazepine lorazepam as a pharmacologic probe (rather than a clinical treatment). The validated phenotypic target can then be used for subgroup assignment and mechanistic outcome-tracking in trials of novel GABAergic agents for HA-PTSD.

The investigators hypothesize that the HA-PTSD group will show greater enhancement in dynamic inhibition than other groups with lorazepam compared to placebo. To test this hypothesis, the investigators propose a randomized crossover study in which HA-PTSD, LA-PTSD, and HC Veterans receive a single dose of the lorazepam and placebo in separate experimental sessions in which they perform the RAMP paradigm. Research suggests that arousal-related neural regions may specifically mediate the benefits of GABAergic modulation in HA-PTSD, which could enable targeting of more specific GABAergic treatments. The investigators will therefore examine specific neural mechanisms of GABAergic modulation using fMRI combined with dynamic inhibition as a phenotypic marker.