Individualized computational assessment of the effects of GABA receptor modulation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is among the most common mental health conditions among all treatment-seeking Veterans, and the critical lack of advancement in pharmacological treatment of this disorder has been termed an urgent crisis by leaders in the field. Progress in developing more effective treatments for PTSD has been hampered by the substantial heterogeneity in this population. Research suggests that a deficit in inhibitory gamma aminobutyiric acid (GABA) signaling may underlie a specific subgroup in PTSD characterized by high anxious arousal relative to general negative affect. We propose a computational goal- directed control paradigm as an objective clinical test based on the premise that a reduction in dynamic inhibition, regulated by GABA signaling, can serve as a specific marker for a high arousal PTSD (HA-PTSD) subgroup. Our study will leverage: 1) a single dose of a benzodiazepine as a robust, acute GABA receptor modulator for phenotypic validation rather than treatment purposes; 2) a novel goal-directed control modeling strategy to precisely measure the acute effects of GABA receptor modulation on dynamic inhibition; 3) functional neuroimaging to assess specific neural mechanisms of GABAergic influence on dynamic inhibition. Given heterogeneity in the PTSD population, a precision phenotyping approach is critical for assigning specific treatments to Veterans most likely to benefit. This application seeks to develop a precision phenotyping approach for Veterans with deficient GABA signaling, who would benefit from novel agents that positively modulate GABA signaling. A crucial step is to validate the proposed phenotyping approach using a benzodiazepine as a robust causal pharmacologic probe of the effects of GABA receptor modulation, before subsequently deploying the phenotyping approach in future clinical trials of novel agents. Our team has 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 a 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. The present application seeks to examine the effect of a single dose of the positive GABA modulator lorazepam on dynamic inhibition in healthy controls (HC) as well as two subgroups of Veterans with PTSD: an HA-PTSD group and an LA-PTSD group. We hypothesize that lorazepam will have a greater effect in increasing dynamic inhibition in the HA-PTSD group compared to both HC as well as LA-PTSD, providing evidence for a distinct biological mechanism in HA-PTSD. Furthermore, we hypothesize that the increase in dynamic inhibition with lorazepam will be correlated with the effect of lorazepam in reducing activity in arousal- related neural regions including dorsal anterior cingulate cortex (dACC), insula, and amygdala. We will test these hypotheses in a crossover study in which each Veteran receives a single dose of lorazepam and placebo in randomized order and performs the RAMP paradigm, with a subset of Veterans performing the task in an fMRI scanner. Once validated as a specific, objective phenotypic target for GABA modulation in HA-PTSD, RAMP dynamic inhibition will be used in future clinical trials of novel agents that modulate GABA signaling (without the downsides long-term benzodiazepines). The ultimate goal is to develop a clinical test to target treatments to individual Veterans, thus improving t Project Number: 1I01CX002872-01 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Jonathon Howlett | Institution: VA SAN DIEGO HEALTHCARE SYSTEM, SAN DIEGO, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 MHBP-F (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11047648