The Role for in vivo Glutamate Modulation in Maintaining Cognitive Control in Trauma-Exposed Adolescents

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Abstract Childhood trauma is highly prevalent in the United States, and can greatly increase the risk for developing anxiety disorders in youth. Experiences of trauma promote heightened emotional responses to potential threats, which in turn may impact cognitive ability. The imbalance between emotional and cognitive processes may contribute to hallmark symptoms of anxiety disorders, such as excessive fear and impaired functioning. It is critical to investigate the biochemical mechanisms underlying cognitive neural engagement to identify novel therapeutic targets and develop better targeted pharmacotherapies aimed at maintaining cognitive control ability in vulnerable populations like trauma-exposed youth. Functional MRI studies demonstrate that the dorsal anterior cingulate cortex (dACC) is a critical component of maintaining cognitive control, and that visual cues of negative affect may interfere with these functions. However, the key barrier to advancing this mechanistic understanding is that the vast majority of current investigations utilize functional MRI, which relies on the hemodynamic response function, and is an imprecise indicator of neural engagement. A more precise measure of neural engagement can be obtained using in vivo ¹H functional MR spectroscopy (¹H fMRS), which is a novel tool sensitive to temporal changes in glutamate under contrasting task-conditions. The objective in this proposal is to investigate the impact of childhood trauma on dACC neural engagement related to cognitive control with and without negative affect, and its association with pediatric anxiety symptoms. We will enroll 60 adolescents (ages 11-15, 50% female) from an urban setting with high rates of trauma exposure (30 trauma-exposed, 30 control). Participants undergo ¹H fMRS scanning while completing a cognitive control task specifically designed to allow direct characterization of the dACC neural engagement during cognitive control following negative affect interference. The task includes two modes that target different components of cognition: sustained attention and response inhibition. Both modes will be tested in the context of threatening faces (negative affect condition), as well as neutral shapes (no affect condition). This proposal hypothesizes that childhood trauma will potentiate negative affect interference with dACC neural engagement necessary for cognitive control functioning – demonstrated by reduced dACC glutamate modulation during the negative affect conditions of the task. This innovative approach will facilitate investigation into the neural processes which maintain cognitive control in the presence of threat in trauma-exposed adolescents. This training project will provide PI France with training in conceptual (neurobiology of trauma and anxiety) and methodological approaches (¹H fMRS and psychological assessments). It will also prepare the PI for a successful F32 submission and future academic research career.