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Distinct dACC Glutamate Modulation during Inhibitory Motor Control Driven by Negative Emotional Stimuli in Trauma-Exposed Youth using ¹H fMRS

John McClellan France¹, Dalal Khatib¹, Sharuel A. Valbrun¹, William M. Davie¹, Jillian Eichstaedt¹, Vaibhav A. Diwadkar¹, Tanja Jovanovic¹, and Jeffrey Stanley¹
¹Wayne State University, Detroit, MI, United States

Synopsis

Keywords: Psychiatric Disorders, Trauma, Adolescent Development

We investigated changes in glutamate in the dACC in children exposed to childhood trauma during motor control function with and without inhibition as well as with and without stimuli depicting negative affect using 1H fMRS. Independent of motor control with/without inhibition, trauma-exposed children exhibited a significant reduction in dACC glutamate when stimuli of negative affect were present, relative to stimuli without affect. These results provide greater insight on the neurochemistry supporting the influence of negative emotional context on motor control and highlight potential novel biomarkers for risk and resilience to posttraumatic stress.

Introduction

Childhood trauma is one of the strongest risk factors for pediatric anxiety disorders ¹. Trauma may contribute to hallmark symptoms of anxiety, such as excessive fear or worry, by heightening negative emotional responses, which in turn may overwhelm cognitive control ability ^2,3. In healthy adolescents, fMRI has implicated the dorsal anterior cingulate cortex (dACC) in facilitating task-related inhibitory control ^4,5, and that dACC engagement is altered in trauma-exposed youth when inhibitory control is performed in the context of negative emotion ^6–8. However, it remains unknown if atypical BOLD fMRI activation of the dACC in trauma-exposed youth is driven by altered excitatory or inhibitory neurotransmission. Both glutamatergic and GABAergic neurons are highly integrated within microcircuits resulting in a net synaptic balance between the excitatory and inhibitory (E/I) drive ⁹. This E/I balance can shift due to changes on the dynamics between the E/I neurotransmission during neural engagement related plasticity, which can be detected through task related changes in glutamate with ¹H fMRS ¹⁰. Therefore, in gaining a greater understanding of neural mechanisms driving altered dACC engagement in trauma-exposed youth, we utilized ¹H fMRS to investigate dynamic changes in glutamate from the dACC during motor control in “Selective” (motor control + inhibition) vs “Non-Selective” (motor control) task modes. Additionally, to assess the impact of affect influencing inhibitory control, Selective and Non-Selective conditions were performed across two task conditions, with and without negative emotional stimuli [i.e., “Negative Affect Faces” vs “No Affect Squares”]. Independent of the Selective or Non-Selective mode, we hypothesized relatively less dACC glutamate during the Negative Affect Faces condition compared to the No Affect Squares condition suggesting inhibitory motor control function is impacted by negative emotional stimuli in trauma-exposed youth.

Methods

Data were collected from 17 trauma-exposed youth (58% female, age=11.8±0.8yrs, trauma=3±2events). Trauma was assessed using the Traumatic Events Screening Inventory, TESI [13] and defined as any DSM-5 criterion A trauma. The ¹H fMRS was conducted on a Siemens 3T Verio system with a 32-channel volume head-coil. Utilizing MPRAGE T₁-weighted images, a single-voxel (1.7x2.0x1.2cm³) was placed in the medial dACC utilizing the AVP approach ¹¹ (Figure 1b). A visual-guided motor control task with distinct Non-Selective and Selective response modes were each executed with and without negative affect stimuli (neutral/negative emotional Faces vs red/green Squares) (Figure 2). During the Non-Selective mode, participants were presented with a flashing stimuli (50%/50% distribution, 100% responses) and were instructed to tap when presented with either stimuli; while during the Selective mode they were instructed to tap on the green/negative emotional face stimuli (80% distribution), but inhibit on the red/neutral face stimuli (20% distribution). The task was conducted as a separate ¹H fMRS scans, with four 32s task epochs interspersed with 16s epochs (Figure 2b). A baseline control condition consisting of crosshair fixation preceded the task runs. Continuous ¹H fMRS measurements were acquired with a temporal resolution of 16s throughout each task run using PRESS with OVS and VAPOR (TE=23ms, TR=4.0s, 13 measurements/task run, 4 averages/measurement, 2048 points, TA/task run=3:12min). The two ¹H fMRS spectra in each task epoch were averaged after applying a phase and frequency shift correction followed by quantification using LCModel (Figure 1). A repeated measures generalized estimating equation (GEE) approach was used to model glutamate level with task condition (baseline condition, Non-Selective, Selective) as the main term for both task conditions with (Negative Affect Faces) and without (No Affect Squares) affect (SAS GENMOD; SAS Institute Inc). An additional GEE was conducted to assess the effect of glutamate across response mode (Non-Selective vs Selective) and affect (Squares vs Faces) and the interaction of the two terms.

Results

Glutamate levels were not significantly different across the three task conditions during the presentation of stimuli without affect (Squares: χ²= .65, p=0.72) or with affect (Faces: χ²= 1.07, p=0.30) (Figure 3a,b). The second set of analyses revealed a significant main effect of affect condition (χ²= 4.18, p=0.04) such that, independent of response mode, trauma-exposed youth demonstrated significantly less glutamate during the Negative Affect Faces condition compared to No Affect Squares condition (Figure 4). The response mode term (χ²= .02, p=0.90) and the interaction between response mode and affect (χ²= .54, p=0.46) were both non-significant (Figure 4)

Discussion

We demonstrate for the first-time distinct task related changes in the dACC glutamate of trauma-exposed youth during inhibitory motor control that were driven by the influence of stimuli with negative affect – i.e., an effect where glutamate was significantly lower during the Negative Affect Faces condition compared to the No Affect Squares condition, independent of inhibitory motor controls (Selective or Non-Selective). This result potentially supports our framework that negative emotional processes may influence cognitive processes related to motor control in trauma-exposed youth. Further research is needed to investigate possible associations with motor control performance or with severity of trauma exposure, and whether glutamate changes driven by affect differ in youth without trauma-exposure.

Acknowledgements

This work was supported by the new investigator grant from the Department of Psychiatry and Behavioral Neurosciences, WSU, the Lycaki-Young Funds from the State of Michigan and the National Institute of Mental Health (R01-MH111682).

References

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Figures

Figure 1: A representative dACC voxel placement (right) and typical 1H MRS spectrum after combining 8 working block measurements per task run as outlined in Figure2b.

Figure 2: A) The Visually-Guided Motor Control Task consisting of 2 motor response modes, Non-Selective and Selective Inhibition, by 2 affect conditions, Negative Affect and No Affect. Participants respond to both cues in the non-selective mode. In the selective inhibition mode, participants respond only to the green square in the no affect condition and the negative faces in the negative affect condition. B) The sequence of 1H MRS measurements for each task run. Each run consists of 4 working blocks interleaved by rest blocks of crosshair fixation.

Figure 3: Comparison of mean percent changes in glutamate relative to baseline across baseline fixation, non-selective response, and selective inhibition for runs of no affect (panel A) and for runs of negative affect (panel B). While no significant differences between runs were observed in the no affect condition, we observed a trending reduction in glutamate during the selective inhibition mode.

Figure 4: Mean percent changes in glutamate relative to baseline during the no affect and negative affect condition of the task separated by task mode. Results show a significant main effect of affect, such that a reduction in glutamate was observed during the negative affect condition, independent of task mode.

Proc. Intl. Soc. Mag. Reson. Med. 31 (2023)

0639

DOI: https://doi.org/10.58530/2023/0639