Hyperarousal Symptoms of PTSD in Veterans Correlate to Neuromelanin-Sensitive MRI Signal in the Locus Coeruleus, a Putative Measure of Norepinephrine System Function

Abstract

Post-traumatic stress disorder (PTSD) is a heterogenous psychiatric condition that affects thousands of individuals each year. Of those who experience this condition, military members including members of the Canadian Armed Forces (CAF) are particularly vulnerable, demonstrating high prevalence rates of PTSD-related symptoms. Moreover, individuals with PTSD are at increased risk for comorbid conditions and are at greater risk for suicide due to the overwhelming, debilitating nature of PTSD symptoms. In previous research, hyperarousal symptoms associated with PTSD have been linked to dysregulation in the locus coeruleus norepinephrine (LC-NE) system, a vast neuromodulatory system responsible for regulating arousal, attention, autonomic and memory-related functions. Advancements in neuroimaging methods have advanced our ability to study connectivity in vivo such that small structures like the LC can be further studied in human samples. Specifically, neuromelanin-sensitive MRI (NM-MRI), a novel, non-invasive neuroimaging method has been shown to detect changes in neuromelanin (NM)-related signal in both the LC and substantia nigra (SN). NM is a dark pigment that accumulates over the lifespan in catecholamine-dominant centers such as the LC and SN and is the by-product of catecholamine oxidation. NM-MRI can be used to image these centers in vivo due to the paramagnetic properties offered by NM. Furthermore, when excess cytosolic catecholamine levels are present in select neurons, NM production is thought to be increased, resulting in increased NM signal from the LC. This could potentially be a marker for dysregulation as many conditions have been associated with variability of this system. Previously, NM-MRI has been used in other clinical settings such as in Parkinson’s disease (PD), Alzheimer’s disease (AD), schizophrenia and depression; however, this current investigation is the first to utilize this imaging modality in the context of PTSD. Specifically, we hypothesized that increased NM-MRI signal in the LC would correlate with increasing severity of hyperarousal symptoms in individuals with PTSD. We also predicted that the opposite would be true for comorbid depression symptom severity, as reduced LC signal has been previously correlated with clinical measures of comorbid depression using NM-MRI. As per our primary hypothesis, we observed a significant positive correlation between NM-MRI signals in the caudal elements of the LC with hyperarousal symptom severity in 22 PTSD subjects (r= 0.54, p= 0.017; partial correlation controlling for depression symptom severity, age, and sex). In contrast, we did not find any evidence to support our secondary hypothesis, because a non-significant trend correlating LC NM-MRI signal and depression symptom severity was obtained (r= -0.30, p=0.22; partial correlation controlling for hyperarousal severity, age, and sex). Based on these results, we were able to build on previously conducted work to further investigate the utility of NM-MRI in the detection of variability in LC-NE system as it pertains to psychiatric conditions known to show dysregulation of this system such as PTSD. In addition, this thesis provides further evidence to support the automation of NM-MRI analytical methods, thus supporting their potential utility for future clinical research. Our findings also provide support for the use of NM-MRI as a potential measure of NE activity; further, this work provided preliminary evidence supporting the use of NM-MRI in a clinical, psychiatric setting, where the technique may serve as a biomarker of PTSD pathology. With these findings in mind, additional validation studies can be conducted to verify the use of NM-MRI as a biomarker for NE system dysregulation. This would potentially allow for advancements in targeted treatment options for PTSD, particularly those targeting the LC-NE system, thus potentially increasing patient stratification and treatment efficacy.