Evidence for Locus Coeruleus-Norepinephrine System Abnormality in Military Posttraumatic Stress Disorder Revealed by Neuromelanin-Sensitive Magnetic Resonance Imaging.

BACKGROUND: The complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)-norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder. METHODS: Study participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32). Clinical measures included the Clinician-Administered PTSD Scale for DSM-5, and neuroimaging measures included a neuromelanin-sensitive magnetic resonance imaging scan to measure the LC signal. Robust linear regression analyses related the LC signal to clinical measures. RESULTS: Compared with control participants, the LC signal was significantly elevated in the PTSD group (t62 = 2.64, p = .010), and this group difference was most pronounced in the caudal LC (t56 = 2.70, Cohen's d = 0.72). The caudal LC signal was also positively correlated with the severity of Clinician-Administered PTSD Scale for DSM-5 hyperarousal symptoms in the PTSD group (t26 = 2.16, p = .040). CONCLUSIONS: These findings are consistent with a growing body of evidence indicative of elevated LC-norepinephrine system function in PTSD. Furthermore, they indicate the promise of neuromelanin-sensitive magnetic resonance imaging as a noninvasive method to probe the LC-norepinephrine system that has the potential to support subtyping and treatment of PTSD or other neuropsychiatric conditions.

'Against everything that got you into the job': experiences of potentially morally injurious events among Canadian public safety personnel.

Background: Moral injury (MI) has become a research and organizational priority as frontline personnel have, both during and in the years preceding the COVID-19 pandemic, raised concerns about repeated expectations to make choices that transgress their deeply held morals, values, and beliefs. As awareness of MI grows, so, too, does attention on its presence and impacts in related occupations such as those in public safety, given that codes of conduct, morally and ethically complex decisions, and high-stakes situations are inherent features of such occupations.Objective: This paper shares the results of a study of the presence of potentially morally injurious events (PMIEs) in the lived experiences of 38 public safety personnel (PSP) in Ontario, Canada.Method: Through qualitative interviews, this study explored the types of events PSP identify as PMIEs, how PSP make sense of these events, and the psychological, professional, and interpersonal impacts of these events. Thematic analysis supported the interpretation of PSP descriptions of events and experiences.Results: PMIEs do arise in the context of PSP work, namely during the performance of role-specific responsibilities, within the organizational climate, and because of inadequacies in the broader healthcare system. PMIEs are as such because they violate core beliefs commonly held by PSP and compromise their ability to act in accordance with the principles that motivate them in their work. PSP associate PMIEs, in combination with traumatic experiences and routine stress, with adverse psychological, professional and personal outcomes.Conclusion: The findings provide additional empirical evidence to the growing literature on MI in PSP, offering insight into the contextual dimensions that contribute to the sources and effects of PMIEs in diverse frontline populations as well as support for the continued application and exploration of MI in the PSP context.

The objective of this study was to understand the types of events that Canadian public safety personnel (PSP) experience as potentially morally injurious events (PMIEs) as well as the impacts that they associate with these events.The findings illuminate that contextual dimensions are significant in the origin of PMIEs, which PSP experience in the completion of routine duties, because of the organizational culture, or as a result of issues in the broader healthcare system, which led to many negative consequences in their personal and professional lives.PMIEs reduced the trust PSP had in their leadership and the healthcare system to protect the public and themselves, were associated with feelings of anger, frustration, resignation, and helplessness, and connected to internal struggles marked by inner conflict and the erosion of self-concept.

Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer's disease.

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer's disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-ß and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-ß positron emission tomography (with [18F]MK6240 and [18F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [18F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t186 = -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-ß burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

One-carbon metabolism supplementation improves outcome after stroke in aged male MTHFR-deficient mice.

The prevalence of stroke increases with age and the ability to absorb all nutrients from our diets decreases with age. Nutrition is a modifiable risk factor for stroke, which is a leading cause of death and disability in world-wide. Deficiencies in one­carbon metabolism, including in methyltetrahydrofolate reductase (MTHFR), have been linked to increased risk of stroke. The Mthfr+/- mice mouse model mimic the phenotype of the MTHFR677C➔T polymorphism, such as elevated levels of homocystine. Using this mouse model, the aim of this study was to investigate the impact of dietary supplementation with 5-methylTHF, vitamin B12, and choline after ischemic stroke. Male Mthfr+/- and wildtype littermate control mice were aged (~1.5-year-old) and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr+/- and wildtype littermate mice were placed on 5-methylTHF, vitamin B12, and choline supplemented diet (SD). Four weeks after PT and SD motor function was assessed using the accelerating rotarod, forepaw asymmetry, and ladder beam walking tasks. Total homocysteine and cysteine levels were measured in blood. Brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. After PT and SD, Mthfr+/- mice were able to stay on the accelerating rotarod longer and used their impaired forepaw to explore more when compared to CD animals. Furthermore, total homocysteine levels in plasma and lesion volume were reduced in Mthfr+/+ and Mthfr+/- SD mice. Within the damage site, there were reduced levels of apoptotic cell death and increased neuroprotective cellular response in the brains of SD treated Mthfr+/- mice. This study reveals a critical role for one­carbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage.