Cortico-striatal activity characterizes human safety learning via Pavlovian conditioned inhibition

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviours. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (UHF) fMRI to examine the neural basis of inhibitory safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat-omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat-omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation. The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular and dorsolateral prefrontal cortex compared to the standard safety signal, whereas the latter evoked greater activation of the ventromedial prefrontal cortex, posterior cingulate and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of stimulus-safety associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.

Expected Rates of Select Adverse Events following Immunization for COVID-19 Vaccine Safety Monitoring

Background: Knowledge of expected rates of potential adverse events of special interest (AESI) that may occur coincidentally following COVID-19 vaccination is essential for vaccine safety surveillance and assessment. We calculated the expected rates of 21 potential AESI following COVID-19 vaccination among vaccinated persons within 1 day, 7 days, and 42 days of vaccination. Methods: We used meta-analytic methods to estimate background rates of 21 medical conditions considered potential AESI and calculated expected rates of each potential AESI within 1 day, 7 days, and 42 days of vaccination. Results: Background rates of three commonly monitored AESI, Guillain-Barre syndrome (GBS), myopericarditis, and all-cause deaths were 2.0 GBS cases/100,000 person-years, 1.3 myopericarditis cases/100,000 person-years, and 863.8 all-cause deaths/100,000 person-years, respectively. Based on these background rates, if 10,000,000 persons are vaccinated, we would expect 0.5, 3.7, and 22.5 GBS cases; 0.3, 2.4, and 14.3 myopericarditis cases; and 236.5, 1655.5, and 9932.8 all-cause deaths to occur in coincident temporal association (i.e., as a result of background incidence) within 1 day, 7 days, and 42 days of vaccination, respectively. Conclusion: Knowledge of expected rates of potential AESI can help contextualize adverse health events associated temporally with immunization, aid in safety signal detection, guide COVID-19 vaccine public health communication, and inform benefit-risk assessments of COVID-19 vaccines.

Cardiac Inflammation after COVID-19 mRNA Vaccines: A Global Pharmacovigilance Analysis

Background To counter the COVID-19 pandemic, mRNA vaccines, namely tozinameran and elasomeran, have been authorized in several countries. These next generation vaccines have shown high efficacy against COVID-19 and demonstrated a favorable safety profile. As widespread vaccinations efforts are taking place, incidents of myocarditis and pericarditis cases following vaccination have been reported. This safety signal has been recently confirmed by the European Medicine Agency and the U.S. Food and Drug Administration. This study aimed to investigate and analyze this safety signal using a dual pharmacovigilance database analysis. Methods This is as an observational study of reports of inflammatory heart reactions associated with mRNA COVID-19 vaccines reported in the World Health Organization's global individual case safety report database (up to June 30th 2021), and in the U.S. Vaccine Adverse Event Reporting System (VAERS, up to May 21st 2021). Cases were described, and disproportionality analyses using reporting odds-ratios (ROR) and their 95% confidence interval (95%CI) were performed to assess relative risk of reporting according to patient sex and age. Results At a global scale, the inflammatory heart reactions most frequently reported were myocarditis (1241, 55%) and pericarditis (851, 37%), the majority requiring hospitalization (n=796 (64%)). Overall, patients were young (median age 33 [21-54] years). The main age group was 18-29 years old (704, 31%), and mostly males (1555, 68%). Pericarditis onset was delayed compared to myocarditis with a median time to onset of 8 [3-21] vs. 3 [2-6] days, respectively (p=0.001). Regarding myocarditis, an important disproportionate reporting in males (ROR, 9.4 [8.3-10.6]) as well as in adolescents (ROR, 22.3 [19.2-25.9]) and 18-29 years old (ROR, 6.6 [5.9-7.5]) compared to older patients were observed. Conclusions The inflammatory heart reactions, namely myocarditis and pericarditis, have been reported world-wide shortly following COVID-19 mRNA vaccination. An important disproportionate reporting among adolescents and young adults, particularly in males, was observed especially for myocarditis. Guidelines must take this specific risk into account and to optimize vaccination protocols according to sex and age. While the substantial benefits of COVID-19 vaccination still prevail over risks, clinicians and the public should be aware of these reactions and seek appropriate medical attention.