Global Disparities in the Presentation and Management of Aneurysmal Subarachnoid Hemorrhage: A Review and Analysis.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality rates. There is a significant gap in the literature describing global disparities in demographics, management, and outcomes among patients with aSAH. We aimed to conduct a systematic review and meta-analysis to assess global disparities in aSAH presentation and management. METHODS: PubMed and Embase databases were queried from earliest records to November 2022 for aSAH literature. Presentation, demographics, comorbidities, treatment methods, and outcomes data were collected. Articles that did not report aSAH-specific patient management and outcomes were excluded. Pooled weighted prevalence rates were calculated. Random effects model rates were reported. RESULTS: After screening, 33 articles representing 10,553 patients were included. The prevalence of Fisher grade 3 or 4 aSAH in high- and lower-income countries (HIC and LIC), respectively, was 79.8% (P < 0.01) and 84.1 (P < 0.01). Prevalence of male aSAH patients in HIC and LIC, respectively, was 35.8% (P < 0.01) and 45.0% (P < 0.01). Prevalence of treatment in aSAH patients was 99.5% (P < 0.01) and 99.4% (P = 0.16) in HIC and LIC, respectively. In HIC, 35% (P < 0.01) of aneurysms in aSAH patients were treated with coiling. No LIC reported coiling for aSAH treatment; LIC only reported rates of surgical clipping, with a total prevalence of 92.4% (P < 0.01) versus 65.6% (P < 0.01) in HIC. CONCLUSION: In this analysis, we found similar rates of high-grade SAH hemorrhages in HIC and LIC but a lack of endovascular coil embolization treatments reported in LIC. Additional research and discussion are needed to identify reasons for treatment disparities and intervenable societal factors to improve aSAH outcomes worldwide.

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

BACKGROUND: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized ArcCreERT2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

( R,S )-ketamine's rapid-acting antidepressant effects are modulated by NR2B-containing NMDA receptors on adult-born hippocampal neurons.

Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. ( R,S )-ketamine, an N -methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the NR2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of NR2B-expressing adult-born granule cells (abGCs). In this study, we examined whether ( R,S )-ketamine's efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the NR2B subunit of the NMDAR from Nestin + cells. To validate our findings, we also used several other transgenic lines including one in which NR2B was deleted from an interneuron (Parvalbumin (PV) + ) population. We report that in male mice, NR2B expression on 6-week-old adult-born neurons is necessary for ( R,S )-ketamine's effects on behavioral despair in the forced swim test (FST) and on hyponeophagia in the novelty suppressed feeding (NSF) paradigm, as well on fear behavior following contextual fear conditioning (CFC). In female mice, NR2B expression is necessary for effects on hyponeophagia in the NSF. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by ( R,S )-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing NR2B partially modulate ( R,S )-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of ( R , S )-ketamine's antidepressant actions.

Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by ( R,S )-ketamine.

INTRODUCTION: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized the ArcCreER T2 x enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact (CCI) model of TBI. Mice were then administered a contextual fear discrimination (CFD) paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if ( R,S )-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the DG, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, ( R,S )-ketamine facilitated fear discrimination and this behavioral improvement was reflected in DG memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces, and that this deficit can be improved with a single injection of ( R,S )-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.