Robust and fast stochastic 4D flow vector-field signature technique for quantifying composite flow dynamics from 4D flow MRI: Application to left atrial flow in atrial fibrillation.

4D flow MRI is an emerging imaging modality that maps voxel-wise blood flow information as velocity vector fields that is acquired in 7-dimensional image volumes (3 spatial dimensions + 3 velocity directions + time). Blood flow in the cardiovascular system is often complex and composite involving multiple flow dynamics and patterns (e.g., vortex flow, jets, stagnating flow) that occur and interact simultaneously. The spectrum of such complex flow dynamics is embedded in the velocity vector field dynamics derived from 4D Flow MRI. However, current flow metrics cannot fully measure high-dimensional vector-field data and embedded complex composite flow data. Instead, these methods need to break down the vector-field data into secondary scalar fields of individual flow components using fluid dynamics operators. These methods are gradient-based and sensitive to data uncertainties, and only focus on individual flow components of the overall composite flow, therefore potentially underestimating the severity of overall flow changes associated with cardiovascular diseases. To address these limitations, in MICCAI 2021, we introduced a novel comprehensive stochastic 4D Flow vector-field signature technique that works directly on the entire spatiotemporal velocity vector field. This technique uses efficient stochastic gradient-free interrogation of multi-million flow vector-pairs per patient to derive the patient's unique flow profile of the complex composite flow alterations and in real-time processing. The signature technique's probabilistic gradient-free formulation should allow for highly robust quantification despite inherent errors in 4D flow MRI acquisitions. Here, we extend the application of the 4D flow vector-field signature technique to the left atrium to analyze complex composite flow changes in patients with atrial fibrillation. In 128 subjects, we performed extensive sensitivity testing and determined that the vector-field signature technique is highly robust to typical sources of data uncertainties in 4D flow MRI: degradation in spatiotemporal resolution, added Gaussian noise, and segmentation errors. We demonstrate the excellent generalizability of the stochastic convergence from the aorta to the left atrium and between different 4D Flow MRI acquisition protocols. We compare the robustness of our technique to existing advanced flow quantification metrics of kinetic energy, vorticity, and energy loss demonstrating a superior performance of up-to 14-fold. Our results show the potential diagnostic and clinical utility of our signature technique in identifying distinctly altered composite flow signatures in atrial fibrillation patients independent of existing flow metrics.

Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest.

BACKGROUND: Neurological injury following successful resuscitation from sudden cardiac arrest (CA) is common. The pathophysiological basis of this injury remains poorly understood, and treatment options are limited. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized. Here, we hypothesize that microglial activation that occurs following brief asystolic CA is associated with neurological injury and represents a potential therapeutic target. METHODS: Adult C57BL/6 male and female mice were randomly assigned to 12-min, KCl-induced asystolic CA, under anesthesia and ventilation, followed by successful cardiopulmonary resuscitation (n = 19) or sham intervention (n = 11). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. Mice were killed at 72 h for histological studies; neuronal degeneration was assessed using Fluoro-Jade C staining. Microglial characteristics were assessed by immunohistochemistry using the marker of ionized calcium binding adaptor molecule 1, followed by ImageJ analyses for cell integrity density and skeletal analyses. RESULTS: Neurological injury in post-cardiopulmonary-resuscitation mice vs. sham mice was evident by poorer neurological scores (difference of 3.626 ± 0.4921, 95% confidence interval 2.618-4.634), sensory and motor functions (worsened by sixfold and sevenfold, respectively, compared with baseline), and locomotion (75% slower with a 76% decrease in total distance traveled). Post-CA brains demonstrated evidence of neurodegeneration and neuroinflammatory microglial activation. CONCLUSIONS: Extensive microglial activation and neurodegeneration in the CA1 region and the dentate gyrus of the hippocampus are evident following brief asystolic CA and are associated with severe neurological injury.

Stage-dependent effects of intermittent hypoxia influence the outcome of hippocampal adult neurogenesis.

Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer's disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.

Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus.

Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30 did not affect paired-pulse facilitation, IH30 suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30 increased the number of proliferating Sox2+ neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30 increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.SIGNIFICANCE STATEMENT Individuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.