Patients with obstructive sleep apnea (OSA) reveal functional changes in brain sites involved in autonomic, cognitive, and mood regulations. However, it is unclear whether these brain changes reverse with short-term positive airway pressure (PAP) treatment. Our aim was to examine brain functional changes in response to 3-months of PAP treatment using regional homogeneity (ReHo) measures, where increased and decreased ReHo value indicates hyper- and hypo-local neural activities, respectively, and considered as functional deficits. We collected brain magnetic resonance imaging data as well as mood, cognitive, and sleep variables from 17 treatment-naïve OSA at baseline and after 3-months of PAP treatment and 25 age- and gender-matched healthy controls. Whole-brain ReHo maps were calculated and compared between OSA and controls and OSA subjects before and after PAP treatment. At baseline, treatment-naïve OSA subjects showed higher ReHo in the bilateral thalamus, putamen, postcentral gyrus, paracentral lobule, supplementary motor area, and right insula, and lower ReHo in the frontal and parietal cortices, compared to controls. After 3-months of PAP treatment, abnormal sleep and mood scores decreased significantly to normal levels. ReHo decreased in the autonomic and somatosensory control areas, including the thalamus, putamen, postcentral gyrus, and insula, and increased in the cognitive and affective regulatory parietal regions. The normalized ReHo was correlated with improved sleep quality and reduced anxiety symptoms. These findings suggest that 3-months of PAP use can improve sleep, mood issues, and partly recover brain activities, however, longer PAP treatment may be required to fully and permanently reverse brain functional deficits.

Heart failure (HF) patients show inability to regulate autonomic functions in response to autonomic challenges. The autonomic deficits may stem from brain tissue injury in central autonomic regulatory areas, resulting from ischemic and hypoxic processes accompanying the condition. However, the direct evaluation of correlations between brain structural injury and functional timing and magnitude of neural signal patterns within affected areas, which may lead to impaired autonomic outflow, is unclear. In this study, we evaluate neural responses to the Valsalva maneuver with blood oxygen level-dependent functional magnetic resonance imaging in 29 HF patients and 35 control subjects and brain structural changes using diffusion tensor imaging-based mean diffusivity in a subsample of 19 HF and 24 control subjects. HF showed decreased neural activation in multiple autonomic and motor control areas, including cerebellum cortices, vermis, left insular, left putamen, and bilateral postcentral gyrus. Structural brain changes emerged in similar autonomic, as well as cognitive and mood regulation areas. Functional MRI responses in cerebellum and insula in HF subjects are delayed or decreased in magnitude to the challenge. The impaired functional responses of insular and cerebellar sites are correlated with the severity of tissue changes. These results indicate that the functions of insular and cerebellar regions, sites that are involved in autonomic regulation, are compromised, and that autonomic deficits in these areas have brain structural basis for impaired functions. Our study enhanced our understanding of brain structural and functional alterations underlying impaired autonomic regulations in HF subjects.

BACKGROUND:Patients with heart failure (HF) show abnormal autonomic activities, which may stem from altered functional connectivity (FC) between different brain sites. METHODS AND RESULTS:We evaluate insular and cerebellar FC with other brain areas, before, during, and after the Valsalva challenge, with functional magnetic resonance imaging in 35 HF and 35 control subjects. Significant insular FC emerged with striatum, thalamus, and anterior cingulate. While left and right cerebellar cortices showed significant FC with each other constituting the cerebellum network, the insula and cerebellum networks showed significant negative FC with each other at baseline, challenge, and recovery phases. The challenge induced increased FC within the insula and the cerebellum networks in both HF and controls. However, patients with HF showed more increased insular network FC, but less enhanced cerebellar FC. During the recovery phase, the negative FC between the insular network and cerebellum enhanced significantly in controls, but not in HF. Lower left ventricle ejection fraction was correlated with lower insula network FC, and impaired negative FC between cerebellum and the insula network in HF. CONCLUSIONS:Increased insular FC in patients with HF might contribute to exaggerated sympathetic tone. While impaired cerebellar FC and diminished negative interactions between cerebellum and insular systems may indicate impaired parasympathetic functions in HF.

Introduction

Brain structural injury and metabolic deficits in the hippocampus and caudate nuclei may contribute to cognitive and emotional deficits found in obstructive sleep apnea (OSA) patients. If such contributions exist, resting-state interactions of these subcortical sites with cortical areas mediating affective symptoms and cognition should be disturbed. Our aim was to examine resting-state functional connectivity (FC) of the hippocampus and caudate to other brain areas in OSA relative to control subjects, and to relate these changes to mood and neuropsychological scores.

Methods

We acquired resting-state functional magnetic resonance imaging (fMRI) data from 70 OSA and 89 healthy controls using a 3.0-Tesla magnetic resonance imaging scanner, and assessed psychological and behavioral functions, as well as sleep issues. After standard fMRI data preprocessing, FC maps were generated for bilateral hippocampi and caudate nuclei, and compared between groups (ANCOVA; covariates, age and gender).

Results

Obstructive sleep apnea subjects showed significantly higher levels of anxiety and depressive symptoms over healthy controls. In OSA subjects, the hippocampus showed disrupted FC with the thalamus, para-hippocampal gyrus, medial and superior temporal gyrus, insula, and posterior cingulate cortex. Left and right caudate nuclei showed impaired FC with the bilateral inferior frontal gyrus and right angular gyrus. In addition, altered limbic-striatal-cortical FC in OSA showed relationships with behavioral and neuropsychological variables.

Conclusions

The compromised hippocampal-cortical FC in OSA may underlie depression and anxious mood levels in OSA, while impaired caudate-cortical FC may indicate deficits in reward processing and cognition. These findings provide insights into the neural mechanisms underlying the comorbidity of mood and cognitive deficits in OSA.

There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.