Ivana Rosenzweig

Sleep apnoea and the brain: a complex relationship

Intermittent hypoxia, reoxygenation, and hypercapnia or hypocapnia occur in both adults and children during untreated apnoea and hypopnoea, along with changes in cerebral blood flow and sleep fragmentation. These effects can result in cognitive deficits with functional effects on work and school efficiency. The assessment of how obstructive sleep apnoea affects cognition depends on the specificity and sensitivity of the tests, which are rarely developed specifically for obstructive sleep apnoea. In this Review, we discuss both the neural adaptive and maladaptive processes in response to hypoxaemia. The net result on cognitive and emotional performance depends on the stage of this dynamic process, effects on other body systems, cognitive reserve, and idiosyncratic susceptibility. We also explore the contribution of fragmented sleep, and the disruption of sleep structure, with focus on the effect at different times in the development of disease. This Review will address the gap in the underlying pathophysiology of new clinical and translational findings, and argue their contribution to the inherent complexity of the association between obstructive sleep apnoea and the brain.

The Association Between Obstructive Sleep Apnea and Alzheimer’s Disease: A Meta-Analysis Perspective

Alzheimer’s disease (AD) and obstructive sleep apnea (OSA) are highly prevalent, chronic conditions with intriguing, yet poorly understood epidemiological overlap. To date, the amount of OSA syndrome present in patients with AD across literature remains unknown. To address this question, we collected all available published clinical data and analyzed them through a quantitative meta-analytical approach. The results of our quantitative meta-analysis suggest that the aggregate odds ratio for OSA in AD vs. healthy control was 5.05 and homogeneous. This reflects that patients with AD have a five times higher chance of presenting with OSA than cognitively non-impaired individuals of similar age. Moreover, these data suggest that around half of patients with AD have experienced OSA at some point after their initial diagnosis. The additive impact of progressive changes in sleep quality and structure, changes in cerebral blood flow and the cellular redox status in OSA patients may all be contributing factors to cognitive decline and may further aggravate AD progression. It is hoped that the high OSA rate in AD patients, as suggested by the findings of our meta-analysis, might provide a sufficient clinical incentive to alert clinicians the importance of screening patients for OSA in AD, and stimulate further research in this area.

Structural and functional neural adaptations in obstructive sleep apnea: an activation likelihood estimation meta-analysis

Highlights • The right basolateral amygdala, the hippocampus and the right insular cortex are important nodes in obstructive sleep apnea (OSA).• Functional characterization of these regions suggested associated dysfunction of emotional, sensory, and limbic processes in OSA.• Connectivity analysis demonstrated that these regions are part of a joint network comprising the anterior insula, posterior-medial frontal cortex and thalamus.

Hippocampal Hypertrophy and Sleep Apnea: A Role for the Ischemic Preconditioning?

The full impact of multisystem disease such as obstructive sleep apnoea (OSA) on regions of the central nervous system is debated, as the subsequent neurocognitive sequelae are unclear. Several preclinical studies suggest that its purported major culprits, intermittent hypoxia and sleep fragmentation, can differentially affect adult hippocampal neurogenesis. Although the prospective biphasic nature of chronic intermittent hypoxia in animal models of OSA has been acknowledged, so far the evidence for increased ‘compensatory’ neurogenesis in humans is uncertain. In a cross-sectional study of 32 patients with mixed severity OSA and 32 non-apnoeic matched controls inferential analysis showed bilateral enlargement of hippocampi in the OSA group. Conversely, a trend for smaller thalami in the OSA group was noted. Furthermore, aberrant connectivity between the hippocampus and the cerebellum in the OSA group was also suggested by the correlation analysis. The role for the ischemia/hypoxia preconditioning in the neuropathology of OSA is herein indicated, with possible further reaching clinical implications.

The impact of sleep and hypoxia on the brain: potential mechanisms for the effects of obstructive sleep apnea.

Purpose of review Obstructive sleep apnea (OSA) is a chronic, highly prevalent, multisystem disease, which is still largely underdiagnosed. Its most prominent risk factors, obesity and older age, are on the rise, and its prevalence is expected to grow further. The last few years have seen an exponential increase in studies to determine the impact of OSA on the central nervous system. OSA-induced brain injury is now a recognized clinical entity, although its possible dual relationship with several other neuropsychiatric and neurodegenerative disorders is debated. The putative neuromechanisms behind some of the effects of OSA on the central nervous system are discussed in this review, focusing on the nocturnal intermittent hypoxia and sleep fragmentation. Recent findings Recent preclinical and clinical findings suggest that neurogenic ischemic preconditioning occurs in some OSA patients, and that it may partly explain variability in clinical findings to date. However, the distinct parameters of the interplay between ischemic preconditioning, neuroinflammation, sleep fragmentation and cerebrovascular changes in OSA-induced brain injury are still largely unclear, and more research is required. Summary Early diagnosis and intervention in patients with OSA is of paramount importance. Future clinical studies should utilize multimodal investigative approaches to enable more reliable referencing for the acuity of the pathological process, as well as its reversibility following the treatment.

Abnormalities in thalamic neurophysiology in schizophrenia: Could psychosis be a result of potassium channel dysfunction?

Psychosis in schizophrenia is associated with source-monitoring deficits whereby self-initiated behaviors become attributed to outside sources. One of the proposed functions of the thalamus is to adjust sensory responsiveness in accordance with the behavioral contextual cues. The thalamus is markedly affected in schizophrenia, and thalamic dysfunction may here result in reduced ability to adjust sensory responsiveness to ongoing behavior. One of the ways in which the thalamus accomplishes the adjustment of sensory processing is by a neurophysiological shift to post-inhibitory burst firing mode prior to and during certain exploratory actions. Reduced amount of thalamic burst firing may result from increased neuronal excitability secondary to a reported potassium channel dysfunction in schizophrenia. Pharmacological agents that reduce the excitability of thalamic cells and thereby promote burst firing by and large tend to have antipsychotic effects.

CrossTalk opposing view: The intermittent hypoxia attending severe obstructive sleep apnoea does not lead to alterations in brain structure and function

Ivana Rosenzweig, Steven C. Williams and Mary J. Morrell Department of Neuroimaging, Institute of Psychiatry, King’s College London, UK Danish Epilepsy Centre, Dianalund, Denmark Academic Unit of Sleep and Breathing, NationalHeart andLung Institute, Imperial College London, and NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK

Changes in Neurocognitive Architecture in Patients with Obstructive Sleep Apnea Treated with Continuous Positive Airway Pressure

Background Obstructive sleep apnea (OSA) is a chronic, multisystem disorder that has a bidirectional relationship with several major neurological disorders, including Alzheimers dementia. Treatment with Continuous Positive Airway Pressure (CPAP) offers some protection from the effects of OSA, although it is still unclear which populations should be targeted, for how long, and what the effects of treatment are on different organ systems. We investigated whether cognitive improvements can be achieved as early as one month into CPAP treatment in patients with OSA. Methods 55 patients (mean (SD) age: 47.6 (11.1) years) with newly diagnosed moderate–severe OSA (Oxygen Desaturation Index: 36.6 (25.2) events/hour; Epworth sleepiness score (ESS): 12.8 (4.9)) and 35 matched healthy volunteers were studied. All participants underwent neurocognitive testing, neuroimaging and polysomnography. Patients were randomized into parallel groups: CPAP with best supportive care (BSC), or BSC alone for one month, after which they were re-tested. Findings One month of CPAP with BSC resulted in a hypertrophic trend in the right thalamus [mean difference (%): 4.04, 95% CI: 1.47 to 6.61], which was absent in the BSC group [− 2.29, 95% CI: − 4.34 to − 0.24]. Significant improvement was also recorded in ESS, in the CPAP plus BSC group, following treatment [mean difference (%): − 27.97, 95% CI: − 36.75 to − 19.19 vs 2.46, 95% CI: − 5.23 to 10.15; P = 0.012], correlated to neuroplastic changes in brainstem (r = − 0.37; P = 0.05), and improvements in delayed logical memory scores [57.20, 95% CI: 42.94 to 71.46 vs 23.41, 95% CI: 17.17 to 29.65; P = 0.037]. Interpretation One month of CPAP treatment can lead to adaptive alterations in the neurocognitive architecture that underlies the reduced sleepiness, and improved verbal episodic memory in patients with OSA. We propose that partial neural recovery occurs during short periods of treatment with CPAP.

Neuroconnectivity and valproic acid: The myelin hypothesis

Neuropsychiatric medications that directly alter the epigenome, such as valproic acid, can under certain conditions reactivate critical developmental periods and thus impact adult neuroconnectivity. In animal models valproic acid was shown to inhibit the process of postnatal myelination and to replicate age-dependent decline in remyelination efficiency. The human central nervous systems myelination process, unlike that of non-human primates commonly used in the experimental models, is an intricate heterochronous process that continues well into adult life and which probably underlies later life neurocognitive changes and plasticity. Chronic exposure to valproic acid, especially in patients with epilepsy and neuropsychiatric disorders, may profoundly affect this process and its developmental trajectory. Further studies using novel MRI methods that allow in vivo mapping of myelination trajectories across the lifespan are urgently required to address the potential effects of valproic acid on brain development.

Functional reorganization in obstructive sleep apnoea and insomnia: A systematic review of the resting-state fMRI.

HighlightsResting state functional MRI studies is a promising non‐invasive tool for better understanding of the pathophysiology of sleep disorders.The salience network is involved in hyperarousal and affective symptoms in insomnia.The posterior default mode network appears to underlie cognitive and depressive symptoms of obstructive sleep apnoea.Disruption of intrinsic networks have been demonstrated in major depression, which is a common co‐morbidity of sleep disorders. ABSTRACT Functional neuroimaging techniques have accelerated progress in the study of sleep disorders. Considering the striking prevalence of these disorders in the general population, however, as well as their strong bidirectional relationship with major neuropsychiatric disorders, including major depressive disorder, their numbers are still surprisingly low. This review examines the contribution of resting state functional MRI to current understanding of two major sleep disorders, insomnia disorder and obstructive sleep apnoea. An attempt is made to learn from parallels of previous resting state functional neuroimaging findings in major depressive disorder. Moreover, shared connectivity biomarkers are suggested for each of the sleep disorders. Taken together, despite some inconsistencies, the synthesis of findings to date highlights the importance of the salience network in hyperarousal and affective symptoms in insomnia. Conversely, dysfunctional connectivity of the posterior default mode network appears to underlie cognitive and depressive symptoms of obstructive sleep apnoea.