Glymphatics, Cranium, and the Brain Homeostasis

Abstract

Despite the human brain accounting for only 2% of total body mass, it consumes 20% of the body’s energy. The average cerebral blood flow, at 70 mL/100 g/minute, is 10x the average blood flow for the rest of the body, at 7 mL/100 g/minute. With such elevated energy demands and synaptic activities, the brain produces 7000 mg of proteinaceous, lipid, and other metabolic waste per day including amyloid beta, tau, and modified cholesterol (24S-hydroxycholesterol and oxysterol, etc.). In the body, the lymphatic system eliminates metabolic wastes, but the brain parenchyma or the neuropil, contains no lymphatics. How does brain rid itself of these metabolites? The discovery of the glymphatic system a decade ago partially answers the question. The word “glymphatics” is derived by condensing “glial” and “lymphatics.” It is comprised of convective flow at 50 µm/s in the perivascular space around pia-penetrating arterioles, entering the interstitial fluid space before draining into the perivascular space of the venules, carrying with it the metabolic wastes. These perivascular spaces, also known as the Virchow-Robin spaces, allow for mixing of CSF and interstitial fluid via astrocytic aquaporin 4 (AQP4) channels, to clear metabolic wastes. The glymphatic flow is highly complex, driven by many mechanisms including the bulk flow due to CSF production, arterial pulsations, respiration, and more. Research into the glymphatic system has explored its relationships with slow wave sleep, aging, neurodegeneration, and traumatic brain injuries. This emerging area of research in glymphatic function and the impacts that craniofacial structure and cranial surgeries have on this system, especially craniosynostosis, are the subject of this review. We aim to explore the clinical considerations in craniofacial surgeries regarding glymphatics. Specifically, we discuss the significance, current limitations, and future directions of applications of glymphatics in both diagnosis and treatment of craniosynostosis.