Garbage Truck of the Brain

Nedergaard, Maiken

doi:10.1126/science.1240514

Cited by 582 publications

(512 citation statements)

References 15 publications

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“…The recently discovered glymphatic brain clearance system uses physiological pulsations to clear the brain tissue by convecting water through the brain tissue via aquaporin AQP4 water channels especially during sleep (Iliff & Nedergaard, 2013; Jessen, Munk, Lundgaard, & Nedergaard, 2015; Nedergaard, 2013). In human brain, glymphatic system may be driven partially by respiratory and vasomotor control waves in addition to cardiac pulses (Kiviniemi et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

“…The results of our study suggest that the physiological pulsations, that drive glymphatic clearance, may be abnormal in drug‐resistant epileptic brain (Kiviniemi et al., 2016; Nedergaard, 2013). As none of our DRE patients had MTS lesions, we suggest that seemingly normal DRE patients’ brain tissue may suffer from failed physiological drive of the glymphatic clearance, rather than direct AQP4 channel loss as in MTS.…”

Section: Discussionmentioning

confidence: 99%

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Altered physiological brain variation in drug‐resistant epilepsy

et al. 2018

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IntroductionFunctional magnetic resonance imaging (fMRI) combined with simultaneous electroencephalography (EEG‐fMRI) has become a major tool in mapping epilepsy sources. In the absence of detectable epileptiform activity, the resting state fMRI may still detect changes in the blood oxygen level‐dependent signal, suggesting intrinsic alterations in the underlying brain physiology.MethodsIn this study, we used coefficient of variation (CV) of critically sampled 10 Hz ultra‐fast fMRI (magnetoencephalography, MREG) signal to compare physiological variance between healthy controls (n = 10) and patients (n = 10) with drug‐resistant epilepsy (DRE).ResultsWe showed highly significant voxel‐level (p < 0.01, TFCE‐corrected) increase in the physiological variance in DRE patients. At individual level, the elevations range over three standard deviations (σ) above the control mean (μ) CVMREG values solely in DRE patients, enabling patient‐specific mapping of elevated physiological variance. The most apparent differences in group‐level analysis are found on white matter, brainstem, and cerebellum. Respiratory (0.12–0.4 Hz) and very‐low‐frequency (VLF = 0.009–0.1 Hz) signal variances were most affected.ConclusionsThe CVMREG increase was not explained by head motion or physiological cardiorespiratory activity, that is, it seems to be linked to intrinsic physiological pulsations. We suggest that intrinsic brain pulsations play a role in DRE and that critically sampled fMRI may provide a powerful tool for their identification.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Altered physiological brain variation in drug‐resistant epilepsy

et al. 2018

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“…Thus, these fluid push -pull movements induced by the arterial pulse favour both the migration of signalling molecules of VT and the extracellular fluid renewal, especially in the cerebral cortex [40]. In 2012 came the pioneering work of Nedergaard and colleagues with the discovery of the glymphatic system of the brain [64,65]. In this brain-wide pathway, CSF enters the brain along para-arterial routes, whereas ECF is cleared from the brain along paravenous routes.…”

Section: (B) On the Renewal And Clearance Of Volume Transmission Signmentioning

confidence: 99%

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

Borroto-Escuela

Agnati

Bechter

et al. 2015

Phil. Trans. R. Soc. B

113

130

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One contribution of 16 to a discussion meeting issue 'Release of chemical transmitters from cell bodies and dendrites of nerve cells'. Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma-dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non-coding regulatory microRNAs. At the soma-dendritic membrane, sets of dynamic postsynaptic heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the heteroreceptor complexes in the postsynaptic membrane.

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“…Indeed, the glial components (astrocyte foot processes) that provide the outer boundary of the PVS within the parenchyma have been proposed to serve a special function for CNS clearance and waste turnover, forming the basis for a so-called 'glymphatic' circulation [91,124] that may potentially allow a more complete exchange of CSF and ISF at both superficial and deep sites spanning the entire neural axis. Such a PVS (Fig.…”

Section: Blood Vessels and The Perivascular Spacementioning

confidence: 99%

“…2). The PVS is unquestionably a site of great importance due to its involvement in disease processes affecting the NVU (e.g., cerebral amyloid angiopathy, present in > 90% of Alzheimer's disease brains and a major cause of intracerebral haemorrhage in the elderly; [70,87,176]), emerging roles in physiology (e.g., immune surveillance, central waste clearance and the proposed 'glymphatic' concepts; [95,121,124,137]), and as a critical gatekeeper for widespread central drug delivery [137]. Historical considerations: CSF/ISF exchange and flow along low-resistance pathways including the PVS It was recognized over one century ago that CSF was primarily formed by the choroid plexuses in the ventricles of the brain, through which it flowed before reaching the cranial and spinal SAS [38,186].…”

Section: Blood Vessels and The Perivascular Spacementioning

confidence: 99%

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

et al. 2018

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Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

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Garbage Truck of the Brain

Abstract: An intercellular “glymphatic” pathway clears cell waste from the brain and may reveal new targets for treating neurodegenerative diseases.

Cited by 582 publications

References 15 publications

Altered physiological brain variation in drug‐resistant epilepsy

Altered physiological brain variation in drug‐resistant epilepsy

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

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