Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance 2024 Jiang-Xie et al

[Andy]

Abstract

The accumulation of metabolic waste is a leading cause of numerous neurological disorders, yet we still have only limited knowledge of how the brain performs self-cleansing. Here we demonstrate that neural networks synchronize individual action potentials to create large-amplitude, rhythmic and self-perpetuating ionic waves in the interstitial fluid of the brain. These waves are a plausible mechanism to explain the correlated potentiation of the glymphatic flow1,2 through the brain parenchyma. Chemogenetic flattening of these high-energy ionic waves largely impeded cerebrospinal fluid infiltration into and clearance of molecules from the brain parenchyma. Notably, synthesized waves generated through transcranial optogenetic stimulation substantially potentiated cerebrospinal fluid-to-interstitial fluid perfusion. Our study demonstrates that neurons serve as master organizers for brain clearance. This fundamental principle introduces a new theoretical framework for the functioning of macroscopic brain waves.

Paywall, https://www.nature.com/articles/s41586-024-07108-6

 

[Andy]

Study Suggests During Sleep, Neural Process Helps Clear the Brain of Damaging Waste

We’ve long known that sleep is a restorative process necessary for good health. Research has also shown that the accumulation of waste products in the brain is a leading cause of numerous neurological disorders, including Alzheimer’s and Parkinson’s diseases. What hasn’t been clear is how the healthy brain “self-cleans,” or flushes out that detrimental waste.

But a new study by a research team supported in part by NIH suggests that a neural process that happens while we sleep helps cleanse the brain, leading us to wake up feeling rested and restored. Better understanding this process could one day lead to methods that help people function well on less sleep. It could also help researchers find potential ways to delay or prevent neurological diseases related to accumulated waste products in the brain.

The findings, reported in Nature, show that, during sleep, neural networks in the brain act like an array of miniature pumps, producing large and rhythmic waves through synchronous bursts of activity that propel fluids through brain tissue. Much like the process of washing dishes, where you use a rhythmic motion of varying speeds and intensity to clear off debris, this process that takes place during sleep clears accumulated metabolic waste products out.

https://directorsblog.nih.gov/2024/...cess-helps-clear-the-brain-of-damaging-waste/

 

[Jonathan Edwards]

I suspect this is yet another high profile piece of pseudoscience.

I am not aware of any brain diseases being due to accumulation of metabolic waste. Metabolic waste normally is cleared by venules, not lymphatics. It is hard to see which direction synchronised neuronal ion shifts could usefully impel fluid. And they seem to have got CSF and interstitial back to front. I could go on...

the things you are liable to read in the Bible...

 

[SNT Gatchaman]

I've posted an open-access paper for background at Waste Clearance in the Brain (2021, Frontiers in Neuroanatomy) —

Homeostasis is critical for the proper functioning of the human body, particularly, homeostasis of high-energy consuming organs like the brain. The substantial amount of toxic metabolic byproducts/interstitial waste products (such as CO2, lactate, proteins including amyloid-β (Aβ) and tau proteins, etc.) released into the brain due to the high metabolic activity of neurons in the brain, require rapid exit by several WC mechanisms.

Otherwise, the accumulation of these metabolic by-products/interstitial waste products may initiate and or exacerbate several neurological diseases, including the accumulation of Aβ in Alzheimer’s disease (AD) and tau in traumatic brain injury (TBI) [...]. Therefore, regulating the entry and exit of various substances in the brain, as well as recycling of neurotransmitters, are essential for proper neuronal functioning and healthy aging.

There are two distinct systems set in place to help the brain with this type of regulation, the CSF and the vascular systems.

CSF is produced in the human brain at a rate of about 0.3–0.4 ml/min, mainly by specialized ependymal cells such as choroid plexus epithelial cells located in each of the ventricles. The CSF travels from the lateral ventricles to the third ventricle via the interventricular foramen of Monro and enters the fourth ventricle via the cerebral aqueduct of Sylvius. CSF then enters the central canal of the spinal cord via the obex and also reaches the subarachnoid space via the median aperture of Magendie and the two lateral apertures of Luschka.

CSF is eventually drained via the arachnoid villi, perineural spaces of spinal and cranial nerves, and meningeal lymphatics [...]. However, part of the CSF is also proposed to enter the brain parenchyma via the periarterial spaces of the penetrating arteries, mixes with interstitial waste products and ISF, enters the perivascular spaces (alongside veins by the glymphatic system or along arteries by IPAD [intramural periarterial drainage] pathway), and finally drains via the WC pathways

 

[SNT Gatchaman]

Some quotes from this paper's intro —

To prevent environmental insults and stochastic autoimmunity, the brain parenchyma is further protected by the blood−brain barrier and is devoid of canonical lymphatic vasculature. All of these evolutionary adaptations create a problem for the brain, namely, how to dispose of its metabolic waste. Insights into this biological dilemma were provided after discovery of the glymphatic system. Here cerebrospinal fluid (CSF) pulsates along the perivascular spaces surrounding penetrating arteries, infuses the brain parenchyma through the aquaporin-4 channels on astrocytes and flushes metabolic wastes into perivenous pathways.

Recent electroencephalography (EEG) studies have revealed that neural activity can be used to predict haemodynamics and CSF oscillations during sleep in humans

Rhythmic ionic waves in ISF boost brain perfusion —

instead of investigating how neural activity contributes to diverse cognitive tasks, we realized that one of its fundamental but unappreciated functions might be regulating brain ISF dynamics. To study the relationship between neuronal activity and brain clearance, we first utilized a ketamine anaesthesia model [...] as it has been shown to enhance the glymphatic system at a level comparable to that in natural sleep

To capture CSF-to-ISF perfusion, a low molecular weight tracer was introduced into the CSF through intracisterna magna (ICM) injection under ketamine anaesthesia while neuronal activity was chemogenetically silenced on one side of the hippocampus. In control mice expressing GFP and given an i.p. injection of uPSEM792, the tracer (yellow) evenly perfused both hemispheres, with stronger signals in the ventral and caudal parts of the brain, producing a typical pattern of glymphatic perfusion after ICM injection. Notably, chemogenetic inhibition impeded CSF infiltration into the hippocampus, whereas perfusion to the contralateral hippocampus was intact.

Moreover, expression of GFAP and the integrity of the bloodbrain barrier was not affected by chemogenetic neuronal silencing. These findings suggest that the rhythmic neuronal activity produced under ketamine anaesthesia is a prerequisite for brain CSF perfusion.

Neurons are highly efficient pumps, and a large proportion of their energy is used to power Na+ /K+ -ATPases, which reset membrane potentials within a couple of milliseconds after each spike. This mechanism enables neurons to flip their membrane potentials up to about 500 times per second.

 

[SNT Gatchaman]

Sleep synchronizes neurons to drive brain CSF perfusion —

We next sought to determine whether principles similar to those described above for ketamine anaesthesia also apply to natural sleep.

It is also worth mentioning that although both sleep and ketamine anaesthesia potentiate brain clearance, they had the opposite effect on neuronal spiking. Therefore, glymphatic function cannot be explained simply in terms of the amount of neuronal activity. This result raised the question of what the underlying commonality is between these two brain states.

Chemogenetic inhibition impairs brain clearance —

Besides glymphatic influx, we were interested in whether neuronal activity is required for waste removal. We utilized a universal phenomenon in which molecules introduced into the CSF through ICM injection have two distinct phases (influx and efflux). In the influx phase, the designated molecules progressively enter the brain parenchyma through CSF perfusion. Later, they are gradually cleared away through the glymphatic system during the efflux phase.

Synthesized waves enhance CSF-to-ISF perfusion —

By taking advantage of newly developed transcranial optogenetics, we were able to generate synthesized ionic waves in the interstitial space without invasive fibre penetration that might disrupt fluid dynamics.

 

[SNT Gatchaman]

Discussion —

Our study established a new experimental paradigm to simultaneously interrogate the influx and efflux of the glymphatic system with bidirectional neuronal perturbation without damaging the brain parenchyma. Leveraging transcranial optogenetics, 9.4 Tesla MRI scanning, multiplexed electrophysiology and fluorescent molecular tracing, we demonstrated that rhythmic neuronal oscillations serve as the master organizer of CSF-to-ISF perfusion and brain clearance.

Neuronal activity produces metabolic waste. This begs the question of how, then, does it also mediate waste removal. The resolution to this apparent paradox resides in the pattern of neuronal activation. Firing of neurons in a highly desynchronized fashion maximizes the information complexity for diverse cognitive tasks during wakefulness. However, owing to out-of-sync spiking, the field potentials generated by individual neurons cancel each other out, thereby producing only small fluctuations in the ISF. By contrast, neurons coordinate their actions to generate large-amplitude, rhythmic ionic oscillations in the ISF during sleep (or ketamine anaesthesia). These high-energy ionic waves facilitate the perfusion of fresh CSF through the parenchyma and the removal of metabolic waste products.

Traditionally, the glymphatic system has been described as a physical conduit that is predominantly driven by vascular pulsations. This system allows fresh CSF to travel from the para-arterial space, flush out metabolic waste in the brain interstitial space and transport them to the perivenous space. However, this model has been challenged by the lack of a significant pressure gradient experimentally observed between para-arterial and paravenous spaces, which would be necessary to drive convection flow through the brain parenchyma.

Our research, along with other studies, identify an important yet overlooked player: the neurons. Neurons not only have the capability to generate ionic waves in ISF but also regulate para-vascular flow through distant neurovascular coupling, as well as efflux transportation across the blood–brain barrier. In essence, neurons are the most ideal cell type that coordinate the dynamics of paravascular flow, brain interstitial fluid and the blood–brain barrier to optimize metabolic waste clearance.

Our research, together with previous reports , also helps clarify the inconsistent results obtained across different laboratories. As glymphatic perfusion requires proper functioning of neurons, the selection of general anaesthetics is crucial. Many commonly used general anaesthetics, such as isoflurane, pentobarbital and avertin, target GABA A receptors to suppress neural activity. Studies that use these anaesthetics often report a lack of significant glymphatic flow.

Synchronization of neuronal spikes also largely increases information redundancy because individual cells begin to behave similarly. This leads to an unconscious state in the nervous system, as exemplified by sleep.