Review Waste Clearance in the Brain, 2021, Kaur et al.

Waste Clearance in the Brain
Kaur, Jasleen; Fahmy, Lara M.; Davoodi-Bojd, Esmaeil; Zhang, Li; Ding, Guangliang; Hu, Jiani; Zhang, Zhenggang; Chopp, Michael; Jiang, Quan

Waste clearance (WC) is an essential process for brain homeostasis, which is required for the proper and healthy functioning of all cerebrovascular and parenchymal brain cells. This review features our current understanding of brain WC, both within and external to the brain parenchyma.

We describe the interplay of the blood-brain barrier (BBB), interstitial fluid (ISF), and perivascular spaces within the brain parenchyma for brain WC directly into the blood and/or cerebrospinal fluid (CSF). We also discuss the relevant role of the CSF and its exit routes in mediating WC. Recent discoveries of the glymphatic system and meningeal lymphatic vessels, and their relevance to brain WC are highlighted. Controversies related to brain WC research and potential future directions are presented.

Link | PDF (Frontiers in Neuroanatomy) [Open Access]

 

Thanks for posting this SNT.

I do think a process like this could explain why cognitive overexertion would produce PEM. If the exertion produces toxic metabolites that can't be cleared quickly in ME/CFS, then one might expect a poisoned feeling, noise and light sensitivity, headaches, vision changes, ect. It would also be difficult to measure as these metabolites would likely change quickly and participants would have to be in PEM at the time of imaging. This could explain why PET brain imagining studies (like the ones seen in Long Covid) show some general inflammation but are not particularly specific. Toxic metabolites may be present in different areas or in different concentrations in different patients.

Another thing I find interesting is that I have always been much more sensitive to the after effects of alcohol and caffeine. Even relatively small amounts can cause headaches and other uncomfortable symptoms. It might make sense that these substances are producing toxic byproducts in the brain that stick around longer in me than the average person. Given my sensitivity is worse now, perhaps the viral infection just worsened the waste clearing process to the level that everyday activities cause issues.

I know we are not at the stage where we have good evidence for this occurring. However, to me it ticks all the boxes for a plausible theory for at least some kinds of PEM.

 

Too funny

More the latter. Though I referenced it in a thread for a recent fascinating Nature paper that @Andy kindly posted*. I'm spending most of my time in literature directly relevant to us, although trying to look widely — "leave no stone unturned". I am also trying to keep up with my day job to some extent (happily some useful overlap). There are a lot of advances in imaging technology, but also fundamental neuroanatomy and related physiology has had something of a revolution in the last decade following the (re)discovery of lymphatics in the brain.

My personal symptom experiences and those I read about from others make me think that issues around the blood-brain barrier will be part of the explanation. The chronic pressure headache and very unusual feeling that my brain continued to spin past its stop-point on head turning, coupled with episodic horrid sensory overload — all make me think of problems with neurofluids. Many people have had MRIs and they come back reported as "normal" or possibly mentioning and dismissing "non-specific increased/enlarged perivascular spaces". I think this will turn out to be a marker of dysfunction of CSF transit along vessels, washing in and out of the brain parenchyma's interstitial fluid. Perhaps they will be filled with waste material - if so I guess better collected there than surrounding the neurons. But as far as I can see though, ME patients don't seem to be over-represented in neurodegenerative diseases; and I think we live long enough to be into the risk age-group, so if it's involved maybe our waste clearance isn't too badly off.

Why might this occur? I suspect it'll come down to immune and metabolic mechanisms (watch-word: immunometabolic), possibly with a contribution from coagulation and endothelial mischief. To my mind the name "myalgic encephalomyelitis" will probably be reasonably on the mark when all is said and done, though its classification as a neuroimmune disorder may be missing a big part of the picture (metabolism/mitochondria).

I'll post some related links below in this thread, rather than making lots of new threads.

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* Why do we sleep? So while unconscious our neurons can hum in unison and help clear the metabolic waste products. Or as they said in the Nature paper: "In essence, neurons that fire together ‘shower’ together".

 

Circadian Mechanisms in Brain Fluid Biology
Velia S. Vizcarra; Ryann M. Fame; Lauren M. Hablitz

The brain is a complex organ, fundamentally changing across the day to perform basic functions like sleep, thought, and regulating whole-body physiology. This requires a complex symphony of nutrients, hormones, ions, neurotransmitters and more to be properly distributed across the brain to maintain homeostasis throughout 24 hours. These solutes are distributed both by the blood and by cerebrospinal fluid. Cerebrospinal fluid contents are distinct from the general circulation because of regulation at brain barriers including the choroid plexus, glymphatic system, and blood-brain barrier.

In this review, we discuss the overlapping circadian (≈24-hour) rhythms in brain fluid biology and at the brain barriers. Our goal is for the reader to gain both a fundamental understanding of brain barriers alongside an understanding of the interactions between these fluids and the circadian timing system.

Ultimately, this review will provide new insight into how alterations in these finely tuned clocks may lead to pathology.

Link | PDF (Circulation Research) [Open Access]

 

Mild Traumatic Brain Injury and Career Stage Associate with Visible Perivascular Spaces in Special Operations Forces Soldiers
Powell, Jacob R.; Zong, Xiaopeng; Weinstein, Joshua M.; DeLellis, Stephen M.; Kane, Shawn F.; Means, Gary E.; Mihalik, Jason P.

Mild traumatic brain injury (mTBI) and occupational blast exposure in military Service Members may lead to impaired brain waste clearance which increases neurological disease risk. Perivascular spaces (PVS) are a key part of the glymphatic system which supports brain waste clearance, preferentially during sleep. Visible PVS on clinical magnetic resonance imaging have been previously observed in patients with neurodegenerative diseases and animal neurotrauma models. The purpose of this study was to determine associations between PVS morphological characteristics, military career stage, and mTBI history in Special Operations Forces (SOF) Soldiers.

Participants underwent T2-weighed neuroimaging to capture three-dimensional whole brain volumes. Segmentation was performed using a previously validated, multi-scale deep convolutional encoder-decoder neural network. Only PVS clusters within the white matter mask were quantified for analyses. Due to non-normal PVS metric distribution, non-parametric Mann–Whitney U tests were used to determine group differences in PVS outcomes. In total, 223 healthy SOF combat Soldiers (age = 33.1 ± 4.3yrs) were included, 217 reported career stage. Soldiers with mTBI history had greater PVS number (z = 2.51, P = 0.013) and PVS volume (z = 2.42, P = 0.016). In-career SOF combat Soldiers had greater PVS number (z = 2.56, P = 0.01) and PVS volume (z = 2.28, P = 0.02) compared to a baseline cohort. Mild TBI history is associated with increased PVS burden in SOF combat Soldiers that are clinically recovered from mTBI. This may indicate ongoing physiological changes that could lead to impaired waste clearance via the glymphatic system. Future studies should determine if PVS number and volume are meaningful neurobiological outcomes for neurodegenerative disease risk and if clinical interventions such as improving sleep can reduce PVS burden.

Link | PDF (Annals of Biomedical Engineering)

 

Overview of the Current Knowledge and Conventional MRI Characteristics of Peri- and Para-Vascular Spaces
Parillo, Marco; Vaccarino, Federica; Di Gennaro, Gianfranco; Kumar, Sumeet; Van Goethem, Johan; Beomonte Zobel, Bruno; Quattrocchi, Carlo Cosimo; Parizel, Paul M.; Mallio, Carlo Augusto

Brain spaces around (perivascular spaces) and alongside (paravascular or Virchow–Robin spaces) vessels have gained significant attention in recent years due to the advancements of in vivo imaging tools and to their crucial role in maintaining brain health, contributing to the anatomic foundation of the glymphatic system.

In fact, it is widely accepted that peri- and para-vascular spaces function as waste clearance pathways for the brain for materials such as ß-amyloid by allowing exchange between cerebrospinal fluid and interstitial fluid. Visible brain spaces on magnetic resonance imaging are often a normal finding, but they have also been associated with a wide range of neurological and systemic conditions, suggesting their potential as early indicators of intracranial pressure and neurofluid imbalance. Nonetheless, several aspects of these spaces are still controversial.

This article offers an overview of the current knowledge and magnetic resonance imaging characteristics of peri- and para-vascular spaces, which can help in daily clinical practice image description and interpretation. This paper is organized into different sections, including the microscopic anatomy of peri- and para-vascular spaces, their associations with pathological and physiological events, and their differential diagnosis.

Link | PDF (Brain Sciences) [Open Access]

 

Yup exactly, sounds like I experience the disease in a similar way to you.

If this were the case there is also likely to be multiple different paths into a pathological state. Resolving the issue could very well require different things in different people.

 

I would just warn that all this stuff is likely to be wrong. Fluid compartment dynamics is something that 90% of medics and physiologists have misunderstood for over a century. The one person who understood this well was J Rodney Levick. He and I worked on synovial joint fluid dynamics in the 1980s. Standard accounts of what lymphatics do and what gives rise to oedema are largely wrong.

I have not read all these papers but would point out:
Metabolites, as far as I now, leave the tissue by crossing blood vessel walls, not via lymphatics.
Amyloid proteins are normally present in tissue. There is a turnover via lymphatics but that is not primarily due to 'waste clearance'. It relates to a very subtle but simple mechanism by which tissue fluid and protein content is controlled by a passive homeostatic mechanism that needs no energy supply.

I suspect that brain lymphatics are largely there to allow lymphocytes and antigen presenting cells to return to lymphoid tissue.

The paper on pumping by 'ionic waves' is littered with misconceptions and factual errors. Bad science is regularly published these days but I am quite surprised this got through power review.
There are no 'ionic races' in brain. Neural activity in conscious processing is not desynchronised - it is highly synchronised in the gamma range. In sleep there is a slower rhythm. I cannot see any possible geometry that would allow local ionic alternations to usefully assist fluid clearance. And so on.

 

I'm curious where the issue with this logic is:

Any theory of ME/CFS should explain why PEM from cognitive exertion occurs. At the most basic level the biological impacts of cognitive exertion are the use of additional energy and the production of some metabolites. Therefore, there has to be an issue with energy use or an issue associated with metabolites in the brain in ME/CFS.

If we assume that PEM from cognitive exertion really does occur, what other ways we can explain this phenomenon? What am I missing about what cognitive exertion actually involves?

Also, has this paper been discussed at all here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393352/ ? I tried to search for it on the forum but found nothing.

 

A fair question but I think there are lots of possible answers.
Moreover, the timing of PEM does not fit with a build up of metabolites because it goes on too long despite rest.

Take the simple example of using a are to clear leaves from a drive. Five minutes of raking produces no ill effects afterwards. But after 13 minutes of raking you realise that there is a sore patch on your index finger and a blister is forming. Three days later there is a hint callus on all your fingers.

Tissue usage can lead to all sorts of microstructure changes. Moreover, it leads to a range of danger signals like histamine and other inflammatory mediators being released. Muscle usage leads to cell turnover, recruitment and growth, which is why we eat protein daily.

We may not normally think of brain activity as leading to microstructure change but it almost certainly must do in order to lay down memory. If you like the neurons are constantly writing to a 'RAM' disc based on their own internal structure to carry over information. Being too tired to do any more revising at 2.00a.m. for a student is not a matter of shortage of energy or build up of metabolites during the day. It is a matter of inhibitory signals saying 'RAM is full - a period of re-formatting is needed'.

 

That is a good point. For me episodes of PEM have always been on the shorter side, but there are certainly those where PEM lasts longer then metabolites would stay in the brain. One possible solution is that excess metabolites trigger different problems in the brain which can then last longer. Seem at least plausible that something like excess lactate could cause certain brain cells to become agitated for a few days or weeks.

Thanks for the explanation. That is a very interesting example. I agree that there are certainly microstructural changes happening all the time. We couldn't store any memories if there were no structural changes taking place. Do we have any idea what these signals are and how they work? You mentioned histamine and other mediators leading to cell growth in tissue. But what kinds of signals should we be looking for in the brain? Would it a chemical, neurons talking to each other in inappropriate ways, or something else entirely?

While I do understand the concept, part of me struggles to see how this would work in ME/CFS. Surely it can't be that the microstructure changes are driving PEM as how would the microstructure reverse itself to its previous state to make the signal go away? With sleep it makes sense that the signals can't be overcome (even with stimulants in the long run) as there is an important process that needs to be run (the re-formatting). However, if the signal is rouge, like it would be in ME/CFS why could we not simply just ignore it or push though it? Why would some people get worse from ignoring the signal? Not suggesting that you think this, but it certainly seem like this is the kind of thing pushed by shoddy brain retaining programs and people like Walitt.

One other quick thing is do we really know that sleep is merely a period of re-formatting? Perhaps there are many functions of sleep including getting rid of metabolites that build up during the day. It seems like sleep must do more than just re-formatting as supposedly even some basic invertebrates without brains have periods of sleep. This is really interesting stuff that I hadn't thought much about before.

 

I’m leaning towards the idea that PEM has something to do with insufficient metabolic pathways.

 

I can only quote one case report. I looked after a patient who had developed lactic acidosis from phenformin (a diabetes drug). She became comatose and had to be ventilated. Her lactic acid levels (everywhere) were higher than my senior colleagues had ever seen. We infused her with bottles of bicarbonate and she woke up and retuned to normal within a couple of days.

My memory is that lactate returns to the circulation through capillary walls - the same way oxygen comes in and carbon dioxide goes out. The brain is very well supplied with capillaries. I don't think we have any good reason to think lactate build up occurs in ME brain. It should be demonstrable with MR spectroscopy I think. I think there is a study that suggests higher ventricular lactate but I not sure what that would mean.

No, not that I am aware of. Within brain I think it is likely to be a neurotransmitter level - something like dopamine. It might be sent through specific synaptic signalling but it could also be a more general diffusional thing producing what are called ephaptic effects.

Nobody seems to know how short term memory is kept in the brain for periods of hours. Very short term memory like remembering an access code may be kept in electrical circuit activity but for hours there probably has to be some macromolecular remodelling of dendrites. It may be that proteins like Tau are used as 'molecular Post-Its' that get adsorbed on to cytoskeletal fibres for periods of hours. During sleep there may be a mechanism for allowing these to detach and return to storage. The microtubules of dendrites are remarkably versatile in functions - including being railroad tracks for nutrients and even mitochondria to zip up and down long distances very quickly.

Basically the inside of a single cell is about as complicated as we tend to think a brain is. So it may not be surprising that simple organisms, even protozoa, may need to sleep, to clean off the day's Post-Its and convert important data into long term structural memory. Even protozoa can remember things.

By and large metabolites move around in time spans of seconds or minutes. What may take longer is flushing through of interstitial proteins. These are not metabolites but they may suffer constant low grade degradation and need recycling. If the mechanism I suggested above involves the outer cell glycocalyx then flushing out used Post-Its might actually involve lymphatic flow. But I am not convinced ny the suggestion that this is achieved with 'ionic waves'.

 

There are these two studies that I have recently found.
https://www.s4me.info/threads/ventr...disorder-2009-mathew-et-al.36734/#post-509948
https://www.s4me.info/threads/multi...bidity-2017-natelson-et-al.37784/#post-522611

Thanks for explaining what the signals might be and how sleep may memory may be connected. Part of me hopes that ME/CFS is not an issue at this level as it seems like we aren't particularly close to understanding these details. However, I have to imagine that whatever the issue is, it should significant enough to be measurable without needing an all encompassing understanding of the brain.

 

I don't drink alcohol but I'm also sensitive to caffeine. It's hit-and-miss. Sometimes a cup of black tea keeps me awake without side effects, but other times I get jittery.

 

It is also very hit-and-miss for me. Several times I have drank a coffee and spent the next twelve hours throwing up with terrible headaches. Other times it doesn't do much at all. I learned it isn't worth the risk but I wonder why there are a variety of responses.