How is your doctor making sure this is working correctly to flush out the toxic wastes and prevent dementia? Oh, your doctor doesn't know anything about the problem and has done nothing? Why the fuck are you seeing them?
brain waste removal (4 posts to February 2018)
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Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? I need an explanation of your incompetence on stroke research and why you're not solving stroke.
The anatomy of brainwashing
Lymphatic
drainage removes metabolic waste and toxins from tissues, which is
crucial for maintaining tissue health. In the central nervous system
(CNS), lymphatic drainage relies on meningeal lymphatic vessels located
in the dura mater and on the glymphatic system, a recently elucidated
network that is responsible for cerebrospinal fluid (CSF) circulation
and waste clearance. The interaction between glymphatic flow and
meningeal lymphatics also ensures vigilant immune monitoring without
perturbing the neuronal environment. How CSF travels through complex
vascular and perivascular pathways, and the interactions between CSF
flow dynamics and brain metabolic demands, are important for
understanding brain health and could lead to the development of
therapeutic approaches that might transform the treatment of a variety
of neurological diseases.
Traditionally, the
CNS was considered “immune-privileged,” meaning that it was thought to
be separated from the immune system, lack proper immune surveillance,
and devoid of classical lymphatic drainage. Indeed, healthy brain
parenchyma contains no lymphatic vessels. The brain is encapsulated by
the meninges, a three-layered membranous cover comprising the dura or
dura mater (the outermost layer, closest to the skull), the pia or pia
mater (the layer attached to the brain), and the arachnoid that
separates them from one another while also forming a subarachnoid space
through which CSF flows. About a decade ago, a network of meningeal
lymphatic vessels was (re)discovered to be housed in the dura (1);
meningeal lymphatic vessels were originally described over 200 years
ago but they were ignored by the scientific community. Although
meningeal lymphatics are not located within the brain parenchyma, they
nevertheless perform the vital function of brain lymphatic drainage (1).
The
presence of meningeal lymphatic vessels in the dura perfectly positions
this to be the site at which immune surveillance of the brain occurs
because antigens from the brain reach the dura before lymphatic
drainage. Indeed, the dura mater, especially at the sites surrounding
the dural sinuses, is highly populated by various immune cells,
including antigen-presenting cells. Dural antigen-presenting cells take
up antigens from the CSF for presentation to patrolling T cells, which
could enter the dura relatively easily through dural sinuses. Migration
of T cells across the dural sinuses is facilitated by the relatively
slow flow of blood, the high expression of adhesion molecules on sinus
endothelial cells, and the expression of chemokines and retention
molecules by dural fibroblasts located in close proximity to the dural
sinuses (1).
Performing immune surveillance in the dura allows monitoring of the
brain for threats and diseases, without the need for direct entry of
immune cells into the brain parenchyma, hence avoiding disturbance of
the neurons.
Arguably, the brain
“immune code” [i.e., peptides presented on major histocompatibility
complex class I (MHCI) and MHCII molecules] represented on dural
antigen-presenting cells would change before diseases ensue. Thus,
detecting changes in this code could possibly serve as an early
diagnostic tool. Dural presentation of brain antigens could also lead to
abnormal immune activation due to viral mimicry, for example, and thus
result in detrimental inflammatory responses [virus-specific lymphocytes
found in the CSF of patients with neurodegenerative and inflammatory
diseases (2, 3)
support this hypothesis], eventually leading to parenchymal
inflammation. Unraveling the immune code of brain tissue and being able
to alter it in the dura mater (for example, through the addition of
missing peptides, altering antigen-presenting cells, or interfering with
protein processing and presentation) could lead to the development of
new therapeutic approaches for neuroinflammatory and neurodegenerative
disorders such as Alzheimer’s disease in which adaptive immune cells
seem to play a role.
Although the advances in
understanding meningeal immunity and its relationship to brain immune
surveillance have provided important answers, several questions remain.
For example, how do antigens from the brain reach the dura? CSF was
believed to mainly provide the brain with buoyancy and to assist with
the removal of waste products. Beyond these basic functions, however,
recent research reveals the physiological complexity and importance of
the CSF. After its production in the choroid plexus, clean CSF travels
through the ventricular network and the subarachnoid space. At the level
of the large cortical arteries entering the brain, the CSF encounters
perivascular structures called the Virchow-Robin spaces, which are
extensions of the subarachnoid space and accompany vessels entering the
brain parenchyma. As the arteries penetrate deeper into the brain, these
spaces become narrower, but they continue throughout the brain’s blood
vessels (excluding capillaries). Arterial pulsation enables CSF from the
perivascular spaces to propel along the arteries and also to enter the
brain parenchyma across astrocytic endfeet (4).
Aquaporin 4 (AQP4) water channels are expressed by astrocytes and
polarized to their endfeet, which in part facilitates the transfer of
fluid from perivascular spaces into the parenchyma, and vice versa (5).
Once inside the brain, this fluid is thought to create a convective
flow through the dense brain parenchyma until it reaches the perivenular
spaces . This passage of the CSF along the arteries, through the brain,
and then out along the veins constitutes the glymphatic system or
glymphatic flow, where “g” stands for the role of glial cells
(astrocytes) in the process that resembles “lymphatic” flow.
Glymphatic-lymphatic anatomical connections
The
meningeal layers surrounding the brain comprise a rich dural immune
environment, meningeal lymphatic vessels, and channels that allow
cerebrospinal fluid (CSF) in the dura to access the skull bone marrow.
Two anatomical structures–the arachnoid granulation and the arachnoid
cuff exit (ACE) point–allow immune monitoring and toxic waste removal
from the brain parenchyma through the CSF.
GRAPHIC: A. FISHER/SCIENCE
The
glymphatic system and meningeal lymphatic vessels are connected because
once the CSF leaves the brain, it drains into the dura, absorbed by the
meningeal lymphatic vessels, and from there into the brain-draining
cervical lymph nodes. To fully understand the glymphatic-lymphatic
connection, some points are to be clarified: for example, how CSF flows
along the arteries, what forces facilitate the convective flow within
the brain parenchyma, and how CSF reaches the meningeal lymphatics
located in the dura .
Cerebral arterial
pulsation is the force driving CSF along the arteries in mice and in
humans, where magnetic resonance imaging (MRI) demonstrated a strong
correlation between CSF flow and arterial pulsatility. Moreover,
perivascular and leptomeningeal macrophages (together referred to as
parenchymal border macrophages, or PBMs) constantly degrade the
extracellular matrix within the perivascular space, allowing CSF passage
(6).
Elimination or dysfunction of PBMs results in a build-up of
extracellular matrix, which physically clogs the perivascular space and
interferes with CSF flow.
To identify and
understand the forces that drive CSF flow within the brain parenchyma,
it is necessary to consider how densely populated the parenchyma is.
Because there is very little interstitial space, some force is essential
to drive the fluid across the parenchyma. Additionally, diffusion alone
is not sufficient to explain the rates of CSF perfusion through the
brain tissue. An elegant study demonstrated the coupling of hemodynamics
and electrophysiological activity with CSF flow using MRI of the fourth
ventricle in humans, suggesting that CSF dynamics become intertwined
with neural and hemodynamic rhythmicity (7). Neural activity has also been shown to correlate with CSF flow in mice and humans (8, 9).
However, direct evidence (in mouse models) that neural activity drives
CSF flow through the brain parenchyma was only recently described (10).
Inhibiting neural activity in a specific brain region disrupted fluid
flow through that area, whereas enhancing neural activity led to
increased perfusion. Although the effects on fluid flow were confined to
the areas where neural activity was altered (10), the intriguing possibility remains that there may be a central circuitry that regulates fluid flow throughout the brain.
A
conundrum encountered with the above mechanism derives from the
empirical finding that during sleep, when arguably fewer neurons are
active, fluid flow through the brain tissue is enhanced relative to its
flow during wakefulness. One possible explanation is the synchronized
neural activity that occurs during sleep (11).
Cortical encephalography recordings reveal that different phases of
sleep are associated with different wavelengths of neural activity. The
slowest waves with high amplitude (delta waves, ranging from 0.5 to 4
Hz) are detected during deep sleep (the most restful phase). The
synchronized neural activity that generates delta waves could produce
sufficient force and directionality to drive interstitial fluid through
the brain tissue (10). This mechanism overcomes discrepancies relating to the production (12)
and removal of waste during the sleep?wake cycle. Thus, fewer neurons
are active during sleep (and less waste is produced), yet their activity
is synchronized, and the waves they produce have enough potential
energy to propel the flow of CSF through the parenchyma. Although this
hypothesis and its preliminary evidence are promising, further
experimental work and new tools that could directly measure movement of
water molecules in the tissues are needed to confirm this mechanism.
How
does the CSF reach the dura mater? Venous blood from the brain is
delivered through bridging veins to the dural sinuses. These veins
pierce the arachnoid to reach the dural sinuses. As the bridging veins
penetrate the arachnoid, they carry a sleeve of arachnoid with them (13).
Upon entering the dura, the arachnoid sleeve along the bridging veins
ends in cuff-like structures called “arachnoid cuff exit” (ACE) points.
ACE points are complex structures composed of arachnoid and dural
fibroblasts, as well as a variety of immune cells. These are critical
sites where the phenotype of endothelial cells changes from that of the
blood–brain barrier (for example, with specialized tight junctions) to
that of peripheral blood vessels as they continue into the dura. Not
only fluid and suspended molecules but also immune cells can traffic
through ACE points, making the regulation of these sites crucial for
brain health. In neuroinflammatory diseases, the initial invasion of
brain parenchyma might happen through ACE points (13)
and in diseases of debris accumulation, these sites may be clogged,
limiting removal of toxic products (such as amyloid-β in Alzheimer’s
disease). The identification of ACE points provides a plausible anatomy
of how brain-derived molecules can reach the dura mater on their way to
meningeal lymphatics, and how dural immune-derived molecules (cytokines)
can reach the brain and affect brain function (1).
Because
mice, like many other small animals with lissencephalic brains, do not
have arachnoid granulations, it could be argued that ACE points simply
represent primitive, arachnoid granulation-like structures. However, ACE
points also exist in humans, facilitating molecular exchange between
the dura and the brain parenchyma (13).
This raises questions about the roles of ACE points and arachnoid
granulations in CSF drainage. Traditionally, it was believed that CSF
exits the brain through arachnoid granulations protruding into the
venous sinuses, thereby spilling directly into the blood circulation.
However, if granulations protrude directly into the sinus, it is unclear
how the area of penetration is sealed to prevent blood leakage.
Moreover, such a system would imply that CSF, carrying brain antigens
and metabolites, drains directly into the blood rather than into the
lymphatic circulation, thereby escaping immune surveillance. Recent
studies in mice and humans have demonstrated that CSF is drained into
the dura before reaching the blood vasculature (13, 14)
and that arachnoid granulations, although closely associated with the
sinuses, do not protrude into them (while a minor portion of
granulations are found inside the sinus, they are separated from the
blood by sinus endothelia) and are densely populated by immune cells (15).
This suggests that arachnoid granulations likely function as an
interface between the CSF and meningeal immunity. It seems plausible
that, as the brain evolved and increased in size, so did the need for
efficient surveillance of its immune code, and the evolution of
arachnoid granulations might have served this purpose.
The
recent discoveries of CSF flow routes, anatomical structures allowing
CSF exit, and forces moving CSF through the brain parenchyma provide a
new conceptual framework for brain cleansing and immune surveillance
(see the figure). Understanding this complex process—comprising numerous
functional compartments, each influencing fluid flow—can be expected to
facilitate the development of new classes of therapeutic interventions
for enhanced brain cleansing. Such interventions—for example, targeting
macrophages residing along the vasculature or astrocytic expression and
function of AQP4—and inducing synchronized neural activity, could affect
neurological disorders in which the accumulation of debris or immune
dysfunction is a factor. There is already a precedent for therapeutic
intervention using neural stimulation to increase CSF flow to eliminate
pathogenic amyloid-β from the brains of people with Alzheimer’s disease
(NCT05637801). A better understanding of the anatomy of brainwashing
would promote further development of efficient ways not only to enhance
brain cleansing but also to improve immune surveillance and effectively
engage the immune system in brain diseases, including brain tumors,
where immune assistance is likely a powerful solution.
Acknowledgments
Thanks
to S. Smith for editing of the manuscript and A. Impagliazzo who
generated the figure. J.K. holds patents and provisional applications
related to topics discussed here.
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