Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 34,102 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke. DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.
What this blog is for:
My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.
Showing posts with label cortical spreading depolarizations. Show all posts
Showing posts with label cortical spreading depolarizations. Show all posts
Hell, I've written about this over 8 years ago and you can see the incompetence here when we are still describing the problem rather than SOLVING IT! This is the result of NO STROKE LEADERSHIP AND NO STROKE STRATEGY. This won't be fixed until we get survivors in charge of everything, including stroke hospitals and the WSO.
Ischemic
injury triggers multiple pathological responses in the brain tissue,
including spreading depolarizations across the cerebral cortex (cortical
spreading depolarizations [CSD]). Microglia have been recently shown to
play a significant role in the propagation of CSD. However, the
intracellular responses of myeloid cells during ischemic stroke have not
been investigated.
Methods:
We
have studied intracellular calcium activity in cortical microglia in
the stroke model of the middle cerebral artery occlusion, using the
murine Polr2a-based and Cre-dependent GCaMP5 and tdTomato reporter
(PC::G5-tdT). High-speed 2-photon microscopy through cranial windows was
employed to record signals from genetically encoded indicators of
calcium. Inflammatory stimuli and pharmacological inhibition were used
to modulate microglial calcium responses in the somatosensory cortex.
Results:
In
vivo imaging revealed periodical calcium activity in microglia during
the hyperacute phase of ischemic stroke. This activity was more frequent
during the first 6 hours after occlusion, but the amplitudes of calcium
transients became larger at later time points. Consistent with CSD
nature of these events, we reproducibly triggered comparable calcium
transients with microinjections of potassium chloride (KCl) into
adjacent cortical areas. Furthermore, lipopolysaccharide-induced
peripheral inflammation, mimicking sterile inflammation during ischemic
stroke, produced significantly greater microglial calcium transients
during CSD. Finally, in vivo pharmacological analysis with CRAC (calcium
release-activated channel) inhibitor CM-EX-137 demonstrated that
CSD-associated microglial calcium transients after KCl microinjections
are mediated at least in part by the CRAC mechanism.
Conclusions:
Our
findings demonstrate that microglia participate in ischemic brain
injury via previously undetected mechanisms, which may provide new
avenues for therapeutic interventions.
For Sources of Funding and Disclosures, see page xxx.
Presented in part at the American Heart Association's Scientific Sessions, November 13, 2020.
Correspondence
to: Petr Tvrdik, PhD, Departments of Neurosurgery and Neuroscience,
University of Virginia School of Medicine, 409 Ln Rd, MR-4, Room 1011,
Charlottesville, VA 22908. Email tvrdik@virginia.edu
Spreading
depolarizations (SDs) are recurrent and ostensibly spontaneous
depolarization waves that may contribute to infarct progression after
stroke. Somatosensory activation of the metastable peri-infarct tissue
triggers peri-infarct SDs at a high rate.
Methods:
We
directly measured the functional activation threshold to trigger SDs in
peri-infarct hot zones using optogenetic stimulation after distal
middle cerebral artery occlusion in Thy1-ChR2-YFP mice.
Results:
Optogenetic
activation of peri-infarct tissue triggered SDs at a strikingly high
rate (64%) compared with contralateral homotopic cortex (8%; P=0.004).
Laser speckle perfusion imaging identified a residual blood flow of
31±2% of baseline marking the metastable tissue with a propensity to
develop SDs.
Conclusions:
Our
data reveal a spatially distinct increase in SD susceptibility in
peri-infarct tissue where physiological levels of functional activation
are capable of triggering SDs. Given the potentially deleterious effects
of peri-infarct SDs, the effect of sensory overstimulation in
hyperacute stroke should be examined more carefully.
Footnotes
For Sources of Funding and Disclosures, see page 2534.
You'll have to ask your doctor what protocol they are using to prevent this problem from the cascade of death. Since they likely have no protocols ask what researchers they are working with to solve this problem. No researcher contact, call the stroke hospital president and ask why incompetency is allowed in their hospital. Delayed cerebral ischemia is too milquetoast a term to suggest immediate critical response needed, the hemorrhage cascade of death should be used since it implies extreme urgency.
Studies
in subarachnoid hemorrhage (SAH) have traditionally focused on delayed
secondary ischemic injury due to vasospasm, but more recently, attention
has turned to early brain injury (EBI) in patients with poor-grade
injury. The predictable and delayed nature of secondary brain injury
makes SAH a unique illness. Large vessel arterial vasospasm occurs in
approximately 70% of patients starting 3 to 5 days after the initial
hemorrhage, peaking at 5 to 10 days, then slowly resolving over the
following week or two.1Delayed cerebral ischemia (DCI),
defined as infarction, neurologic deterioration, or both from large
vessel vasospasm occurs in about 20% of patients with SAH. Interventions
and clinical investigation have long focused on DCI. Large trials have
failed to improve long-term neurologic outcome despite ameliorating
vasospasm.2 This has led to novel concepts of DCI
pathophysiology, including microthrombosis, neuroinflammation, and
cortical spreading depolarization (SD).1
How will our stroke researchers use this knowledge to come up with prevention protocols post-stroke? Or will nothing be done because we have NO stroke leadership and they are waiting forSOMEONE ELSE TO SOLVE THE PROBLEM?
Inquiring minds want to know specifically whom is going to solve this problem? Specific names, not just put in a 10 year goal that will never be accomplished. We need to start taking names and firing all the incompetent people in stroke. My manager used to assign many of the most difficult programming problems to me since I would keep at it until the original cause was found and fixed. Whom is that person in stroke research? Every stroke doctor and stroke hospital should be able to immediately roll that persons name off their tongue.
Death is a part of life, and while much of life is poorly understood,
death is shrouded in mystery. What goes on in our brains before we die?
Neuroscientists in Germany and the US have recently shown that “brain
tsunamis,” waves of cell depolarization – massive short-circuits of the neurons
– sweep the cortex within ten minutes of cardiac arrest. These waves of
spreading depolarization mark the beginning of the end, and trigger a gradual
poisoning of neurons. They recorded brain tsunamis not just as people died but also
after other critical events, such as a brain hemorrhage. Their findings could
have immediate application in ERs and critical-care wards.
Measuring what happens in the brain immediately after a stroke or cardiac
arrest is difficult, but Jens Dreier, at the Center for Stroke Research Berlin,
and Jed Hartings, at the University of Cincinnati, saw an opportunity in their
work in neurocritical care. Their centers monitor the brain activity of patients
with certain conditions, such as traumatic brain injury or bleeding after an
aneurysm. This neuromonitoring involves putting electrodes either directly onto
the surface of the brain or deep into the cerebral cortex. Clinicians can then record
electrical activity directly from the cortex.
Some
patients suffering from such
brain injuries did not respond to treatment. After family discussion and
agreement, the doctors withdrew life-sustaining therapy while
neuromonitoring
continued as the patient died. What the neuroscientists observed was
striking, says
Jed Hartings. “Previously, it was thought that
the end occurs when the brain stops its electrical activity and goes silent,”
he says. “But it doesn’t. We show that the brain remains in a viable state for
several minutes after this flatline. And then the final brain tsunami occurs: A
wave of depolarization sweeps through the cortex.” This brain activity reflects what happens to the neurons as the heart
stops pumping fresh oxygen to it, explains Jens Dreier. “After cardiac arrest, blood
flow to the brain stops. Neurons and astrocytes detect that the oxygens levels
drop, even before their own metabolism is affected. The neurons then switch off
their function to get into an energy-saving mode: electrical activity stops,
the neurons no longer send any signals. This is the flatline.” But while the
neurons use less energy in this mode, they don’t use none--they still need some
to maintain their internal metabolism. Normally, ion pumps monitor and
maintain a difference in charge between the inside and outside of neurons; this
difference is essential for neurons to send their signals. But the pumps need
energy, and this is where the system fails, Dreier says. “Eventually, there is
no longer enough energy to keep the ion pump going. The ion gradients collapse: Ions from inside the neurons stream
out, and those from the outside stream in.” As cells, and neurons in particular, have a carefully balanced
chemistry, this change in the concentrations has dramatic consequences. “A massive depolarization occurs as the ion gradients collapse
completely, releasing a great amount of energy,” Dreier says. “The massive
depolarization isn’t localized though, waves of depolarization spread into the
neighboring regions. This is the brain tsunami, or spreading depolarization.” First results in
humans Spreading depolarizations, for all their dramatic impact, are nothing
new. In 1944, the Brazilian physiologist Aristides Leo first
described seeing waves of suppressed function in the cortex of rats after he
stimulated the cortex intensely, in what he called “spreading depression.” From
the 1980s onwards, medics increasingly accepted that spreading depolarization
was relevant to brain injuries. By the 1990s, researchers had proven in animals
that brain tsunamis cause the death of
brain tissue, but because spreading depolarization is so hard to record, it
remained unobserved in humans until this century. Finally, in 2002, neuroscientists
demonstrated spreading depolarization in the human brain. Since then, COSBID, a clinical
research collaboration of which Dreier and Hartings
are members, and others have studied spreading depolarizations in brain
injuries in hospitals across Europe and the US. Notably, spreading depolarization does not mark the onset of cell death,
but instead starts the clock counting
down to cell death. Leão
already showed that spreading depolarization is – in principle – reversible. If blood flow
isn’t restored after a certain time, neurons are unable to recover and will die
– this is the commitment point. However, even if depolarization is reversed, the neurons
don’t necessarily survive, says Dreier. “After depolarization, there is complete chaos in the cells,” he says. “Calcium
levels, for example, increase a thousand-fold. These changes are highly toxic
to the neuron. However, when blood flow sets in again and energy is provided to
the brain, some cells can re-polarize and
may recover their function. But it is fiendish: Although the depolarization is
reversed, the neuron might still die from apoptosis.” The commitment point, the beginning of the end, is elusive. “As
spreading depolarization is, in principle, reversible, the commitment point at
which neurons start dying and at which there is no going back is hard to define,”
Dreier says. “Actually, we can only define this point in retrospect. Death is a
process that takes some time.” For Dreier and others, the findings have a concrete call to action. “We see that patients live longer after a cardiac arrest if some
circulation remains. So resuscitation attempts are very important. Even if the heart
doesn’t start pumping again immediately, as long as the blood flow is kept
going, the brain is kept in a state in which it is able to survive for longer.” Clues to hemorrhage mystery Spreading depolarization could also explain the puzzling clinical course
seen in patients with sub-arachnoid
hemorrhage (aSAH), or bleeding in the space between the brain and the tissues
covering it, another recent
study by Dreier and Hartings suggests. Patients
with aneurysmal sub-arachnoid haemorrhage are likely to develop a series of
complications about a week after the initial bleeding. “This condition has
remained enigmatic, as the causes for delayed deterioration were unknown,” Hartings says. “Previously, not much focus was
put on the brain damage that occurs soon after the aneurysm ruptures. This was
considered too early to medically intervene. But we found that the aneurysm itself causes a significant amount
of brain damage.” Dreier
and Hartings analyzed recordings from 11
patients with aSAH and found that spreading depolarizations occur frequently in
the initial days after aSAH. “Just the bleeding in the subarachnoid space itself
is a trigger for brain tsunamis in humans, causing brain damage,” Hartings says.
“The spreading depolarizations signal that a brain infarct [stroke] is
developing.” In these patients, clusters of spreading depolarizations occurred
again and again. The spreading depolarizations lasted progressively longer and were
a marker of neurons dying. These
results could also change treatment for aSAH, Hartings
hopes. “Through neuromonitoring, spreading depolarizations can act as an early
warning system for clinicians before brain damage is irreversible,” he says. “Clinicians
could, for example, pay close attention
to whether the brain receives enough blood flow and oxygen.” The
two papers advanced the field of spreading depolarization significantly, says
Bill Shuttleworth, Regent’s Professor of Neurosciences at the University of New
Mexico, who is part of the COSBID consortium but not involved in the studies. “Previously,
the real impact of spreading depolarizations in humans was questioned, but
these studies take the step to real
relevance of spreading depolarization in the clinic.” “Looking
at the end of life, the researchers tied together death and spreading
depolarization in a very controlled clinical setting with strong data. This is
an amazing observation, finding other ways in which spreading depolarizations
impact the brain,” Shuttleworth says. “And by looking at subarachnoid hemorrhages, the researchers found the first
electrophysiological signature for the events causing brain damage.” “The spreading
depolarization shows that brain cells are dying, and gives a tremendously
useful marker in the clinic for when something is really hurting the brain,” he
says. This is not just a curiosity, but something actionable in intensive
care.”
Video: A recording of brain
electrical activity, played back 44x normal rate, in a patient who experienced a
traumatic head injury. The crackling sound is the normal activity of brain
cells; the periods of silence are short-circuits of electrical activity caused
by brain tsunamis, waves of depolarization that spread across injured areas of
the brain, causing a local loss of function. The brain’s electrical activity
recovers, but with each brain tsunami, damage to cells may worsen. Video posted to YouTube by Mayfield Brain & Spine
The phrase "time is brain" could take on new
meaning when applied to the treatment of subarachnoid hemorrhage, a
type of bleeding stroke, thanks to research partially funded by the
Mayfield Education & Research Foundation and the United States
government.
Subarachnoid hemorrhage, caused by the rupture of a brain aneurysm,
affects an estimated 10 to 15 of every 100,000 individuals each year.
An international team of researchers has established that the blood from
this type of hemorrhage launches deadly "brain tsunamis" within hours,
leading to permanent brain damage. This damage,
known as infarction, occurs in the cerebral cortex near the hemorrhage
and can cause permanent disability and in some cases death.
Brain tsunamis, scientifically known as cortical spreading
depolarizations, are travelling waves of brain dysfunction that spread
out from an injury site and contribute to worse outcomes in patients.
They affect patients who suffer trauma to the brain as well as those who
suffer various types of stroke. In subarachnoid hemorrhage, blood from a
ruptured aneurysm or shredded artery pools in the space between the
arachnoid membrane and the brain itself.
A team of researchers led by Principal Investigator Jed Hartings,
PhD, Research Associate Professor in the Department of Neurosurgery at
the University of Cincinnati, used a novel animal model to study what
happens immediately after a subarachnoid hemorrhage. The team also
monitored 23 patients who were surgically treated for subarachnoid
hemorrhage at hospital locations of Charité University Medicine in
Berlin. Monitoring was accomplished by placing electrode strips on the
surface of the brains of animal models as well as patients.
The team's findings of secondary damage within 6 hours were published online today in the journal Brain.
"We found that patients who suffered brain damage in their frontal
lobes were more likely to have experienced spreading depolarizations
than those who had no damage," Dr. Hartings says. "The animal studies
showed that these pathological changes can arise as a direct result of
the blood accumulation in the grooves of the brain – that the presence
of blood in the wrong place is toxic to the brain."
In the past, researchers have focused primarily on delayed
complications—such as the narrowing of major cerebral arteries known as
vasospasm— that occur 5 to 14 days after subarachnoid hemorrhage. Those
complications account for only a minority of deaths (13 percent),
however; the majority of deaths from subarachnoid hemorrhage (86
percent) occur in the early hours and days after an aneurysm rupture
occurs. The present study sheds new light on these early events and
suggests that they may be preventable.
"This is the first evidence that brain tsunamis are a clinical marker, and mechanism, of early brain injury,"
Dr. Hartings says. "As such, they provide us with an opportunity to
pursue therapeutic interventions that could improve outcomes for
patients. By treating or preventing brain tsunamis, we could potentially
stop many victims of bleeding stroke from suffering additional, often
catastrophic, brain damage."
Listen to a cortical spreading depolarization
The early damage caused by subarachnoid hemorrhage has been
underappreciated, Hartings says, because it often cannot be observed
with routine CT brain imaging. "There has also been a sense that early
damage could not be prevented, but perhaps that perception is starting
to change."
Looking ahead, the researchers propose the investigation in animal
models of therapies that target spreading depolarizations in an effort
to interrupt or prevent secondary injury processes.
When a brain injury occurs, nerve cells in the brain (which act like
batteries by storing electrical and chemical energy) malfunction and
effectively short-circuit. Because all nerve cells in the brain are
connected, this depolarization causes all the neighboring cells to
short-circuit as well; this subsequent leakage of precious electrical
charge moves like a tsunami through the brain, with the potential to
cause additional permanent tissue damage.
To document the cascade of events that immediately follows subarachnoid hemorrhage,
the research team used a novel swine model, whose brain, with grooves
and fissures, more closely resembles the human brain than previously
studied rodent models. The researchers found that clots that quickly
formed in the grooves of the swine brain mirrored the results in the
human brain;
in both situations, the clots caused repetitive spreading
depolarizations and lesions (infarcts) in the cerebral cortex shortly
after an aneurysm rupture and subarachnoid hemorrhage.
The study's collaborating scientists and clinicians are members of COSBID (Co-Operative Studies on Brain Injury Depolarizations.
In the evolution of the cerebral cortex,
the sophisticated organization in a steady state far away from
thermodynamic equilibrium
has produced the side effect of two fundamental
pathological network events: ictal epileptic activity and spreading
depolarization.
Ictal epileptic activity describes the partial
disruption, and spreading depolarization describes the near-complete
disruption
of the physiological double Gibbs–Donnan steady
state. The occurrence of ictal epileptic activity in patients has been
known
for decades. Recently, unequivocal
electrophysiological evidence has been found in patients that spreading
depolarizations
occur abundantly in stroke and brain trauma. The
authors propose that the ion changes can be taken to estimate relative
changes
in Gibbs free energy from state to state. The
calculations suggest that in transitions from the physiological state to
ictal
epileptic activity to spreading depolarization to
death, the cortex releases Gibbs free energy in a stepwise fashion.
Spreading
depolarization thus appears as a twilight state
close to death. Consistently, electrocorticographic recordings in the
core
of focal ischemia or after cardiac arrest display a
smooth transition from the initial spreading depolarization component
to the later ultraslow negative potential, which is
assumed to reflect processes in cellular death.
Cortical
spreading depolarization (CSD) promotes the progression of neuronal
injury after cerebral ischemia. However, the mechanisms of propagation
of postischemic CSD events are still unclear. In this study we
characterized the role of the main neuronal gap junction protein
connexin 36 (Cx36) in generating postischemic CSDs.
In
Cx36-deficient mice and controls we occluded the distal middle cerebral
artery. To detect CSD events we recorded the direct current and laser
Doppler flow. In addition, locomotor function and the infarct size were
determined.
Cx36-deficient mice had significantly
fewer and shorter CSD events than wild-type controls. Additionally, Cx36
deletion is neuroprotective, leading to a better functional outcome and
decreased infarct size after ischemia.
These results suggest a detrimental role for Cx36 after ischemia, possibly by promoting CSD.
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