Vacation til Nov. 14

 Las Vegas, Hoover Dam, Death Valley, Mammoth Lakes(replacement for closed Kings Canyon), Yosemite,Lake Tahoe, Hearaldsburg for wine tasting,San Francisco.

Will have to visit Death Valley in summer to experience the heat. Hopefully we can do a day trip to Sequoia/KingsCanyon to see General Grant and Sherman.

No posts in that time, I don't do that on my phone.

But it's not a vacation since retirement.

Scientific fields don't advance if too many papers are published.

 From Deric Bownds MindBlog. Is this the problem in stroke? Or do the leading researchers need to die?

Does Science Advance One Funeral at a Time?

The latest here:

Scientific fields don't advance if too many papers are published.

Study finds statin symptoms usually nocebo

Friends who complained about statin side effects certainly thought they were real and never mentioned about a doctor suggesting there might be side effects.

Study finds statin symptoms usually nocebo

 

 

Naveed Saleh, MD, MS|October 20, 2021

Statin nonadherence is a major issue, with most patients who start the drugs eventually discontinuing them due to complaints over adverse effects. Ultimately, more than half the clinical benefit is lost to discontinuance.  

Approximately 50% of patients who start statins discontinue them at some point due to side effects. A new study sheds light on this issue.

Statins, or HMG-CoA reductase inhibitors, are used to treat high cholesterol and to lower the risk of heart attack, stroke, and other heart problems in individuals with coronary heart disease, type 2 diabetes, or other risk factors. 

Results from a study published in the Journal of the American College of Cardiology in September indicate that most symptoms due to statin tablets were nocebo. “Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo,” they wrote. 

In the study, researchers assessed the daily symptom scores on statin, placebo, and no treatment in 60 patients randomized to complete a 12-month protocol including 1-month medication bottles: four containing atorvastatin (Lipitor) 20 mg; four, placebo; and four, empty. Of note, 49 participants completed the trial.

They found that the mean symptom score did not differ between statin and placebo months. The nocebo ratio was 0.90, and per individual data, neither symptom intensity on starting nor extent of symptom relief on stopping distinguished statin from placebo use. Notably, there was no difference in the stopping of statins and placebo, with symptom relief after stopping similar in both groups. Six months after the trial ended, 30 of 60 patients who started the study resumed taking statins.

The primary outcome was the nocebo ratio, which was calculated as: symptom intensity on placebo – symptom intensity on no-tablets/symptom intensity on statins – symptom intensity on no-tablets.

The authors of the current study provided three takeaways. First, even “severe, convincing, and intolerable symptoms” that patients complain of, do not resurface during formal evaluations entailing daily documentation. Second, formal documentation of symptom scores can implicate background fluctuations in symptom intensity to be the cause—despite the intake of tablets. Third, although there are more verifiable adverse effects due to statins, these adverse effects were similar in intensity in statin vs placebo arms. This last finding suggests that even reproducible induction of symptoms via statin tablets yields no information about whether the cause was the statin moiety or the tablet moiety.

Prepared for physicians, by physicians, Clinical Commentary brings critical medical research from benchtop to bedside.

The authors noted that it is incorrect to infer that the rapid symptom decline secondary to the cessation of tablets points to statins as the cause because such decline was evidenced in both statin and placebo users.

The authors described several possible reasons underlying statin adverse effects, which their study was designed to compensate for. Statins interfere with liver metabolism to reduce the production of cholesterol. The elevation of concentrations of liver enzymes does not lead to complaints of adverse effects. When a patient discovers they are taking statins, however, they then complain of adverse effects, according to the results of previous trials.

Patients who start statins may sense a fluctuation in background symptoms and correctly note that these have increased. 

Patients may be primed to expect symptoms by family members, media, and the internet, with adverse effects detailed in patient pamphlets. These pamphlets, for instance, don’t distinguish adverse effects secondary to statins or placebo. Moreover, when a physician addresses complaints of adverse effects by changing the dosage, frequency, or agent, the patient’s conception that the statin was the cause is reinforced. “Unfortunately, without a preplanned schedule, the statin tends to be stopped when symptoms are maximal (and naturally tend to decline) and restarted when symptoms have resolved (and can only get worse),” wrote the authors. “These informal experiments replace uncertainty with confident, incorrect conclusions.”

The authors cautioned against the current practice of informally experimenting with statin use in patients. Although the investigators found that the quick onset and cessation of symptoms does happen after starting or stopping tablets, this phenomenon is caused by the tablet itself and not the statin component. Of note, the kinetics are similar between the placebo and statin tablets.

Although such informal testing is recommended in North America, the United Kingdom, and Europe, even if symptoms are scored and a preplanned schedule instituted, without a placebo, nocebo symptoms are blamed on the statin. This misinterpretation contributes to the fact that 50% of those who start statins stop at some point. 

Studies link formal education to reduced risk of Alzheimer's

But this from February 2019 says the opposite.  A friends dad with a Ph.D got full blown Alzheimers.

I fully depleted my cognitive reserve just surviving my stroke. so it needs to be rebuilt with NO protocols to follow, just guessing on my part. 

Education May Not Protect Against Dementia February 2019

The latest here:

Studies link formal education to reduced risk of Alzheimer's

The benefits of getting a good education may go beyond landing a good job, and continue to pay off long after retirement. Evidence has shown that formal education, like high school and college, may reduce a person’s risk of developing Alzheimer’s.

Research published in 2020 by The Lancet Commission that examined dementia interventions found 7% of worldwide dementia cases could be prevented by increasing early-life education. The study found higher childhood education levels and higher lifelong educational attainment could reduce dementia risk. Exactly how education helps is a mystery, but researchers have several theories.
 

Education expands your mind

Scientists believe the intense, structured learning obtained through formal education could increase “cognitive reserve,” which is the brain’s ability to resist and compensate for damage. A person with high cognitive reserve could be better positioned to deal with the damaging effects of Alzheimer’s in the brain than someone with lower reserve.

“The brain is like a muscle; the more the brain is used, the stronger it becomes,” says Ozioma Okonkwo, Ph.D., associate professor at the Wisconsin Alzheimer’s Disease Research Center at the University of Wisconsin.

A study co-authored by Okonkwo and published in JAMA Neurology in 2015 showed that older adults who completed at least 16 years of education — and therefore were considered to have higher than average cognitive reserve — had less evidence of Alzheimer’s biomarkers in their cerebrospinal fluid than people with fewer years of education. The research suggests that formal education may protect the brain from developing Alzheimer’s, while also allowing those with the disease to mentally function longer and “better compensate for any cognitive hits,” Okonkwo says. More research is needed to prove the link.
 

Socioeconomic impact 

Another theory suggests that although education might not directly change the brain, it is often associated with a higher socioeconomic status and quality of life that helps keep people healthy and lowers dementia risk.

Education can impact the type of job a person has, the environment they live in, the quality of food they can eat and the health care they receive. A combination of these factors over time may add up to higher or lower Alzheimer’s risk.

“It may be this whole host of factors that may not have a direct impact on the brain, but overall enhance your health in a way to protect you and reduce your risk of developing the disease,” says Miguel Arce Renteria, Ph.D., associate research scientist and clinical neuropsychologist at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, located at Columbia University.
 

Quality and quantity

While many studies have focused on the benefits of high school and college education, other studies have shown that even the basic act of learning to read and write may also lower dementia risk.

Research published in Neurology in 2019 showed that illiterate study participants were almost three times more likely to have dementia compared to literate participants, and twice as likely to eventually develop dementia.

The study illustrates how important early life experiences are to the brain, and how missing those opportunities can impact health later in life, says Arce Renteria, the study’s lead author.

Researchers have found it is not just the quantity of education that may lower dementia risk, but also the quality. Recently, Arce Renteria co-led another study examining if formal education reduced dementia risk across different racial and ethnic groups. The study found education protected White Americans at higher rates than Black and Hispanic Americans — likely due to a difference in the quality of education they received, Arce Renteria says.

Can Alzheimer's be prevented?

Researchers are exploring how to prevent Alzheimer's. While prevention has no definitive answers, research has shown that we can take action to reduce our risk of developing it.

“If somebody was Black and went to high school in the segregated South, their quality of education is not the same as those people who went to school in the North,” Arce Renteria says.

“Even today, across the country — rural, urban — education quality differs a lot. It is important to make sure we can optimize the quality of people’s education early on, across the board, so that hopefully everyone can benefit and see a cascade of changes throughout their life.”
 

Never stop learning

The majority of dementia risk studies have examined the benefits of obtaining education early in life. But Okonkwo says some studies have shown that learning new skills and working in jobs that are cognitively complex in mid and late life could also help protect the brain. For example, a 2015 study co-authored by Okonkwo found middle-aged adults who worked in mentally demanding occupations — especially dynamic jobs requiring frequent interaction and socialization with people — had higher cognitive reserve.

While the perfect equation for reducing your risk of dementia is still being determined, combining formal education with other potential risk reduction factors — like managing blood pressure and getting exercise — could have the biggest benefit for adults, Arce Renteria says.

Multidimensional phase I dose ranging trials for stroke recovery interventions: Key challenges and how to address them

This is so fucking simple to explain why stroke rehab doesn't work. 

1. You have too many dead neurons; The neuronal cascade of death  is causing billions of neurons to die the first week.

2. You don't know how to make neuroplasticity exactly repeatable.

3. You don't have the correct goal of 100% recovery, as a result your researchers are going for little incremental wins, not BHAGs(Big Hairy Audacious Goals.

Multidimensional phase I dose ranging trials for stroke recovery interventions: Key challenges and how to address them

Neurorehabilitation and Neural Repair , Volume 35(8) , Pgs. 663-679.

NARIC Accession Number: J87242.  What's this?
ISSN: 1044-2073.
Author(s): Dalton, Emily J. ; Churilov, Leonid ; Lannin, Natasha A. ; Corbett, Dale ; Campbell, Bruce C. V. ; Hayward, Kathryn S..
Publication Year: 2021.
Number of Pages: 17.
Abstract: Article describes the problem of insufficient use of a systematic approach to early-phase, multidimensional dose articulation research and proposes a solution that applies this approach to design a multidimensional phase I trial to identify the maximum tolerated dose. Despite an increase in the amount of published stroke recovery research, interventions have failed to markedly affect the trajectory of recovery poststroke. The authors argue that early-phase research to systematically investigate dose is an important contributor to advance the science underpinning stroke recovery. They present a design template as a decision-support tool to increase knowledge of how to develop a phase I dose-ranging trial for nonpharmaceutical stroke recovery interventions. This solution has the potential to advance the development of efficacious stroke recovery interventions, which include activity-based rehabilitation interventions.
Descriptor Terms: HEALTH PROMOTION, INTERVENTION, REHABILITATION SERVICES, RESEARCH METHODOLOGY, SERVICE DELIVERY, STROKE.


Can this document be ordered through NARIC's document delivery service*?: Y.

Citation: Dalton, Emily J. , Churilov, Leonid , Lannin, Natasha A. , Corbett, Dale , Campbell, Bruce C. V. , Hayward, Kathryn S.. (2021). Multidimensional phase I dose ranging trials for stroke recovery interventions: Key challenges and how to address them.  Neurorehabilitation and Neural Repair , 35(8), Pgs. 663-679. Retrieved 10/23/2021, from REHABDATA database.

New study finds that COVID-19 can damage brain cells, impairing cognitive function

Well shit didn't we know that a long time ago? 

Earlier has these reports:

1. The researchers observed that, in slices of hamster brain, SARS-CoV-2 blocks the functioning of receptors on pericytes, causing capillaries in the tissue to constrict. “It turns out this is a big effect,” says Attwell.

2. Evidence has also accumulated that SARS-CoV-2 can affect the brain by reducing blood flow to it — impairing neurons’ function and ultimately killing them.

3. A new study offers the first clear evidence that, in some people, the coronavirus invades brain cells, hijacking them to make copies of itself. The virus also seems to suck up all of the oxygen nearby, starving neighboring cells to death.

 

You already had enough brain damage from your stroke, don't add to it, get vaccinated. 

The latest here:

New study finds that COVID-19 can damage brain cells, impairing cognitive function

 

Julian Kossoff

Sun, October 24, 2021, 9:53 AM

Medical imaging service in a hospital in Savoie, France. A technician monitors a brain MRI scan session. BSIP/Universal Images Group via Getty Images

• A new study has found that COVID-19 can damage specific brain cells known as endothelial cells.

• It may be an explanation for the 84% of COVID-19 patients who report neurological symptoms.

• There's hope that the damage may be reversible.

A new study has found that COVID-19 can cause damage to blood vessels in the brain, damaging cognitive function.

The study, conducted by scientists from Germany, France, and Spain, reveals that COVID-19 can kill brain cells known as endothelial cells.

Studies have previously found that up to 84% of COVID-19 patients suffer from neurological symptoms, anosmia (loss of sense of taste or smell), epileptic seizures, strokes, loss of consciousness, and confusion, and this may be an explanation as to why.

Insider's Yelena Dzhanova previously covered how patients of COVID-19 suffer memory loss, even months after contracting the virus.

The study was conducted by scanning the brains of corpses who had died from COVID-19.

The results of the research showed string vessels, a dead cell that cannot allow blood to flow, and is a sign of cognitive impairment, and has a number of medical risks, including micro strokes.

-Nature Neuroscience (@NatureNeuro) October 21, 2021

There is hope, however, that this new facet of COVID-19 may be reversible.

"We have seen that in hamsters, who develop very minor forms of Covid-19, the phenomenon is apparently reversible, so we can hope that it could also be reversible in humans," a co-author of the paper, Vincent Prévot, from the Inserm research center in Lille, told RFI news.

COVID-19 is still a new virus, with a lot more information still being uncovered about it.

Read the original article on Business Inside

Volition and imagery in neurorehabilitation

15 years! HAS YOUR STROKE HOSPITAL DONE ONE DAMN THING WITH THIS? Or is incompetence reigning supreme, and you are letting it fester?

Volition and imagery in neurorehabilitation

 

Lotze, Martin MD^*; Cohen, Leonardo G. MD^†

Author Information

Cognitive and Behavioral Neurology: September 2006 - Volume 19 - Issue 3 - p 135-140

doi: 10.1097/01.wnn.0000209875.56060.06

• Buy

Abstract

New interventional approaches have been proposed in the last few years to treat the motor deficits resulting from brain lesions. Training protocols represent the gold-standard of these approaches. However, the degree of motor recovery experienced by most patients remains incomplete. It would be important to improve our understanding of the mechanisms underlying functional recovery. This chapter examines the role of two possible mechanisms that could operate to improve motor function in this setting: volition and motor imagery. It is argued that both represent possible strategies to enhance training effects.

More than Clearing the Clutter: The Imperative Role of Efferocytosis in Repair and Immune Reprogramming in the Damaged Nervous System

230 pages for your doctor to consume.

More than Clearing the Clutter: The Imperative Role of Efferocytosis in Repair and Immune Reprogramming in the Damaged Nervous System

 by Lucas D. Huffman A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2021 Doctoral Committee Professor Roman J. Giger, Chair Associate Professor Catherine A. Collins Professor Gabriel Corfas Professor Daniel J. Goldman Professor Benjamin M. Segal Lucas D. Huffman lucashu@umich.edu ORCID iD: 0000-0002-7779-086X © Lucas D. Huffman 2021

 

The efects of an object’s height and weight on force calibration and kinematics when post‑stroke and healthy individuals reach and grasp

18 pages in total for your doctor to analyze and implement. These are obviously high functioning individuals already. I have zero grasping ability and very distorted reaching, both problems as a result of spasticity.  You have to cure spasticity first before this helps most survivors.

The efects of an object’s height and weight on force calibration and kinematics when post‑stroke and healthy individuals reach and grasp

 p Ronit Feingold‑Polak1,6, AnnaYelkin1,2,6, Shmil Edelman3 , Amir Shapiro3 & Shelly Levy‑Tzedek1,4,5* 

Impairment in force regulation and motor control impedes the independence of individuals with stroke by limiting their ability to perform daily activities. There is, at present, incomplete information about how individuals with stroke regulate the application of force and control their movement when reaching, grasping, and lifting objects of diferent weights, located at diferent heights. In this study, we assess force regulation and kinematics when reaching, grasping, and lifting a cup of two diferent weights (empty and full), located at three diferent heights, in a total of 46 participants: 30 sub-acute stroke participants, and 16 healthy individuals. We found that the height of the reached target afects both force calibration and kinematics, while its weight afects only the force calibration when poststroke and healthy individuals perform a reach-to-grasp task. There was no diference between the two groups in the mean and peak force values. The individuals with stroke had slower, jerkier, less efcient, and more variable movements compared to the control group. This diference was more pronounced with increasing stroke severity. With increasing stroke severity, post-stroke individuals demonstrated altered anticipation and preparation for lifting, which was evident for either cortical lesion side. Upper limb function following stroke. Cerebrovascular accidents (CVAs) are a leading cause of longterm disability worldwide1 , leaving up to 75% of survivors with persistent upper limb (UL) sensorimotor defcits2,3 . Impaired UL function post-stroke signifcantly impedes ability to perform activities of daily living (ADLs) such as reaching, picking up, and holding objects4 . Tese defcits limit performance and social participation, negatively afecting quality of life3,5–7 . Reach‑to‑grasp movement in healthy and post‑stroke individuals. Reach-to-grasp (RTG) movements are a primary means of interacting with the environment, allowing people to obtain and manipulate objects around them8 . RTG movement entails both the transport component, which is the change in position of the hand over time, and the grasp component9 . Both are synchronized such that the hand opens and closes, in coordination with hand movements when grasping objects10. RTG movements require precise application of grip forces11, e.g., when we move our arm while holding an object between our fngers, we unconsciously increase the grip forces to prevent the object from slipping12 or sliding13. Skilled grip force relies on prediction and sensory feedback14, such that during a grip-lif task, healthy individuals are able to rapidly establish an association between an arbitrary sensory cue with a given weight and scale grip force precisely to the actual OPEN 1 Department of Physical Therapy, Recanati School for Community Health Professions, Ben-Gurion University of the Negev, Ben‑Gurion Blvd, Beer‑Sheva, Israel. 2 Beit Hadar Rehabilitation Center, Ashdod, Israel. 3 Department of Mechanical Engineering, Ben-Gurion University of the Negev, Beer‑Sheva, Israel. 4 Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer‑Sheva, Israel. 5 Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany. 6These authors contributed equally: Ronit Feingold-Polak and Anna Yelkin. *email: shelly@bgu.ac.i

 

Irisin Rescues Blood-Brain Barrier Permeability following Traumatic Brain Injury and Contributes to the Neuroprotection of Exercise in Traumatic Brain Injury

 Will this work for stroke? WHOM do we ask to answer that simple question?

Your doctor should have been doing something with irisin for years.

• irisin (6 posts to October 2013)

Irisin Rescues Blood-Brain Barrier Permeability following Traumatic Brain Injury and Contributes to the Neuroprotection of Exercise in Traumatic Brain Injury

 

---

Peipei Guo,^1,2 Zhao Jin,² Jin Wang,² Aming Sang,² and Huisheng Wu^1,2

¹Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province 230022, China

²Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan City, Hubei Province 430071, China

Academic Editor: Xiaoyuan Zhou

Received13 May 2021

Revised21 Aug 2021

Accepted28 Sep 2021

Published16 Oct 2021

Abstract

Traumatic brain injury (TBI) has a high incidence, mortality, and morbidity all over the world. One important reason for its poor clinical prognosis is brain edema caused by blood-brain barrier (BBB) dysfunction after TBI. The mechanism may be related to the disorder of mitochondrial morphology and function of neurons in damaged brain tissue, the decrease of uncoupling protein 2 (UCP2) activity, and the increase of inflammatory reaction and oxidative stress. In this study, we aimed to investigate the effects of exogenous irisin on BBB dysfunction after TBI and its role in the neuroprotective effects of endurance exercise (EE) in mice. The concentrations of irisin in cerebrospinal fluid (CSF) and plasma of patients with mild to severe TBI were measured by ELISA. Then, male C57BL/6J mice and UCP2 knockout mice with C57BL/6J background were used to establish the TBI model. The BBB structure and permeability were examined by transmission electron microscopy and Evans blue extravasation, respectively. The protein expressions of irisin, occludin, claudin-5, zonula occludens-1 (ZO-1), nuclear factor E2-related factor 2(Nrf2), quinine oxidoreductase (NQO-1), hemeoxygenase-1 (HO-1), cytochrome C (Cyt-C), cytochrome C oxidase (COX IV), BCL2-associated X protein (Bax), cleaved caspase-3, and UCP2 were detected by western blot. The production of reactive oxygen species (ROS) was evaluated by the dihydroethidium (DHE) staining. The levels of inflammatory factors were detected by ELISA. In this study, we found that the CSF irisin levels were positively correlated with the severity of disease in patients with TBI and both EE and exogenous irisin could reduce BBB damage in a mouse model of TBI. In addition, we used UCP2^−/− mice and further found that irisin could improve the dysfunction of BBB after TBI by promoting the expression of UCP2 on the mitochondrial membrane of neurons, reducing the damage of mitochondrial structure and function, thus alleviating the inflammatory response and oxidative stress. In conclusion, the results of this study suggested that irisin might alleviate brain edema after TBI by promoting the expression of UCP2 on the mitochondrial membrane of neurons and contribute to the neuroprotection of EE against TBI.

1. Introduction

The huge advances in society, economy, transportation, and infrastructure have produced an increasingly convenient life, while resulted in people’s higher probability of developing trauma [1, 2]. Accordingly, the incidence of traumatic brain injury (TBI) has been annually rising worldwide and remains at a continuingly high level. TBI, a common emergent and critical illness in clinic, bears an extremely high risk for disability and mortality and has an inadequately satisfying clinical prognosis. One of the main causes for a series of adverse outcomes is brain edema which is not only a consequence of TBI but also a major factor for further aggravating TBI damage [3].

TBI can destroy tight junction (TJ) proteins, the main structure of the blood-brain barrier (BBB), and cause the apoptosis of cerebrovascular endothelial cells. This allows substances that could not have access to the brain tissue to quickly permeate into it in large quantities, so that fluids accumulate in the extracellular space, resulting in vasogenic brain edema [4, 5]. The mechanism may be that reactive oxygen species (ROS) increase after TBI, which leads to neuroinflammatory response and oxidative stress response [6]. Meanwhile, the mitochondrial membrane potential (MMP) is a significant factor accounting for the increase of ROS levels, so MMP, to some extent, is positively correlated with ROS [7]. Recently, there is increasing evidence that uncoupling protein 2 (UCP2) can dramatically reduce the production of ROS by reducing MMP [8]. The “uncoupling survival” hypothesis related to UCP2 has been further confirmed in the traumatic brain injury model [9].

It is well-established that endurance exercise (EE) can effectively exert neuroprotective effects [10–13] but the underlying mechanism has remained to be elucidated. Exercised skeletal muscle can secrete PGC-1α, and downstream factors regulated by this protein can be sheared and modified to form a hormone called irisin. Irisin has been a focus of recent studies in the fields of metabolism and the nervous system [12, 14]. Our previous research has demonstrated that irisin worked effectively on alleviating cerebral ischemia-reperfusion injury [15]. Thus in this study, we tested whether irisin could reduce brain edema after TBI and explored its specific mechanisms. In addition, we also observed whether the neuroprotective effects of EE were related to irisin.

More at link,

 

An ultra detailed map of the brain region that controls movement, from mice to monkeys to humans

 You can ask your doctor how this knowledge is going to get you recovered.  No response, your doctor needs to be removed for not keeping up-to-date of how survivors recover.  A lot of my problems are from damage to the secondary motor cortex which isn't listed here.

An ultra detailed map of the brain region that controls movement, from mice to monkeys to humans

Hundreds of neuroscientists built a ‘parts list’ of the motor cortex, laying groundwork to map the whole brain and better understand brain diseases

October 6, 2021

A new study from the Allen Institute compares human brain cells’ molecular features to those of the marmoset monkey and mouse in a region of the brain that controls movement, the primary motor cortex. Using a technique known as single-cell transcriptomics, the researchers compared the suite of genes each individual brain cell switches on, across thousands of cells from each of the three species. Shown here, transcriptomic data clustered by type of brain cell, in the human (left), marmoset monkey (middle), and mouse brain (right)

Before you read any further, bring your hand to your forehead. 

It probably didn’t feel like much, but that simple kind of motion required the concerted effort of millions of different neurons in several regions of your brain, followed by signals sent at 200 mph from your brain to your spinal cord and then to the muscles that contracted to move your arm. 

At the cellular level, that quick motion is a highly complicated process and, like most things that involve the human brain, scientists don’t fully understand how it all comes together. 

Now, for the first time, the neurons and other cells involved in a region of the human, mouse and monkey brains that controls movement have been mapped in exquisite detail. Its creators, a large consortium of neuroscientists brought together by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, say this brain atlas will pave the way for mapping the entire mammalian brain as well as better understanding mysterious brain diseases — including those that attack the neurons that control movement, like amyotrophic lateral sclerosis, or ALS. 

The atlas is described in a special package of 17 articles published today in the journal Nature, including a single flagship paper that describes the entire atlas.  

“In a human brain, there are more than 160 billion cells. Our brain has more than 20 times more cells than there are people in this world,” said Hongkui Zeng, Ph.D., Executive Vice President and Director of the Allen Institute for Brain Science, a division of the Allen Institute, and lead investigator on several BRAIN Initiative-funded studies. “To understand how a system works, you need to first build a parts list. Then you have to understand what each part is doing and put the pieces together to understand how the whole system works. That’s what we’re doing with the brain.” 

The massive BRAIN Initiative-funded collaboration involved dozens of research teams around the country who worked together to complete a cell-by-cell atlas of the primary motor cortex, a part of the mammalian brain that controls movement. Combining more than a dozen different techniques to define brain “cell types” across three different species of mammals, the resulting open-access data collection is by far the most comprehensive and detailed map of any part of the mammalian brain ever released. The researchers classified the millions of neurons and other kinds of brain cells present in the motor cortex into many different cell-type categories — the actual number of different brain cell types in this region depends on how they are being measured, but ranges from several dozen to more than 100. 

Interact with slider on the image above to see tissue with and without neuron reconstructions.

Digital reconstructions of human neurons overlaid on a slice of brain tissue donated by a brain surgery patient. Allen Institute researchers are able to capture electrical information from these live human neurons, as well as their 3D shape and gene expression, through a technique known as Patch-seq. This image shows several different types of human neurons in the medial temporal gyrus of the neocortex, the outermost shell of the mammalian brain.

The researchers picked the primary motor cortex in part because it’s similar across all mammalian species — while humans, monkeys and mice have many differences between our brains, the way we control movement is very similar — and because it’s representative of the neocortex, the outermost shell of the mammalian brain that not only integrates sensory and motor information but also gives rise to our complex cognitive functions. This completed atlas is one large step in the effort to create a catalog or census of all brain cell types through the BRAIN Initiative Cell Census Network, or BICCN. The NIH launched the BICCN in 2017, awarding nine collaborative network grants, three of which are led by Allen Institute for Brain Science researchers.  

Like a population census, the cell census aims to catalog all different types of brain cells, their properties, their relative proportions and their physical addresses to get a picture of the cell populations that together form our brains. Knowing the “normal” brain’s cellular makeup is a key step to understanding what goes wrong in disease.  

“If we really want to understand how the brain works, we have to get down to its fundamental unit. And that is the cell,” said Ed Lein, Ph.D., Senior Investigator at the Allen Institute for Brain Science and lead investigator on several BRAIN Initiative studies focused on the human brain. “This is also clinically important because cells are the locus of disease. By understanding which cells are vulnerable in different brain diseases, we can better understand and ultimately treat the diseases themselves. The hope with these studies is that by making this fundamental classification of cell types, we can lay the groundwork for understanding the cellular basis of disease.” 

A diagram showing the different types of neurons and other brain cells in the mouse primary motor cortex, and their organization. 

The atlas’s creators used several different methods to measure a variety of cellular properties to define a cell type by correlating and integrating these properties, which include the complete set of genes a cell switches on; a cell’s “epigenetic” landscape, which defines how genes are regulated; cells’ 3D shapes; their electrical properties; and how they connect to other cells. The single-cell gene expression and epigenetic data were especially important as the researchers were able to use these data to integrate all the other kinds of cell-type data, creating a common framework to classify cell types and compare them within and between species.  

The studies required not only collaboration among researchers to design and execute the experiments, but also coordination and public sharing of the data that resulted from the atlas project and other projects under the BICCN. The Brain Cell Data Center, or BCDC, is headquartered at the Allen Institute. The data center, led by Allen Institute for Brain Science Investigator Michael Hawrylycz, Ph.D., helps to organize the BICCN consortium and provides a single point of access to the study’s data-archiving centers across the country. 

“One of our many limitations in developing effective therapies for human brain disorders is that we just don’t know enough about which cells and connections are being affected by a particular disease, and therefore can’t pinpoint with precision what and where we need to target,” said John Ngai, Ph.D., Director of the NIH BRAIN Initiative. “The Allen Institute has played an important role in coordinating the large amounts of data produced by the BRAIN cell census project that provide detailed information about the types of cells that make up the brain and their properties. This information will ultimately enable the development of new therapies for neurologic and neuropsychiatric diseases.”  

Scientists at the Allen Institute for Brain Science played a role in nine of the 17 published studies and led or co-led six of them. The four primary Allen Institute-led studies explored: 

• How cell types in the primary motor cortex compare across mice, humans and marmoset monkeys. The research team found that most motor cortex brain cell types have similar counterparts across all three species, with species-specific differences at the level of proportions of cells, their shapes and electrical properties, and individual genes that are switched on and off. For example, humans have about twice as many excitatory neurons as inhibitory neurons in this region of the brain, while mice have five times as many. The researchers also delved into the famous Betz cells, enormous neurons that project to the spinal cord that exist in us, monkeys and many other larger mammals, and captured the first known electrical recordings from human Betz cells, which degenerate in ALS. Mice have evolutionarily related neurons based on shared genetic programs, but their shapes and electrical properties are very different from those in humans. See related news story for more information, New insights about evolution of human brain region that controls voluntary movement, including rare, large neurons vulnerable in ALS.

• A broader analysis of cell types in the human brain, looking at the second and third layers of the 6-layered neocortex. These layers, and the neocortex overall, are much larger and contain a larger diversity of cells in humans and other primates as compared to rodents. Allen Institute researchers used a three-prong technique known as Patch-seq to measure the electrical properties, genes and the 3D shapes of several kinds of neurons in these layers in tissue samples donated by brain surgery patients. The study characterizes these neurons in living human tissues and demonstrates an increased diversity of the types of neurons specialized to communicate between different regions of the human cortex, including delving into a specialized type of human neuron that is especially vulnerable in Alzheimer’s disease. See related news story for more information, Living brain donors are helping us better understand our own neurons — including those potentially linked to Alzheimer’s disease. 

• The largest collection to date of complete brain-wide reconstructions of more than 1,700 different neurons in the mouse brain. This form of 3D neuron-tracing is extensive and complicated due to the cells’ lengthy and delicate axons and dendrites, but it yields important information about the long-distance connections different neuron types make through their axon arbors reaching faraway brain regions. Allen Institute researchers find that these neurons’ axon arbors show extremely diverse patterns, some with just a few focused branches while others spread across large areas. For example, some neurons in the structure known as the claustrum send axon arbors in a crown-like fashion around the entire circumference of the neocortex. Characteristic connection patterns like these are a critical attribute used to help classify a brain cell type.

• The cellular makeup of the mouse primary motor cortex, sorting approximately 500,000 neurons and other brain cells into cell-type categories based on the suite of genes each cell switches on (the “transcriptome”) as well as the gene-regulatory modifications on a cell’s chromosomes (the “epigenome”).  Using a range of techniques, Allen Institute researchers and their collaborators generated seven types of transcriptomic and two types of epigenomic datasets, then developed computational and statistical methods to integrate these datasets into shared “evolutionary tree” of cell types. The study led to the discovery of thousands of marker genes and other DNA sequences specific for each of these cell types.  

The research described in this press release was supported by several awards from the National Institutes of Health, including award numbers U19MH114830, U01MH114812, U01MH105982, R01EY023173, and U24MH114827 to Allen Institute for Brain Science researchers. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH and its subsidiary institutes.

 

 

First-in-human study of DBS for post-stroke rehabilitation shows encouraging results

 Hopefully your doctor tells you about this problem. That’s a problem with PD (basal ganglia), less common location for stroke; per friend Ze'ev

“My family say they grieve for the old me” – profound personality changes after deep brain stimulation

The latest here:

First-in-human study of DBS for post-stroke rehabilitation shows encouraging results

 

Targeting the dentate nucleus with deep brain stimulation (DBS) was safe and feasible for promoting post-stroke rehabilitation in a first-in-human study at Cleveland Clinic.

Treatment response in the phase I EDEN trial of dentate nucleus DBS for upper extremity hemiparesis from stroke was encouraging, enabling the procedure to advance to a phase II randomized controlled trial to evaluate safety and efficacy, reported principal investigators Andre Machado, M.D., Ph.D., and Kenneth Baker, Ph.D., in a late-breaking abstract presentation at the annual meeting of the Congress of Neurological Surgeons (CNS) on Oct. 20.

We hypothesized that stimulating the dentatothalamocortical pathway, which connects the cerebellum and the cortex, would facilitate the spared perilesional cortex following ischemic stroke. We further proposed that this stimulation, when paired with physical training, would promote greater functional restoration than could be achieved with physical training alone. That is what we observed in this phase I study, as patients with even minimal residual distal function responded well."

Dr Machado, Chair, Neurological Institute, Cleveland Clinic

The findings build on more than a decade of preclinical work led by Dr. Machado and Dr. Baker (Neurosurgery. 2013;73:344-353) showing that DBS of the dentate nucleus enhanced perilesional excitability along with perilesional motor cortical reorganization and synaptogenesis. "These results show that the effects seen in our preclinical models appear to translate to humans. They argue for further investigation in larger patient samples."

The EDEN trial (Electrical Stimulation of the Dentate Nucleus for Upper Extremity Hemiparesis Due to Ischemic Stroke) (NCT02835443) was a single-arm, open-label study conducted at Cleveland Clinic. It enrolled 12 patients with chronic, moderate to severe hemiparesis of the upper extremity following unilateral middle cerebral artery stroke 12 to 36 months previously.

All patients began supervised physical rehabilitation -; i.e., physical and occupational therapy -; prior to implantation of a DBS lead at the dentate nucleus contralateral to their stroke lesion. After implantation, patients underwent physical rehabilitation for two months followed by a month of DBS programming over several sessions.

"All patients had three months of structured rehabilitation before the stimulation was turned on, to maximize the benefit to be achieved from rehabilitation alone," Dr. Machado explains.

This was followed by at least four months of combined rehabilitation therapy and DBS. The study's adaptive design allowed for extension beyond four months if patients continued to show month-over-month improvement. Treatment response was defined as an improvement of 4.5 points or more on the Fugl-Meyer assessment of upper extremity function (FMA-UE). Additionally, the investigators evaluated event-related EEG and local field potentials perioperatively.

All 12 patients completed the study. There were no deaths, hemorrhages, infections or other major perioperative complications. The first three patients experienced DBS-related nausea in the first postoperative days. "This appeared to be related to how we placed the electrodes, so we changed that and subsequent patients had no nausea," Dr. Machado notes.

Related Stories

• Targeted drug shows promising activity in kidney cancer patients with brain metastases
• Study maps neurons essential for social behavior and healthy relationships within groups
• MRI study suggests link between SARS-CoV-2 and brain lesions in COVID-19 patients with pneumonia

Treatment response (≥ 4.5-point improvement on the FMA-UE) was achieved by nine of 12 patients. Mean FMA-UE improvement was 11.8 points (± 7.1 SD). Among the seven patients who entered the study with at least minimal distal motor function, the mean improvement was 16.4 points (± 3.9 SD) and was associated with significant improvement in activities of daily living (ADLs).

"This suggests that patients who have a bit of the neuronal pathway preserved offer us more to work with," Dr. Machado said. "There appear to be some neurons surviving that the stimulation and physical training can activate and boost."

Follow-up continued for up to eight months for some patients, in order to capture cumulative functional improvement prior to plateauing. Additionally, perioperative stimulation of the dentate nucleus combined with EEG revealed that DBS was associated with topography- and frequency-specific modulation of movement-related cortical activity, the investigators reported. They were also able to study the activity of the dentate nucleus during movement and movement planning. "This is the first reported direct investigation of movement-related local field potentials in the human dentate nucleus," Dr. Machado notes.

The quality-of-life implications for study participants who responded to therapy have been significant. At the CNS meeting, Dr. Machado shared a video of a patient throwing a ball with her affected hand. "Prior to DBS and physical training, this patient was unable to unclench her hand and release a ball," he explains. "Now she can coordinate all the movements needed to throw -; extending and opening the fingers, extending the wrist and so forth -; and execute them in an organized fashion."

This ability has translated to ADL improvements for this patient such as the ability to put dishes away and tend to countless household tasks. Additional examples include a patient who has regained the ability to write messages using a marker and another who can buckle his pants again, enabling him to independently visit restrooms in public.

The degree of mean FMA-UE improvement achieved in the study -; nearly triple the clinically meaningful threshold of 4.5 points -; surprised the investigators. "We were not expecting this magnitude of functional recovery in phase I testing," Dr. Machado says.

In the wake of these findings, Cleveland Clinic is planning a randomized, sham-controlled study of dentate nucleus DBS in up to 40 post-stroke patients. Dr. Machado says recruitment will be limited to patients with at least modest residual distal upper extremity function, in view of the superior response in this patient subgroup. He adds that the next study will also incorporate refinements in implantation techniques adopted over the course of the phase I study.

"About half of chronic stroke patients have a residual neurological deficit severe enough to require assistance with ADLs, even after extensive rehabilitative training," Dr. Machado concludes. "We clearly need a tool that enhances the effects of physical training. DBS of the dentate nucleus shows encouraging promise to be such a tool. We are eager to investigate it further."

Source:

Cleveland Clinic

When a doctor turns patient: For years he helped people recover from strokes, then he had one.

 I don't think he has yet had the epiphany yet that everything in stroke is a failure.

When a doctor turns patient: For years he helped people recover from strokes, then he had one.

 

As a medical provider, Dr. Mahesh Ramachandran encouraged his patients to keep working as hard as they could in physical therapy, knowing that more effort could yield more results.

But then, he became a patient himself. And it left him with a new appreciation for the neurological work the patients put in every day as part of their rehabilitation.

Ramachandran, the chief medical officer of Marianjoy Rehabilitation Hospital in Wheaton, landed in recovery there after suffering a stroke over Memorial Day weekend.

It caused weakness to his left side, leaving him in need of therapy to help relearn things like getting dressed. “I had a very hard time buttoning a shirt, putting on a belt,” he said. “Tying shoelaces were pretty much impossible for me to do on my own. Day-to-day simple things like that, because you use both your hands for those tasks.”

Dr. Mahesh Ramachandran at his office at Marianjoy Rehabilitation Center in Wheaton on Oct. 21, 2021. Ramachandran experienced a stroke and recovered at his own hospital. (Antonio Perez / Chicago Tribune)

After stumbling in his backyard in May and feeling a bit confused, Ramachandran went inside. About half an hour later, he noticed his left arm felt weak. He grew alarmed and asked his wife to call 911.

[Most read] Daily horoscope for October 23, 2021 »

As a stroke specialist, he knows what feeling weak on one side could mean. And he also knew that speed mattered; by getting to the hospital quickly, he was able to be diagnosed and begin care.

Doctors told him he’d had a stroke on the right side of his brain. “Fortunately, it didn’t affect my speech, my cognition,” Ramachandran said.

But he still had a journey ahead.

He hoped to do outpatient therapy, coming to Marianjoy for appointments and sleeping at home. But it quickly became clear he would need to stay at the hospital, as he had difficulties walking and worried about his wife needing to lift and carry him at home.

Coming in as a patient through the doors of Marianjoy he’d so often entered as chief medical officer “was a completely different perspective,” he said.

[Most read] Estate of Richard Driehaus lists his Lake Geneva mansion for $39M »

On a scientific level, he was familiar with the kind of stroke he’d had. “I felt very good about my chances of recovery,” he said. He noted many people assume all strokes are the same, but they vary in location, intensity and recovery.

A stroke happens when blood supply to part of the brain is interrupted, preventing the brain from getting oxygen or nutrients. According to the Mayo Clinic, symptoms include trouble speaking or understanding others, paralysis or numbness of the face, arm or leg, headache or problems seeing in one or both eyes. Getting care quickly is key.

Despite Ramachandran’s wealth of scientific knowledge about his body, the experience was still difficult for him. “The actual going through the symptoms and the therapy and being a patient was quite eye-opening,” he said.

His neurological recovery included physical therapy to strengthen muscles and improve balance, occupational therapy to relearn things like picking up cups, and speech therapy, where a therapist checked things like swallowing and speech production.

Mahesh Ramachandran, Marianjoy Rehabilitation Hospital chief medical officer, stands next to an ArmeoPower, a robotic exoskeleton for rehabilitation of the arm, which he used during his recovery at the hospital following a stroke. (Antonio Perez / Chicago Tribune)

Ramachandran remembers an exercise he found difficult — a type of video game where patients used one hand to maneuver a joystick. “Initially I had a very hard time moving objects,” he said. “After 10 to 15 seconds, I would just be exhausted, and my left arm would not move anymore.” Eventually he worked his way up to minutes at a time.

During frustrations and victories alike, he also saw a new side of his staff as one of their patients, he said, making him feel “both happy and proud to be part of the program.”

One of the big things he learned was how much of a barrier fatigue can be.

“It takes a lot more energy, because of the weakness you have on one side of the body, to do simple activities,” he said. “One of the things that I realized is that even though studies show the more therapy you do, the better you get, your body also needs to rest. … It’s probably not something that I realized as much as a physician.”

By August, he had returned to work full time. And his work feels different. He knows he will remember that fatigue, and balance that memory with his urge to motivate his patients.

“That’s kind of a change in my practice, that I’ll say: You need to work hard, but you also need to get that rest so your body can recharge,” he said.

Ramachandran also gained a new appreciation for how family and friends support sick relatives, and the mental aspect of recovering from a stroke.

“This is a life-altering event, so the emotional and psychological aspects of it are tremendous, because they don’t know if they can return back to their way of living. Can they go back to work? Can they go back to driving? And so on,” he said.

And, for the first time, he can tell those he treats how he, too, has been at Marianjoy as a patient. He hopes encouragement to keep going will hold more weight.

“I think sometimes if you just say that as a physician, it may not have the impact that I can have now,” he said.

Ramachandran can tell patients, “I’ve lived through it.”

abowen@chicagotribune.com

Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review

Finally someone looking to solve the 5 causes of the neuronal cascade of death in the first week saving billions of neurons. The first mention of cascade of death I've seen is in a Rockefeller University paper in 2009. So 12 years to finally work on solving that. All as a result of NO LEADERSHIP AND NO STRATEGY IN STROKE. This is why we need survivors in charge, your children and grandchildren can't wait for that incompetence to continue forever.

Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review

• I. A. Mulder,
• E. T. van Bavel,
• H. E. de Vries &
• J. M. Coutinho 

Fluids and Barriers of the CNS volume 18, Article number: 46 (2021) Cite this article

• 140 Accesses

• 2 Altmetric

• Metrics details

Abstract

With the introduction of endovascular thrombectomy (EVT), a new era for treatment of acute ischemic stroke (AIS) has arrived. However, despite the much larger recanalization rate as compared to thrombolysis alone, final outcome remains far from ideal. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This review provides an overview of compounds tested in clinical AIS trials and gives insight into which of these drugs warrant a re-evaluation as an add-on therapy for AIS in the era of EVT. A literature search was performed using the search terms “ischemic stroke brain” in title/abstract, and additional filters. After exclusion of papers using pre-defined selection criteria, a total of 89 trials were eligible for review which reported on 56 unique compounds. Trial compounds were divided into 6 categories based on their perceived mode of action: systemic haemodynamics, excitotoxicity, neuro-inflammation, blood–brain barrier and vasogenic edema, oxidative and nitrosative stress, neurogenesis/-regeneration and -recovery. Main trial outcomes and safety issues are summarized and promising compounds for re-evaluation are highlighted. Looking at group effect, drugs intervening with oxidative and nitrosative stress and neurogenesis/-regeneration and -recovery appear to have a favourable safety profile and show the most promising results regarding efficacy. Finally, possible theories behind individual and group effects are discussed and recommendation for promising treatment strategies are described.

Significance statement

Dozens of clinical stroke trials have been performed in the search for additional therapeutic strategies next to thrombolysis, but all failed to consistently improve outcome. With the introduction of endovascular thrombectomy, a new era for treatment of AIS has arrived. We summarized therapeutic strategies and clinical trial results. This review will function as an important enchiridion for future clinical stroke trials and it will provide an insight into which of these drugs warrant a re-evaluation in combination with thrombectomy.

Introduction

About 25 years ago the NINDS trial established intravenous thrombolysis (IVT) with tPA as the first effective medical therapy for acute ischemic stroke (AIS) [1]. Still, a large proportion of patients are not eligible for, or do not benefit from IVT. In the following years, dozens of clinical trials have been performed in the search for additional therapeutic strategies to reduce infarct volume and improve clinical outcome. Preclinical evidence is usually the trigger for making the clinical translation. Unfortunately, none of the compounds tested in these trials consistently showed to improve patient outcome, despite promising pre-clinical data, illustrating a translational gap [2]

With the introduction of endovascular thrombectomy (EVT), a new era for treatment of AIS has arrived [3]. With EVT, rapid recanalization of the major vessels can be achieved in the vast majority of the patients with a large vessel occlusion [4]. Up to 38% of all acute ischemic strokes are large vessel occlusions [5]. Despite the much larger recanalization rate as compared to IVT alone, final outcome remains far from ideal, with approximately 50% of patients having a poor outcome at 90 days [4]. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This question was also discussed in two extensive reviews by Savitz et al. [6, 7], where the whole aspect of “if, how and when” additional therapies next to reperfusion could be useful, is elaborated including recommendations and guidelines for clinical and per-clinical stroke trials.

After large vessel occlusion in the brain occurs, several multi-phased cascades start to unroll, with necrosis as devastating endpoints. Although these cascades are all intertwined and interact with one another, several main mechanisms can be identified, namely compounds acting on systemic haemodynamic, excitotoxicity, oxidative (and nitrosative) stress, neuro-inflammation and blood–brain barrier damage and vasogenic edema. In this review, we discuss the therapeutic strategies to target these pathways, and systematically review the results from clinical trials in which these various compounds have been tested. This review aims to provide an insight into which of these drugs may warrant a re-evaluation as an add-on therapy for acute ischemic stroke in the era of EVT.

More at link.