Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective 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.

Monday, February 28, 2022

Structural Basal Ganglia Correlates of Subjective Fatigue in Middle-Aged and Older Adults

Don't let your doctor tell you your fatigue is subjective. Mine idiotically told me to get more cardiovascularly fit, not testing me to find out I had the cardiovascular fitness of an athlete already.

Structural Basal Ganglia Correlates of Subjective Fatigue in Middle-Aged and Older Adults 

First Published February 24, 2022 Research Article 

Fatigue is among the most common complaints in community-dwelling older adults, yet its etiology is poorly understood. Based on models implicating frontostriatal pathways in fatigue pathogenesis, we hypothesized that smaller basal ganglia volume would be associated with higher levels of subjective fatigue and reduced set-shifting in middle-aged and older adults without dementia or other neurologic conditions.

Forty-eight non-demented middle-aged and older adults (Mage = 68.1, SD = 9.4; MMMSE = 27.3, SD = 1.9) completed the Fatigue Symptom Inventory, set-shifting measures, and structural MRI as part of a clinical evaluation for subjective cognitive complaints. Associations were examined cross-sectionally.

Linear regression analyses showed that smaller normalized basal ganglia volumes were associated with more severe fatigue (β = −.29, P = .041) and poorer Trail Making Test B-A (TMT B-A) performance (β = .30, P = .033) controlling for depression, sleep quality, vascular risk factors, and global cognitive status. Putamen emerged as a key structure linked with both fatigue (r = −.43, P = .003) and TMT B-A (β = .35, P = .021). The link between total basal ganglia volume and reduced TMT B-A was particularly strong in clinically fatigued patients.

This study is among the first to show that reduced basal ganglia volume is an important neurostructural correlate of subjective fatigue in physically able middle-aged and older adults without neurological conditions. Findings suggest that fatigue and rapid set-shifting deficits may share common neural underpinnings involving the basal ganglia, and provide a framework for studying the neuropathogenesis and treatment of subjective fatigue.

 

Long-term administration of salvianolic acid A promotes endogenous neurogenesis in ischemic stroke rats through activating Wnt3a/GSK3β/β-catenin signaling pathway

Well shit this from September 2016 was never followed up with human research so why expect anything from the latest?

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice

 September 2016

The latest here:

Long-term administration of salvianolic acid A promotes endogenous neurogenesis in ischemic stroke rats through activating Wnt3a/GSK3β/β-catenin signaling pathway

Abstract

Stroke is the major cause of death and disability worldwide. Most stroke patients who survive in the acute phase of ischemia display various extents of neurological deficits. In order to improve the prognosis of ischemic stroke, promoting endogenous neurogenesis has attracted great attention. Salvianolic acid A (SAA) has shown neuroprotective effects against ischemic diseases. In the present study, we investigated the neurogenesis effects of SAA in ischemic stroke rats, and explored the underlying mechanisms. An autologous thrombus stroke model was established by electrocoagulation. The rats were administered SAA (10 mg/kg, ig) or a positive drug edaravone (5 mg/kg, iv) once a day for 14 days. We showed that SAA administration significantly decreased infarction volume and vascular embolism, and ameliorated pathological injury in the hippocampus and striatum as well as the neurological deficits as compared with the model rats. Furthermore, we found that SAA administration significantly promoted neural stem/progenitor cells (NSPCs) proliferation, migration and differentiation into neurons, enhanced axonal regeneration and diminished neuronal apoptosis around the ipsilateral subventricular zone (SVZ), resulting in restored neural density and reconstructed neural circuits in the ischemic striatum. Moreover, we revealed that SAA-induced neurogenesis was associated to activating Wnt3a/GSK3β/β-catenin signaling pathway and downstream target genes in the hippocampus and striatum. Edaravone exerted equivalent inhibition on neuronal apoptosis in the SVZ, as SAA, but edaravone-induced neurogenesis was weaker than that of SAA. Taken together, our results demonstrate that long-term administration of SAA improves neurological function through enhancing endogenous neurogenesis and inhibiting neuronal apoptosis in ischemic stroke rats via activating Wnt3a/GSK3β/β-catenin signaling pathway. SAA may be a potential therapeutic drug to promote neurogenesis after stroke.

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Newer generation, clot-busting stroke medication cuts the risk of serious bleeding in half

 NOT GOD ENOUGH!  You could probably cut that risk to zero if you were to do the following.

The real solution to this is reducing the size of the bolus substantially.

You mean stroke leadership completely fucking failed at putting together magnetic nanoparticles delivering smaller loads of tPA resulting in much less chance of bleeds? Solving doctor reluctance.

We should have been using magnetic nanoparticles to deliver tPA for years.

Maybe this solution from March, 2015

Magnetic nanoparticles could stop blood clot-caused strokes

Or this from  May, 2012

Future of med devices: Nanorobots in your blood stream

The latest here:

Newer generation, clot-busting stroke medication cuts the risk of serious bleeding in half

Credit: CC0 Public Domain

In an international registry, patients with clot-caused strokes (ischemic) treated with the newer generation single injection clot-busting medication tenecteplase had  half as many serious complications involving bleeding into the brain compared to people who received the standard medication alteplase, according to preliminary research to be presented at the American Stroke Association's International Stroke Conference 2022.

Alteplase, the current standard of care for , is administered by injection followed by an hour-long infusion and has been FDA-approved for treating clot-caused strokes since 1996. Tenecteplase is a newer generation medication administered by a single injection into a blocked blood vessel. Both medications are approved for use in dissolving clots in blocked heart arteries, and tenecteplase is sometimes used off-label to treat ischemic strokes. The latest ischemic stroke treatment guidelines from the American Heart Association recommend it might be reasonable to consider tenecteplase for ischemic stroke in select . Several recent clinical trials focused on ischemic stroke have directly compared alteplase and tenecteplase, however, large, Phase 3 trials are still ongoing.

"No single trial has proved that tenecteplase is superior, however, in combination, the evidence has shown that tenecteplase is at least as good as alteplase in preventing long-term disability after a stroke and is more effective in dissolving large clots," said Steven J. Warach, M.D., Ph.D., lead author of the study and professor of neurology at the Dell Medical School at the University of Texas at Austin, medical director for Ascension hospitals in Texas and chair of Ascension's national stroke group.

The current study examined tenecteplase use at hospitals in New Zealand, Australia and the United States. The data registry among the hospitals launched in 2021 and included data for the previous three years: from July 2018 through June 2021. Stroke centers within the participating hospital systems began using tenecteplase after July 2018, and some administer only alteplase. All patients treated with thrombolytics (medications to dissolve blood clots) were included, enabling researchers to have a tenecteplase-treated group and an alteplase-treated group for comparison.

"The effects of a medicine used in real world is not always the same as those observed in the controlled environment of clinical trials. The goal of our analysis was to evaluate whether tenecteplase is as safe as alteplase when used to treat in routine clinical practice," Warach said.

The researchers analyzed data on 6,429 patients (average age of 70 years; 48.7% female) who received alteplase and 1,462 (average age of 73 years; 44.1% female) who received tenecteplase. On average, patients in both groups had experienced moderate .

The patients who received tenecteplase had slightly worse scores on the National Institutes of Health Stroke Scale (NIHSS) compared to the patients who received alteplase. (NIHSS is the international standard used to measure stroke severity.) Patients who received tenecteplase were also more likely to undergo a minimally invasive procedure to mechanically remove a large clot in the brain (thrombectomy). Thrombectomy is needed for many stroke patients who have larger artery blockages and more severe strokes. Researchers noted the difference in outcomes between the two patient groups was anticipated because some stroke centers only gave tenecteplase to patients with large clots after 2018, when clinical trials confirmed that tenecteplase was better than alteplase in those patients.

To evaluate the safety of tenecteplase, researchers compared the incidence of symptomatic intracranial hemorrhage after treatment with alteplase vs. tenecteplase. (sICH is bleeding within the brain that worsened the patient's NIHSS score by at least 4 points.)

"Thrombolysis treatment involves the administration of powerful blood-thinning medication, and bleeding into the brain is the most serious side effect. Intracranial hemorrhage information was available for all our study patients since it is routinely recorded by all stroke centers," Warach said.

The results were adjusted for age, severity of stroke and the need for thrombectomy. The analysis found:

  • The sICH rate was 43% lower among patients who received tenecteplase (3.71% in the alteplase group, and 2.13% in the tenecteplase group);
  • Among patients who did not undergo thrombectomy, the sICH rate was 42% lower among those who received tenecteplase (3% for the alteplase group, and 1.74% for the tenecteplase group); and
  • Among patients who required thrombectomy, the sICH rate was 59% lower for patients who received tenecteplase (6.8% for the alteplase group, and 2.8% for the tenecteplase group).

"The significantly lower rates of sICH surprised us. Our finding that tenecteplase had about half the risk of sICH when compared with alteplase in routine clinical practice provides reassurance that tenecteplase does not result in harmful bleeding when used routinely for stroke treatment," Warach said.

"Our data show no safety concerns when tenecteplase is used in routine practice, however, safety outcome is only one aspect to consider. Functional outcomes of patients—incidence of disability from stroke and recovery time—are also important. The registry does include data on patients' recovery and disability outcomes; however, we have not yet performed an analysis of those outcomes. A number of clinical trials in progress comparing tenecteplase to alteplase are assessing whether tenecteplase improves the chances of functional recovery. Clinicians may elect to wait until results of these trials are published, however, our results provide reassurance that routine tenecteplase use is safe," Warach said.

Results from this retrospective, observational study cannot prove a cause-and-effect relationship between the type of clot-buster used and the risk of intracranial hemorrhage. In addition, the clinicians assessing the patients are aware of the treatments received, which may introduce bias in the results. Although many more patients received alteplase, the analysis adjusted for this imbalance.

The registry is continuing to add data on more patients from more stroke centers with the goal of addressing additional questions about whether tenecteplase treatment leads to quicker treatment initiation and better recovery from ischemic stroke.



Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations

 'May', so lots of research to do on this. WHOM will be doing that?

Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations

Yingzhi Xu1,2,3, Yue Hu4, Shixin Xu5,6, Fengzhi Liu3 and Ying Gao1,2*
  • 1Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, China
  • 2Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
  • 3Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
  • 4School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
  • 5Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
  • 6Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China

The morbidity and mortality rates of ischemic stroke (IS) are very high, and IS constitutes one of the main causes of disability and death worldwide. The pathogenesis of ischemic stroke includes excitotoxicity, calcium overload, oxygen radical injury, inflammatory reactions, necrosis/apoptosis, destruction of the blood-brain barrier (BBB), and other pathologic processes. Recent studies have shown that exosomes are critical to the pathogenesis, diagnosis, and treatment of cerebral infarctions resulting from ischemic stroke; and there is growing interest in the role of exosomes and exosomal miRNAs in the diagnosis and treatment of IS. Exosomes from central nervous system cells can be found in cerebrospinal fluid and peripheral bodily fluids, and exosomal contents have been reported to change with disease occurrence. Exosomes are small membranous extracellular vesicles (EVs), 30–150 nm in diameter, that are released from the cell membrane into the depressions that arise from the membranes of multivesicular bodies. Exosomes carry lipids, proteins, mRNAs, and microRNAs (miRNAs) and transport information to target cells. This exosomal transfer of functional mRNAs/miRNAs and proteins ultimately affects transcription and translation within recipient cells. Exosomes are EVs with a double-membrane structure that protects them from ribonucleases in the blood, allowing exosomal miRNAs to be more stable and to avoid degradation. New evidence shows that exosomes derived from neural cells, endothelial cells, and various stem cells create a fertile environment that supports the proliferation and growth of neural cells and endothelial cells, inhibits apoptosis and inflammatory responses, and promotes angiogenesis. In the present review, we discuss how circulating exosomes—and exosomal miRNAs in particular—may provide novel strategies for the early diagnosis and treatment of ischemic stroke via their potential as non-invasive biomarkers and drug carriers.

Introduction

Ischemic stroke (IS) is one of the major causes of disability and mortality worldwide, and exhibits high rates of incidence and recurrence. In 2019, stroke was ranked second of the 10 leading causes of disability-adjusted life years (DALYs) for both individuals 50–74 years of age and those ≥ 75 years of age (1, 2). IS exhibits high rates of mortality and physical disability, and has become a heavy burden for individuals and society, especially in low-income and middle-income countries. The principal type of stroke is IS, which accounts for 84.4%; primary hemorrhagic stroke accounts for the majority of the remainder (1). Cerebral ischemia can lead to a series of pathologic changes that ultimately lead to irreparable neuronal damage. The accompanying pathogenesis includes excitotoxicity, calcium overload, oxygen-radical injury, inflammatory reactions, necrosis/apoptosis, destruction of the blood-brain barrier (BBB), and other pathologic processes.

Due to the scarcity of treatment methods and the thrombolytic time-window, the thrombolysis rate in stroke patients is very low (3). Thus, clinical diagnosis of IS now primarily depends on magnetic resonance imaging and computed tomography; however, due to a patient's physical manifestations, such as the placement of a metal stent or steel plate implantation, it is not reasonable to accept MRI as the sole modality. In addition, most community medical institutions lack the appropriate professional technicians and testing equipment, which limits the clinical application of MRI. Therefore, an optimized and clinically operable biomarker is needed for the early and accurate diagnosis of IS. Importantly, recent studies have shown that exosomes occupy a significant position in the pathogenesis, diagnosis, and treatment of cerebral infarction. Some nerve cells can synthesize and release exosomes after stroke, which then pass through the BBB. For example, exosomes released from brain cells are detectable in peripheral blood and/or cerebrospinal fluid (CSF) (46). In addition, endothelial and blood cells release exosomes into the blood after a stroke, while nerve cells release exosomes into the cerebrospinal fluid; with the latter distributed within and outside the brain through the BBB (7). These exosomes may therefore be useful as biomarkers that reflect stroke-induced pathologic processes, and might have potential as drug carriers for promoting recovery.

An exosome is a small membranous extracellular vesicle (EV) produced by the membrane of multivesicular bodies (MVBs), and when the endosomes or MVBs fuse with the plasma membrane, exosomes are released extracellularly (8). Exosomes have a diameter of 30–150 nm (9, 10), and transfer lipids, proteins, mRNAs, and microRNAs (miRNAs) (11). Furthermore, they play an important role in intercellular communication, maintenance of myelin sheaths, and the elimination of cellular waste (12, 13). Exosomes can cross the BBB and possess a double- membrane structure that protects them from ribonucleases in blood, making exosomal miRNAs highly stable and preventing them from undergoing degradation (1416). Thus, exosomal miRNAs may represent an ideal biomarker for circulating bodily fluids. As exosomal contents also change commensurately with disease development, neurocyte-derived exosomes that cross the BBB can be used as valuable biomarkers of nervous system diseases (17, 18). Exosomes from miRNA-overexpressing cells—e.g., stem cells and other cultured cells—have been shown to protect against ischemia-induced neural injury, the underlying mechanisms of which are related to inhibiting inflammatory reactions, promoting angiogenesis, regulating autophagy, and promoting neural repair. In this review, we principally discuss the most recent understanding of exosomes and exosomal miRNAs, and introduce the potential of using exosomal miRNAs in treating ischemic diseases. We also examine the mechanisms involving exosomes in these processes and review the research on circulating exosomal miRNAs as potential diagnostic biomarkers for stroke at different stages. Finally, we highlight important characteristics of exosomes and exosomal miRNAs in the potential diagnosis and treatment of IS so as to better understand the potential governing mechanisms and provide more-effective strategies for the use of exosomal miRNA in the diagnosis and treatment of IS.

More at link.

 

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance

 But is it caffeine or the other compounds in coffee?

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance

Abstract

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.

Introduction

Increased levels of circulating low-density lipoprotein cholesterol (LDLc) are tightly linked to the development of cardiovascular disease (CVD). Despite the approval of several therapies that lower LDLc, many patients fail to reach their LDL lowering goal due to intolerance, adverse events, or simply the high cost of medications. An important regulator of LDLc is the sterol regulatory element-binding protein 2 (SREBP2), which is an endoplasmic reticulum (ER)-resident transcription factor. SREBP2 is activated by reductions in intracellular cholesterol and loss of ER Ca2+, which then triggers translocation to the nucleus and the induction of cholesterol regulatory genes including the proprotein convertase subtilisin/kexin type 9 (PCSK9), the low-density lipoprotein receptor (LDLR), and HMG-CoA reductase (HMGR)1. Recent advancements in therapies available for the management of dyslipidemia and CVD have led to the characterization of PCSK9 as a hepatocyte-secreted circulating factor capable of enhancing the degradation of cell-surface LDLR2,3,4,5. By extension, PCSK9 also reduces the ability of metabolically active tissues, such as the liver, to remove excess LDLc from the blood. Based on these seminal discoveries, anti-PCSK9 antibodies are now available to patients at high risk of CVD, yielding an unprecedented 60–70% reduction of LDLc levels6. Although efficacious, the high cost and/or need for subcutaneous administration of anti-PCSK9 antibodies poses a limit to their availability to patients worldwide7. Such circumstances warrant the need for additional studies examining the molecular mechanisms that modulate the expression and secretion of PCSK9 from hepatocytes in order to develop more cost-effective therapies.

Caffeine (CF) or 1,3,7 trimethylxanthine, is best known as a stimulant alkaloid of the central nervous system found in various plants and is commonly found in coffee and tea. The majority of published literature demonstrates that the average adult habitual caffeine drinker consumes between 400 and 600 mg of CF daily and organizations like Health Canada and the Food and Drug Administration conclude that such doses are not negatively associated with toxicity, cardiovascular effects, bone status, calcium imbalance, behavior, the incidence of cancer or effects on male fertility8. On the contrary, accumulating evidence now suggests that moderate to high levels of CF (>600 mg), consumed daily in the form of non-alcoholic beverages, are associated with a reduction in CVD risk8,9. Although biochemical studies have shown that CF increases intracellular Ca2+ levels and induces vasodilation of the vascular endothelium via release of nitric oxide10,11, a cellular process known to be cardioprotective12, molecular mechanisms supporting clinical evidence are currently lacking.

In the current study, we demonstrate that clinically relevant concentrations of caffeine suppress SREBP2 transcriptional activation in liver hepatocytes, thereby leading to a reduction of PCSK9 in both mice and humans. Using structure/activity relationships (SAR), we have also generated several xanthine derivatives with heightened antagonism against SREBP2 and PCSK9, compared to CF. Overall, these studies characterize the mechanism by which CF impacts the expression of genes well-known to mediate CVD risk.

More at link.

 

Cooperative ankle-exoskeleton control can reduce effort to recover balance after unexpected disturbances during walking

 Is this good enough to do research in stroke subjects? WHOM will be doing that research?

Cooperative ankle-exoskeleton control can reduce effort to recover balance after unexpected disturbances during walking

 

Abstract

Background

In the last two decades, lower-limb exoskeletons have been developed to assist human standing and locomotion. One of the ongoing challenges is the cooperation between the exoskeleton balance support and the wearer control. Here we present a cooperative ankle-exoskeleton control strategy to assist in balance recovery after unexpected disturbances during walking, which is inspired on human balance responses.

Methods

We evaluated the novel controller in ten able-bodied participants wearing the ankle modules of the Symbitron exoskeleton. During walking, participants received unexpected forward pushes with different timing and magnitude at the pelvis level, while being supported (Exo-Assistance) or not (Exo-NoAssistance) by the robotic assistance provided by the controller. The effectiveness of the assistive strategy was assessed in terms of (1) controller performance (Detection Delay, Joint Angles, and Exerted Ankle Torques), (2) analysis of effort (integral of normalized Muscle Activity after perturbation onset); and (3) Analysis of center of mass COM kinematics (relative maximum COM Motion, Recovery Time and Margin of Stability) and spatio-temporal parameters (Step Length and Swing Time).

Results

In general, the results show that when the controller was active, it was able to reduce participants’ effort while keeping similar ability to counteract and withstand the balance disturbances. Significant reductions were found for soleus and gastrocnemius medialis activity of the stance leg when comparing Exo-Assistance and Exo-NoAssistance walking conditions.

Conclusions

The proposed controller was able to cooperate with the able-bodied participants in counteracting perturbations, contributing to the state-of-the-art of bio-inspired cooperative ankle exoskeleton controllers for supporting dynamic balance. In the future, this control strategy may be used in exoskeletons to support and improve balance control in users with motor disabilities.

Background

Wearable exoskeletons are powerful solutions that can be applied to reinforce and enhance mobility in able-bodied subjects [1, 2], or to restore lost functions of people with motor problems, such as those resulting from aging [3, 4], neurological disorders as spinal cord injury [5,6,7], or others [8,9,10]. Although these robotic devices are reliable in assisting individuals’ locomotion, researchers still struggle to design smart controllers for exoskeletons that also support balance when needed. Balance support is currently a serious demand and an often-heard wish of exoskeletons stakeholders, who consider this a fundamental and necessary skill [11, 12]. Especially during walking, balance becomes even more challenging, as recovery reactions to unexpected disturbances are often required to continue the gait cycle. During dynamic tasks, humans can exploit different balance recovery strategies, and the selected strategy may depend not only on the magnitude and direction of perturbation, but also on the perturbation timing within the gait cycle [13, 14]. Ideally, controllers for exoskeletons should be developed to take into account all these possible reactions.

One of the main issues of current lower-limb exoskeletons to achieve the challenge of balance is the insufficiency of human–robot interaction. This interaction is particularly significant when the prone-to-fall user still has some residual control. In these situations, cooperative controllers should be used to support in restoring balance only when necessary (e.g. onset of a potential fall). This may be known as “assist-when-needed” approach.

Recent studies with exoskeletons that developed “assist-when-needed” approaches to support balance were primarily focused on hip control [15,16,17]. The proposed controllers, provide hip torque to adjust the stepping location, either by supporting hip abduction-adduction (step-width adaptation) or hip flexion-extension (step-length adaptation). The assistance is triggered and modulated when perturbations are detected by using different feedback signals, such as the hip angle [15], the extrapolated center of mass (XcoM) [16], or the estimated leg force [17]. These approaches are not intended to replace human control, but rather to augment the user’s balance by providing the required assistance in synergy with the human wearer just after the onset of an imminent fall.

Although the hip joint is important for controlling the swing leg and preparing for foot placement, previous studies provided evidence that also the ankle joint during stance is crucial in balance maintenance [13, 14, 18]. The torque generated around the ankle acts to decrease the body’s velocity in the direction of the perturbation. Vlutters et al. [14] demonstrated that humans modulate the ankle joint torque of the stance leg as a response to antero-posterior (AP) pelvis perturbations. This ankle torque modulation scales with the provided perturbation magnitude, and thereby with subject’s center of mass (COM) kinematics after perturbation. Using the ankle strategy, subjects were able to eventually slow down the body movement provoked by the external disturbance.

Despite the demonstrated importance of the ankle joint, studies centered on ankle-exoskeleton controllers for assisting in balance during gait, and their effective evaluation with human users, are still scarce. Some preliminary approaches specifically designed for ankle balance support were mainly centered on stance situations. An example is the work presented in [19], in which the authors demonstrate that standing balance can effectively be supported by a strategy based on the user’s COM kinematics. Another example is the work of Ugurlu et al. [20], where the authors propose a real-time variable ankle stiffness as a balance control technique for standing with exoskeletons. Unfortunately this approach was not tested with the human wearer in the loop. Other methods that do use cooperative ankle-controllers during human locomotion did not address their effectiveness in counteracting balance recovery [21]. Finally, there have also been control approaches based on neuromuscular models that propose ankle balance assistance during walking with prosthetic legs [22]. Unfortunately, these models do not demonstrate the ability to generate cooperative human-like balance responses without specific supplementary additions [23].

In this work we have the aim of developing a “simple” bio-inspired control strategy for ankle-exoskeletons that works in synchrony with the human and effectively cooperates and assists balance recovery during walking. In our approach, we first detect disturbances to the COM in real-time by using human’s kinematics responses. Based on this detection, we trigger the robotic ankle assistance to recover stability. The assistance delivered by the controller tries to mimic humans ankle torque modulation [14], scaling with body kinematics and distributed proportionally over both ankles based on the weight supported by the corresponding leg. Our controller presents high levels of transparency during unperturbed locomotion [24], and provides appropriate support in synchrony with the human’s reaction, ensuring the “assist-when-needed” approach. A specific advantage of the proposed method is that it does not require specific subject personalization and thereby it can be easily applied without time-consuming tuning.

Our main hypothesis is that the developed ankle-exoskeleton controller is capable of reducing able-bodied users’ effort required to counteract unexpected perturbations during walking without detriment of their stability. Moreover, we expect the controller to be reliable in both, detecting the perturbations and providing assistance that works in sync with the user to eventually help in recovering balance.

More at link.

COVID Brain Changes Show Parallels With Alzheimer's Disease

You're already at risk for Alzheimers, so get vaccinated. 

 COVID Brain Changes Show Parallels With Alzheimer's Disease

 
 

Findings may point to potential mechanism for brain fog in people with long COVID

A cross section slice of a brain with Alzheimer’s disease

Brains of COVID-19 patients had some of the same pathological changes seen in Alzheimer's disease, which may explain the memory problems people with long COVID experience, a small study suggested.

The study, based on autopsies of 10 people who died with COVID-19, linked the inflammatory response found in SARS-CoV-2 infection with pathways causing tau hyperphosphorylation typically associated with Alzheimer's disease, reported Andrew Marks, MD, of Columbia University in New York City, and co-authors.

The data also indicated a role for leaky ryanodine receptor 2 (RyR2) in the pathophysiology of SARS-CoV-2 infection, the researchers wrote in Alzheimer's & Dementia.

"The study shows that long COVID-19 brain fog may be a form of Alzheimer's disease, but much more research needs to be done before we can make more definitive conclusions," Marks told MedPage Today.

"The major strength of the paper is that they identified abnormalities in several molecules which help characterize the neuroglial dysfunction in these patients at a biochemical level," noted Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who wasn't involved with the study.

"However no histology was performed for Alzheimer's type pathology and the implications for development of Alzheimer's disease would be hard to extrapolate from this study," Nath pointed out.

Defective ryanodine receptors have been implicated in diverse processes, including heart and lung disease. Inside neurons, they previously have been linked to an increase in phosphorylated tau.

Persistent brain fog and cardiac symptoms in people with COVID-19 led Marks and co-authors to investigate how ryanodine receptors were affected in COVID-19. "What we found is really, I think, quite unexpected," Marks said. "Not only did we find defective ryanodine receptors in the hearts and lungs of deceased COVID patients, we also found them in their brains."

The researchers analyzed signaling molecules in brain lysates of COVID-19 patients and controls and found evidence linking SARS-CoV-2 infection to activation of TGF-β signaling and oxidative overload. They also found high levels of phosphorylated tau in COVID-19 patients' brains, both in areas where tau is typically located in Alzheimer's and in other sites. No changes in pathways leading to amyloid beta formation were seen.

The findings may mean that a COVID-19 immune response causes brain inflammation which leads to dysfunctional ryanodine receptors and altered cellular calcium dynamics, then to increases in phosphorylated tau, Marks and colleagues noted. "We propose a potential mechanism that may contribute to the neurological complications caused by SARS-CoV-2: defective intracellular Ca2+ regulation and activation of Alzheimer's disease-like neuropathology," they wrote.

Leaky RyR2 channels may be a therapeutic target to ameliorate some of the cognitive defects associated with SARS-CoV-2 infection and long COVID, the researchers suggested.

Lab studies that treated COVID-19 patient brain samples with a drug targeting RyR2 channels prevented the calcium leak. The treatment, known as ARM210, currently is undergoing clinical testing at NIH for RyR1-related myopathy.

"Future experiments will explore calcium channels as a potential therapeutic target for the neurological complications associated with COVID-19," Marks and co-authors wrote.

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

The research was supported by the NIH.

Marks and Columbia University own stock in Armgo Pharma, which is developing compounds targeting the ryanodine receptor, and have patents on the compounds. One co-author has consulted for Armgo Pharma. All other authors declared no competing interests or conflicts.