Role of SPAK-NKCC1 Signaling Cascade in the Choroid Plexus Blood-CSF Barrier Damage After Stroke

What will your doctors and hospital do to get this testing(Pharmacological blockade of the SPAK-NKCC1 pathway protected the ChP barrier integrity) done in humans? If nothing you don't have a functioning stroke hospital.

Role of SPAK-NKCC1 Signaling Cascade in theChoroid Plexus Blood-CSF Barrier Damage After Stroke

Jun Wang, Ruijia Liu, Md Nabiul Hasan, Sydney Fischer, Matt Como, Victoria M Fiesler, Gulnaz Begum, Yang Chen, Mohammad Iqbal H. Bhuiyan, Shuying Dong, Eric Li, Kristopher T Kahle, Jinwei Zhang, Xianming Deng, Arohan R Subramanya, Yan Yin, Dandan Sun

DOI:

10.21203/rs.3.rs-1189368/v1

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LICENSE:

This work is licensed under a CC BY 4.0 License. Read Full License

Background: 

The mechanisms underlying dysfunction of choroid plexus (ChP) blood-cerebrospinal fluid (CSF) barrier and lymphocyte invasion in neuroinflammatory responses to stroke are not well understood. In this study, we investigated whether stroke damaged the blood-CSF barrier integrity due to dysregulation of major ChP ion transport system Na+-K+-Cl- cotransporter (NKCC1) and regulatory Ste20-related proline-alanine-rich kinase (SPAK). 

Methods: 

Sham or ischemic stroke was induced in C57Bl/6J mice. Changes of the SPAK-NKCC1 complex and tight junction proteins (TJs) in the ChP were quantified by immunofluorescence staining and immunoblotting. Immune cell infiltration in the ChP was assessed by flow cytometry and immunostaining. Cultured ChP epithelium cells (CPECs) and cortical neurons were used to evaluate H2O2-mediated oxidative stress in stimulating the SPAK-NKCC1 complex and cellular damage. In vivo or in vitro pharmacological blockade of the ChP SPAK-NKCC1 cascade with SPAK inhibitor ZT-1a or NKCC1 inhibitor bumetanide were examined. 

Results: 

Ischemic stroke stimulated activation of the CPECs apical membrane SPAK-NKCC1 complex, NF-κB, and MMP9, which was associated with loss of the blood-CSF barrier integrity and increased immune cell infiltration into the ChP. Oxidative stress directly activated SPAK-NKCC1 pathway and resulted in apoptosis, neurodegeneration, and NKCC1-mediated ion influx. Pharmacological blockade of the SPAK-NKCC1 pathway protected the ChP barrier integrity, attenuated ChP immune cell infiltration or neuronal death. 

Conclusion: 

Stroke-induced pathological stimulation of the SPAK-NKCC1 cascade caused CPECs damage and disruption of TJs at the blood-CSF barrier. The ChP SPAK-NKCC1 complex emerged as a therapeutic target for attenuating ChP dysfunction and lymphocyte invasion after stroke.

KEYWORDS

bumetanide, choroid plexus, H2O2, Na+-K+-Cl- cotransporter, SPAK, ZT-1a

Multimodal Imaging Biomarker-Based Model Using Stratification Strategies for Predicting Upper Extremity Motor Recovery in Severe Stroke Patients

 And you really think predicting failure to recover is of ANY FUCKING USE AT ALL TO SURVIVORS? Do you have any usable brain cells at all?

 

Multimodal Imaging Biomarker-Based Model Using Stratification Strategies for Predicting Upper Extremity Motor Recovery in Severe Stroke Patients

Show all authors

Jungsoo Lee, PhD, Heegoo Kim, BS, Jinuk Kim, MS, ...

First Published December 31, 2021 Research Article 

https://doi.org/10.1177/15459683211070278

Article information

Abstract

Background. 

 Various prognostic biomarkers for upper extremity (UE) motor recovery after stroke have been reported. However, most have relatively low predictive accuracy in severe stroke patients.

Objective. 

This study suggests an imaging biomarker-based model for effectively predicting UE recovery in severe stroke patients.

Methods. 

 Of 104 ischemic stroke patients screened, 42 with severe motor impairment were included. All patients underwent structural, diffusion, and functional magnetic resonance imaging at 2 weeks and underwent motor function assessments at 2 weeks and 3 months after stroke onset. According to motor function recovery at 3 months, patients were divided into good and poor subgroups. The value of multimodal imaging biomarkers of lesion load, lesion volume, white matter integrity, and cortical functional connectivity for motor recovery prediction was investigated in each subgroup.

Results. 

Imaging biomarkers varied depending on recovery pattern. The integrity of the cerebellar tract (P = .005, R² = .432) was the primary biomarker in the good recovery group. In contrast, the sensory-related corpus callosum tract (P = .026, R² = .332) and sensory-related functional connectivity (P = .001, R² = .531) were primary biomarkers in the poor recovery group. A prediction model was proposed by applying each biomarker in the subgroup to patients with different motor evoked potential responses (P < .001, R² = .853, root mean square error = 5.28).

Conclusions. 

 Our results suggest an optimized imaging biomarker model for predicting UE motor recovery after stroke. This model can contribute to individualized management of severe stroke in a clinical setting.

Keywords

stroke, recovery, multimodal imaging, prediction

Introduction

Understanding the recovery mechanisms and predicting recovery patterns are important for establishing individually tailored rehabilitation strategies and allowing patients to set realistic goals in clinics.¹ Previous studies have reported diverse prognostic factors related to upper extremity (UE) recovery, such as injury of the corticospinal tract (CST).^1,2 A previous neuroimaging study used CST lesion load, which measures damage to the CST, to predict UE motor recovery after events including severe stroke.³ However, the predictive accuracy of CST lesion load tended to decline when applied in severe stroke patients.³ Another factor with prognostic value for motor recovery is motor evoked potential (MEP). The positive predictive value for MEP status is high, but the negative predictive value is low.¹ Because patients with severe motor impairments have a higher rate of negative MEP response, predicting UE motor recovery in these patients is challenging.

Therefore, there is a need among clinicians and investigators to identify novel neuroimaging biomarkers with better recovery prediction of UE motor function among patients with severe stroke. Multimodal neuroimaging data such as magnetic resonance imaging (MRI) images have been useful for predicting motor recovery of severe stroke patients.¹ Considering that severe stroke patients exhibit a large degree of inter-individual variability in functional recovery,⁴ it is conceivable that different neuroimaging biomarkers contribute to good or poor recovery. Various imaging biomarkers have been reported. In anatomical imaging, the CST lesion load is a representative biomarker, as mentioned above, and lesion volume is a well-known biomarker even though it is not the most predictive.⁵ In diffusion tensor imaging (DTI), the integrity of the CST or partial regions of the CST is a predictive neuroimaging biomarker with the greatest consensus among experts.⁶ Also, the integrity of the cortico-cerebellar tract and that of the corpus callosum are worth noting as predictive biomarkers.^7-9 The cerebellum is connected densely to motor areas and is involved in motor learning and control.^10,11 The corpus callosum is the largest white matter structure that plays an important role in the transfer of motor and sensory information.¹² In resting-state functional magnetic resonance imaging (rs-fMRI), interhemispheric connectivity is related to prediction of motor outcomes.^13-16 Disruption of interhemispheric connectivity is the most noticeable characteristic and a good indicator of bihemispheric imbalance after stroke.^14,17 We hypothesized that there are distinct neuroimaging biomarkers predicting good and poor recovery. We examined neuroimaging biomarkers in patients who showed good or poor recovery, and these biomarkers were applied to patients with a positive or negative response to MEP.^18,19 Then, we examined whether certain neuroimaging biomarkers could improve the predictive accuracy of UE motor recovery compared to previously established neuroimaging biomarkers and MEP response alone.

More at link.

 

Mirror Therapy Rehabilitation in Stroke: A Scoping Review of Upper Limb Recovery and Brain Activities

You mean your mentors and senior researchers are so out-of-date that they didn't realize mirror therapy has been proven for years? And they let you do this waste of time and money? 

• mirror therapy (96 posts to October 2012 )

Mirror Therapy Rehabilitation in Stroke: A Scoping Review of Upper Limb Recovery and Brain Activities

---

Nurulhuda Jaafar,¹ Ahmad Zamir Che Daud,¹ Nor Faridah Ahmad Roslan,² and Wahidah Mansor^3,4,5

¹Centre for Occupational Therapy Studies, Faculty of Health Sciences, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia

²Department of Rehabilitation Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia

³Microwave Research Institute, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia

⁴School of Electrical Engineering, College of Engineering, UiTM Shah Alam, Malaysia

⁵Computational Intelligence Detection, Health & Wellness ReNeU, UiTM Shah Alam, Malaysia

Academic Editor: Valentina Varalta

Received21 Jun 2021

Accepted10 Dec 2021

Published31 Dec 2021

Abstract

Background. 

Mirror therapy (MT) has been used as a treatment for various neurological disorders. Recent application of electroencephalogram (EEG) to the MT study allows researchers to gain insight into the changes in brain activity during the therapy.  

Objective. 

This scoping review is aimed at mapping existing evidence and identifying knowledge gaps about the effects of MT on upper limb recovery and its application for individuals with chronic stroke.  

Methods and Materials. 

A scoping review through a systematic literature search was conducted using PubMed, CINAHL, PsycINFO, and Scopus databases. Twenty articles published between 2010 and 2020 met the inclusion criteria. The efficacy of MT on upper limb recovery and brain activity during MT were discussed according to the International Classification of Functioning, Disability and Health (ICF).  

Results. A majority of the studies indicated positive effects of MT on upper limb recovery from the body structure/functional domain. All studies used EEG to indicate brain activation during MT.  

Conclusion. 

MT is a promising intervention for improving upper limb function for individuals with chronic stroke. This review also highlights the need to incorporate EEG into the MT study to capture brain activity and understand the mechanism underlying the therapy.

1. Introduction

Stroke is the second largest cause of early death and secondary disabilities [1]. Motor skills are among the crucial areas affected by stroke, and recovery from stroke typically takes more than six months, especially in the upper limbs. Evidence shows that about 83% of stroke survivors are able to walk again; however, only 5% to 20% of survivors achieve full functional recovery of affected upper limbs [2].

Several therapies using different technological sophistication levels have emerged to restore motor function after stroke. Dr. Ramachandran introduced mirror therapy (MT) in the 1990s to manage numerous other conditions, including motor disorders [3]. This therapy is based on visual stimulation. Visual feedback is given to the individual using a mirror that reflects the nonaffected limb to make the brain believe that what the individual sees is the affected limb moving without difficulty [4]. Unilateral and bilateral procedures have been implemented since the introduction of MT. In the unilateral procedure, activities are performed only on the unaffected limb. In the bilateral procedure, the individual attempts to move the affected limb as much as possible to mimic the reflected movements of the unaffected limb. Although there are different variations in MT setup and procedure, all methods serve to aid the recovery of the affected limb by stimulating the regions of the brain associated with movement, sensation, and pain [5]. The literature suggests that recovery between the first three to six months of onset is largely natural [6]. Recovery in the stroke context is defined as restoring the ability to perform a movement in the same way as before the injury [7].

The selection and classification of outcomes in stroke rehabilitation are primarily based on the International Classification of Functioning, Disability and Health (ICF) framework. The domains in the ICF include human functioning, which comprises body structure/function, activity, and participation. In any intervention study focusing on the stroke population, it may be crucial for scholars to address the effects of the interventions on the body structure/function domain. However, it is equally crucial to examine the effects of these changes on individual activity and participation domains [8].

Advanced electroencephalogram (EEG) technology for analysing brainwave signals has brought a new perspective in stroke research by capturing meaningful electrophysiological features of neuron activities [9]. Predicting therapy outcomes is more difficult in the chronic phase where the duration since stroke onset is six months or more. This is because motor recovery is not necessarily linked to the degree of the initial injury. Several complex mechanisms of dynamic neuroplasticity occurs after the initial stroke lesion [10]. Therefore, predicting motor function requires the use of complementary techniques. EEG is one of the neurophysiological techniques that can provide helpful information for predicting clinical outcomes. EEG is not only used for “for predicting clinical outcomes.” Evidence also suggests that EEG may provide insightful information on neural activity changes and interhemispheric differences [11, 12]. It is presently feasible for researchers to objectively evaluate changes in brain activity before and after the intervention. The MT study continues to evolve with various protocols and different targeted populations. The previous MT reviews have focused on all stroke phases [5, 13]; however, there are limited studies that emphasised the changes in brain activity after MT for individuals having chronic stroke only. Therefore, the purpose of this review is to map existing evidence and knowledge gaps concerning MT on brain activity and upper limb recovery among individuals with chronic stroke.

 

Determination of Brain Death

I wonder what the explanation is used on death certificates for people dying from stroke effects. People do not die from the stroke, they die from brain damage. Until this reporting is changed we never will be able to determine the reason for dying. Stoke is way too simplistic and uninformative. We used to have the category of dying from old age, that was eliminated because it told us nothing useful.

Determination of Brain Death

• David M. Greer, M.D.

The determination of brain death is typically made on the basis of clinical assessment (shown in a video) and requires demonstration of the permanent loss of all brain function, including brainstem function, in the absence of factors that may confound the assessment. If these factors cannot be eliminated, or if the examination cannot be safely or fully performed, ancillary testing is conducted.

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Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

The author thanks Dr. Rafael Ortega for his assistance with the videos of the examination for the determination of brain death.

Author Affiliations

From the Boston University School of Medicine and Boston Medical Center — both in Boston.

Dr. Greer can be contacted at dgreer@bu.edu or the Department of Neurology, 85 East Concord St., Rm. 1145, Boston, MA 02118.

 

Does Spasticity Reduction by Botulinum Toxin Type A Improve Upper Limb Functionality in Adult Post-Stroke Patients? A Systematic Review of Relevant Studies

So no improvement seen in functional activity. Is your doctor still using botox after 8 years of knowing this? I saw zero improvement  in my left arm functionality after my shots, 2 courses of them. Of course I wasn't treated with Sativex since that was after my stroke and I'm not in the UK. 

Sativex, a cannabis based spray, was approved in England in 2019 for use in moderate to severe spasticity(only MS) when other treatments haven’t worked.

Currently, Sativex is not approved for any indication in the US, so you are totally screwed unless you are in a legal marijuana state and want to experiment on your own. But you can't, that would only be allowed if prescribed by your doctor. And your doctor will never prescribe marijuana.

 

Does Spasticity Reduction by Botulinum Toxin Type A Improve Upper Limb Functionality in Adult Post-Stroke Patients? A Systematic Review of Relevant Studies

Domenico Intiso

Andrea Santamato

2013, Journal of Neurology & Neurophysiology

 Domenico Intiso
1
*, Valentina Simone
2
, Filomena Di Rienzo
1
, Andrea Santamato
3
, Mario Russo
1
, Maurizio Tolfa
1
, and Mario Basciani
1
1
Neuro-Rehabilitation Unit, Scientic Institute, Hospital ‘Casa Sollievo della Sofferenza’, Italy
2
Foundation rehabilitation “Gli Angeli di P.Pio”, San Giovanni Rotondo, Italy
3
Department of Physical Medicine and Rehabilitation, “OORR Hospital”, University of Foggia, Italy
*Corresponding author:
 Domenico Intiso MD, Neuro-Rehabilitation Unit, Hospital
Scientic Institute “Casa Sollievo della Sofferenza”, Viale dei Cappuccini, 71013 San Giovanni Rotondo (FG), Italy, Tel: 039 882 410 942; Fax: 039 882 410 942; E-mail: d.intiso@operapadrepio.it
,
 d.intiso@alice.it
Received
 
July 02, 2013;
Accepted
 October
 09, 2013;
Published
 October
 15
,
2013
Citation:
 Intiso D, Simone
V, Rienzo FD
, Santamato A, Russo
M, et al.
 
(2013)
Does
Spasticity Reduction by Botulinum Toxin Type A Improve Upper Limb Functionality in Adult Post-Stroke Patients? A Systematic Review of Relevant Studies.
 J Neurol
Neurophysiol 4: 167. doi:10.4172/2155-9562.1000167
Copyright:
 © 2013
Intiso D
. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keyword
:
Botulinum toxin; Spasticity; Stroke; Upper limb; Functionality
Introduction
Spasticity is a common disabling disorder that occurs from 17 to 43% in patients with stroke affecting both the upper and the lower limb [1-4]. If le󰀀 untreated, it can hamper functional outcome by promoting persistent abnormal posture that in turn produces muscular-tendon contractures and bone deformity. Several functional limitations arise from spasticity including impaired movement, hygiene, self-care, poor self-esteem, body image, pain and pressure ulcers that increase carer burden. Furthermore, patients with severe spasticity can develop poor social participation and quality of life (QOL) [5]. Because of these concerns and related high social costs [6], many therapeutic strategies have been proposed for the treatment of this disorder including surgical, medical and rehabilitative procedures. Among these, botulinum toxin type A (BTX-A) is became the first line to treat focal/multifocal spasticity, in the clinical practice. ere is now, a well-established body of evidence demonstrating the effectiveness of BTX-A for post-stroke spasticity reduction both in the upper and the lower limb [7-18]. Nevertheless, its impact on motor performance and functional outcome remains controversial [19,20]. In particular, the effect of reduced spasticity on upper limb ability recovery a󰀀er stroke is unclear. e central thread in treating spasticity is the assumption that it contributes to the limitation of activities, and that its reduction will bring about an improvement in function. e aim of present review was to ascertain if the reduction of spasticity by use of BTX-A was linked to a functional gain in upper limb or in activity of daily living in post-stroke patients. erefore, relevant studies addressing upper limb (UL) spasticity reduction and functional improvement a󰀀er BTX-A treatment in adult post-stroke patients were reviewed.
Method
Search of relevant studies was conducted on MEDLINE (from 1995 to July 2012), the Cochrane Central Register of Controlled Trials and EMBASE (1995 to July 2012). Search terms varied slightly across databases but included: “cerebrovascular accident” or “stroke” and the terms “botulinum toxin”, “spasticity” as either MeSH terms, key words, or subject headings. Only randomized studies (RT) treating patients with UL post-stroke spasticity by BTX-A injection were included. Studies of treatment for both lower and/or UL spasticity were included if the results for patients with UL spasticity were reported separately. Prospective open label, case series, cohort studies and case reports were excluded. Furthermore, because confounding results, RTs were also excluded whether: i) post-stroke spasticity was treated by different serotype neurotoxin; ii) botulinum toxin was given early a󰀀er the stroke, before clinical evidence of severe spasticity was established; iii) mixed sample of subjects with spasticity secondary to stroke or other neurological disorders was enrolled; iv) spasticity followed a non-

Abstract

Objective: 

 

Botulinum toxin type A (BTX-A) use reduces upper limb (UL) spasticity in stroke patients, but the effects on functional recovery remain uncertain. The aim of present review was to ascertain if the reduction of spasticity by use of BTX-A was linked to a functional gain of UL or in activity of daily living in post-stroke patients.
 

Data source: 

 

Search of relevant studies was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (1995 to July 2012).
 

Study selection: 

 

Only randomized studies (RT) treating patients with UL post-stroke spasticity by BTX-A injection were included. Prospective open label, case series, cohort studies and case reports were excluded.
 

Data synthesis: 

 

Thirty-four RTs were individuated, but only 16 were considered in the analysis. Trials varied widely in methodological design and measures used in assessing UL ability. Benet in UL functional recovery was reported in 13 studies, but only in six the result was signicant.
 

Conclusion: 

 

Some oriented-focused movements of UL unequivocally improve after reduced spasticity by BTX-A treatment, but evidence that arm functionality in adult post-stroke patients signicantly benet from this intervention is still doubt. No improvement in global functionality of activity daily living was observed.
 

 

One more good reason to exercise

 It is your doctor's responsibility to get you to be able to exercise enough in 35 days to generate GH(growth hormone), or I suppose second best would be to administer it to get the benefits. What is your doctor's solution? No solution, fire them.

One more good reason to exercise

As we start the New Year with a fervent hope that it’s better than the last two, many people are making a resolution to get more exercise. A new study suggests that might not just benefit the body, it could also help the brain. At least if you are a mouse.

Researchers at the University of Queensland Brain Institute found that 35 days of exercise could improve brain function and memory.

Futurity, Dan Blackmore, one of the lead researchers on the study, says they not only showed the benefits of exercise, but also an explanation for why it helps.

“We tested the cognitive ability of elderly mice following defined periods of exercise and found an optimal period or ‘sweet spot’ that greatly improved their spatial learning. We found that growth hormone (GH) levels peaked during this time, and we’ve been able to demonstrate that artificially raising GH in sedentary mice also was also effective in improving their cognitive skills. We discovered GH stimulates the production of new neurons in the hippocampus—the region of the brain critically important to learning and memory.

The study was published in the journal iScience.

Obviously, this is great for mice, but they hope that future research could show similar benefits for people. But don't wait for that study to come out, there's already plenty of evidence that exercising has terrific benefits for the body. Here's just seven ways it can give you a boost.

Kevin McCormack | January 3, 2022 at 11:28 am | Tags: Dan Blackmore, Exercise, Futurity, Growth hormon, Hippocampus, iScience, University of Queensland | Categories: Aging, Basic Research, Brain stem cells, Discovery Research, Mental Health, Neurological Disorders, Stem cell research | URL: https://wp.me/p4BBpx-57M

Meet the World Stroke Academy Team!

 Not a single person has the responsibility of solving stroke(100% recovery). Two have social media responsibilities so I should expect both to be contacting me immediately.

Meet the World Stroke Academy Team!