Faculty Opinions recommendation of Stroke research at a crossroad: asking the brain for directions.

Stroke is the second leading cause of death and a major contributor to disability worldwide. The prevalence of stroke is highest in developing countries, with ischemic stroke being the most common type. Considerable progress has been made in our understanding of the pathophysiology of stroke and the underlying mechanisms leading to ischemic insult. Stroke therapy primarily focuses on restoring blood flow to the brain and treating stroke-induced neurological damage. Lack of success in recent clinical trials has led to significant refinement of animal models, focus-driven study design and use of new technologies in stroke research. Simultaneously, despite progress in stroke management, post-stroke care exerts a substantial impact on families, the healthcare system and the economy. Improvements in pre-clinical and clinical care are likely to underpin successful stroke treatment, recovery, rehabilitation and prevention. In this review, we focus on the pathophysiology of stroke, major advances in the identification of therapeutic targets and recent trends in stroke research.

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Deep-Tissue Oxygen Monitoring in the Brain of Rabbits for Stroke Research

Stroke ◽

10.1161/strokeaha.114.007324 ◽

2015 ◽

Vol 46 (3) ◽

Cited By ~ 14

Author(s):

Nadeem Khan ◽

Huagang Hou ◽

Clifford J. Eskey ◽

Karen Moodie ◽

Sangeeta Gohain ◽

...

Keyword(s):

Tissue Oxygen ◽

Deep Tissue ◽

Stroke Research ◽

Oxygen Monitoring ◽

The Brain

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Optimizing functional outcome endpoints for stroke recovery studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19875212 ◽

2019 ◽

Vol 39 (12) ◽

pp. 2323-2342 ◽

Cited By ~ 5

Author(s):

Mustafa Balkaya ◽

Sunghee Cho

Keyword(s):

Animal Models ◽

Functional Outcome ◽

Recovery Of Function ◽

Emotional Disturbances ◽

Stroke Recovery ◽

Preclinical Research ◽

Stroke Research ◽

Recovery Potential ◽

Functional Outcome Measures ◽

The Brain

Novel therapeutic intervention that aims to enhance the endogenous recovery potential of the brain during the subacute phase of stroke has produced promising results. The paradigm shift in treatment approaches presents new challenges to preclinical and clinical researchers alike, especially in the functional endpoints domain. Shortcomings of the “neuroprotection” era of stroke research are yet to be fully addressed. Proportional recovery observed in clinics, and potentially in animal models, requires a thorough reevaluation of the methods used to assess recovery. To this end, this review aims to give a detailed evaluation of functional outcome measures used in clinics and preclinical studies. Impairments observed in clinics and animal models will be discussed from a functional testing perspective. Approaches needed to bridge the gap between clinical and preclinical research, along with potential means to measure the moving target recovery, will be discussed. Concepts such as true recovery of function and compensation and methods that are suitable for distinguishing the two are examined. Often-neglected outcomes of stroke, such as emotional disturbances, are discussed to draw attention to the need for further research in this area.

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The impact of ischemic stroke on connectivity gradients

10.1101/481689 ◽

2018 ◽

Cited By ~ 1

Author(s):

Şeyma Bayrak ◽

Ahmed A. Khalil ◽

Kersten Villringer ◽

Jochen B. Fiebach ◽

Arno Villringer ◽

...

Keyword(s):

Functional Connectivity ◽

Three Dimensional ◽

Connectivity Matrix ◽

Continuous Space ◽

Functional Deficits ◽

Stroke Research ◽

Low Dimensional ◽

The Impact ◽

The Relationship ◽

The Brain

AbstractUnderstanding the relationship between localized anatomical damage, reorganization, and functional deficits is a major challenge in stroke research. Previous work has shown that localized lesions cause widespread functional connectivity alterations in structurally intact areas, thereby affecting a whole network of interconnected regions. Recent advances suggest an alternative to discrete functional networks by describing a connectivity space based on a low-dimensional embedding of the full connectivity matrix. The dimensions of this space, described as connectivity gradients, capture the similarity of areas’ connections along a continuous space. Here, we defined a three-dimensional connectivity space template based on functional connectivity data from healthy controls. By projecting lesion locations into this space, we demonstrate that ischemic strokes resulted in dimension-specific alterations in functional connectivity over the first week after symptoms onset. Specifically, changes in functional connectivity were captured along connectivity Gradients 1 and 3. The degree of change in functional connectivity was determined by the distance from the lesion along these connectivity gradients regardless of the anatomical distance from the lesion. Together, these results provide a novel framework to study reorganization after stroke and suggest that, rather than only impacting on anatomically proximate areas, the indirect effects of ischemic strokes spread along the brain relative to the space defined by its connectivity.

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Basement membrane and stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18801467 ◽

2018 ◽

Vol 39 (1) ◽

pp. 3-19 ◽

Cited By ~ 19

Author(s):

Yao Yao

Keyword(s):

Basement Membrane ◽

Neurological Disorders ◽

Circulation System ◽

Cerebral Blood Vessels ◽

Future Directions ◽

Future Studies ◽

Stroke Research ◽

New Ideas ◽

The Brain ◽

Comprehensive Reference

Located at the interface of the circulation system and the CNS, the basement membrane (BM) is well positioned to regulate blood–brain barrier (BBB) integrity. Given the important roles of BBB in the development and progression of various neurological disorders, the BM has been hypothesized to contribute to the pathogenesis of these diseases. After stroke, a cerebrovascular disease caused by rupture (hemorrhagic) or occlusion (ischemic) of cerebral blood vessels, the BM undergoes constant remodeling to modulate disease progression. Although an association between BM dissolution and stroke is observed, how each individual BM component changes after stroke and how these components contribute to stroke pathogenesis are mostly unclear. In this review, I first briefly introduce the composition of the BM in the brain. Next, the functions of the BM and its major components in BBB maintenance under homeostatic conditions are summarized. Furthermore, the roles of the BM and its major components in the pathogenesis of hemorrhagic and ischemic stroke are discussed. Last, unsolved questions and potential future directions are described. This review aims to provide a comprehensive reference for future studies, stimulate the formation of new ideas, and promote the generation of new genetic tools in the field of BM/stroke research.

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Determination of the Brain–Blood Partition Coefficient for Water in Mice Using MRI

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.160 ◽

2010 ◽

Vol 30 (11) ◽

pp. 1821-1824 ◽

Cited By ~ 22

Author(s):

Christoph Leithner ◽

Susanne Müller ◽

Martina Füchtemeier ◽

Ute Lindauer ◽

Ulrich Dirnagl ◽

...

Keyword(s):

Partition Coefficient ◽

Deuterium Oxide ◽

Proton Density ◽

Resonance Imaging ◽

Density Measurements ◽

Stroke Research ◽

Mri Protocol ◽

Magnetic Resonance Imaging Mri ◽

The Brain

Cerebral blood flow (CBF) quantification is a valuable tool in stroke research. Mice are of special interest because of the potential of genetic engineering. Magnetic resonance imaging (MRI) provides repetitive, noninvasive CBF quantification. Many MRI techniques require the knowledge of the brain–blood partition coefficient ( BBPC) for water. Adopting an MRI protocol described by Roberts et al (1996) in humans, we determined the BBPC for water in 129S6/SvEv mice from proton density measurements of brain and blood, calibrated with deuterium oxide/water phantoms. The average BBPC for water was 0.89±0.03 mL/g, with little regional variation within the mouse brain.

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Abstract WP95: Splenectomy Protects Aged Mice From Cerebral Injury in the Experimental Stroke Model

Stroke ◽

10.1161/str.48.suppl_1.wp95 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Anjali Chauhan ◽

Meaghan Roy-O’Reilly ◽

Abdullah Mamun ◽

Nia Harris ◽

Javiera Bravo-Alegria ◽

...

Keyword(s):

T Cells ◽

Functional Recovery ◽

Artery Occlusion ◽

Cerebral Injury ◽

Neurological Deficits ◽

Experimental Stroke ◽

Aged Mice ◽

Stroke Research ◽

New Information ◽

The Brain

Introduction: Aging is a non-modifiable risk factor for stroke. Although aged animals tend to have smaller infarcts they have worse functional recovery after stroke, suggesting difference in mechanisms between young and aged. Splenectomy reduces infarct in animal models, but how the spleen contributes to brain injury in aged mice has not been as well studied. Hypothesis: We hypothesized that peripheral inflammation increases over the lifespan. We predicted that the detrimental effects of the spleen would be reversed by splenectomy in aged mice. Methods: Young and aged male mice were splenectomized (n= 8-9), 2 weeks prior to induction of 1 hour of middle cerebral artery occlusion. Ninety-six hours after reperfusion, behavioral and infarct area was assessed. In a separate cohort, peripheral and central immune cells were quantified by flow cytometry. Results: After stroke, there was 13.3, 17.7, 25.9 and 5.88% mortality in spleen intact young, splenecyomized young, spleen intact aged and splenctomized aged mice respectively. Splenectomy led to improved behavioral deficits in aged mice as seen by lower neurological deficits scores,(1.63 ± 0.26 Vs 2.57 ± 0.20) and reduction in number of right turns in the corner test. There was significant reduction in infarct size in the splenectomized aged mice (p<0.05) as compared to spleen-intact mice. Splenectomy in aged mice lead to reduction in the frequency of CD3CD44+ T cells. Additionally, there was significant decrease in TNF-α, IL-6, IL-4, IL-12MIP-1b and RANTES levels in the aged splenectomized aged mice as compared to spleen-intact aged mice (p<0.05). In the brain, the frequency of CD45hiCD11b+ cells was reduced in the splenectomized MCAo aged as compared to spleen-intact stroke mice (p<0.05). Conclusions: Splenectomy reduced the peripheral activation of T cells in the aged mice. Also less peripheral leukocyte infiltration was observed, which mirrored improved functional recovery and reduced infarct damage in splenectomized aged mice. Hence, this study provides new information regarding age specific peripheral immune responses and interaction with the brain after experimental stroke highlighting a need for the incorporation of aged mice in the basic stroke research. Funding: 16POST27490032

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The decade of the brain: challenge and opportunities in stroke research.

Stroke ◽

10.1161/01.str.21.3.373 ◽

1990 ◽

Vol 21 (3) ◽

pp. 373-374 ◽

Cited By ~ 14

Author(s):

M Goldstein

Keyword(s):

Stroke Research ◽

The Brain

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Abstract W P209: Development of a Useful Brain Ischemic Stroke Model via a Transient Occlusion of Middle Cerebral Artery in the Nonhuman Primate

Stroke ◽

10.1161/str.45.suppl_1.wp209 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Eiketsu Sho ◽

Zhenghua Zhu ◽

Yuchao Zhao ◽

Jiqiao Chen ◽

Daomei He ◽

...

Keyword(s):

Blood Flow ◽

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Nonhuman Primate ◽

Stroke Model ◽

Cynomolgus Monkeys ◽

Stroke Research ◽

Reperfusion Period ◽

The Brain

Objectives: Most experimental stroke research is carried out in rodents, but given differences between rodents and human, the nonhuman primate (NHP) models may provide a valuable tool to study the clinical therapy. We developed a surgical method for transient occlusion of the middle cerebral artery (MCA-M1) in the Cynomolgus monkeys to evaluate the MCA territory blood flow, the model stability, animal clinical neurological behavior, morphology changes under magnetic resonance imaging (MRI) and histopathology. Methods: The left brain sylvian fissure was exposed by a small fronto-temporal craniotomy. The MCA-M1 was exposed by microsurgical dissection and clipped for 4 hours. The brain blood flow was measured in the MCA territory during the ischemia period and early phase of reperfusion period. The clinical neurological examinations and MRI were carried out at regular post-operative course till 4 weeks of stroke. Results: During MCA occlusion, the MCA territory blood flow was decreased significantly in 80%. This territory was reflowed right after reperfusion and showed an overload in about 20% over pre ischemia flow within 1hr after reperfusion and gradually returned to previous flow (Fig 1). Animal neurological behavior changed significantly within 1 week and became a steady status of neurological impairment. MRI demonstrated extensive MCA territory infarction. Histologically, at the end of 4 week stroke the brain showed a clear board of glia proliferation between infarct and normal brain tissue. Conclusion: These results indicate a stable ischemic stroke model in cynomolgus monkeys after complete MCA-M1 occlusion, which will be a useful NHP stroke model for stroke research and the clinical therapeutic studies. Fig 1 Changes in MCA territory blood flow during ischemia-reperfusion period

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Beyond the Brain: The Systemic Pathophysiological Response to Acute Ischemic Stroke

Journal of Stroke ◽

10.5853/jos.2019.02978 ◽

2020 ◽

Vol 22 (2) ◽

pp. 159-172

Author(s):

Maria H.H. Balch ◽

Shahid M. Nimjee ◽

Cameron Rink ◽

Yousef Hannawi

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Systemic Disease ◽

Glucose Deprivation ◽

Future Research ◽

Ischemic Brain ◽

Excitatory Neurotransmitter ◽

Stroke Research ◽

Bidirectional Interactions ◽

The Brain

Stroke research has traditionally focused on the cerebral processes following ischemic brain injury, where oxygen and glucose deprivation incite prolonged activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, reactive oxygen species proliferation, and ultimately neuronal death. A recent growing body of evidence, however, points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, peripheral immunodepression in conjunction with hyperstimulation of autonomic and neuroendocrine pathways and motor pathway impairment result in dysfunction of the respiratory, urinary, cardiovascular, gastrointestinal, musculoskeletal, and endocrine systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke. Using a pathophysiology-based approach, this current review discusses the pathophysiological mechanisms following ischemic brain insult that result in end organ dysfunction. By characterizing stroke as a systemic disease, future research must consider bidirectional interactions between the brain and peripheral organs to inform treatment paradigms and develop effective, comprehensive therapeutics for acute ischemic stroke.

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