More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke

2021 ◽  
pp. 0271678X2110058
Author(s):  
Sonia Sanchez-Bezanilla ◽  
Rebecca J Hood ◽  
Lyndsey E Collins-Praino ◽  
Renée J Turner ◽  
Frederick R Walker ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Motor Impairment ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Spatiotemporal Analysis ◽  
Motor Recovery ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Cortical Stroke ◽  
Photothrombotic Stroke

There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.

scholarly journals Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Zidan Zhao ◽  
Rebecca J. Hood ◽  
Lin Kooi Ong ◽  
Giovanni Pietrogrande ◽  
Sonia Sanchez Bezanilla ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Amyloid Beta ◽  
Neuronal Loss ◽  
Treatment Phase ◽  
Experimental Stroke ◽  
Low Oxygen ◽  
Associate Learning ◽  
Atmospheric Air ◽  
Post Stroke ◽  
Cognitive Benefits

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O2) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aβ) burden. These findings provide further insight into the pro-cognitive benefits of LOPC.

scholarly journals Bringing proportional recovery into proportion: Bayesian modelling of post-stroke motor impairment

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2189-2206 ◽  
Author(s):  
Anna K Bonkhoff ◽  
Thomas Hope ◽  
Danilo Bzdok ◽  
Adrian G Guggisberg ◽  
Rachel L Hawe ◽  
...  
Keyword(s):  
Model Comparison ◽  
Motor Impairment ◽  
Synthetic Data ◽  
Motor Recovery ◽  
Stroke Recovery ◽  
Future Research ◽  
Single Subject ◽  
Post Stroke ◽  
Specific Fraction ◽  
Explained Variance

Abstract Accurate predictions of motor impairment after stroke are of cardinal importance for the patient, clinician, and healthcare system. More than 10 years ago, the proportional recovery rule was introduced by promising that high-fidelity predictions of recovery following stroke were based only on the initially lost motor function, at least for a specific fraction of patients. However, emerging evidence suggests that this recovery rule is subject to various confounds and may apply less universally than previously assumed. Here, we systematically revisited stroke outcome predictions by applying strategies to avoid confounds and fitting hierarchical Bayesian models. We jointly analysed 385 post-stroke trajectories from six separate studies—one of the largest overall datasets of upper limb motor recovery. We addressed confounding ceiling effects by introducing a subset approach and ensured correct model estimation through synthetic data simulations. Subsequently, we used model comparisons to assess the underlying nature of recovery within our empirical recovery data. The first model comparison, relying on the conventional fraction of patients called ‘fitters’, pointed to a combination of proportional to lost function and constant recovery. ‘Proportional to lost’ here describes the original notion of proportionality, indicating greater recovery in case of a more severe initial impairment. This combination explained only 32% of the variance in recovery, which is in stark contrast to previous reports of >80%. When instead analysing the complete spectrum of subjects, ‘fitters’ and ‘non-fitters’, a combination of proportional to spared function and constant recovery was favoured, implying a more significant improvement in case of more preserved function. Explained variance was at 53%. Therefore, our quantitative findings suggest that motor recovery post-stroke may exhibit some characteristics of proportionality. However, the variance explained was substantially reduced compared to what has previously been reported. This finding motivates future research moving beyond solely behaviour scores to explain stroke recovery and establish robust and discriminating single-subject predictions.

scholarly journals Does Cathodal vs. Sham Transcranial Direct Current Stimulation Over Contralesional Motor Cortex Enhance Upper Limb Motor Recovery Post-stroke? A Systematic Review and Meta-analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Joyce L. Chen ◽  
Ashley Schipani ◽  
Clarissa Pedrini Schuch ◽  
Henry Lam ◽  
Walter Swardfager ◽  
...  
Keyword(s):  
Systematic Review ◽  
Motor Cortex ◽  
Direct Current ◽  
Transcranial Direct Current Stimulation ◽  
Meta Analysis ◽  
Motor Impairment ◽  
Motor Recovery ◽  
Controlled Trials ◽  
Post Stroke ◽  
Cathodal Tdcs

Background: During recovery from stroke, the contralesional motor cortex (M1) may undergo maladaptive changes that contribute to impaired interhemispheric inhibition (IHI). Transcranial direct current stimulation (tDCS) with the cathode over contralesional M1 may inhibit this maladaptive plasticity, normalize IHI, and enhance motor recovery.Objective: The objective of this systematic review and meta-analysis was to evaluate available evidence to determine whether cathodal tDCS on contralesional M1 enhances motor re-learning or recovery post-stroke more than sham tDCS.Methods: We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials for participants with stroke (>1 week post-onset) with motor impairment and who received cathodal or sham tDCS to contralesional M1 for one or more sessions. The outcomes included a change in any clinically validated assessment of physical function, activity, or participation, or a change in a movement performance variable (e.g., time, accuracy). A meta-analysis was performed by pooling five randomized controlled trials (RCTs) and comparing the change in Fugl–Meyer upper extremity scores between cathodal and sham tDCS groups.Results: Eleven studies met the inclusion criteria. Qualitatively, four out of five cross-over design studies and three out of six RCTs reported a significant effect of cathodal vs. sham tDCS. In the quantitative synthesis, cathodal tDCS (n = 65) did not significantly reduce motor impairment compared to sham tDCS (n = 67; standardized mean difference = 0.33, z = 1.79, p = 0.07) with a little observed heterogeneity (I2 = 5%).Conclusions: The effects of cathodal tDCS to contralesional M1 on motor recovery are small and consistent. There may be sub-populations that may respond to this approach; however, further research with larger cohorts is required.

scholarly journals Electrical Stimulation of the Mesencephalic Locomotor Region Attenuates Neuronal Loss and Cytokine Expression in the Perifocal Region of Photothrombotic Stroke in Rats

2019 ◽  
Vol 20 (9) ◽  
pp. 2341 ◽  
Author(s):  
Michael K. Schuhmann ◽  
Guido Stoll ◽  
Arne Bohr ◽  
Jens Volkmann ◽  
Felix Fluri
Keyword(s):  
Neuronal Apoptosis ◽  
Neuronal Loss ◽  
Border Zone ◽  
Experimental Stroke ◽  
High Frequency Stimulation ◽  
Tunel Staining ◽  
Ischemic Penumbra ◽  
Mesencephalic Locomotor Region ◽  
Photothrombotic Stroke ◽  
Stimulation Of

Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.

Abstract P736: Memantine, an NMDA Antagonist and Aging Alter the Thalamic Gliosis in Experimental Stroke in Mice

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Gab Seok Kim ◽  
Jessica Stephenson ◽  
Ting Wu ◽  
Abdullah Mamun ◽  
Monica G Goss ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Time Course ◽  
Nmda Antagonist ◽  
Cresyl Violet ◽  
Experimental Stroke ◽  
Secondary Injury ◽  
Post Stroke ◽  
Cortical Infarction ◽  
Cortical Stroke ◽  
Young Mice

Secondary injury in the thalamus has been observed following cortical stroke in rodents and humans and is associated with worsened recovery. Interruption of this progressive injury reflects an important therapeutic goal. However, the mechanisms whereby primary cortical infarction leads to remote injury in distant regions of brain are not well defined. We used a mouse model of cortical stroke (which demonstrates delayed thalamic injury) to define the time course of thalamic gliosis and neuronal injury and then test the potential of delayed memantine treatment (an NMDA receptor antagonist) to attenuate this secondary injury. Methods: Cortical infarction was induced by permanent occlusion of the distal middle cerebral artery (pdMCAO) in male C57BL/6J mice (young and aged) and CCR2-RFP mice. Brain infarct, cell-specific injury, and gliosis were measured by cresyl violet, Fluoro-jade C (FJC), TTC, FACS, and immunofluorescence. In young mice, memantine was injected at 4 and 24 hours post-stroke (100 and 50 mg/kg, ip). Brains were evaluated at post-stroke day 3 and 14 (PSD3 and PSD14). Results: At PSD3, the primary infarct was restricted to the cortex of the MCA territory, with no infarct detected in the thalamus of young mice. However, by PSD 14, neurons in the ipsilateral thalamus exhibited significant injury (FJC positive, condensed pyknotic nuclei). Gliosis was first detectable in the ipsilateral thalamus at PSD3 and progressively increased to PSD14 (anti-GFAP and Iba1). Infiltration of peripheral-derived monocytes was determined to be one source of the activated microglia in the thalamus (CCR2-RFP reporter mice, n=3). Interestingly, pdMCAO mice allowed to recover for two years demonstrated persistent astrogliosis (cortex and thalamus), though microgliosis was no longer evident (n=2). Aged mice subjected to pdMCAO also demonstrated gliosis in thalamus at PSD14, albeit to a lesser extent than young mice (n=5 each age). Finally, delayed treatment with memantine resulted in significantly attenuated gliosis and neuronal loss in the thalamus at PSD14 (young mice, n=9 each). Conclusions: These results further define gliosis in the mechanism of secondary injury and importantly demonstrate attenuation of secondary injury by delayed NMDA receptor antagonism.

scholarly journals Low oxygen post conditioning improves stroke-induced cognitive impairment

2018 ◽  
Author(s):  
Zidan Zhao ◽  
Lin Kooi Ong ◽  
Giovanni Pietrogrande ◽  
Sonia Sanchez Bezanilla ◽  
Kirby Warren ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Learning Task ◽  
Experimental Stroke ◽  
Low Oxygen ◽  
Absolute Level ◽  
Associate Learning ◽  
Air Exposure ◽  
Post Stroke ◽  
Biochemical Analyses

AbstractPost-stroke cognitive impairment has proven to be notoriously difficult to treat. In the current study, we sought to both better understand cellular changes that underpin cognitive deficits and to consider the potential restorative benefits of low oxygen post conditioning (LOPC). We were motivated to use LOPC as an intervention as it is one of the few experimental interventions previously shown to improve cognitive function post-stroke. Experimental stroke was induced by photothrombotic occlusion in adult male C57BL/6 mice. Mice were randomly assigned to either a normal atmospheric air exposure or low oxygen (11% O2) exposure groups three days post-occlusion. On day 17 post-stroke, mice were euthanized for histology or biochemical analyses. Stroked mice exposed to LOPC was associated with marked reductions in amyloid-beta both in its absolute level and in the extent of its oligomerization. Exposure to LOPC post-stroke also improved cellular deficits induced by stroke including an increase in vessel density, a reduction in vascular leakage, and restoration of AQP4 polarisation. Critically, stroked mice exposed to LOPC exhibited robust improvements in cognitive function post-stroke, assessed using a touchscreen based paired- associate learning task. These findings provide compelling pre-clinical evidence of the potential clinical utility of LOPC for enhancing recovery post-stroke.

scholarly journals Targeting CDK5 post-stroke provides long-term neuroprotection and rescues synaptic plasticity

2016 ◽  
Vol 37 (6) ◽  
pp. 2208-2223 ◽  
Author(s):  
Johanna A Gutiérrez-Vargas ◽  
Herman Moreno ◽  
Gloria P Cardona-Gómez
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Neurotrophic Factor ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Brain Derived Neurotrophic Factor ◽  
Cyclin Dependent Kinase ◽  
Post Stroke ◽  
Cyclin Dependent Kinase 5

Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion. Cyclin-dependent kinase 5 RNA interference prevented the impairment of reversal learning four months after ischemia as well as neuronal loss, tauopathy, and microglial hyperreactivity. Additionally, cyclin-dependent kinase 5 silencing increased the expression of brain-derived neurotrophic factor in the hippocampus. Furthermore, deficits in hippocampal long-term potentiation produced by excitotoxic stimulation were rescued by pharmacological blockade of cyclin-dependent kinase 5. This recovery was blocked by inhibition of the TRKB receptor. In summary, these findings demonstrate the beneficial impact of cyclin-dependent kinase 5 reduction in preventing long-term post-ischemic neurodegeneration and cognitive impairment as well as the role of brain-derived neurotrophic factor/TRKB in the maintenance of normal synaptic plasticity.

Is Cerebral Amyloid-β Deposition Related to Post-stroke Cognitive Impairment?

2021 ◽  
Author(s):  
Fubing Ouyang ◽  
Zimu Jiang ◽  
Xinran Chen ◽  
Yicong Chen ◽  
Jiating Wei ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Amyloid Β ◽  
Post Stroke ◽  
Cerebral Amyloid

scholarly journals Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gab Seok Kim ◽  
Jessica M. Stephenson ◽  
Abdullah Al Mamun ◽  
Ting Wu ◽  
Monica G. Goss ◽  
...  
Keyword(s):  
Neuronal Loss ◽  
Secondary Injury ◽  
Age Dependency ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Post Stroke ◽  
Memantine Treatment ◽  
Cortical Stroke ◽  
Effects Of Aging ◽  
Distal Middle Cerebral Artery

AbstractSecondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.

scholarly journals TMS-Induced Central Motor Conduction Time at the Non-Infarcted Hemisphere is Associated with Spontaneous Motor Recovery of the Paretic Upper Limb after Severe Stroke

2021 ◽  
Vol 11 (5) ◽  
pp. 648
Author(s):  
Maurits Hoonhorst ◽  
Rinske Nijland ◽  
Cornelis Emmelot ◽  
Boudewijn Kollen ◽  
Gert Kwakkel
Keyword(s):  
Ischemic Stroke ◽  
Upper Limb ◽  
Normative Data ◽  
Motor Impairment ◽  
Motor Recovery ◽  
Conduction Time ◽  
Stroke Patients ◽  
Severe Stroke ◽  
Central Motor Conduction Time ◽  
Post Stroke

Background: Stroke affects the neuronal networks of the non-infarcted hemisphere. The central motor conduction time (CMCT) induced by transcranial magnetic stimulation (TMS) could be used to determine the conduction time of the corticospinal tract of the non-infarcted hemisphere after a stroke. Objectives: Our primary aim was to demonstrate the existence of prolonged CMCT in the non-infarcted hemisphere, measured within the first 48 h when compared to normative data, and secondly, if the severity of motor impairment of the affected upper limb was significantly associated with prolonged CMCTs in the non-infarcted hemisphere when measured within the first 2 weeks post stroke. Methods: CMCT in the non-infarcted hemisphere was measured in 50 patients within 48 h and at 11 days after a first-ever ischemic stroke. Patients lacking significant spontaneous motor recovery, so-called non-recoverers, were defined as those who started below 18 points on the FM-UE and showed less than 6 points (10%) improvement within 6 months. Results: CMCT in the non-infarcted hemisphere was prolonged in 30/50 (60%) patients within 48 h and still in 24/49 (49%) patients at 11 days. Sustained prolonged CMCT in the non-infarcted hemisphere was significantly more frequent in non-recoverers following FM-UE. Conclusions: The current study suggests that CMCT in the non-infarcted hemisphere is significantly prolonged in 60% of severely affected, ischemic stroke patients when measured within the first 48 h post stroke. The likelihood of CMCT is significantly higher in non-recoverers when compared to those that show spontaneous motor recovery early post stroke.

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