Excitatory-Inhibitory Homeostasis and Diaschisis: Tying the Local and Global Scales in the Post-stroke Cortex

Maintaining a balance between excitatory and inhibitory activity is an essential feature of neural networks of the neocortex. In the face of perturbations in the levels of excitation to cortical neurons, synapses adjust to maintain excitatory-inhibitory (EI) balance. In this review, we summarize research on this EI homeostasis in the neocortex, using stroke as our case study, and in particular the loss of excitation to distant cortical regions after focal lesions. Widespread changes following a localized lesion, a phenomenon known as diaschisis, are not only related to excitability, but also observed with respect to functional connectivity. Here, we highlight the main findings regarding the evolution of excitability and functional cortical networks during the process of post-stroke recovery, and how both are related to functional recovery. We show that cortical reorganization at a global scale can be explained from the perspective of EI homeostasis. Indeed, recovery of functional networks is paralleled by increases in excitability across the cortex. These adaptive changes likely result from plasticity mechanisms such as synaptic scaling and are linked to EI homeostasis, providing a possible target for future therapeutic strategies in the process of rehabilitation. In addition, we address the difficulty of simultaneously studying these multiscale processes by presenting recent advances in large-scale modeling of the human cortex in the contexts of stroke and EI homeostasis, suggesting computational modeling as a powerful tool to tie the meso- and macro-scale processes of recovery in stroke patients.

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Longitudinal Effects of Lesions on Functional Networks after Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.80 ◽

2013 ◽

Vol 33 (8) ◽

pp. 1279-1285 ◽

Cited By ~ 51

Author(s):

Smadar Ovadia-Caro ◽

Kersten Villringer ◽

Jochen Fiebach ◽

Gerhard Jan Jungehulsing ◽

Elke van der Meer ◽

...

Keyword(s):

Ischemic Stroke ◽

Resting State ◽

Large Scale ◽

Clinical Symptoms ◽

Resting State Fmri ◽

Functional Change ◽

Stroke Recovery ◽

Focal Lesion ◽

Supporting Evidence ◽

Post Stroke

While ischemic stroke reflects focal damage determined by the affected vascular territory, clinical symptoms are often more complex and may be better explained by additional indirect effects of the focal lesion. Assumed to be structurally underpinned by anatomical connections, supporting evidence has been found using alterations in the functional connectivity of resting-state functional magnetic resonance imaging (fMRI) data in both sensorimotor and attention networks. To assess the generalizability of this phenomenon in a stroke population with heterogeneous lesions, we investigated the distal effects of lesions on a global level. Longitudinal resting-state fMRI scans were acquired at three consecutive time points, beginning during the acute phase (days 1, 7, and 90 post-stroke) in 12 patients after ischemic stroke. We found a preferential functional change in affected networks (i.e., networks containing lesions changed more during recovery when compared with unaffected networks). This change in connectivity was significantly correlated with clinical changes assessed with the National Institute of Health Stroke Scale. Our results provide evidence that the functional architecture of large-scale networks is critical to understanding the clinical effect and trajectory of post-stroke recovery.

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Abstract 14: Effects of Lesion Laterality on Post-Stroke Motor Performance: An ENIGMA Stroke Recovery Analysis

Stroke ◽

10.1161/str.48.suppl_1.14 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Sook-Lei Liew ◽

Neda Jahanshad ◽

Lisa Aziz-Zadeh ◽

Niels Birbaumer ◽

Michael Borich ◽

...

Keyword(s):

Motor Performance ◽

Statistical Significance ◽

Motor Recovery ◽

Small Sample ◽

Stroke Recovery ◽

Intracranial Volume ◽

Brain Volumes ◽

Post Stroke ◽

Small Sample Sizes ◽

Cortical Regions

The laterality of the lesioned hemisphere is often overlooked in stroke recovery research due to small sample sizes. Here, we used a well-powered dataset from ENIGMA Stroke Recovery (a consortium that harmonizes post-stroke MRIs and behavioral data worldwide; http://enigma.usc.edu) to analyze the effects of left (LHL) versus right (RHL) hemisphere lesions on motor performance. Given the different functional roles of each hemisphere, we hypothesized that the LHL group should show better motor performance, and, consequently, different brain-behavior relationships, compared to the RHL group. Data from over 2000 stroke patients across 20 sites worldwide has been committed. To date, structural T1-weighted MRIs from n=343 (10 sites) have been analyzed (LHL n=174; RHL n=169). ENIGMA protocols extracted volumes of subcortical regions of interest and provided quality control. Regression analyses examined brain volumes as predictors of motor outcomes. Motor scores were combined across scales/sites, with each score expressed as a percentage of the maximum score. Covariates (e.g., age, sex, intracranial volume) and manually marked lesion effects were also modeled. Statistical significance was assessed nonparametrically by permutation. As anticipated, the LHL group had better motor performance compared to the RHL group (t(1,341)=3.07, p=0.0023). In addition, while the combined LHL+RHL analyses showed significant associations between motor scores and volumes of the basal ganglia/lateral ventricles, separate group analyses showed strong associations for the LHL group, but only one association for the RHL group (Table 1). This may suggest that motor recovery following RH lesions is more heterogeneous or relies more on cortical regions/networks that were not assessed here. While further research is needed, these results suggest that laterality of the lesioned hemisphere affects neural patterns related to motor recovery and should be carefully examined.

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Cellular-resolution monitoring of ischemic stroke pathologies in the rat cortex

10.1101/2021.05.27.446026 ◽

2021 ◽

Author(s):

Sergiy Chornyy ◽

Aniruddha Das ◽

Julie A Borovicka ◽

Davina Patel ◽

Hugh H Chan ◽

...

Keyword(s):

Ischemic Stroke ◽

Primary Motor Cortex ◽

Activity Patterns ◽

Recovery Process ◽

Cortical Reorganization ◽

Western World ◽

Fluorescence Signal ◽

Functional Changes ◽

Post Stroke ◽

Cortical Regions

Stroke is a leading cause of disability in the Western world. Current post-stroke rehabilitation treatments are only effective in approximately half of the patients. Therefore, there is a pressing clinical need for developing new rehabilitation approaches for enhancing the recovery process, which requires the use of appropriate animal models. Here we study the activity patterns of multiple cortical regions in the rat brain using two-photon microscopy. We longitudinally recorded the fluorescence signal from thousands of neurons labeled with a genetically-encoded calcium indicator before and after an ischemic stroke injury, and found substantial functional changes across motor, somatosensory, and visual cortical regions during the post-stroke cortical reorganization period. We show that a stroke injury in the primary motor cortex has an effect on the activity patterns of neurons not only in the motor and somatosensory cortices, but also in the more distant visual cortex, and that these changes include modified firing rates and kinetics of neuronal activity patterns in response to a sensory stimulus. Changes in neuronal population activity provided animal-specific, circuit-level information on the post-stroke cortical reorganization process, which may be essential for evaluating the efficacy of new approaches for enhancing the recovery process.

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Large-scale imaging of cortical dynamics during sensory perception and behavior

Journal of Neurophysiology ◽

10.1152/jn.01056.2015 ◽

2016 ◽

Vol 115 (6) ◽

pp. 2852-2866 ◽

Cited By ~ 107

Author(s):

Joseph B. Wekselblatt ◽

Erik D. Flister ◽

Denise M. Piscopo ◽

Cristopher M. Niell

Keyword(s):

Large Scale ◽

Temporal Dynamics ◽

Dorsal Surface ◽

Global Scale ◽

Orientation Discrimination ◽

Cortical Dynamics ◽

Two Photon Microscopy ◽

Two Photon ◽

Cortical Regions ◽

And Behavior

Sensory-driven behaviors engage a cascade of cortical regions to process sensory input and generate motor output. To investigate the temporal dynamics of neural activity at this global scale, we have improved and integrated tools to perform functional imaging across large areas of cortex using a transgenic mouse expressing the genetically encoded calcium sensor GCaMP6s, together with a head-fixed visual discrimination behavior. This technique allows imaging of activity across the dorsal surface of cortex, with spatial resolution adequate to detect differential activity in local regions at least as small as 100 μm. Imaging during an orientation discrimination task reveals a progression of activity in different cortical regions associated with different phases of the task. After cortex-wide patterns of activity are determined, we demonstrate the ability to select a region that displayed conspicuous responses for two-photon microscopy and find that activity in populations of individual neurons in that region correlates with locomotion in trained mice. We expect that this paradigm will be a useful probe of information flow and network processing in brain-wide circuits involved in many sensory and cognitive processes.

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Abstract W P96: Optogenetic Neuronal Stimulation Enhances Neurotrophin Expression in the Contralesional Motor Cortex After Stroke

Stroke ◽

10.1161/str.45.suppl_1.wp96 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Michelle Y Cheng ◽

Eric H Wang ◽

Corinne L Bart ◽

Alex R Bautista ◽

Wyatt J Woodson ◽

...

Keyword(s):

Motor Cortex ◽

Functional Recovery ◽

Primary Motor Cortex ◽

Recovery Process ◽

Cortical Reorganization ◽

Stroke Recovery ◽

Post Stroke ◽

Neuronal Stimulation ◽

Activity Dependent

Objective: Functional recovery after stroke has been observed and is currently attributed to both brain remodeling and plasticity. One form of cortical reorganization involves the balance of interhemispheric interactions between ipsilesional and contralesional cortex. Stimulation of ipsilesional primary motor cortex (iM1) has been shown to be beneficial, however, the role of the contralesional M1 (cM1) remains controversial. Recently we showed that optogenetic stimulations of iM1 post-stroke promote functional recovery. In this study, we investigate the role of contralesional cortex in recovery by optogenetically stimulating iM1 or cM1 and examine the involvement of activity-dependent neurotrophins. Methods: Thy-1-ChR2-YFP line-18 transgenic male mice were used. Mice underwent stereotaxic surgery to implant a fiber cannula in either iM1 or cM1, followed by an intraluminal middle cerebral artery suture occlusion. Optogenetic stimulation began at day5 post-stroke and continued until day14 post-stroke. Sensorimotor behavior tests were used to assess their recovery at day 0, 2, 7, 10 and 14 post-stroke. Mice were sacrificed at day15 post-stroke and neurotrophin expressions were examined using quantitative PCR. Results: Repeated iM1 stimulations promoted functional recovery at day14 post-stroke, with improved motor performance on the rotating beam test (p<0.01). Real-time PCR revealed significant increases of neurotrophin expressions in contralesional M1 at day15 post-stroke, including brain-derived neurotrophic factor (BDNF) (p<0.05), nerve growth factor (NGF) (p<0.05) and neurotrophin 3 (NTF3) (p<0.05). BDNF and NTF3 expression were also significantly increased in the contralesional S1 of stimulated mice (p<0.05). Conclusion: Our data suggest that activity-dependent neurotrophins in the contralesional cortex may be an important mechanism mediating stroke recovery. Current studies include specific stimulation and inhibition of the iM1 or cM1 post-stroke to elucidate the neurocircuitry mediating stroke recovery. In addition, the expression of neurotrophins will be examined in these studies to elucidate their role in the recovery process.

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Progress in Clinical Neurosciences: Stroke Recovery and Rehabilitation

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100005308 ◽

2006 ◽

Vol 33 (4) ◽

pp. 357-364 ◽

Cited By ~ 37

Author(s):

Robert Teasell ◽

Nestor Bayona ◽

Katherine Salter ◽

Chelsea Hellings ◽

Jamie Bitensky

Keyword(s):

Cortical Reorganization ◽

Stroke Recovery ◽

Neurological Recovery ◽

Complex Environments ◽

Post Stroke ◽

Brain Reorganization ◽

Intact Cortex ◽

The Individual ◽

Insight Into

ABSTRACT:Background:Recent literature has provided new insights into the role of rehabilitation in neurological recovery post-stroke. The present review combines results of animal and clinical research to provide a summary of published information regarding the mechanisms of neural recovery and impact of rehabilitation.Methods:Plasticity of the uninjured and post-stroke brain is examined to provide a background for the examination of brain reorganization and recovery following stroke.Summary and Conclusions:Recent research has confirmed many of the basic underpinnings of rehabilitation and provided new insight into the role of rehabilitation in neurological recovery. Recovery post stroke is dependent upon cortical reorganization, and therefore, upon the presence of intact cortex, especially in areas adjacent to the infarct. Exposure to stimulating and complex environments and involvement in tasks or activities that are meaningful to the individual with stroke serves to increase cortical reorganization and enhance functional recovery. Additional factors associated with neurological recovery include size of stroke lesion, and the timing and intensity of therapy.

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Neurorehabilitation Potentials of Repetitive Transcranial Magnetic Stimulation in Post-stroke Motor and Speech Recovery

University of Western Ontario Medical Journal ◽

10.5206/uwomj.v87is1.4815 ◽

2019 ◽

Author(s):

Henry Liu

Keyword(s):

Ischemic Stroke ◽

Transcranial Magnetic Stimulation ◽

Magnetic Stimulation ◽

Neuronal Excitability ◽

Repetitive Transcranial Magnetic Stimulation ◽

Stroke Recovery ◽

Post Stroke ◽

Speech Rehabilitation ◽

Cortical Regions ◽

The Brain

Ischemic stroke is a consequence of diminished cerebral blood flow to cortical regions, resulting in subsequent reductions in excitability. The brain undergoes immense cortical remapping following a stroke, which can be facilitated by neuronal excitability. However, analyses of electrophysiologic recordings, cortical stimulation, and fMRI reveal a decline in the excitability of the ipsilesional hemisphere following an ischemic stroke and an increase in interhemispheric inhibition by the contralesional hemisphere. Recent findings have implicated non-invasive stimulation with post-stroke recovery through the induction of synaptic plasticity and recruitment of neurotrophic factors to the peri-infarct region. The aim of this paper is to review recent research that has beendevoted to repetitive transcranial magnetic stimulation (rTMS) and its use as a therapeutic tool in motor and speech rehabilitation via the alteration of excitability in the brain post-ischemic stroke.

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Therapy of post-stroke depression – a systematic review

Die Psychiatrie ◽

10.1055/s-0038-1670863 ◽

2013 ◽

Vol 10 (02) ◽

pp. 108-129 ◽

Cited By ~ 1

Author(s):

W. Gaebel ◽

W. Wannagat ◽

J. Zielasek

Keyword(s):

Systematic Review ◽

Large Scale ◽

Repetitive Transcranial Magnetic Stimulation ◽

Placebo Control ◽

Post Stroke ◽

Pharmacological Studies ◽

Post Stroke Depression ◽

Control Procedures ◽

Antidepressant Pharmacotherapy

SummaryWe performed a systematic review of randomized placebo-controlled pharmacological and non-pharmacological trials for the therapy and prevention of post-stroke depression that have been published between 1980 and 2011. We initially identified 2 260 records of which 28 studies were finally included into this review. A meta-analytic approach was hampered by considerable differences regarding the kinds of therapeutic regimens and the study durations. Modest effects favoring treatment of post-stroke depression could be found for pharmacological treatment as well as repetitive transcranial magnetic stimulation. For the prevention of post-stroke depression, antidepressant pharmacotherapy showed promising results. However, large-scale studies with better standardized study populations, optimized placebo control procedures in non-pharmacological studies, and replication in larger follow-up studies are still necessary to find the optimal therapeutic regimens to prevent and treat post-stroke depression.

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