Exploring the predictive value of lesion topology on motor function outcomes in a porcine ischemic stroke model

AbstractHarnessing the maximum diagnostic potential of magnetic resonance imaging (MRI) by including stroke lesion location in relation to specific structures that are associated with particular functions will likely increase the potential to predict functional deficit type, severity, and recovery in stroke patients. This exploratory study aims to identify key structures lesioned by a middle cerebral artery occlusion (MCAO) that impact stroke recovery and to strengthen the predictive capacity of neuroimaging techniques that characterize stroke outcomes in a translational porcine model. Clinically relevant MRI measures showed significant lesion volumes, midline shifts, and decreased white matter integrity post-MCAO. Using a pig brain atlas, damaged brain structures included the insular cortex, somatosensory cortices, temporal gyri, claustrum, and visual cortices, among others. MCAO resulted in severely impaired spatiotemporal gait parameters, decreased voluntary movement in open field testing, and higher modified Rankin Scale scores at acute timepoints. Pearson correlation analyses at acute timepoints between standard MRI metrics (e.g., lesion volume) and functional outcomes displayed moderate R values to functional gait outcomes. Moreover, Pearson correlation analyses showed higher R values between functional gait deficits and increased lesioning of structures associated with motor function, such as the putamen, globus pallidus, and primary somatosensory cortex. This correlation analysis approach helped identify neuroanatomical structures predictive of stroke outcomes and may lead to the translation of this topological analysis approach from preclinical stroke assessment to a clinical biomarker.

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Atlas registration for edema-corrected MRI lesion volume in mouse stroke models

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17726635 ◽

2017 ◽

Vol 39 (2) ◽

pp. 313-323 ◽

Cited By ~ 17

Author(s):

Stefan Koch ◽

Susanne Mueller ◽

Marco Foddis ◽

Thomas Bienert ◽

Dominik von Elverfeldt ◽

...

Keyword(s):

Vasogenic Edema ◽

Lesion Size ◽

Artery Occlusion ◽

Brain Atlas ◽

Mathematical Framework ◽

Lesion Volume ◽

Atlas Registration ◽

Stroke Models ◽

Volume Measurements ◽

Automated Image Registration

Lesion volume measurements with magnetic resonance imaging are widely used to assess outcome in rodent models of stroke. In this study, we improved a mathematical framework to correct lesion size for edema which is based on manual delineation of the lesion and hemispheres. Furthermore, a novel MATLAB toolbox to register mouse brain MR images to the Allen brain atlas is presented. Its capability to calculate edema-corrected lesion size was compared to the manual approach. Automated image registration performed equally well in in a mouse middle cerebral artery occlusion model (Pearson r = 0.976, p = 2.265e-11). Information encapsulated in the registration was used to generate maps of edema induced tissue volume changes. These showed discrepancies to simplified tissue models underlying the manual approach. The presented techniques provide biologically more meaningful, voxel-wise biomarkers of vasogenic edema after stroke.

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Abstract TMP33: Repair of Ischemic Intestinal Epithelial Stem Cells: Potential Therapy to Improve Stroke Outcomes

Stroke ◽

10.1161/str.51.suppl_1.tmp33 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Kathiresh Kumar Mani ◽

Farida Sohrabji

Keyword(s):

Stem Cells ◽

Motor Function ◽

Stroke Recovery ◽

Female Rats ◽

Stem Cell Marker ◽

Left Middle Cerebral Artery ◽

Intestinal Epithelial ◽

Epithelial Stem Cells ◽

Stroke Outcomes ◽

Sensory Motor

Background: Nearly 50% of all stroke patients experience “leaky” gut, gut hemorrhage and gut epithelium damage. Gut leakiness may increase circulating inflammatory cytokines and other gut products such as endotoxins, which can impair stroke recovery. Here we tested the hypothesis that normalizing gut function via transplantation of intestinal epithelial stem cells (IESC) after stroke may stimulate repair of gut structures and improve stroke outcomes. Methods: Reproductive senescent female Sprague-Dawley rats used for this study and assigned to the following groups: Control (no stroke); stroke with sham transplant (vehicle); stroke with IESC transplantation. Rats were subjected to stereotaxic surgery to occlude the left middle cerebral artery by using Endothelin-1. Primary IECs were isolated from young female rats to prepare organoids cultures. Dissociated organoids were labeled with PKH26 and injected iv either once (48h after stroke) or 3 times (4h/24h/48h after stroke). Behavioral assays and saphenous blood draws were performed pre-stroke, 2d and 5d after stroke. Trunk blood, brain tissue and a segment of small intestine was collected at termination and processed for the expression of the stem cell marker Lgr5+, Na/K ATPase-α, and tight junction proteins. Results: Significant deterioration of the gut architecture was observed after stroke, including blunted or absent villi and irregular crypts. In animals that received PKH26-labeled organoid tranplants at 48h post stroke, labeled cells were seen in the center of the villus and a few organoid cells were immunositve for Lgr5+. Animals that received 3 organoid injections showed PKH26-labeled cells incorporated in both the villus and crypts. In these animals, villus were well formed and appeared no different from non-stroke controls. Sensory motor function assessed by adhesive removal test on the side contralateral to the infarction was severely impaired in the stroke/no transplant animals (120+secs/timed out), while this impairment was attenuated in the group that received 3 organoid injections (31±11 secs). Conclusion: These data suggest that transplantation of IESC after stroke may promote repair of gut villus and crypts, with a concomitant improvement in sensory motor function.

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Prediction of motor recovery using indirect connectivity in a lesion network after ischemic stroke

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286420925679 ◽

2020 ◽

Vol 13 ◽

pp. 175628642092567

Author(s):

Jungsoo Lee ◽

Eunhee Park ◽

Ahee Lee ◽

Won Hyuk Chang ◽

Dae-Shik Kim ◽

...

Keyword(s):

Prediction Model ◽

Motor Function ◽

Brain Network ◽

Reference Network ◽

Lesion Volume ◽

Motor Impairments ◽

Rehabilitation Programs ◽

Time Courses ◽

The Impact ◽

The Brain

Background: Recovery prediction can assist in the planning for impairment-focused rehabilitation after a stroke. This study investigated a new prediction model based on a lesion network analysis. To predict the potential for recovery, we focused on the next link-step connectivity of the direct neighbors of a lesion. Methods: We hypothesized that this connectivity would contribute to recovery after stroke onset. Each lesion in a patient who had suffered a stroke was transferred to a healthy subject. First link-step connectivity was identified by observing voxels functionally connected to each lesion. Next (second) link-step connectivity of the first link-step connectivity was extracted by calculating statistical dependencies between time courses of regions not directly connected to a lesion and regions identified as first link-step connectivity. Lesion impact on second link-step connectivity was quantified by comparing the lesion network and reference network. Results: The lower the impact of a lesion was on second link-step connectivity in the brain network, the better the improvement in motor function during recovery. A prediction model containing a proposed predictor, initial motor function, age, and lesion volume was established. A multivariate analysis revealed that this model accurately predicted recovery at 3 months poststroke ( R 2 = 0.788; cross-validation, R 2 = 0.746, RMSE = 13.15). Conclusion: This model can potentially be used in clinical practice to develop individually tailored rehabilitation programs for patients suffering from motor impairments after stroke.

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A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17738701 ◽

2017 ◽

Vol 38 (10) ◽

pp. 1818-1827 ◽

Cited By ~ 17

Author(s):

Raghavendar Chandran ◽

TaeHee Kim ◽

Suresh L Mehta ◽

Eshwar Udho ◽

Vishal Chanana ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Motor Function ◽

Neurological Dysfunction ◽

Vehicle Group ◽

Lesion Volume ◽

Post Injury ◽

Cortical Contusion ◽

Nrf2 Activator

Uncontrolled oxidative stress contributes to the secondary neuronal death that promotes long-term neurological dysfunction following traumatic brain injury (TBI). Surprisingly, both NADPH oxidase 2 (NOX2) that increases and transcription factor Nrf2 that decreases reactive oxygen species (ROS) are induced after TBI. As the post-injury functional outcome depends on the balance of these opposing molecular pathways, we evaluated the effect of TBI on the motor and cognitive deficits and cortical contusion volume in NOX2 and Nrf2 knockout mice. Genetic deletion of NOX2 improved, while Nrf2 worsened the post-TBI motor function recovery and lesion volume indicating that decreasing ROS levels might be beneficial after TBI. Treatment with either apocynin (NOX2 inhibitor) or TBHQ (Nrf2 activator) alone significantly improved the motor function after TBI, but had no effect on the lesion volume, compared to vehicle control. Whereas, the combo therapy (apocynin + TBHQ) given at either 5 min/24 h or 2 h/24 h improved motor and cognitive function and decreased cortical contusion volume compared to vehicle group. Thus, both the generation and disposal of ROS are important modulators of oxidative stress, and a combo therapy that prevents ROS formation and potentiates ROS disposal concurrently is efficacious after TBI.

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Investigating the Relationship Between Lower Limb Flexibility With Motor Function and Risk of Falling in Visually Impaired Individuals

Physical Treatments - Specific Physical Therapy ◽

10.32598/ptj.11.2.429.2 ◽

2021 ◽

pp. 93-102

Author(s):

Kamal Mohammad Khani ◽

◽

Mohammad Karimizadeh Ardakani ◽

Mohammad Hani Mansori ◽

◽

...

Keyword(s):

Range Of Motion ◽

Motor Function ◽

Significant Relationship ◽

Fall Risk ◽

Visually Impaired ◽

Pearson Correlation ◽

Influential Factor ◽

Lower Limbs ◽

Risk Of Falling ◽

The Relationship

Objective: The present study aimed to investigate the flexibility of the ankle and knee joints and to determine its relationship with balance, motor function, and risk of falling in visually impaired individuals. Methods: The sample consisted of 32 blind males, 20-30 years old. They were selected by the purposeful sampling method. We used modified stork tests, tendon gait, and Berg balance scale to evaluate their balance. The Tinetti test was used to evaluate motor performance and the Timed Up and Go (TUG) test to assess the risk of falling. The SLR test and Lunge test were used to assess the range of motion of the knee and ankle joint, respectively. This study was conducted in the men’s dormitories of Tehran University in the fall of 2019. The obtained data were normalized using the Shapiro-Wilk test and Pearson correlation coefficient at the significant level of 0.05 to investigate the relationship between the variables. Results: The results of the Pearson correlation test showed a significant relationship between balance (P=0.001), motor function (P=0.002), and TUG fall risk test (P=0.010) (ankle motor restriction). On the other hand, there was a significant relationship between balance (P=0.002), motor function (P=0.001), and TUG fall risk test (P=0.003) with hamstring flexibility test (knee motor restriction). Conclusion: Given the significant relationship between the range of motion of the lower limbs with balance and motor function, the use of stretching exercises can be an influential factor in increasing the range of motion of the ankle and knee in blind people, which improves balance, motor function, and reduced risk of falling in blindness.

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Liver metastases in mCRPC patients post-therapy with abiraterone (Abi) and/or abiraterone/enzalutamide (Enza).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.250 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 250-250

Author(s):

Lahiru Ranasinghe ◽

Patrick Cotogno ◽

Elisa M. Ledet ◽

Allie E. Steinberger ◽

Allison H. Feibus ◽

...

Keyword(s):

Liver Metastases ◽

Gleason Score ◽

Pearson Correlation ◽

Subsequent Development ◽

Liver Lesion ◽

Cancer Center ◽

Lesion Volume ◽

Total Liver ◽

Increased Risk ◽

Significant Difference

250 Background: Liver metastases (mets) are a particularly poor prognostic group among mCRPC patients. The objective of this study is to characterize mCRPC patients who have had treatment with Abi or Enza to identify risk factors that may be associated with subsequent development of liver mets. Methods: A sample of 67 patients (n = 17 liver mets and 50 non-liver met patients matched by treatment history) seen at Tulane Cancer Center were selected for analysis. All patients had prior Abi and or Abi/Enza. Race, age at PCa diagnosis and Gleason Score at PCa diagnosis were assessed. For patients with liver mets, total liver metastatic volume was measured using CT scans and correlated against PSA, LDH and AST values at the time of the scan. Wilcoxon rank sum tests were run analyzing PSA, LDH and AST at the start of Abi treatment, end of Abi treatment as well the duration of Abi treatment, and the nadir PSA for these patients. Results: Patients were predominantly Caucasian, had a median Gleason Score of 8 at diagnosis and were at a median age of 57 for those with liver mets and 62 for non-liver met at PCa diagnosis. Pearson correlation analysis of the total liver lesion volume and lab values revealed a significant correlation for LDH (R = 0.491, < 0.01) and AST (R = 0.368, p < 0.05), but not for PSA. Further evaluation of PSA and AST values at the start and end of Abi treatment as well as at nadir PSA revealed no statistically significant differences between liver met patients and non-liver met patients. However, there was a significant difference (p = 0.015) between LDH levels at the end of Abi treatment with a median of 347 U/L for liver met and 238 U/L for non-liver met patients. Conclusions: LDH and AST levels correlate with extent of liver metastases. Additionally, elevated LDH at the end of Abi treatment is indicative of an increased risk for developing liver metastases. Larger sample sizes and molecular characterization of these tumors are required to gain more insights into this important patient population.

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Abstract TP330: Insular Cortex Lesions are Associated With Early Mortality in Patients With Intracerebral Hemorrhage

Stroke ◽

10.1161/str.48.suppl_1.tp330 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Luis Prats-Sánchez ◽

Fernando Fayos ◽

Elba Pascual-Goñi ◽

Celia Painous ◽

Pol Camps-Renom ◽

...

Keyword(s):

Glasgow Coma Scale ◽

Intracerebral Hemorrhage ◽

Independent Predictor ◽

Tertiary Care ◽

Insular Cortex ◽

Brain Atlas ◽

Lesion Volume ◽

Care Hospital ◽

Cox Regression Analysis ◽

Coma Scale

Introduction: Insular lesions have been described as an independent predictor of death in acute ischemic stroke. This study was undertaken to determine the influence of insular damage on the mortality of patients with intracerebral hemorrhage (ICH). Hypothesis: Insular cortex lesions are an independent predictor of death in acute ICH. Methods: This is an observational study of consecutive patients with spontaneous acute ICH who were admitted to a tertiary care hospital. The following data were collected prospectively: age, sex, traditional vascular risk factors, vital signs, CT findings (secondary intraventricular hemorrhage, hematoma volume), Glasgow Coma Scale score, time and cause of death within hospitalization. The insular cortex damage (right, left or any) was assessed by a blind evaluator using an interactive brain atlas. The association between insular lesions and mortality was investigated by use of logistic regression and Cox proportional hazards models. Results: We included 276 patients whose mean age was 77±14.3 years; 52.7% of them were men. During a median of 7 days (interquartile range 2-15) of hospitalization, 91 (32.9%) deaths were recorded. We observed 72 (26%) patients with insular cortex lesions (right insula=34, left insula=38). Cox regression analysis showed that age (adjusted hazard ratio [aHR] 1.02, 95% CI 1.00-1.04; p<0.001), Glasgow Coma Scale (aHR 0.84, 95% CI 0.80-0.89; p<0.001), lesion volume (aHR 1.10, 95% CI 1.06-1.15; p<0.001) and any insular damage (aHR 2.19, 95% CI 1.40-3.42, p=0.002) were significant predictors of death within hospitalization. Conclusions: In conclusion, insular cortex lesions adversely influence survival after spontaneous ICH. This finding was observed even after adjustment for other well-known predictors of ICH mortality.

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CT Perfusion in Acute Stroke Predicts Final Infarct Volume- Inter-observer Study

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

10.1017/cjn.2015.349 ◽

2016 ◽

Vol 43 (1) ◽

pp. 93-97 ◽

Cited By ~ 12

Author(s):

Jai Jai Shiva Shankar ◽

Gavin Langlands ◽

Steve Doucette ◽

Stephen Phillips

Keyword(s):

Computed Tomography ◽

Medical Student ◽

Blood Volume ◽

Cerebral Blood Volume ◽

Ct Perfusion ◽

Infarct Volume ◽

Pearson Correlation ◽

Correlation Coefficients ◽

Kappa Statistics ◽

Lesion Volume

AbstractBackground: Computed tomography perfusion (CTP) is increasingly being used in the setting of acute ischemic stroke (AIS). The aim of the current study was to compare the prognostic utility of, and inter-observer variation between, baseline appearances on non-contrast CT (using Alberta Stroke Program Early CT score(ASPECTS)) and on CTP for predicting final infarct volume. We also assessed impact of training on interpretation of these images. Methods: Retrospectively, plain head computed tomography (CT) and CTP images at presentation and CT or diffusion imaging on follow up of patients with AIS were analyzed. The lesion volume on different CTP parameters was then correlated with the final infarct volume. This analysis was done by a Neuroradiologist, a stroke Neurologist and a medical student. Kappa statistics and Intra-class correlation coefficients were used for agreement between readers. Pearson correlation coefficients were used.Results: Thirty eight patients with AIS met all inclusion criteria. There was very good agreement among all readers for the CTP parameters. There was only fair agreement for ASPECT score. Correlation coefficient (r-square) between CTP parameters and final infarct volume showed that cerebral blood volume was the best parameter to predict the final infarct volume followed by cerebral blood flow and time to peak. The best reader to predict the final infarct volume on the initial CT perfusion study was the neuroradiologist followed by medical student and stroke neurologist. Conclusions: Cerebral blood volume defect correlated the best with the final infarct volume. There was a very good inter-observer agreement for all the CTP maps in predicting the final infarct volume despite the wide variation in the experience of the readers.

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Sex differences in recovery of motor function in a rhesus monkey model of cortical injury

Biology of Sex Differences ◽

10.1186/s13293-021-00398-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Karen R. Bottenfield ◽

Bethany G. E. Bowley ◽

Monica A. Pessina ◽

Maria Medalla ◽

Douglas L. Rosene ◽

...

Keyword(s):

Sex Differences ◽

Rhesus Monkey ◽

Motor Function ◽

Primary Motor Cortex ◽

Cortical Lesion ◽

Fine Motor ◽

Lesion Volume ◽

Male And Female ◽

Cortical Injury ◽

Monkey Model

Abstract Background Stroke disproportionately affects men and women, with women over 65 years experiencing increased severity of impairment and higher mortality rates than men. Human studies have explored risk factors that contribute to these differences, but additional research is needed to investigate how sex differences affect functional recovery and hence the severity of impairment. In the present study, we used our rhesus monkey model of cortical injury and fine motor impairment to compare sex differences in the rate and degree of motor recovery following this injury. Methods Aged male and female rhesus monkeys were trained on a task of fine motor function of the hand before undergoing surgery to produce a cortical lesion limited to the hand area representation of the primary motor cortex. Post-operative testing began two weeks after the surgery and continued for 12 weeks. All trials were video recorded and latency to retrieve a reward was quantitatively measured to assess the trajectory of post-operative response latency and grasp pattern compared to pre-operative levels. Results Postmortem analysis showed no differences in lesion volume between male and female monkeys. However, female monkeys returned to their pre-operative latency and grasp patterns significantly faster than males. Conclusions These findings demonstrate the need for additional studies to further investigate the role of estrogens and other sex hormones that may differentially affect recovery outcomes in the primate brain.

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Deficiency in Androgen Receptor Aggravates Traumatic Brain Injury-Induced Pathophysiology and Motor Deficits in Mice

Molecules ◽

10.3390/molecules26206250 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6250

Author(s):

Yu-Hsin Chen ◽

Yen-Chou Chen ◽

Ling-Ling Hwang ◽

Liang-Yo Yang ◽

Dah-Yuu Lu

Keyword(s):

Brain Injury ◽

Motor Function ◽

Brain Injuries ◽

Brain Lesion ◽

Motor Deficits ◽

Breakdown Product ◽

Lesion Volume ◽

Wild Type ◽

Neuroprotective Effects

Androgens have been shown to have a beneficial effect on brain injury and lower reactive astrocyte expression after TBI. Androgen receptors (ARs) are known to mediate the neuroprotective effects of androgens. However, whether ARs play a crucial role in TBI remains unknown. In this study, we investigated the role of ARs in TBI pathophysiology, using AR knockout (ARKO) mice. We used the controlled cortical impact model to produce primary and mechanical brain injuries and assessed motor function and brain-lesion volume. In addition, the AR knockout effects on necrosis and autophagy were evaluated after TBI. AR knockout significantly increased TBI-induced expression of the necrosis marker alpha-II-spectrin breakdown product 150 and astrogliosis marker glial fibrillary acidic protein. In addition, the TBI-induced astrogliosis increase in ARKO mice lasted for three weeks after a TBI. The autophagy marker Beclin-1 was also enhanced in ARKO mice compared with wild-type mice after TBI. Our results also indicated that ARKO mice showed a more unsatisfactory performance than wild-type mice in a motor function test following TBI. Further, they were observed to have more severe lesions than wild-type mice after injury. These findings strongly suggest that ARs play a role in TBI.

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