Mild Motor Impairment Research Articles

Structural and Functional Connectivity Correlate With Motor Impairment in Chronic Supratentorial Stroke

To identify differences in structural and functional brain connectivity between post-stroke mild and severe motor impairment.

Parent-Provided Cognitive Opportunities and Infant Mobility During Play for Children With Motor Impairments

Abstract Date Presented 04/05/19 For infants with mild motor impairments, parent-provided cognitive opportunities during play continue to increase after mobility is achieved, in contrast to those with severe motor impairment, where cognitive opportunities decrease, as gross motor abilities remain stable. This analysis of two infants demonstrates this difference and will be confirmed in the analysis of 90 children with mild, moderate, and severe impairment. These findings have implications for early-intervention service providers. Primary Author and Speaker: Audrey Kane Additional Authors and Speakers: Stacey Dusing Contributing Authors: Emily Marcinowski, Lin-Ya Hsu

Nigrostriatal Dopaminergic Dysfunction and Altered Functional Connectivity in REM Sleep Behavior Disorder With Mild Motor Impairment.

Rapid eye movement sleep behavior disorder is parasomnia characterized by symptoms of dream enactment and loss of muscle atonia during rapid eye movement sleep. Mild motor impairment is present in some patients with rapid eye movement sleep behavior disorder and presumed to be a risk factor for conversion to synucleinopathies. The purpose of this study is to identify patients with mild motor impairment by evaluating finger tapping and to investigate its pathophysiology. Twenty-three patients with rapid eye movement sleep behavior disorder and 20 healthy control subjects were recruited in the present study. We accurately evaluated finger tapping including amplitude, peak open, and close speed with a magnetic sensing device and identified patients with mild motor impairment. Moreover, we performed 123I-2β-carbomethoxy-3β-(4-iodophenyl) nortropane SPECT and resting state functional MRI. 123I-2β-carbomethoxy-3β-(4-iodophenyl) nortropane uptake for each bilateral caudate, anterior putamen, and posterior putamen was calculated and the resting state functional connectivity of sensorimotor network was analyzed. Using finger tapping parameters, we identified eight patients with mild motor impairment. In patients with mild motor impairment, all finger tapping parameters were significantly impaired when compared to patients with normal motor function, while they exhibited no significant differences in Unified Parkinson's Disease Rating Scale part III score. 123I-2β-carbomethoxy-3β-(4-iodophenyl) nortropane uptake in the right posterior putamen, bilateral anterior putamen, and caudate was significantly lower when compared to healthy controls or patients with rapid eye movement sleep behavior disorder with normal motor function. These patients also exhibited decreased cortico-striatal functional connectivity and increased cortico-cerebellar functional connectivity when compared to healthy controls or patients with normal motor function. Our results show that mild motor impairment in rapid eye movement sleep behavior disorder evaluated by finger tapping task presented mild nigrostriatal dopaminergic dysfunction as well as alterations in resting state sensorimotor network. Although longitudinal follow up is necessary, such patients may have higher risk of short-term conversion to synucleinopathies.

Medical Diagnosis of Cerebral Palsy Rehabilitation Using Eye Images in Machine Learning Techniques.

Cerebral Palsy (CP) is a non progressive neurological disorders commonly associated with a spectrum of developmental disabilities such as strabismus (misalignment of eye). The Eye image are captured through camera, this make the quick diagnosis and examination the periodical assessment for CP kids. By capturing the Eye Movement of 40 children with CP (aged 3-11years) with relatively mild motor-impairment and also we have analyzed the performance of CP children periodically. Nowadays, Bio-Medical image processing and Machine learning Classification algorithm used for detection and diagnosis the certain diseases and plays the important tool to decrease the risk of any diseases. This work presents a computational methodology to automatically diagnose the Improvement of CP children and performance can be evaluated. The alternate medical evaluation techniques have shown their potential for the treatment and diagnosis of disease like strabismus and nystagmus for CP kids. The proposed method is used to measure and quantify the performance improvement by classify the abnormal eye condition of CP kids and these results attained by machine learning method. The results show the best classification accuracy of 94.17% calculated from Neural Network Classifier. Specificity Rate were absorbed as 0.9800 and Sensitivity Rate were absorbed as 0.9165 respectively. The proposed method for non-invasive and automatic detection of abnormalities in CP kids and evaluates the performance improvement more accurately.

Strabismus Is Correlated with Gross Motor Function in Children with Spastic Cerebral Palsy

ABSTRACTPurpose: To investigate the correlation between clinical features of strabismus and motor dysfunction classified according to the Gross Motor Function Classification System (GMFCS) in patients with spastic cerebral palsy (CP).Methods: In this retrospective, cross-sectional study in single tertiary medical center, 62 patients who are diagnosed with spastic CP who had an ophthalmic examination between 2006 and 2014 were included. Only patients with vision sufficient to fixate were included and patients with restrictive or paralytic strabismus were excluded. The types of CP were classified as diplegia, hemiplegia, or quadriplegia for distribution of motor impairment. The GMFCS was used to grade gross motor dysfunction, which was then classified as mild (grade 1, 2 and 3) or severe (grade 4 and 5) motor impairment. Strabismus was investigated in terms of direction, constancy, and deviation angle. The relationship between strabismus characteristics and the level of GMFCS and type of CP were assessed.Results: Thirty-eight and 24 patients had mild or severe motor deficit, respectively. Forty patients had strabismus, which was more frequent in patients with severe motor impairment.(P = .014) Exotropia and esotropia occurred with similar frequency. Constant and large-angle strabismus was frequently observed in patients with severe motor impairment.(P < .005, 0.027) The topographical subtype of CP was not related to clinical features of strabismus.Conclusions: The prevalence of strabismus is higher in severe motor impairment. The constancy and angle of strabismus was related to the severity of motor impairment while the topographical subtype of CP has no significant relationship.

Classification of Mild Stroke: A Mapping Review.

Persons with mild stroke experience motor and cognitive impairments that negatively affect their health and quality of life. To address these deficits, it is essential for clinicians and researchers to precisely identify mild stroke survivors. Despite the fact that half of all strokes are categorized as mild, no standards exist on what constitutes a "mild" stroke. The purpose of this study is to summarize the current classification of mild stroke using a mapping review approach. Strategies to categorize "mild stroke" severity were explored in 188 papers indexed in the PubMed database. The results indicate that there was substantial variability in the procedures and scoring criteria used to determine mild stroke. To identify persons with mild stroke, researchers have largely applied assessment instruments developed to inform acute stroke care (eg, National Institutes of Health Stroke Scale, Modified Rankin Scale, Barthel Index). Unfortunately, these approaches demonstrate floor effects and fail to detect the long-term disabling impairments that often limit the outcomes of mild stroke survivors. Additional research is warranted to suggest an evidence-based mild stroke categorization strategy that enhances diagnosis, treatment, and referral decisions to the benefit of mild stroke survivors.

Structural and functional connectivity correlates with motor impairment in chronic supratentorial stroke: a multimodal magnetic resonance imaging study.

The aim of this study was to identify differences in structural and functional brain connectivity between poststroke mild and severe motor impairment. Twenty-four chronic stroke patients who underwent resting-state functional MRI and diffusion tensor image were retrospectively included. All patients were classified into two groups (mild motor impairment: 11 patients and severe motor impairment: 13 patients) according to their Fugl-Meyer motor assessment score. Tract-based spatial statistics and group independent component analyses were applied to investigate between-group differences in structural and functional connectivity, respectively. The fractional anisotropy values of motor-related brain regions in the affected hemisphere were significantly higher in mild motor impairment than in severe motor impairment (corrected P<0.05). The internetwork functional connectivity between (i) the supplementary motor area and primary motor cortex in the affected hemisphere, (ii) the supplementary motor area and dorsolateral prefrontal cortex in the unaffected hemisphere, and (iii) the ischemic lesion and primary motor cortex in the unaffected hemisphere was significantly higher in mild motor impairment than in severe motor impairment (PFWE<0.05). Better motor recovery after stroke could be facilitated by means of treatments aimed at enhancing structural and functional connectivity among motor-related brain regions such as noninvasive brain stimulation and neurodevelopmental therapy.

Can Neonatal Systemic Inflammation and Hypoxia Yield a Cerebral Palsy-Like Phenotype in Periadolescent Mice?

Cerebral palsy (CP) is one of the most common childhood-onset motor disabilities, attributed to injuries of the immature brain in the foetal or early postnatal period. The underlying mechanisms are poorly understood, rendering prevention and treatment strategies challenging. The aim of the present study was to establish a mouse model of CP for preclinical assessment of new interventions. For this purpose, we explored the impact of a double neonatal insult (i.e. systemic inflammation combined with hypoxia) on behavioural and cellular outcomes relevant to CP during the prepubertal to adolescent period of mice. Pups were subjected to intraperitoneal lipopolysaccharide (LPS) injections from postnatal day (P) 3 to P6 followed by hypoxia at P7. Gene expression analysis at P6 revealed a strong inflammatory response in a brain region-dependent manner. A comprehensive battery of behavioural assessments performed between P24 and P47 showed impaired limb placement and coordination when walking on a horizontal ladder in both males and females. Exposed males also displayed impaired performance on a forelimb skilled reaching task, altered gait pattern and increased exploratory activity. Exposed females showed a reduction in grip strength and traits of anxiety-like behaviour. These behavioural alterations were not associated with gross morphological changes, white matter lesions or chronic inflammation in the brain. Our results indicate that the neonatal double-hit with LPS and hypoxia can induce subtle long-lasting deficits in motor learning and fine motor skills, which partly reflect the symptoms of children with CP who have mild gross and fine motor impairments.

Self-efficacy and Reach Performance in Individuals With Mild Motor Impairment Due to Stroke

Background: Persistent deficits in arm function are common after stroke. An improved understanding of the factors that contribute to the performance of skilled arm movements is needed. One such factor may be self-efficacy (SE). Objective: To determine the level of SE for skilled, goal-directed reach actions in individuals with mild motor impairment after stroke and whether SE for reach performance correlated with actual reach performance. Methods: A total of 20 individuals with chronic stroke (months poststroke: mean 58.1 ± 38.8) and mild motor impairment (upper-extremity Fugl-Meyer [FM] motor score: mean 53.2, range 39 to 66) and 6 age-matched controls reached to targets presented in 2 directions (ipsilateral, contralateral). Prior to each block (24 reach trials), individuals rated their confidence on reaching to targets accurately and quickly on a scale that ranged from 0 (not very confident) to 10 (very confident). Results: Overall reach performance was slower and less accurate in the more-affected arm compared with both the less-affected arm and controls. SE for both reach speed and reach accuracy was lower for the more-affected arm compared with the less-affected arm. For reaches with the more-affected arm, SE for reach speed and age significantly predicted movement time to ipsilateral targets (R2 = 0.352), whereas SE for reach accuracy and FM motor score significantly predicted end point error to contralateral targets (R2 = 0.291). Conclusions: SE relates to measures of reach control and may serve as a target for interventions to improve proximal arm control after stroke.

Cognitive impairment in an animal model of multiple sclerosis and its amelioration by glatiramer acetate

The severe motor impairment in the MS animal model experimental autoimmune encephalomyelitis (EAE) obstructs the assessment of cognitive functions. We developed an experimental system that evaluates memory faculties in EAE-affected mice, irrespective of their motor performance, enabling the assessment of cognitive impairments along the disease duration, the associated brain damage, and the consequences of glatiramer acetate (GA) treatment on these manifestations. The delayed-non-matching to sample (DNMS) T-maze task, testing working and long term memory was adapted and utilized. Following the appearance of clinical manifestations task performances of the EAE-untreated mice drastically declined. Cognitive impairments were associated with disease severity, as indicated by a significant correlation between the T-maze performance and the clinical symptoms in EAE-untreated mice. GA-treatment conserved cognitive functions, so that despite their exhibited mild motor impairments, the treated mice performed similarly to naïve controls. The cognitive deficit of EAE-mice coincided with inflammatory and neurodegenerative damage to the frontal cortex and the hippocampus; these damages were alleviated by GA-treatment. These combined findings indicate that in addition to motor impairment, EAE leads to substantial impairment of cognitive functions, starting at the early stages and increasing with disease aggravation. GA-treatment, conserves cognitive capacities and prevents its disease related deterioration.

A Novel Tool for Quantifying and Promoting Physical Activity in Youths With Typical Development and Youths Who Are Ambulatory and Have Motor Disability

Several device-based instruments have been validated in the pediatric population, but none of these are clinically applicable and provide real-time feedback on actual physical activity in terms of postures and movements. A new device (Activ8) is promising for that purpose. The objective was to investigate the criterion validity of the Activ8 for measuring static (sitting, standing) and dynamic (walking, bicycling, running) activities, and for separating postures and movements within basic and complex activities in children and adolescents (youths) with typical development (TD) and peers with motor disability (not typical development [NTD]). This was a criterion validation study. Ten participants with TD (mean age [standard deviation]=14 [2.5] years) and 10 participants with NTD (mean age=12.9 [2.1] years) performed a standardized series of basic and daily life (complex) activities. The Activ8 measured postures and movements, while camera recording served as a reference. The outcome measures were the mean time differences between the Activ8 output and video data for the merged categories "static" and "dynamic" and for the separate postures and movements. For the merged categories static and dynamic, the criterion validity was found to be excellent both in participants with TD and participants with NTD within basic activities, and was found to be good to excellent in participants with TD and moderate to good in participants with NTD within complex activities. The detection of separate postures and movements was found to be poor to excellent in both groups within complex activities. The sample of youths with NTD was small and limited to youths who could be considered to be at least ambulatory within a household. Activ8 is a valid tool when the merged categories static and dynamic are used to interpret physical activity in daily life in both youths with TD and youths with NTD and mild motor impairment. To optimize the quantification of separate postures and movements, adjustment of the existing algorithm is required.

Жизнестойкость и копинг-стратегии подростков с нарушениями опорно-двигательного аппарата

The article presents results of the study on hardiness and coping strategies of adolescents with motor impairments. 67 adolescents with different motor impairments aged 13-16 years, 33 of them are adolescents with severe impairments and 34 of them are adolescents with mild impairments surveyed. The comparison group consisted of 112 healthy adolescents. The empirical data collecting made by the short version of the Hardiness Test, the Questionnaire of Coping Strategies, expert interviews of teachers, analysis of documents. The results show that in case of mild motor impairments there is no reduction of hardiness, in the case of severe impairments the hardiness is lower than in the comparison group. Adolescents with motor impairments have more adaptive coping strategies, in comparison with healthy peers, mainly in the aspect of emotionally-oriented coping. In the case of severe motor impairments, hardiness is correlated with the ability to maintain emotional well-being, in the case of severe motor impairments it also matters to abandon nonadaptive behavioral coping strategies.

Performance Evaluation of Visual Therapy Method Used for Cerebral Palsy Rehabilitation

Cerebral Palsy (CP) is a non progressive neurological disorders commonly associated with a spectrum of developmental disabilities such as strabismus (misalignment of eye). In this study, by quantitatively assess the performance analysis of Visual Therapy Method used for CP children. By capturing the Eye Movement of 25 children with CP (aged 3–15 years) with relatively mild motor-impairment and also analyzed the performance of CP children periodically. The Eye image are captured through camera, this make the quick diagnosis and examination the periodical assessment of CP kids. By Visual Therapy Function the CP children vision improvement develops as fast as or even faster. Proposed area of the research segments the eye image into Pupil, Iris, Eyelids and Eye corner detection using different image processing algorithms as well as measure the deviation position of pupil for abnormal eyes taking the normal eye as the reference or threshold value. To further enhance these compare deviation Position of the normal and the abnormal eyes and to find the severity affection of abnormal eye and to measure the performance improvement achievement by Visual Therapy Method for CP rehabilitation. The improvement analyzed for CP kids were maintained and recorded for the periodical month of Initial, 6th and 12th month. As a result, the Physicians can use this report to guide the CP kids in Rehabilitation Center and also this image processing technique offers the greater flexibility for the prospective subjects of improvement in CP Rehabilitation by Visual Therapy Method. In this context, Image processing techniques are being recommended as a performance evaluation tool in children with CP and each of these processes are suggesting method for developing a more systematic understanding of Oculomotor abnormalities.

The cooking therapy for cognitive rehabilitation of cerebellar damage: A case report and a review of the literature

Background and importanceThe therapeutic approach for cerebellar damages heavily relies on neurorehabilitation since there are no medications that may improve clinical symptoms mainly those related to cognitive dysfunctions. Nevertheless, neurorehabilitation programs tailored to cerebellar damages have never been validated. Here we describe a new rehabilitation approach based on cooking training (CT). The idea that cooking may stimulate cerebellar activity relies on previous evidence demonstrating the beneficial effect on the executive functions as well as in promoting neural plasticity within the cerebellum. Indeed, CT requires motor/mental coordination, thinking flexibly, planning, implementing strategies, shifting and self-monitoring behaviors, all functions drastically affected in cerebellar disorders. Case descriptionA 68-year-old male stroke patient with isolated right cerebellar ischemia in the posterior cerebellum characterized by mild executive dysfunctions. After intensive six weekly two-hour sessions, we found that CT was effective in improving some cognitive abilities in a context of mild motor impairment. In particular, deficits in the execution of the Symbol digit modality test and Wisconsin card-sorting test were recovered. ConclusionThe comparison of our data with those reported in previous studies confirmed the Schmahmann’s hypothesis on the effectiveness of neurorehabilitation approaches in cerebellar patients acting as external timekeeping of conscious thoughts.

Home-based training of rhythmic skills with a serious game in Parkinson's disease: Usability and acceptability.

To evaluate the adherence, usability and acceptance of a rehabilitation protocol with a music-based serious game (SG) and its effect on rhythmic skills in Parkinson disease (PD). Sixteen PD patients with mild cognitive and motor impairments were included (mean [SD] age 65 [7.28] years and Hoehn & Yahr score 2-3). Rehabilitation consisted of a 6-week at-home training program targeting rhythmic skills with a dedicated SG, Rhythm Workers, implemented on a tablet device. Patients were asked to play the game at least 30min, 3 times a week. Two half-day evaluations were conducted before and after rehabilitation. Time played and average game scores were recorded. Suitability was evaluated by a questionnaire inspired by the Suitability Evaluation Questionnaire (SEQ) and rhythmic skills by the Beat Alignment Test from the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA). Patients played a mean (SD) of 313 (243) min, namely 57.9% of the expected time; the mean game score was 48.8/100 (19.5). The mean SEQ score for 12 patients was 29.2/45 (8.2); suitability was good to excellent for 10 patients. Beat perception reflecting rhythmic skills improved significantly in all but 5 patients. This study showed good to excellent suitability of an SG used on a tablet interface for rhythmic training in PD and the feasibility of this type of training in this population.

MiR-7 Replacement Therapy in Parkinson's Disease.

The present review examines whether the microRNA 7 (miR-7) holds potential for slowing Parkinson's disease (PD) progression. First, the accurate expression of miR-7 allows for normal development, physiology, and neurogenesis in the central nervous system, also keeping alpha-synuclein (α-Syn) at the physiological level. Second, patients with PD and parkinsonian MPTP-induced animals exhibit a significant decrease of miR-7 in brain areas associated with dopaminergic neurodegeneration. Depletion of miR-7 in the substantia nigra of clinical samples is related to α-Syn accumulation, loss of dopaminergic cells, and reduction of dopamine in the striatum. Therefore, the goal of a miR-7- replacement therapy is to downregulate α-Syn and other PD-related genes, achieving multi-target benefits regarding oxidative stress, mitochondrial health, cell glycolysis, apoptosis, and inhibition of inflammasome activation. While a disease-modifying drug is a major unmet need for the clinical management of PD, an miR-7-replacement therapy presents a striking potential against critical mechanisms of neuropathology. Such innovative treatment would reduce α-Syn accumulation in the Lewy bodies and preserve remaining neurons yet viable at the time of diagnosis, thus slowing disease progression from the early phase of PD characterized by a relatively mild motor impairment to an advanced and more disabling stage.

Posterior limb of the internal capsule predicts poor quality of life in patients with Parkinson's disease: connectometry approach.

Psychiatric symptoms and motor impairment are major contributions to the poor quality of life in patients with Parkinson's disease (PD). Here, we applied a novel diffusion-weighted imaging approach, diffusion MRI connectometry, to investigate the correlation of quality of life, evaluated by Parkinson's Disease Questionnaire (PDQ39) with the white matter structural connectivity in 27 non-demented PD patients (disease duration of 5.3±2.9years, H and Y stage=1.5±0.6, UPDRS-III=13.7±6.5, indicating unilateral and mild motor involvement). The connectometry analysis demonstrated bilateral posterior limbs of the internal capsule(PLIC) with increased connectivity related to the higher quality of life (FDR=0.027) in a multiple regression model. The present study suggestsfor the first time a neural basis of the quality of life in PD in the light of major determinants of poor quality of life in these patients: anxiety, depression, apathy and motor impairment. Results in our sample of non-demented PD patients with relatively mild motor impairment and no apparent sign of depression/anxiety also identify a unique and inexplicable association of the PLIC to the quality of life in PD patients.

Multimodal MR imaging in hepatic encephalopathy: state of the art.

Hepatic encephalopathy (HE) is a neurological or neuropsychological complication due to liver failure or portosystemic shunting. The clinical manifestation is highly variable, which can exhibit mild cognitive or motor impairment initially, or gradually progress to a coma, even death, without treatment. Neuroimaging plays a critical role in uncovering the neural mechanism of HE. In particular, multimodality MR imaging is able to assess both structural and functional derangements of the brain with HE in focal or neural network perspectives. In recent years, there has been rapid development in novel MR technologies and applications to investigate the pathophysiological mechanism of HE. Therefore, it is necessary to update the latest MR findings regarding HE by use of multimodality MRI to refine and deepen our understanding of the neural traits in HE. Herein, this review highlights the latest MR imaging findings in HE to refresh our understanding of MRI application in HE.

O204 Simultaneous bi-hemispheric repetitive transcranial magnetic stimulation for upper limb motor recovery in chronic stroke: A double blind placebo controlled study

Objective repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for the treatment of post-stroke motor deficits. Since the crucial role of non-primary motor cortices and contralesional brain areas is emerging for motor recovery in chronic stroke; we assessed safety and efficacy of bilateral rTMS over the motor areas associated to physical training (PT) on upper extremity (UE) motor function. Methods double-blind, placebo-controlled trial on 20 patients with chronic stroke conditioning moderate to mild upper limb motor impairment. Eleven sessions of high frequency rTMS were delivered with the H-coil over the motor areas bilaterally. Subjects were randomly allocated to the real rTMS plus PT or the placebo (sham) rTMS plus PT. UE impairment was evaluated by the Fugl-Meyer assessment for UE (FM-UE), Modified Ashworth Scale (MAS) and hand grip strength at baseline (T0), after treatment (T1) and one-month follow-up (T2). Results no serious adverse events were reported. At T1 FM-UE significantly improved in both groups, while at T2 the improvement was significant only for the real group. The improvement was significantly higher in the real compared with the sham group. In the real group, greater improvement in FM-UE was found in patients moderately impaired compared with less impaired at baseline. Spasticity and hand grip strength also significantly improved in the real group at T1 and amelioration of spasticity persisted also at T2. Conclusion bilateral high-frequency rTMS with H-coil associated with PT is safe and enhances the effect of PT alone. Although plegic patients were not included, subjects with moderate rather than mild motor impairment may mainly benefit from this stimulation protocol.

Reproducible Motor Deficit Following Aortic Occlusion in a Rat Model Of Spinal Cord Ischemia.

Spinal cord ischemia is a fatal complication following thoracoabdominal aortic aneurysm surgery. Researchers can investigate the strategies for preventing and treating this complication using experimental models of spinal cord ischemia. The model described here demonstrates varying degrees of paraplegia that relate to the length of occlusion following thoracic aortic occlusion in a rat spinal cord ischemia model. A 2-Fr. balloon-tipped catheter was advanced through the femoral artery into the descending thoracic aorta until the catheter tip was placed at the left subclavian artery in anesthetized male Sprague-Dawley rats. Spinal cord ischemia was induced by inflating the catheter balloon. After a set period of occlusion (9, 10, or 11 min), the balloon was deflated. Neurologic assessment was performed using the motor deficit index at 24 h after surgery, and the spinal cord was harvested for histopathological examination. Rats that underwent 9 min of aortic occlusion showed mild and reversible motor impairment in the hind limb. Rats subjected to 10 min of aortic occlusion presented with moderate but reversible motor impairment. Rats subjected to 11 min of aortic occlusion displayed complete and persistent paralysis. The motor neurons in the spinal cord sections were more preserved in rats subjected to shorter duration of aortic occlusion. Researchers can achieve a reproducible hind limb motor deficit following thoracic aortic occlusion using this spinal cord ischemia model.