Extent Of Functional Recovery Research Articles

Evaluation of renal function after pyeloplasty determined by 99mTc DTPA renogram

Background: Hydronephrosis (HDN) due to pelviureteric junction (PUJ) obstruction is a common congenital anomaly of urinary tract which is generally treated by pyeloplasty. But the extent of functional recovery is still debated. Considering the existing controversies, this study was designed to evaluate the changes of renal function after pyeloplasty measured by 99mTc-DTPA renography.
 Methods: This study was done in the department of urology, National Institute of Kidney Diseases and Urology (NIKDU) and Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) General Hospital from July 2014 to December 2020. Sixty patients were included in this study and underwent Anderson-Hynes (A-H) dismembered pyeloplasty for PUJ obstruction. All patients were evaluated with diuretic 99mTc-DTPA renogoam before and at 3 and 6 months after pyeloplasty. Improvement of renal function was evaluated by comparing preoperative and postoperative differential renal function (DRF) and glomerular filtration rate (GFR).
 Results: Sixty patients (34 male and 26 female) with unilateral HDN due to PUJ obstruction were included in this study with mean age of 15.6 years (ranged from 3 – 38 years). Out of 60 patients, 56.7% had left sided HDN and 43.3% had right sided HDN. The mean preoperative DRF was 16.72 ± 8.35% at baseline which increased to 26.03 ± 7.08% at the end of 3rd month and 28.15 ± 5.84% at the end of 6th month. The mean preoperative GFR was 14.29 ± 6.73 ml/min/1.73 m2 at baseline which increased to 24.13 ± 5.31ml/min/1.73 m2 at the end of 3rd month and 27.38 ± 4.78 ml/min/1.73 m2 at the end of 6th month.
 Conclusion: The result demonstrates that, after pyeloplasty renal function improves. Highest recovery of renal function noted in patients with poor pre-operative DRF and GFR.
 BIRDEM Med J 2022; 12(2): 142-146

Genetic polymorphisms for BDNF, COMT, and APOE do not affect gait or ankle motor control in chronic stroke: A preliminary cross-sectional study

ABSTRACT Background: Motor deficits after stroke are a primary cause of long-term disability. The extent of functional recovery may be influenced by genetic polymorphisms. Objectives: Determine the effect of genetic polymorphisms for brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), and apolipoprotein E (APOE) on walking speed, walking symmetry, and ankle motor control in individuals with chronic stroke. Methods: 38 participants with chronic stroke were compared based upon genetic polymorphisms for BDNF (presence [MET group] or absence [VAL group] of a Met allele), COMT (presence [MET group] or absence [VAL group] of a Met allele), and APOE (presence [ε4+ group] of absence [ε4- group] of ε4 allele). Comfortable and maximal walking speed were measured with the 10-m walk test. Gait spatiotemporal symmetry was measured with the GAITRite electronic mat; symmetry ratios were calculated for step length, step time, swing time, and stance time. Ankle motor control was measured as the accuracy of performing an ankle tracking task. Results: No significant differences were detected (p ≥ 0.11) between the BDNF, COMT, or APOE groups for any variables. Conclusions: In these preliminary findings, genetic polymorphisms for BDNF, COMT, and APOE do not appear to affect walking speed, walking symmetry, or ankle motor performance in chronic stroke.

Protocol for a multicenter observational prospective study of functional recovery from stroke beyond inpatient rehabilitation - The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE)

IntroductionStroke and its long-term consequences pose major challenges for the lives of those affected and healthcare systems. Neurological rehabilitation therefore primarily attempts to improve function in order to increase independence in activities of daily living, and to enable social participation. There is only scarce data on dynamics of functional recovery after patients discharge from inpatient neurological rehabilitation. Even less is known about the patient’s perspective on long-term recovery from stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) aims to address this knowledge gap by providing new insights into the dynamics and extent of functional recovery from stroke beyond inpatient rehabilitation treatment.MethodsWe provide the protocol for an observational, longitudinal, multicenter study conducted in an Universitary Stroke Center in cooperation with five Neurological Rehabilitation Centers in Northern Germany. Patients who suffered from ischemic or hemorrhagic stroke will be enrolled by the end of inpatient rehabilitation and followed up to 1 year. In addition, a group of chronic stroke patients and a group of craniocerebral trauma patients will be enrolled as a comparison group. Data on stroke characteristics, vascular risk factors, co-morbidities, social support, and demographics will be recorded. Comprehensive clinical evaluation will be performed at baseline, three, six, and twelve months after enrollment. The assessments and scores used reflect the three components of the International Classification of Functioning, Disability and Health (ICF), some of them are tests regularly used in rehabilitation settings. Tests of motor function, cognition, and mood are included, as are tests of self-reported health-related quality of life. Primary outcome measure is a hand motor score, built by the sum of the hand items of the Fugl-Meyer Assessment as an objective measurement of hand function at 12 months after enrollment. Predictors of the primary outcome will be analyzed using linear regression analysis.PerspectiveThe results of IMPROVE will inform about the long-term dynamics of functional stroke recovery after patients’ discharge from inpatient rehabilitation and will provide insights into the association of clinical and demographic factors with recovery of function.Trial registrationThe protocol is registered at ClinicalTrials.gov (NCT04119479).

The Neuronal Activation of Deep Cerebellar Nuclei Is Essential for Environmental Enrichment-Induced Post-Stroke Motor Recovery.

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation.

Asymmetric and Distant Effects of a Unilateral Lesion of the Primary Motor Cortex on the Bilateral Supplementary Motor Areas in Adult Macaque Monkeys.

A restricted lesion of the hand area in the primary motor cortex (M1) leads to a deficit of contralesional manual dexterity, followed by an incomplete functional recovery, accompanied by plastic changes in M1 itself and in other cortical areas on both hemispheres. Using the marker SMI-32 specific to pyramidal neurons in cortical layers III and V, we investigated the impact of a focal unilateral M1 lesion (hand representation) on the rostral part (F6) and caudal part (F3) of the supplementary motor area (SMA) in both hemispheres in nine adult macaque monkeys compared with four intact control monkeys. The M1 lesion induced a consistent interhemispheric asymmetry in density of SMI-32-positive neurons in F3 layer V (statistically significant in 8 of 9 lesioned monkeys), highly correlated with the lesion volume and with the duration of functional recovery, but not with the extent of functional recovery itself. Such interhemispheric asymmetry was neither present in the intact monkeys, as expected, nor in F6 in all monkeys. In addition, the M1 lesion also impacted on the basal dendritic arborization of F3 layer V neurons. Neuronal density was clearly less affected by the M1 lesion in F3 layer III compared with layer V. We interpret the remote effect of M1 lesion onto the density of SMI-32-positive neurons and dendritic arborization in the SMAs bilaterally as the consequence of multiple factors, such as changes of connectivity, diaschisis and various mechanisms involved in cortical plasticity underlying the functional recovery from the M1 lesion.SIGNIFICANCE STATEMENT The motor system of macaque monkeys, in addition to be similarly organized as in humans, is a good candidate to study the impact of a focal lesion of the main contributor to voluntary movements, the primary motor cortex (M1), on non-primary motor cortical areas also involved in manual dexterity, both at behavioral and structural levels. Our results show that a unilateral permanent lesion of M1 hand area in nine monkeys affects the interhemispheric balance of the number of SMI-32-positive pyramidal neurons in the cortical layer V of the supplementary motor area, in a way strongly correlated to the lesion volume and duration of the incomplete functional recovery.

Applications of In Vivo Functional Testing of the Rat Tibialis Anterior for Evaluating Tissue Engineered Skeletal Muscle Repair.

Despite the regenerative capacity of skeletal muscle, permanent functional and/or cosmetic deficits (e.g., volumetric muscle loss (VML) resulting from traumatic injury, disease and various congenital, genetic and acquired conditions are quite common. Tissue engineering and regenerative medicine technologies have enormous potential to provide a therapeutic solution. However, utilization of biologically relevant animal models in combination with longitudinal assessments of pertinent functional measures are critical to the development of improved regenerative therapeutics for treatment of VML-like injuries. In that regard, a commercial muscle lever system can be used to measure length, tension, force and velocity parameters in skeletal muscle. We used this system, in conjunction with a high power, bi-phase stimulator, to measure in vivo force production in response to activation of the anterior crural compartment of the rat hindlimb. We have previously used this equipment to assess the functional impact of VML injury on the tibialis anterior (TA) muscle, as well as the extent of functional recovery following treatment of the injured TA muscle with our tissue engineered muscle repair (TEMR) technology. For such studies, the left foot of an anaesthetized rat is securely anchored to a footplate linked to a servomotor, and the common peroneal nerve is stimulated by two percutaneous needle electrodes to elicit muscle contraction and dorsiflexion of the foot. The peroneal nerve stimulation-induced muscle contraction is measured over a range of stimulation frequencies (1-200 Hz), to ensure an eventual plateau in force production that allows for an accurate determination of peak tetanic force. In addition to evaluation of the extent of VML injury as well as the degree of functional recovery following treatment, this methodology can be easily applied to study diverse aspects of muscle physiology and pathophysiology. Such an approach should assist with the more rational development of improved therapeutics for muscle repair and regeneration.

Applications of <em>In Vivo</em> Functional Testing of the Rat Tibialis Anterior for Evaluating Tissue Engineered Skeletal Muscle Repair

Despite the regenerative capacity of skeletal muscle, permanent functional and/or cosmetic deficits (e.g., volumetric muscle loss (VML) resulting from traumatic injury, disease and various congenital, genetic and acquired conditions are quite common. Tissue engineering and regenerative medicine technologies have enormous potential to provide a therapeutic solution. However, utilization of biologically relevant animal models in combination with longitudinal assessments of pertinent functional measures are critical to the development of improved regenerative therapeutics for treatment of VML-like injuries. In that regard, a commercial muscle lever system can be used to measure length, tension, force and velocity parameters in skeletal muscle. We used this system, in conjunction with a high power, bi-phase stimulator, to measure in vivo force production in response to activation of the anterior crural compartment of the rat hindlimb. We have previously used this equipment to assess the functional impact of VML injury on the tibialis anterior (TA) muscle, as well as the extent of functional recovery following treatment of the injured TA muscle with our tissue engineered muscle repair (TEMR) technology. For such studies, the left foot of an anaesthetized rat is securely anchored to a footplate linked to a servomotor, and the common peroneal nerve is stimulated by two percutaneous needle electrodes to elicit muscle contraction and dorsiflexion of the foot. The peroneal nerve stimulation-induced muscle contraction is measured over a range of stimulation frequencies (1-200 Hz), to ensure an eventual plateau in force production that allows for an accurate determination of peak tetanic force. In addition to evaluation of the extent of VML injury as well as the degree of functional recovery following treatment, this methodology can be easily applied to study diverse aspects of muscle physiology and pathophysiology. Such an approach should assist with the more rational development of improved therapeutics for muscle repair and regeneration.

Abstract W P142: White Matter Lesion Severity and Functional Recovery Following Inpatient Rehabilitation After Ischemic Stroke

Background and purpose: Functional outcome after stroke mainly depends on the stroke severity. However, extent of functional recovery varies between individual patients of same degree of disability in stroke rehabilitation. The aim of this study is to investigate the association between white matter lesion (WML) severity and the extent of functional recovery following intensive rehabilitation after ischemic stroke. Methods: The study included patients who were moved to a rehabilitation unit within 2 months after onset of ischemic stroke. Patients with diagnosed dementia or patients with cognitive decline who needed care before stroke were excluded. The degree of WMLs, the location and size of stroke lesions were assessed using brain MRI performed in an acute phase. Separate visual ratings were made for the periventricular hyperintensities and deep white matter hyperintensities on FLAIR images. Functional status was measured using the Functional Independence Measure (FIM) when a patient was moved to a rehabilitation unit and at the time of discharge. Functional recovery was quantified by the change in FIM score (FIM gain). We retrospectively investigated the association between WML severity and FIM gain. Results: A total of 292 patients (166 men and 126 women, mean age 73.3 ± 9.8 years) were included in the study. The mean time interval between stroke onset and rehabilitation start was 35.0 days and the mean length of stay in the unit was 71.6 days. FIM gain was associated with age, stroke severity, functional status before stroke, lobar stroke lesions, and both periventricular and deep white matter hyperintensity scores. Infarct size was not significantly associated with FIM gain. On the other hand, deep white matter hyperintensity score was independently associated with lower FIM gain after adjusting for age, sex, timing of rehabilitation start, length of stay, functional status before stroke, and NIHSS score on admission. Conclusion: In patients with subacute ischemic stroke, severity of cerebral WMLs is an independent factor affecting functional recovery following intensive rehabilitation.

Absence of chloride intracellular channel 4 (CLIC4) predisposes to acute kidney injury but has minimal impact on recovery

BackgroundCLIC4, a member of the CLIC family of proteins, was recently demonstrated to translocate to the nucleus in differentiating keratinocytes where it potentiates TGFβ-driven gene regulation. Since TGFβ signaling is known to play important roles in the fibrotic response to acute kidney injury, and since CLIC4 is abundantly expressed in kidney, we hypothesized that CLIC4 may play a role in the response to acute kidney injury.MethodsPreviously described Clic4 null mice were analyzed for the effect of absence of CLIC4 on growth, development and response to kidney injury. Kidney size, glomerular counts and density of peritubular capillaries of matched WT and Clic4 null mice were determined. Cohorts of WT and Clic4 null mice were subjected to the folic acid model of acute kidney injury. Extent of acute injury and long term functional recovery were assessed by plasma blood urea nitrogen (BUN); long term fibrosis/scarring was determined by histochemical assessment of kidney sections and by residual renal mass. Activation of the TGFβ signaling pathway was assessed by semi-quantitative western blots of phosphorylated SMADs 2 and 3.ResultsCLIC4 is abundantly expressed in the apical pole of renal proximal tubule cells, and in endothelial cells of glomerular and peritubular capillaries. CLIC4 null mice are small, have smaller kidneys with fewer glomeruli and less dense peritubular capillary networks, and have increased proteinuria. The Clic4 null mice show increased susceptibility to folic acid-induced acute kidney injury but no difference in recovery from acute injury, no nuclear redistribution of CLIC4 following injury, and no significant difference in activation of the TGFβ-signaling pathway as reflected in the level of phosphorylation of SMADs 2 and 3.ConclusionsAbsence of CLIC4 results in morphologic changes consistent with its known role in angiogenesis. These changes may be at least partially responsible for the increased susceptibility to acute kidney injury. However, the absence of CLIC4 has no significant impact on the extent of functional recovery or fibrosis following acute injury, indicating that CLIC4 does not play a major non-redundant role in the TGFβ signaling involved in response to acute kidney injury.

Structural Changes in Spinal Nerve Sensory Ganglia on Repeated Magnetic Stimulation in a Model of Ischemic Myelopathy

The aim of the present work was to identify links between morphological changes in spinal nerve sensory ganglia (SNG) and clinical symptomatology in rats with experimental ischemic myelopathy (IM) treated with repeated magnetic stimulation (RMS) and without treatment. Electron microscopic studies of 16 rats with IM were performed to study the efficacy and mechanisms of action of RMS on sensory SNG. After treatment, sensory SNG, both distant from the lesion site (lumbar SNG) and close to the lesion site (cervical SNG) showed morphological signs of regenerative-repair processes both in cells and nerve fibers (restoration of the structure of cytoplasmic organelles in neurons and neurolemmocytes, increases in the numbers of the latter, and remyelination of fibers). The extent of structural changes correlated with the extent of functional recovery.

Personal Motion Sensor Directed Rehabilitation after Lower Limb Reconstruction

INTRODUCTION: Open tibial fractures are managed in a variety of ways, but current practice fails to objectively assess short and long-term outcomes. Not only does this limit the scope for evaluation of management strategies, but it also prevents the provision of regular patient feedback and implementation of adaptive personalised rehabilitation programmes. As a result, total recovery time and the extent of functional recovery are likely to be suboptimal, with consequential poor rates of return to work. Advances in miniaturised, wireless sensor technology allows resource-sparing, pervasive data capture of multiple patient features in a non-specialised environment.1 Our aim was to develop and validate a robust, objective assessment method using a novel motion sensing system worn by the patient for use in both clinical and community settings (Hamlyn instrumented Functional Mobility Assessment – HiFMA). METHODS: We implemented a lightweight (7.4g) ear-worn accelerometer (e-AR sensor, Imperial College London) and tablet interface into a short activity protocol made up of tasks previously validated to assess different aspects of functional mobility.2–4 Twenty 3-month post-open tibial fracture patients and 10 healthy subjects completed the protocol, as well as a short-form health survey (SF-36) for comparison. Subjects’ performances were rated through extraction of multiple kinematic features from the accelerometer data; techniques previously validated using high-speed cameras and a force plate-instrumented treadmill.5 A psychometric evaluation was conducted to ascertain the reliability and validity of the HiFMA tool. RESULTS: The HiFMA demonstrated excellent reliability (Intraclass Correlation Coefficient > 0.90, p<0.001) and internal consistency (Cronbach’s Alpha = 0.94). Concurrent validity was demonstrated by correlation between HiFMA and SF-36 scores (Spearman’s Rho = 0.668, p = 0.005). Significant differences in HiFMA scores between healthy subjects and patients, sub-grouped according to Gustilo-Anderson fracture classification, were shown (KW-ANOVA, X2 = 18.6, p<0.001) (Figure 1).Figure 1: Performance scores from HiFMA tool compared to SF-36 health status.CONCLUSION: The HiFMA shows satisfactory reliability and validity to be considered for implementation into routine follow-up of patients with open tibial fractures. This will improve our ability to objectively profile and compare a wide variety of patient outcomes, whilst creating a platform for remote patient surveillance and early detection of complications. Furthermore, the methods described provide a real opportunity to revamp the recovery paradigm through dynamic, self-directed rehabilitation, with huge potential for positive impact in the cost and care quality of everyday clinical services.

The potential for functional recovery of upper extremity function following cervical spinal cord injury without major bone injury

This was a retrospective observational study. The objectives were to describe the prognosis of upper extremity function following cervical spinal cord injury (CSCI), and to identify prognostic factors for functional recovery. Spinal Injuries Center, Japan. Sixty patients with C3-4 CSCI without major bone injury participated in the study. Patients were treated nonsurgically and evaluated using the American Spinal Injury Association (ASIA) scales for the upper and lower extremities, their residual cervical motor functions, the modified Frankel grade and an upper extremity function scale. We compared the findings for the upper extremity function scale at 6 months with those for the residual cervical motor functions and modified Frankel grade obtained 3 days after injury. Most patients with CSCI who could flex their hip and knee from a supine position (95%) or who showed some active elbow extension (86%) 3 days after their injury could use a spoon at 6 months. We compared patients who used their fingers at 6 months to those who could not, and observed significant differences in age and ASIA scores for the upper and lower extremities obtained 3 days after injury. A strong correlation was observed between the initial motor scores and the extent of functional recovery at 6 months. Hip and knee flexion from the supine position and elbow extension 3 days after injury significantly predicted a positive prognosis for upper extremity function. Younger age and higher ASIA motor scores obtained 3 days after injury were factors associated with neurological recovery.

Upregulation of TrkB by forskolin facilitated survival of MSC and functional recovery of memory deficient model rats

Mesenchymal stem cells (MSCs) are effective vectors in delivering a gene of interest into degenerating brain. In ex vivo gene therapy, viability of transplanted MSCs is correlated with the extent of functional recovery. It has been reported that BDNF facilitates survival of MSCs but dividing MSCs do not express the BDNF receptor, TrkB. In this study, we found that the expression of TrkB is upregulated in human MSCs by the addition of forskolin (Fsk), an activator of adenylyl cyclase. To increase survival rate of MSCs and their secretion of tropic factors that enhance regeneration of endogenous cells, we pre-exposed hMSCs with Fsk and transduced with BDNF-adenovirus before transplantation into the brain of memory deficient rats, a degenerating brain disease model induced by ibotenic acid injection. Viability of MSCs and expression of a GABA synthesizing enzyme were increased. The pre-treatment improved learning and memory, as detected by the behavioral tests including Y-maze task and passive avoidance test. These results suggest that TrkB expression of hMSCs elevates the neuronal regeneration and efficiency of BDNF delivery for treating degenerative neurological diseases accompanying memory loss.

Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates

The nonhuman primate model is suitable to study mechanisms of functional recovery following lesion of the cerebral cortex (motor cortex), on which therapeutic strategies can be tested. To interpret behavioral data (time course and extent of functional recovery), it is crucial to monitor the properties of the experimental cortical lesion, induced by infusion of the excitotoxin ibotenic acid. In two adult macaque monkeys, ibotenic acid infusions produced a restricted, permanent lesion of the motor cortex. In one monkey, the lesion was monitored over 3.5 weeks, combining laser speckle imaging (LSI) as metabolic readout (cerebral blood flow) and anatomical assessment with magnetic resonance imaging (T2-weighted MRI). The cerebral blood flow, measured online during subsequent injections of the ibotenic acid in the motor cortex, exhibited a dramatic increase, still present after one week, in parallel to a MRI hypersignal. After 3.5 weeks, the cerebral blood flow was strongly reduced (below reference level) and the hypersignal disappeared from the MRI scan, although the lesion was permanent as histologically assessed post-mortem. The MRI data were similar in the second monkey. Our experiments suggest that LSI and MRI, although they reflect different features, vary in parallel during a few weeks following an excitotoxic cortical lesion.

Time course and extent of functional recovery during the first postoperative year after minimally invasive total hip arthroplasty with two different surgical approaches—a randomized controlled trial

While others have reported short-term comparisons between various minimally invasive surgical (MIS) approaches to total hip arthroplasty (THA) and their conventional analogues, longer-term data is lacking, as is information indicating whether MIS approaches to THA provide a biomechanically complete recovery. Furthermore, different MIS approaches have not been compared. Our approaches of interest were a one-incision modified Watson-Jones, and a two-incision approach. Hypotheses: (1) There are significant differences in gait recovery patterns between the two surgical groups and (2) THA subjects have significant differences in function one year after surgery compared to control subjects. To test these hypotheses, THA candidates ( n=26) were randomized to receive one of these MIS approaches and evaluated preoperatively, and postoperatively at 3 weeks, and at 3, 6 and 12 months. Evaluations included three-dimensional gait analysis and 24-hour step-counts. The same data were obtained from 25 control subjects. Recovery time-course was assessed using repeated measures ANOVA. T-tests were used to compare controls with the pooled group of THA subjects. We found no differences between the two THA surgical groups regarding the time-course of recovery ( p≥0.591). Although recovery was statistically complete by 3 months postoperatively for all variables, there were significant differences from controls at 12 months. Most notably, the external hip adduction moment, which reflects hip abductor function, was more than one standard deviation below normal ( p<0.001). THA subject inactivity could not explain the gait differences, since one year after surgery daily step counts were not significantly different from controls ( p=0.346). More work is necessary to determine ways to improve biomechanical outcomes for today’s patients with high expectations for function and implant longevity.

Effects of Unilateral Motor Cortex Lesion on Ipsilesional Hand's Reach and Grasp Performance in Monkeys: Relationship With Recovery in the Contralesional Hand

Manual dexterity, a prerogative of primates, is under the control of the corticospinal (CS) tract. Because 90-95% of CS axons decussate, it is assumed that this control is exerted essentially on the contralateral hand. Consistently, unilateral lesion of the hand representation in the motor cortex is followed by a complete loss of dexterity of the contralesional hand. During the months following lesion, spontaneous recovery of manual dexterity takes place to a highly variable extent across subjects, although largely incomplete. In the present study, we tested the hypothesis that after a significant postlesion period, manual performance in the ipsilesional hand is correlated with the extent of functional recovery in the contralesional hand. To this aim, ten adult macaque monkeys were subjected to permanent unilateral motor cortex lesion. Monkeys' manual performance was assessed for each hand during several months postlesion, using our standard behavioral test (modified Brinkman board task) that provides a quantitative measure of reach and grasp ability. The ipsilesional hand's performance was found to be significantly enhanced over the long term (100-300 days postlesion) in six of ten monkeys, with the six exhibiting the best, though incomplete, recovery of the contralesional hand. There was a statistically significant correlation (r = 0.932; P < 0.001) between performance in the ipsilesional hand after significant postlesion period and the extent of recovery of the contralesional hand. This observation is interpreted in terms of different possible mechanisms of recovery, dependent on the recruitment of motor areas in the lesioned and/or intact hemispheres.

Survival of neurally induced mesenchymal cells may determine degree of motor recovery in injured spinal cord rats

We recently developed a new method for efficient generation of neural-like cells from mice bone marrow (BM)-derived mesenchymal stem cells (MSC) by exposing MSCs to epigenetic modifiers and a neural stem cell environment. These neurally induced MSCs (NI-MSCs) differentiate into neuronal- and glial-like cells in vitro, release neurotrophic factors NGF and BDNF, survive and integrate after transplantation in intact spinal cord. The aim of this study was to determine whether transplanted NI-MSCs survive, differentiate, and integrate in injured spinal cord (ISC) rats and promote functional recovery. Twenty rats, half grafted with MSCs and half with NI-MSCs, were used for survival and differentiation studies. Results were analyzed using triple-labeled immunohistochemistry. For motor function studies the 3 group of adult female Sprague Dawley rats received PBS (vehicle), MSCs, or NI-MSCs, respectively. Functional outcome was measured using the BBB scale. Results demonstrated gradual improvement of locomotor function in NI-MSC-transplanted rats in comparison to vehicle and non-modified MSC-transplanted animals, with statistically significant differences at 7, 14, and 21 days post transplantation. Immunocytochemical studies revealed poor survival of NI-MSCs within the ISC as early as 3 weeks after transplantation. Thus, there is a correlation between the degree of surviving NI-MSCs and extent of functional recovery.

Cardioprotection of neonatal heart using normothermic hyperkalaemia: the importance of delivery and terminal cardioplegia

Cardioprotection of immature hearts remains controversial and largely based on the use of hypothermic cardioplegia. Recent clinical trials in pediatric open-heart surgery suggest that normothermic cardioplegic arrest is also cardioprotective. However, the advantages of using normothermic cardioplegia delivered as single- or multi-dose with or without terminal cardioplegia are unknown. This work investigates the efficacy of these techniques and the mechanism(s) underlying their protective effect. Neonatal (7-10 days) rabbit hearts in a working mode were exposed to normothermic global ischemia (60 or 90 min) protected with one of the following cardioplegic (hyperkalaemic buffer) protocols: single-dose, multi-dose infused every 30 min, single-dose or multi-dose with terminal cardioplegia. The extent of functional recovery (e.g., aortic and coronary flow), ischemic stress (e.g., myocardial ATP, lactate) and reperfusion injury (lactate dehydrogenase (LDH) release) were assessed. Recovery following 60 min global ischemia was improved (p < 0.05) by single-dose and multi-dose cardioplegic delivery (from 5% to 60% and 80%, respectively). Improved recovery was augmented by 2 min terminal cardioplegia (to 90% and 97% for single-dose and multi-dose, respectively). Extending ischemia to 90 min with single-dose resulted in 0% recovery that was not improved by 2 min terminal cardioplegia. However, 5 min (not 10 min) terminal cardioplegia significantly improved recovery (32%). Multi-dose followed by 5 min terminal cardioplegia resulted in full recovery. Cardioprotective interventions were associated with a reduction in LDH release and attenuated changes in myocardial metabolites. During normothermic cardioplegic arrest of neonatal heart: (i) multi-dose is superior to single-dose; (ii) terminal cardioplegia confers additional protection to single-dose and multi-dose; and (iii) protection is likely to be due to metabolic preservation.

Recovery of canine retina and optic nerve function after acute elevation of intraocular pressure: implications for canine glaucoma treatment

To characterize the timing and extent of functional recovery in healthy canine eyes exposed to acute elevation of intraocular pressure (IOP). Acute elevation of IOP was induced in 14 healthy Beagles by elevating IOP above the levels of systolic blood pressure for 60 min (average elevation was between 100 and 160 mmHg). Menace, dazzle and pupillary light reflexes (PLR) were tested at 1, 7, 14 and 28 days post elevation. Optical coherence tomography was used to evaluate retinal thickness preoperatively and at 15 and 30 days post elevation. One day post elevation all animals were blind in the operated eye (no positive menace), 5/14 had positive PLR and 10/14 had positive dazzle response. Seven days post elevation 4/14 animals had positive menace response and all animals (14/14) had positive dazzle and PLR responses. Fourteen and 28 days post elevation all animals had positive menace, PLR and dazzle responses. Optical coherence tomography analysis revealed significant thinning of the inferior retina (pre elevation: 156.3 +/- 4.8 microm; 15 days post elevation: 125 +/- 10.4 microm; 30 days post elevation 123 +/- 11.9 microm; P < 0.01, anova). The superior retina, however, did not show any detectable decrease in thickness compared to control eyes (pre elevation: 193.8 +/- 2.6 microm; 15 days post elevation: 176.9 +/- 8.5 microm; 30 days post elevation 176.9 +/- 7 microm; P = 0.057, anova). Detailed functional and morphologic analysis revealed precise information about retinal damage after acute elevation of IOP. Canine retina has the capacity to recover at least some visual function even at 14 days after acute elevation of the IOP. More aggressive medical and surgical treatment of canine glaucomatous patients may be indicated despite complete loss of visual function, PLR and dazzle responses in early days after development of an acute glaucomatous attack.

Strategies for axonal repair in central nervous system diseases

Significant functional recovery after spinal cord injury can be observed in rodents, in spite of the presence of extensive irreversible structural damage. One potential mechanism for functional regeneration of the corticospinal tract may involve the formation of new spinal circuits remote from the lesion that allow the lesion site to be by-passed and contact re-established with the original targets of the transected axons. In both traumatic and inflammatory lesions of the spinal cord, transection at the thoracic level is followed by extensive collateral sprouting at higher levels of the spinal cord. These collaterals can make contact with long propriospinal neurones in the cervical cord, which project to the lumbar ventral horn via the ventral funiculus. These new connections can serve as a ‘bridge’ to reconnect the corticospinal neurone to its target anterior horn cell. The integrity of this circuitry has been demonstrated by retrograde tracing with pseudorabies virus. Recuperation of electromyographic activity following stimulation of the motor cortex indicates that these new spinal circuits are functionally active. Such remodelling of spinal circuitry following spinal injury may play an important role in determining the extent of functional recovery.