Initial Impairment Research Articles

Sensitivity to change and responsiveness of the Segmental Assessment of Trunk Control (SATCo) in children with spinal cord injury

ABSTRACTPurpose: The purpose of this study was to assess the sensitivity and responsiveness of the Segmental Assessment of Trunk Control (SATCo) for evaluating trunk control in children with spinal cord injury (SCI) receiving activity-based locomotor training (AB-LT).Methods: Prospective study of nine outcomes for consecutively enrolled children in outpatient AB-LT. To evaluate sensitivity to change, linear-mixed models were constructed and adjusted for covariates: age at and time since SCI. To evaluate responsiveness, standardized response means and 95% confidence intervals were estimated per outcome.Results: SATCo scores increased significantly (p < 0.05) regardless of chronicity, initial score, and injury level. The SATCo was the most responsive measure and the only outcome demonstrating a large effect size after 3 months of therapy.Conclusions: Children with SCI receiving AB-LT improved trunk control regardless of chronicity, initial impairment, or prior experience. SATCo sensitivity and responsiveness support its usefulness in measuring trunk control in children with SCI.

Using network analysis for the prediction of treatment dropout in patients with mood and anxiety disorders: A methodological proof-of-concept study

There are large health, societal, and economic costs associated with attrition from psychological services. The recently emerged, innovative statistical tool of complex network analysis was used in the present proof-of-concept study to improve the prediction of attrition. Fifty-eight patients undergoing psychological treatment for mood or anxiety disorders were assessed using Ecological Momentary Assessments four times a day for two weeks before treatment (3,248 measurements). Multilevel vector autoregressive models were employed to compute dynamic symptom networks. Intake variables and network parameters (centrality measures) were used as predictors for dropout using machine-learning algorithms. Networks for patients differed significantly between completers and dropouts. Among intake variables, initial impairment and sex predicted dropout explaining 6% of the variance. The network analysis identified four additional predictors: Expected force of being excited, outstrength of experiencing social support, betweenness of feeling nervous, and instrength of being active. The final model with the two intake and four network variables explained 32% of variance in dropout and identified 47 out of 58 patients correctly. The findings indicate that patients’ dynamic network structures may improve the prediction of dropout. When implemented in routine care, such prediction models could identify patients at risk for attrition and inform personalized treatment recommendations.

Early functional MRI activation predicts motor outcome after ischemic stroke: a longitudinal, multimodal study.

An accurate prediction of long term outcome after stroke is urgently required to provide early individualized neurorehabilitation. This study aimed to examine the added value of early neuroimaging measures and identify the best approaches for predicting motor outcome after stroke. This prospective study involved 34 first-ever ischemic stroke patients (time since stroke: 1-14 days) with upper limb impairment. All patients underwent baseline multimodal assessments that included clinical (age, motor impairment), neurophysiological (motor-evoked potentials, MEP) and neuroimaging (diffusion tensor imaging and motor task-based fMRI) measures, and also underwent reassessment 3 months after stroke. Bivariate analysis and multivariate linear regression models were used to predict the motor scores (Fugl-Meyer assessment, FMA) at 3 months post-stroke. With bivariate analysis, better motor outcome significantly correlated with (1) less initial motor impairment and disability, (2) less corticospinal tract injury, (3) the initial presence of MEPs, (4) stronger baseline motor fMRI activations. In multivariate analysis, incorporating neuroimaging data improved the predictive accuracy relative to only clinical and neurophysiological assessments. Baseline fMRI activation in SMA was an independent predictor of motor outcome after stroke. A multimodal model incorporating fMRI and clinical measures best predicted the motor outcome following stroke. fMRI measures obtained early after stroke provided independent prediction of long-term motor outcome.

Synergistic Effects of Enriched Environment and Task-Specific Reach Training on Poststroke Recovery of Motor Function.

Reach training in concert with environmental enrichment provides functional benefits after experimental stroke in rats. The present study extended these findings by assessing whether intensive task-specific reach training or enrichment initiated alone would provide similar functional benefit. Additionally, we investigated whether the 70% recovery rule, or a combined model of initial poststroke impairment, cortical infarct volume, and rehabilitation intensity, could predict recovery in the single-pellet task, as previously found for the Montoya staircase. Rats were trained on single-pellet reaching before middle cerebral artery occlusion via intracerebral injection of ET-1 (endothelin-1). There were 4 experimental groups: stroke+enrichment, stroke+reaching, stroke+enrichment+reaching, and sham+enrichment+reaching. Reaching rehabilitation utilized a modified Whishaw box that encouraged impaired forelimb reaching for 6 hours per day, 5 days per week, for 4 weeks. All treatment paradigms began 7 days after ischemia with weekly assessment on the single-pellet task during rehabilitation and again 4 weeks after rehabilitation concluded. Rats exposed to the combination of enrichment and reaching showed the greatest improvement in pellet retrieval and comparable performance to shams after 3 weeks of treatment, whereas those groups that received a monotherapy remained significantly impaired at all time points. Initial impairment alone did not significantly predict recovery in single-pellet as the 70% rule would suggest; however, a combined model of cortical infarct volume and rehabilitation intensity predicted change in pellet retrieval on the single-pellet task with the same accuracy as previously shown with the staircase, demonstrating the generalizability of this model across reaching tasks. Task-specific reach training and environmental enrichment have synergistic effects in rats that persist long after rehabilitation ends, and this recovery is predicted by infarct volume and rehabilitation intensity.

Pycnogenol® supplementation in minimal cognitive dysfunction.

Impairments in cognitive function are difficult to evaluate and measure. In most cases, subjects do not perceive any alteration in their own status, particularly in case of mild cognitive impairment. In case of minimal alterations of cognitive function, no real treatment exists at the moment. Functional and/or temporary alterations in the cerebral microcirculation may be involved in cognitive impairment, and some aspects of MCI may be theoretically caused by perfusional problems. Metabolic problems and sleep disturbances can also be associated to cognitive impairment. Pycnogenol® (Horphag) is a natural compound extracted from the bark of French maritime pine, and it is a highly standardized supplement. The aim of this registry was to evaluate the effects of supplementation with Pycnogenol® over a two-month-period in otherwise healthy individuals with minimal cognitive impairment and initial cognitive dysfunction selected on the basis of their MMSE score. Eighty-seven healthy subjects with a MMSE score ranging from 18 to 23 (mild impairment) were included. Their BMI was <26 kg/m2, and no metabolic disorders were present. Participants were divided into two groups: one group was treated with standard management (SM) only (N.=44), whereas the other group received Pycnogenol® supplementation (150 mg/day) in addition to SM (N.=43). In the Pycnogenol® group MMSE score at inclusion was on average 21.64±1.5; after 8 weeks of supplementation, the average MMSE score increased significantly to 25.64±1.4 (P<0.05). In controls, the initial MMSE score was 22.43±1.2, comparable to the supplement group; however, in these subjects it did not show significant improvement after 8 weeks (average after treatment: 23.00±1.3). The median increase was 18% with Pycnogenol® vs. 2.48% in the SM group (P<0.05). Pycnogenol® has shown a large number of positive effects in subjects with initial cognitive impairment, due to its effects on oxidative stress levels. The safety and tolerability of Pycnogenol® are good, and thus the supplementation regimen should be tested in larger studies with a longer follow-up.

Acute prediction of outcome and cognitive-communication impairments following traumatic brain injury: The influence of age, education and site of lesion

BackgroundCommunication impairment following a traumatic brain injury (TBI) has been well documented, yet information regarding communication skills in the acute period following the injury is limited in the literature. Also, little is known about the influence of TBI severity (mild, moderate or severe) on cognitive-communication impairments and how these impairments are related to short-term functional outcome. The goal of this study was to assess the performance of adults with mild, moderate and severe TBI on different language tests and to determine how this performance is related to functional capacity. We also aimed to explore which variables among age, sex, education, TBI severity and site of cerebral damage would predict initial language impairments. MethodsSeveral language tests were administered to a sample of 145 adult patients with TBI of a range of severities admitted to an acute care service and to 113 healthy participants from the community. ResultsTBI patients of a range of severities performed poorly on all language tests in comparison to the healthy controls. In addition, patients with mild TBI performed better than the moderate and severe groups, except on the reading test and on the semantic naming test. In addition, their performance on verbal fluency, conversational discourse and procedural discourse tasks predicted acute functional outcome. Finally, age, education and TBI severity and site of lesion predicted some language performance. A left temporal lesion was associated with poorer performance in conversational discourse and auditory comprehension tasks, a left frontal lesion with a decrease in the verbal fluency results and a right parietal lesion with decreased auditory comprehension and reasoning skills. ConclusionHealth care professionals working in the acute care setting should be aware of the possible presence of cognitive-communication impairments in patients with TBI, even for those with mild TBI. These deficits can lead to functional communication problems and assistance may be required for tasks frequently encountered in acute care requiring intact comprehension and expression.

Genome-wide Translation Profiling by Ribosome-Bound tRNA Capture

In the ribosome complex, tRNA is a critical element of mRNA translation. A rich repertoire of cell regulation is hypothesized to occur during the recruitment of specific tRNAs in polypeptide formation. However, this basic question in nascent chain biology remains unaddressed due to the lack of technologies to report the complete tRNA complement inside ribosomes during active translation. Here, we characterize a technique for profiling ribosome-embedded tRNA and their modifications. With this method, wegenerated a comprehensive survey of the quantity and quality of intra-ribosomal tRNAs. In cells underenvironmental stress, we show that methionine tRNA inside ribosomes is a robust biomarker for the impairment of translation initiation or elongation steps. Concurrent tRNA/mRNA ribosome profiling revealed a stress-dependent incorporation of damaged and uncharged tRNAs into ribosomes causing translation arrest. Thus, tRNA ribosome profiling can provide insights on translation control mechanisms in diverse biological contexts.

Absence of the Na‐Glucose Cotransporter SGLT1 Ameliorates Kidney Recovery in a Murine Model of Acute Kidney Injury

The renal Na‐glucose cotransporter SGLT1 reabsorbs ~3% of the filtered glucose in the late proximal tubule, a hypoxia‐sensitive tubular segment that enters the outer medulla. Pharmacological blockade of SGLT2, which in the early proximal tubule reabsorbs most of the filtered glucose, was found protective in a mouse model of acute kidney injury (AKI) induced by ischemia‐reperfusion (IR). Since little is known about the role of SGLT1 in this context, we determined whether lack of SGLT1 affects kidney injury or recovery following IR.SGLT1‐knockout (KO) and WT mice (C57BL/6J males) underwent IR or sham surgery. IR was induced by 20 minutes of bilateral renal artery clamping, while body temperature was maintained at 36–37□. Sham operation was similar to IR surgery without artery clamping. All groups (WT Sham, WT IR, SGLT1‐KO Sham and SGLT1‐KO IR, n=7–8/group) were fed a low‐glucose high‐protein diet to prevent diarrhea in SGLT1‐KO. Urine and blood were collected at several time points during recovery. GFR was measured 14 days after IR by plasma elimination kinetics of FITC‐sinistrin in conscious mice. Kidneys were harvested on day 16.On day 1 after IR, plasma creatinine (by LC‐MS‐MS) increased to similar levels in SGLT1‐KO and WT (0.554±0.08 vs. 0.470±0.1 mg/dL, p=0.351), indicating similar initial kidney impairment. In accordance, IR reduced urine osmolality and increased plasma osmolality to similar levels in SGLT1‐KO and WT on day 1, possibly as a consequence of impaired urine concentration or renal retention of waste products. This was associated with a greater increase in fractional glucose excretion in SGLT1‐KO (1 to 19%) vs WT (0.1 to 7%) (p=0.003) indicating a prominent role of SGLT1 in glucose reabsorption at this time point. On day 14, GFR was significantly lower in WT IR vs SGLT1‐KO IR (6.56±0.6 vs. 9.13±0.8 μL/min/g BW, p&lt;0.05), associated with higher plasma creatinine levels on harvest day (0.130±0.016 vs. 0.093±0.009 mg/dL, p&lt;0.05). Moreover, plasma osmolality remained elevated in WT IR but was normalized in SGLT1‐KO IR on day 16 (345±11 vs. 316±4 mosm/kg, p=0.006). On day 16, plasma urea levels in sham groups were higher in SGLT1 KO vs WT (18.0±0.3 vs. 13.2±0.9 mmol/L, p=0.028), possibly reflecting a proposed role of SGLT1 in renal urea secretion, unmasked by high protein diet. Plasma urea was strongly increased in WT IR vs sham (24.6±2.2 vs. 13.2±0.9 mmol/L, p&lt;0.001), whereas levels were preserved in SGLT1‐KO IR vs sham. RT‐qPCR analyses on whole kidney tissue revealed that Na‐2Cl‐K cotransporter NKCC2 mRNA expression was decreased in WT IR but preserved in SGLT1‐KO IR, whereas renal mRNA expression of markers of injury, fibrosis and inflammation (KIM‐1, type 1 collagen, MCP‐1) was lower in SGLT1‐KO IR vs WT IR.Lack of SGLT1 improved kidney recovery in a mouse model of IR‐induced AKI. The results may reflect a deleterious role of SGLT1 activity in the late proximal tubule for outer medullary integrity in the aftermath of IR‐induced AKI. This may impair tubular function (reduced NKCC2) with consequences on GFR, kidney integrity, and body homeostasis, and have therapeutical implications.Support or Funding InformationNIH R01DK106102, R01DK112042, P30DK079337, and the Department of Veterans AffairsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

TAR DNA-Binding Protein 43 and Disrupted in Schizophrenia 1 Coaggregation Disrupts Dendritic Local Translation and Mental Function in Frontotemporal Lobar Degeneration

BackgroundNeurodegenerative diseases involving protein aggregation often accompany psychiatric symptoms. Frontotemporal lobar degeneration (FTLD) associated with TAR DNA-binding protein 43 (TDP-43) aggregation is characterized by progressive neuronal atrophy in frontal and temporal lobes of cerebral cortex. Furthermore, patients with FTLD display mental dysfunction in multiple behavioral dimensions. Nevertheless, their molecular origin for psychiatric symptoms remains unclear. MethodsIn FTLD neurons and mouse models with TDP-43 aggregates, we examined coaggregation between TDP-43 and disrupted in schizophrenia 1 (DISC1), a key player in the pathology of mental conditions and its effects on local translation in dendrites and psychiatric behaviors. The protein coaggregation and the expression level of synaptic proteins were also investigated with postmortem brains from patients with FTLD (n = 6). ResultsWe found cytosolic TDP-43/DISC1 coaggregates in brains of both FTLD mouse model and patients with FTLD. At the mechanistic levels, the TDP-43/DISC1 coaggregates disrupted the activity-dependent dendritic local translation through impairment of translation initiation and, in turn, reduced synaptic protein expression. Behavioral deficits detected in FTLD model mice were ameliorated by exogenous DISC1 expression. ConclusionsOur findings reveal a novel role of the aggregate-prone TDP-43/DISC1 protein complex in regulating local translation, which affects aberrant behaviors relevant to multiple psychiatric dimensions.

Axial diffusivity changes in the motor pathway above stroke foci and functional recovery after subcortical infarction.

Secondary degeneration of the fiber tract of the motor pathway below infarct foci and functional recovery after stroke have been well demonstrated, but the role of the fiber tract above stroke foci remains unclear. This study aimed to investigate diffusion changes in motor fibers above the lesion and identify predictors of motor improvement within 12 weeks after subcortical infarction. Diffusion tensor imaging and the Fugl-Meyer (FM) scale were conducted 1, 4, and 12 weeks (W) after a subcortical infarct. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Region of interest analysis was used to assess diffusion changes in the motor pathway above and below a stroke lesion. Multivariable linear regression was employed to identify predictors of motor improvement within 12 weeks after stroke. Axial diffusivity (AD) in the underlying white matter of the ipsilesional primary motor area (PMA) and cerebral peduncle (CP) in both proportional and poor recovery groups was lower at W1 compared to the controls and values in the contralesional PMA and CP (all P < 0.05). Subsequently, AD in the ipsilesional CP became relatively stable, while AD in the ipsilesional PMA significantly increased from W4 to W12 after stroke (P < 0.05). In all of the patients, changes in the FM scores were greater in those with higher changes in AD of the ipsilesional PMA. Only initial impairment or lesion volume was predictive of motor improvement within 12 weeks after stroke in patients with proportional or poor recovery. Increases of AD in the motor pathway above stroke foci may be associated with motor recovery after subcortical infarction. Early measurement of diffusion metrics in the ipsilesional non-ischemic motor pathway has limited value in predicting future motor improvement patterns (proportional or poor recovery).

Predicting recovery in acute poststroke aphasia.

Many stroke patients show remarkable recovery of language after initial severe impairment, but it is difficult to predict which patients will show good recovery. We aimed to identify patient and lesion characteristics that together predict the best naming outcome in 4 studies. We report 2 longitudinal studies that identified 2 variables at onset that were strongly associated with good recovery of naming (the most common residual deficit in aphasia) in the first 6 months after stroke: damage to left posterior superior temporal gyrus (pSTG) and/or superior longitudinal fasciculus/arcuate fasciculus (SLF/AF), and selective serotonin reuptake inhibitor (SSRI) use. We then tested these variables in 2 independent cohorts of chronic left hemisphere stroke patients, using chi-square tests and multivariate logistic regression for dichotomous outcomes and t tests for continuous outcomes. Lesion load in left pSTG and SLF/AF was associated with poorer naming outcome. Preservation of these areas and use of SSRIs were associated with naming recovery, independent of lesion volume, time since stroke, and depression. Patients with damage to these critical areas showed better naming outcome if they took SSRIs for 3 months after stroke. Those with preservation of these critical areas achieved good recovery of naming regardless of SSRI use. Lesion load in left pSTG and SLF/AF at onset predicts later naming performance. Although based on a small number of patients, our preliminary results suggest outcome might be modulated by SSRIs, but these associations need to be confirmed in a larger randomized controlled trial. Ann Neurol 2018;83:612-622.

Maladaptive Personality Traits and 10-Year Course of Psychiatric and Medical Symptoms and Functional Impairment Following Trauma.

Personality is a major predictor of many mental and physical disorders, but its contributions to illness course are understudied. The current study aimed to explore whether personality is associated with a course of psychiatric and medical illness over 10 years following trauma. World Trade Center (WTC) responders (N = 532) completed the personality inventory for DSM-5, which measures both broad domains and narrow facets. Responders' mental and physical health was assessed in the decade following the WTC disaster during annual monitoring visits at a WTC Health Program clinic. Multilevel modeling was used in an exploratory manner to chart the course of health and functioning, and examine associations of maladaptive personality domains and facets with intercepts (initial illness) and slopes (course) of illness trajectories. Three maladaptive personality domains-negative affectivity, detachment and psychoticism-were uniquely associated with initial posttraumatic stress disorder (PTSD); detachment and psychoticism were also associated with initial functional impairment. Five facets-emotional lability, anhedonia, callousness, distractibility and perceptual dysregulation-were uniquely associated with initial mental and physical health and functional impairment. Anxiousness and depressivity facets were associated with worse initial levels of psychiatric outcomes only. With regard to illness trajectory, callousness and perceptual dysregulation were associated with the increase in PTSD symptoms. Anxiousness was associated with greater persistence of respiratory symptoms. Several personality domains and facets were associated with initial levels and long-term course of illness and functional impairment in a traumatized population. Results inform the role of maladaptive personality in the development and maintenance of chronic mental-physical comorbidity. Personality might constitute a transdiagnostic prognostic and treatment target.

Abstract 21: Motor Tract Impairment is an Independent Predictor of Lower Limb Motor Recovery

Introduction: Initial motor impairment assessed in the acute stroke phase (as measured by the Fugl-Meyer (FM) Assessment) is a strong predictor of lower extremity (LE) motor impairment at 3 months (Smith et al., 2017). The predictive value of measures of motor tract integrity, lesion size and location is not known. For our analysis we combined two motor tracts that might be particularly important in the control of proximal leg muscles to create a canonical tract of the corticospinal tract proper (CST) and the corticorubrospinal tract (CRST)(Lindenberg et al., 2010; Rueber et al., 2012). In previous work (Feng et al., 2015) we have shown that weighted CST-Lesion Load (a combined variable of lesion size and location) is a significant predictor of 3 months outcome for the UE. Hypothesis: Weighted CST-CRST Lesion-Load (wCST/CRST-LL) can improve the FM-based predictions of lower limb motor recovery. Methods: Ischemic stroke patients with a upper limb paresis (UE-FM&lt;66) and lower limb paresis (LE-FM&lt;34) were assessed between 48-72h and 3 months poststroke with the FM scale. Lesion maps drawn on diffusion-weighted images were used to calculate lesion loads of a combined CST-CRST probabilistic tract derived from matched elderly healthy control subjects. Then, several variables that have been shown to predict outcome (e.g., FM, lesion load, age, hemisphere) were subjected to individual regression analyses. Significant variables (at p&lt;0.05) were entered into a multiple regression model to assess predictors of lower limb motor recovery (i.e., actual difference in LE-FM between 3 months and initial stroke phase assessment). Results: Both baseline and 3-months follow-up were available for 134 patients. Initial motor impairment (FM-LE) and wCST/CRST-LL were independent strong predictors of lower limb motor recovery (respectively p&lt;0.0001 and p=0.0005). Combining initial motor impairment and wCST/CRST lesion load was a much better model than FM-LE by itself (respectively R2=0.43 and R2=0.46, p=0.003) which was confirmed by the Akaike Information Criterion (AIC). Conclusion: wCST/CRST-LL, a combined measure of lesion size/location, adds significant power to a combined model with FM, but is also a strong predictor of lower limb motor recovery by itself.

Circadian dysfunction and fluctuations in gait initiation impairment in Parkinson's disease.

In people with Parkinson's disease (PD), anticipatory postural adjustments may be prolonged, reduced in amplitude, or absent, contributing to impaired gait initiation. In addition to motor symptoms, disturbance of the circadian rhythm (CR) is one of the common non-motor symptoms of PD. The purpose of this study was to investigate whether time of day modulates the magnitude of gait initiation impairment, and furthermore, if there is any relationship between CR dysfunction and impaired postural control in PD. Seven consecutive 24-h periods of wrist actigraphy (as a measure of CR), and then gait initiation studies (at two different times, 9:00a.m. and 2:30p.m., of the same day) were conducted in two cohorts of ten subjects each: people with PD, and age-matched control subjects. We found that in the PD group, the amplitude of medial/lateral center of pressure (CoP) excursions were significantly reduced in the afternoon as compared with the morning session across all trials (p < 0.05). Actigraphy results showed that CR amplitude was significantly decreased (p < 0.05) in the PD group, which suggests that the PD group suffered from CR disruption. More importantly, changes in medial/lateral CoP displacement were correlated with abnormal CR amplitude in the PD group. These findings provide novel evidence that diurnal fluctuations in treatment-resistant motor symptoms of PD, such as postural and gait initiation deficits, are associated with CR dysfunction. This study supports the idea that therapeutic correction of circadian misalignment should be considered in combination with pharmaceutical and rehabilitation treatments of motor symptoms in PD.

Does Stroke Rehabilitation Really Matter? Part A: Proportional Stroke Recovery in the Rat

Background. In human upper-limb stroke, initial level of functional impairment or corticospinal tract injury can accurately predict the degree of poststroke recovery, independent of rehabilitation practices. This proportional recovery rule implies that current rehabilitation practices may play little or no role in brain repair, with recovery largely a result of spontaneous biological recovery processes. Objective. The present study sought to determine if similar biomarkers predict recovery of poststroke function in rats, indicating that an endogenous biological recovery process might be preserved across mammalian species. Methods. Using a cohort of 593 male Sprague-Dawley rats, we predicted poststroke change in pellet retrieval in the Montoya staircase-reaching task based on initial impairment alone. Stratification of the sample into “fitters” and “nonfitters” of the proportional recovery rule using hierarchical cluster analysis allowed identification of distinguishing characteristics of these subgroups. Results. Approximately 30% of subjects were identified as fitters of the rule. These rats showed recovery in proportion to their initial level of impairment of 66% (95% CI = 62%-70%). This interval overlaps with those of multiple human clinical trials. A number of variables, including less severe infarct volumes and initial poststroke impairments distinguished fitters of the rule from nonfitters. Conclusions. These findings suggest that proportional recovery is a cross-species phenomenon that can be used to uncover biological mechanisms contributing to stroke recovery.

Does Stroke Rehabilitation Really Matter? Part B: An Algorithm for Prescribing an Effective Intensity of Rehabilitation

Background. The proportional recovery rule suggests that current rehabilitation practices may have limited ability to influence stroke recovery. However, the appropriate intensity of rehabilitation needed to achieve recovery remains unknown. Similarities between rodent and human recovery biomarkers may allow determination of rehabilitation thresholds necessary to activate endogenous biological recovery processes. Objective. We determined the relative influence that clinically relevant biomarkers of stroke recovery exert on functional outcome. These biomarkers were then used to generate an algorithm that prescribes individualized intensities of rehabilitation necessary for recovery of function. Methods. A retrospective cohort of 593 male Sprague-Dawley rats was used to identify biomarkers that best predicted poststroke change in pellet retrieval in the Montoya staircase-reaching task using multiple linear regression. Prospective manipulation of these factors using endothelin-1-induced stroke (n = 49) was used to validate the model. Results. Rehabilitation was necessary to reliably predict recovery across the continuum of stroke severity. As infarct volume and initial impairment increased, more intensive rehabilitation was required to engage recovery. In this model, we prescribed the specific dose of daily rehabilitation required for rats to achieve significant motor recovery using the biomarkers of initial poststroke impairment and infarct volume. Conclusions. Our algorithm demonstrates an individualized approach to stroke rehabilitation, wherein imaging and functional performance measures can be used to develop an optimized rehabilitation paradigm for rats, particularly those with severe impairments. Exploring this approach in human patients could lead to an increase in the proportion of individuals experiencing recovery of lost motor function poststroke.

Essential Dynamic Transformation as Specific Highly Characterizable Indices of Progression of the Initial Mild Cognitive Impairment Phase of Alzheimer Patients

Essential Dynamic Transformation as Specific Highly Characterizable Indices of Progression of the Initial Mild Cognitive Impairment Phase of Alzheimer Patients

Longitudinal imaging of reading and naming recovery after stroke

ABSTRACTBackground: Functional neuroimaging techniques can provide a unique window into the neural basis of language recovery after a stroke. The functional neuroimaging literature on post-stroke language recovery is complex; multiple factors such as the time post-stroke, degree of initial impairment, nature of the task, and lesion location and size influence recovery patterns. Some of these factors may not be applicable across different stroke participants, and therefore, influence recovery trajectories in vastly different manners across patients.Aims: The aim of this paper is to examine longitudinal changes in brain activation patterns of reading and naming recovery in participants with posterior cerebral artery (PCA) strokes with varying degrees of initial language impairment.Methods & Procedures: Five participants with PCA strokes and five healthy controls underwent language testing and functional MRI with a covert reading task and an overt picture-naming task.Stroke participants underwent language testing and scanning at the three time points: 2–5 weeks (T1, subacute phase), 4–7 months (T2, chronic phase), and 11–13 months (T3, chronic phase). Healthy controls underwent language testing and fMRI once.Outcomes & Results: Language testing indicated that there were varying degrees of reading and naming recovery or decline from the subacute to the chronic phase. With regard to task-based fMRI, we found that for most participants, naming consistently activated a diffuse bilateral network of frontal, temporal, parietal, and occipital regions across the three time points. In contrast, for the reading task, functional activation across the three time points was more left lateralized with a right to left shift in peak activation from the subacute to the chronic phase.Conclusions: These results indicate that the patterns of activation during language processing is highly dependent on the task and phase of recovery, and these results may have implications for neurally targeted non-invasive brain stimulation techniques.

Health-Related Quality of Life in an Inception Cohort of Children With Juvenile Idiopathic Arthritis: A Longitudinal Analysis.

To describe changes in health-related quality of life (HRQoL) over time in children with juvenile idiopathic arthritis (JIA), relative to other outcomes, and to identify predictors of unfavorable HRQoL trajectories. Children with JIA in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort were included. The Juvenile Arthritis Quality of Life Questionnaire (JAQQ, a standardized instrument), health-related Quality of My Life (HRQoML, an instrument based on personal valuations), and JIA core variables were completed serially. Analyses included median values, Kaplan-Meier survival curves, and latent trajectory analysis. A total of 1,249 patients enrolled at a median of 0.5 months after diagnosis were followed for a median of 34.2 months. The degree of initial HRQoL impairment and probabilities of reaching the best possible HRQoL scores varied across JIA categories (best for oligoarthritis, worst for rheumatoid factor-positive polyarthritis). Median times to attain best possible HRQoL scores (JAQQ 59.3 months, HRQoML 34.5 months), lagged behind those for disease activity, pain, and disability measures. Most patients followed trajectories with minimal or mild impairment; however, 7.6% and 13.8% of patients, respectively, followed JAQQ and HRQoML trajectories with persistent major impairment in HRQoL. JIA category, aboriginal ethnicity, and baseline disease activity measures distinguished between membership in trajectories with major and minimal impairments. Improvement in HRQoL is slower than for disease activity, pain, and disability. Improvement of a measure based on respondents' preferences (HRQoML) is more rapid than that of a standardized measure (JAQQ). Higher disease activity at diagnosis heralds an unfavorable HRQoL trajectory.

Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension.

It is widely accepted that impaired bioavailability of endothelial nitric oxide (NO) plays a critical role in the pathophysiology of pulmonary arterial hypertension (PAH). However, there are published data that show that relatively many PAH patients respond favorably to acetylcholine‐induced pulmonary vasodilation during their follow‐up period, when diverse stages of the disorder are included. We hypothesized that NO bioavailability varies depending on the progression of PAH. Adult rats were exposed to the VEGF receptor blocker Sugen5416 and 3 weeks of hypoxia followed by return to normoxia for various additional weeks. All rats developed increased right ventricular systolic pressure (RVSP) and occlusive lesion formation at 1, 3, 5, and 8 weeks after the Sugen5416 injection. Acute NO synthase blockade did not change the elevated RVSP at the 1‐week time point, while it further increased RVSP markedly at the 3‐, 5‐, and 8‐week time points, leading to death in all rats tested at 8 weeks. Acetylcholine caused significant reduction in RVSP at the 8‐week but not the 1‐week time point, whereas sodium nitroprusside decreased the pressure similarly at both time points. Increased NO‐mediated cGMP production was found in lungs from the 8‐week but not the 1‐week time point. In conclusion, despite its initial impairment, NO bioavailability is restored and endogenous NO plays a critical protective role by counteracting severe pulmonary vasoconstriction in established stages of PAH in the Sugen5416/hypoxia/normoxia‐exposed rats. Our results provide solid pharmacological evidence for a major contribution of a NO‐suppressed vasoconstrictor component in the pathophysiology of established PAH.