Abortive Infection of Animal Cells: What Goes Wrong.

Even if a virus successfully binds to a cell, defects in any of the downstream steps of the viral life cycle can preclude the production of infectious virus particles. Such abortive infections are likely common in nature and can provide fundamental insights into the cell and host tropism of viral pathogens. Research over the past 60 years has revealed an incredible diversity of abortive infections by DNA and RNA viruses in various animal cell types. Here we discuss the general causes of abortive infections and provide specific examples from the literature to illustrate the range of abortive infections that have been reported. We also discuss how abortive infections can have critical roles in shaping host immune responses and in the development of virus-induced cancers. Finally, we describe how abortive infections can be applied to basic and clinical research, underscoring the importance of understanding these fascinating aspects of virus biology.

Genome-wide CRISPR activation screen identifies JADE3 as an antiviral activator of NF-kB-dependent IFITM3 expression.

The innate immune system features a web of interacting pathways that require exquisite regulation. To identify novel nodes in this immune landscape, we conducted a gain-of-function, genome-wide CRISPR activation screen with influenza A virus. We identified both appreciated and novel antiviral genes, including Jade family PHD zinc finger 3 (JADE3) a protein involved in directing the histone acetyltransferase histone acetyltransferase binding to ORC1 complex to modify chromatin and regulate transcription. JADE3 is both necessary and sufficient to restrict influenza A virus infection. Our results suggest a distinct function for JADE3 as expression of the closely related paralogs JADE1 and JADE2 does not confer resistance to influenza A virus infection. JADE3 is required for both constitutive and inducible expression of the well-characterized antiviral gene interferon-induced transmembrane protein 3 (IFITM3). Furthermore, we find JADE3 activates the NF-kB signaling pathway, which is required for the promotion of IFITM3 expression by JADE3. Therefore, we propose JADE3 activates an antiviral genetic program involving NF-kB-dependent IFITM3 expression to restrict influenza A virus infection.

FEAR antiviral response pathway is independent of interferons and countered by poxvirus proteins.

The human facilitates chromatin transcription (FACT) complex is a chromatin remodeller composed of human suppressor of Ty 16 homologue (hSpt16) and structure-specific recognition protein-1 subunits that regulates cellular gene expression. Whether FACT regulates host responses to infection remained unclear. We identify a FACT-mediated, interferon-independent, antiviral pathway that restricts poxvirus replication. Cell culture and bioinformatics approaches suggest that early viral gene expression triggers nuclear accumulation of SUMOylated hSpt16 subunits required for the expression of E26 transformation-specific sequence-1 (ETS-1)-a transcription factor that activates virus restriction programs. However, biochemical studies show that poxvirus-encoded A51R proteins block ETS-1 expression by outcompeting structure-specific recognition protein-1 binding to SUMOylated hSpt16 and by tethering SUMOylated hSpt16 to microtubules. Furthermore, A51R antagonism of FACT enhances poxvirus replication in human cells and virulence in mice. Finally, we show that FACT also restricts rhabdoviruses, flaviviruses and orthomyxoviruses, suggesting broad roles for FACT in antiviral immunity. Our study reveals the FACT-ETS-1 antiviral response (FEAR) pathway to be critical for eukaryotic antiviral immunity and describes a unique mechanism of viral immune evasion.

Exploiting Bacterial Effector Proteins to Uncover Evolutionarily Conserved Antiviral Host Machinery.

Arboviruses are a diverse group of insect-transmitted pathogens that pose global public health challenges. Identifying evolutionarily conserved host factors that combat arbovirus replication in disparate eukaryotic hosts is important as they may tip the balance between productive and abortive viral replication, and thus determine virus host range. Here, we exploit naturally abortive arbovirus infections that we identified in lepidopteran cells and use bacterial effector proteins to uncover host factors restricting arbovirus replication. Bacterial effectors are proteins secreted by pathogenic bacteria into eukaryotic hosts cells that can inhibit antimicrobial defenses. Since bacteria and viruses can encounter common host defenses, we hypothesized that some bacterial effectors may inhibit host factors that restrict arbovirus replication in lepidopteran cells. Thus, we used bacterial effectors as molecular tools to identify host factors that restrict four distinct arboviruses in lepidopteran cells. By screening 210 effectors encoded by seven different bacterial pathogens, we identify six effectors that individually rescue the replication of all four arboviruses. We show that these effectors encode diverse enzymatic activities that are required to break arbovirus restriction. We further characterize Shigella flexneri-encoded IpaH4 as an E3 ubiquitin ligase that directly ubiquitinates two evolutionarily conserved proteins, SHOC2 and PSMC1, promoting their degradation in insect and human cells. We show that depletion of either SHOC2 or PSMC1 in insect or human cells promotes arbovirus replication, indicating that these are ancient virus restriction factors conserved across invertebrate and vertebrate hosts. Collectively, our study reveals a novel pathogen-guided approach to identify conserved antimicrobial machinery, new effector functions, and conserved roles for SHOC2 and PSMC1 in virus restriction.

Relationships between mediolateral step modulation and clinical balance measures in people with chronic stroke.

BACKGROUND: Many people with chronic stroke (PwCS) exhibit walking balance deficits linked to increased fall risk and decreased balance confidence. One potential contributor to these balance deficits is a decreased ability to modulate mediolateral stepping behavior based on pelvis motion. This behavior, hereby termed mediolateral step modulation, is thought to be an important balance strategy but can be disrupted in PwCS. RESEARCH QUESTION: Are biomechanical metrics of mediolateral step modulation related to common clinical balance measures among PwCS? METHODS: In this cross-sectional study, 93 PwCS walked on a treadmill at their self-selected speed for 3-minutes. We quantified mediolateral step modulation for both paretic and non-paretic steps by calculating partial correlations between mediolateral pelvis displacement at the start of each step and step width (ρSW), mediolateral foot placement relative to the pelvis (ρFP), and final mediolateral location of the pelvis (ρPD) at the end of the step. We also assessed several common clinical balance measures (Functional Gait Assessment [FGA], Activities-specific Balance Confidence scale [ABC], self-reported fear of falling and fall history). We performed Spearman correlations to relate each biomechanical metric of step modulation to FGA and ABC scores. We performed Wilcoxon rank sum tests to compare each biomechanical metric between individuals with and without a fear of falling and a history of falls. RESULTS: Only ρFP for paretic steps was significantly related to all four clinical balance measures; higher paretic ρFP values tended to be observed in participants with higher FGA scores, with higher ABC scores, without a fear of falling and without a history of falls. However, the strength of each of these relationships was only weak to moderate. SIGNIFICANCE: While the present results do not provide insight into causality, they justify future work investigating whether interventions designed to increase ρFP can improve clinical measures of post-stroke balance in parallel.

Genome-wide CRISPR activation screen identifies JADE3 as an antiviral activator of NF-kB.

The innate immune system features a web of interacting pathways that require exquisite regulation. To identify novel nodes in this immune landscape we conducted a gain of function, genome-wide CRISPR activation screen with influenza A virus. We identified both appreciated and novel antiviral genes, including JADE3 a protein involved in directing the histone acetyltransferase HBO1 complex to modify chromatin and regulate transcription. JADE3 is both necessary and sufficient to restrict influenza A virus infection. Interestingly, expression of the closely related paralogues JADE1 and JADE2 are unable to restrict influenza A virus infection, suggesting a distinct function of JADE3. We identify both shared and unique transcriptional signatures between uninfected cells expressing JADE3 and JADE2. These data provide a framework for understanding the overlapping and distinct functions of the JADE family of paralogues. Specifically, we find that JADE3 expression activates the NF-kB signaling pathway, consistent with an antiviral function. Therefore, we propose JADE3, but not JADE1 or JADE2, activates an antiviral genetic program involving the NF-kB pathway to restrict influenza A virus infection.

A FACT-ETS-1 Antiviral Response Pathway Restricts Viral Replication and is Countered by Poxvirus A51R Proteins.

The FACT complex is an ancient chromatin remodeling factor comprised of Spt16 and SSRP1 subunits that regulates specific eukaryotic gene expression programs. However, whether FACT regulates host immune responses to infection was unclear. Here, we identify an antiviral pathway mediated by FACT, distinct from the interferon response, that restricts poxvirus replication. We show that early viral gene expression triggers nuclear accumulation of specialized, SUMOylated Spt16 subunits of FACT required for expression of ETS-1, a downstream transcription factor that activates a virus restriction program. However, poxvirus-encoded A51R proteins block ETS-1 expression by outcompeting SSRP1 for binding to SUMOylated Spt16 in the cytosol and by tethering SUMOylated Spt16 to microtubules. Moreover, we show that A51R antagonism of FACT enhances both poxvirus replication in human cells and viral virulence in mice. Finally, we demonstrate that FACT also restricts unrelated RNA viruses, suggesting a broad role for FACT in antiviral immunity. Our study reveals the F ACT- E TS-1 A ntiviral R esponse (FEAR) pathway to be critical for eukaryotic antiviral immunity and describes a unique mechanism of viral immune evasion.

Transcranial Direct Current Stimulation Electrode Montages May Differentially Impact Variables of Walking Performance in Individuals Poststroke: A Preliminary Study.

PURPOSE: Transcranial direct current stimulation (tDCS) has mixed effects on walking performance in individuals poststroke. This is likely the result of variations in tDCS electrode montages and individualized responses. The purpose of this study was to quantify the effects of a single session of tDCS using various electrode montages on poststroke walking performance. METHODS: Individuals with chronic stroke ( n = 16) participated in a double-blind, randomized cross-over study with sham stimulation and three tDCS electrode montages. Gait speed, paretic step ratio, and paretic propulsion were assessed prestimulation and poststimulation at self-selected and fastest comfortable speeds. Changes in muscle activation patterns with self-selected walking were quantified by the number of modules derived from nonnegative matrix factorization of EMG signals for hypothesis generation. RESULTS: There was no significant effect of active stimulation montages compared with sham. Comparisons between each participant's best response to tDCS and sham show personalized tDCS may have a positive effect on fastest comfortable overground gait speed ( P = 0.084), paretic step ratio ( P = 0.095) and paretic propulsion ( P = 0.090), and self-selected paretic step ratio ( P = 0.012). Participants with two or three modules at baseline increased module number in response to the all experimental montages and sham, but responses were highly variable. CONCLUSIONS: A single session of tDCS may affect clinical and biomechanical walking performance, but effects seem to be dependent on individual response variability to different electrode montages. Findings of this study are consistent with responses to various tDCS electrode montages being the result of underlying neuropathology, and the authors recommend examining how individual factors affect responses to tDCS.

A feasibility study of objective outcome measures used in clinical trials of freezing of gait.

BACKGROUND: Freezing of gait (FOG) is notoriously difficult to quantify, which has led to the use of multiple markers as outcomes for clinical trials. The instrumented timed up and go (TUG) and the many parameters that can be derived from it are commonly used as objective markers of FOG severity in clinical trials; however, it is unknown if they represent actual FOG severity. OBJECTIVE: To determine the specificity and responsiveness of objective surrogate markers of FOG severity commonly utilized in FOG studies. METHODS: Study design: We compared the specificity and responsiveness of commonly used markers in FOG clinical trials. Markers compared included velocity, step/stride length, step/stride length variability, TUG, and turn duration. Data was collected in four conditions (ON and OFF dopaminergic drugs, with and without a dual task). Unified Parkinson's Disease Rating Scale (UPDRS) was administered in the ON and OFF states. RESULTS: Thirty-three subjects were recruited (17 PD subjects without FOG (PD-control) and 16 subjects with PD and dopa-responsive FOG PD-FOG). The UPDRS motor scores were 24.9 for the PD-control group in the ON state, 24.8 for the FOG group in the ON state, and 42.4 for the FOG group in the OFF state. Significant mean differences between the ON and OFF conditions were observed with all surrogate markers (p < 0.01). However, only dual task turn duration and step variability showed trends toward significance when comparing PD-control and ON-FOG (p = 0.08). Test-retest reliability was high (ICC > 0.90) for all markers except standard deviations. Step length variability was the only marker to show an area under the ROC curve analysis > 0.70 comparing ON-FOG vs. PD-control. CONCLUSIONS: Multiple candidate surrogate markers for FOG severity showed responsiveness to levodopa challenge; however, most were not specific for FOG severity.

Post-stroke deficits in mediolateral foot placement accuracy depend on the prescribed walking task.

People with chronic stroke (PwCS) are susceptible to mediolateral losses of balance while walking, possibly due in part to inaccurate control of mediolateral paretic foot placement. We hypothesized that mediolateral foot placement errors when stepping to stationary or shifting visual targets would be larger for paretic steps than for steps taken by neurologically-intact individuals, hereby referred to as controls. Secondarily, we hypothesized that paretic foot placement errors would be correlated with previously identified deficits in isolated paretic hip abduction accuracy. 34 PwCS and 12 controls walked overground on an instrumented mat used to quantify foot placement location relative to parallel lines separated by various widths (10, 20, 30 cm). With stationary step width targets, foot placement errors were larger for paretic steps than for either non-paretic or control steps, most notably for the narrowest prescribed step width (mean absolute errors of 3.9, 2.3, and 1.9 cm, respectively). However, no differences in foot placement accuracy were observed immediately following visual target shifts, as all groups required multiple steps to achieve the new prescribed step width. Paretic hip abduction accuracy was moderately correlated with mediolateral foot placement accuracy when stepping to stationary targets (r = 0.49), but not shifting targets (r = 0.16). The present results suggest that a reduced ability to accurately abduct the paretic leg contributes to inaccurate paretic foot placement. However, the need to ensure mediolateral walking balance through mechanically-appropriate foot placement may often override the prescribed goal of stepping to visual targets, a concern of particular importance for narrow steps.

Paired inhibitory stimulation and gait training modulates supplemental motor area connectivity in freezing of gait.

INTRODUCTION: Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD). Evidence suggests patients with FOG have increased cortical control of gait. The supplementary motor area (SMA) may be a key structure due to its connectivity with locomotor and cognitive networks. The objectives of this study were to determine (1) if SMA connectivity is disrupted in patients with FOG and (2) if "inhibitory" repetitive transcranial magnetic stimulation can decrease maladaptive SMA connectivity. METHODS: Two experiments were performed. In experiment 1 resting-state (T2* BOLD imaging) was compared between 38 PD freezers and 17 PD controls. In experiment 2, twenty PD patients with FOG were randomized to either 10 sessions of real or sham rTMS to the SMA (1 Hz, 110% motor threshold, 1200 pulses/session) combined with daily gait training. RESULTS: (Experiment 1) Freezers had increased connectivity between the left SMA and the vermis of the cerebellum and decreased connectivity between the SMA and the orbitofrontal cortex (pFDR-corr <0.05). (Experiment 2) 10 sessions of active TMS reduced SMA connectivity with the anterior cingulate, angular gyrus and the medial temporal cortex, whereas sham TMS did not reduce SMA connectivity. From a behavioral perspective, both groups showed nFOG-Q improvements (F(4, 25.7) = 3.87, p = 0.014). CONCLUSIONS: The SMA in freezers is hyper-connected to the cerebellum, a key locomotor region which may represent maladaptive compensation. In this preliminary study, 1 Hz rTMS reduced SMA connectivity however, this was not specific to the locomotor regions. Intervention outcomes may be improved with subject specific targeting of SMA.

Increased on-state cortico-mesencephalic functional connectivity in Parkinson disease with freezing of gait.

BACKGROUND: The objective of this study was to evaluate ON-state resting state functional connectivity (FC) from the mesencephalic locomotor regions (MLR) to distributed sensorimotor cortical regions in patients with Freezing of Gait (FOG) and its association with gait performance. METHODS: 54 individuals with PD were recruited for this study (50% of whom had FOG). All individuals received a resting state functional MRI in the ON state, and underwent a series of gait assessments during single and dual task conditions. FC with the MLR was calculated using a whole brain seed to voxel approach wherein the left and right MLR seeds were extracted from a published atlas. General linear regression was used to determine differences in connectivity between the individuals with ('freezers') and without ('non-freezers') FOG as well as the correlation between MLR connectivity and gait performance in the freezers. RESULTS: Freezers had significantly higher MLR connectivity to a network of sensorimotor regions compared to non-freezers. Additionally, among the freezers, higher FC with these regions was related to longer single-task and dual-task performance. There were no regions in which non-freezers had higher connectivity than freezers (p < 0.05, FWE corrected clusters for all analyses). CONCLUSION: These data support the hypothesis that freezers have significantly higher ON-state FC between the MLR and a network of cortical structures than non-freezers. Additionally, this elevated connectivity is directly related to worsening FOG severity. These data add to a theoretical foundation which suggests that cortical hyperconnectivity to the MLR is central to the underlying pathophysiology of FOG.

Post-stroke deficits in the step-by-step control of paretic step width.

BACKGROUND: Humans partially maintain gait stability by actively controlling step width based on the dynamic state of the pelvis - hereby defined as the "dynamics-dependent control of step width". Following a stroke, deficits in the accurate control of paretic leg motion may prevent use of this stabilization strategy. RESEARCH QUESTION: Do chronic stroke survivors exhibit paretic-side deficits in the dynamics-dependent control of step width? METHODS: Twenty chronic stroke survivors participated in this cross-sectional study, walking on a treadmill at their self-selected (0.57 ± 0.25 m/s; mean ± s.d.) and fastest-comfortable (0.81 ± 0.30 m/s) speeds. To quantify the dynamics-dependent control of step width, we calculated the proportion of the step-by-step variance in step width that could be predicted from mediolateral pelvis dynamics, and used partial correlations to differentiate the relative effects of pelvis displacement and velocity. Secondarily, we calculated the mean and standard deviation of more traditional gait metrics: step width; lateral foot placement; and mediolateral margin of stability (MoS). We used repeated measures ANOVA to test for significant effects of leg (paretic vs. non-paretic) and speed (self-selected vs. fastest-comfortable) on these measures. RESULTS: Relative to non-paretic steps, paretic steps exhibited a weaker (p ≤ 0.005) link between step width and pelvis dynamics, attributable to a decreased partial correlation between step width and pelvis displacement (p ≤ 0.001). Paretic steps were also placed more laterally (p < 0.0001), with a larger (p < 0.0001) and more variable (p = 0.003) MoS. The only effect of faster walking speeds was a narrower step width (p < 0.0001). SIGNIFICANCE: Pelvis displacement was less tightly linked to step width for paretic steps than for non-paretic steps, indicating a decrease in the step-by-step reactive control normally used to ensure mediolateral stability. Instead, stroke survivors placed their paretic leg farther laterally to ensure a larger MoS, behavior consistent with a greater reliance on a generalized feed-forward gait stabilization strategy.

FES-assisted Cycling Improves Aerobic Capacity and Locomotor Function Postcerebrovascular Accident.

PURPOSE: After a cerebrovascular accident (CVA) aerobic deconditioning contributes to diminished physical function. Functional electrical stimulation (FES)-assisted cycling is a promising exercise paradigm designed to target both aerobic capacity and locomotor function. This pilot study aimed to evaluate the effects of an FES-assisted cycling intervention on aerobic capacity and locomotor function in individuals post-CVA. METHODS: Eleven individuals with chronic (>6 months) post-CVA hemiparesis completed an 8-wk (three times per week; 24 sessions) progressive FES-assisted cycling intervention. V˙O2peak, self-selected, and fastest comfortable walking speeds, gait, and pedaling symmetry, 6-min walk test (6MWT), balance, dynamic gait movements, and health status were measured at baseline and posttraining. RESULTS: Functional electrical stimulation-assisted cycling significantly improved V˙O2peak (12%, P = 0.006), self-selected walking speed (SSWS, 0.05 ± 0.1 m·s, P = 0.04), Activities-specific Balance Confidence scale score (12.75 ± 17.4, P = 0.04), Berg Balance Scale score (3.91 ± 4.2, P = 0.016), Dynamic Gait Index score (1.64 ± 1.4, P = 0.016), and Stroke Impact Scale participation/role domain score (12.74 ± 16.7, P = 0.027). Additionally, pedal symmetry, represented by the paretic limb contribution to pedaling (paretic pedaling ratio [PPR]) significantly improved (10.09% ± 9.0%, P = 0.016). Although step length symmetry (paretic step ratio [PSR]) did improve, these changes were not statistically significant (-0.05% ± 0.1%, P = 0.09). Exploratory correlations showed moderate association between change in SSWS and 6-min walk test (r = 0.74), and moderate/strong negative association between change in PPR and PSR. CONCLUSIONS: These results support FES-assisted cycling as a means to improve both aerobic capacity and locomotor function. Improvements in SSWS, balance, dynamic walking movements, and participation in familial and societal roles are important targets for rehabilitation of individuals after CVA. Interestingly, the correlation between PSR and PPR suggests that improvements in pedaling symmetry may translate to a more symmetric gait pattern.

Combining therapeutic approaches: rTMS and aerobic exercise in post-stroke depression: a case series.

Objective and importance Residual effects of stroke include well-documented functional limitations and high prevalence of depression. Repetitive transcranial magnetic stimulation (rTMS) and aerobic exercise (AEx) are established techniques that improve depressive symptoms, but a combination of the two has yet to be reported. The purpose of this case series is to examine the safety, feasibility, and impact of combined rTMS and AEx on post-stroke depression and functional mobility. Clinical presentation Three participants with a history of stroke and at least mild depressive symptoms (Patient Health Questionare-9 ≥5). Intervention Both rTMS and AEx were completed 3 times/week for 8-weeks. rTMS was applied to the left dorsolateral prefrontal cortex, 5000 pulses/session at 10 Hz, at an intensity of 120% of resting motor threshold. AEx consisted of 40 min of treadmill walking at 50-70% of heart rate reserve. Results Depressive symptoms improved in all three participants, with all demonstrating response (≥50% improvement in symptoms) and likely remission. All participants improved their Six Minute Walk Test distance and Participants 1 and 2 also improved Berg Balance Scale scores. Participants 1 and 3 improved overground walking speeds. No serious adverse events occurred with the application of rTMS or AEx and the participants' subjective reports indicated positive responses. Adherence rate for both rTMS and AEx was 98%. Conclusion Combined treatment of rTMS and AEx appears safe, feasible, and tolerable in individuals with a history of stroke and at least mild depressive symptoms. All participants had good compliance and demonstrated improvements in both depressive symptoms and walking capacity.

POWER training in chronic stroke individuals: differences between responders and nonresponders.

BACKGROUND: Lower extremity muscle weakness is a primary contributor to post-stroke dysfunction. Resistance training is an effective treatment for hemiparetic weakness and improves walking performance. Post-stroke subject characteristics that do or do not improve walking speed following resistance training are unknown. OBJECTIVE: The purpose of this paper was to describe baseline characteristics, as well as responses to training, associated with achieving a minimal clinically important difference (MCID) in walking speed (≥0.16 m/s) following Post-stroke Optimization of Walking Using Explosive Resistance (POWER) training. METHODS: Seventeen participants completed 24 sessions of POWER training, which included intensive progressive leg presses, jump training, calf raises, sit-to-stands, step-ups, and over ground fast walking. Outcomes included SSWS, FCWS, DGI, FMA-LE, 6-MWT, paretic knee power, non-paretic knee power, and paretic step ratio. RESULTS: Specific to those who reached MCID in SSWS (e.g. "responders"), significant improvements in SSWS, FCWS, 6-MWT, paretic knee power, and non-paretic knee power was realized. Paretic knee power and non-paretic knee power significantly improved in those who did not achieve MCID for gait speed (e.g. "non-responders"). CONCLUSION: The potential for POWER training to enhance general locomotor function was confirmed. Baseline paretic knee strength/power may be an important factor in how an individual responds to this style of training. The lack of change within the non-responders emphasizes the contribution of factors other than lower extremity muscle power improvement to locomotor dysfunction.

Effects of hip abduction and adduction accuracy on post-stroke gait.

BACKGROUND: Gait instability often limits post-stroke function, although the mechanisms underlying this instability are not entirely clear. Our recent work has suggested that one possible factor contributing to post-stroke gait instability is a reduced ability to accurately control foot placement. The purpose of the present experiments was to investigate whether post-stroke gait function is related to the ability to accurately abduct and adduct the hip, as required for accurate foot placement. METHODS: 35 chronic stroke survivors and 12 age-matched controls participated in this experiment. Participants performed hip oscillation trials designed to quantify hip abduction/adduction accuracy, in which they lay supine and moved their leg through a prescribed range of motion in time with a metronome. Stroke survivors also performed overground walking trials at their self-selected speed. FINDINGS: 28 of the 35 stroke survivors had sufficient active range of motion to perform the prescribed hip oscillation task. In comparison to controls, these 28 stroke survivors were significantly less accurate at matching the abduction target, matching the adduction target, and moving in time with the metronome. Across these stroke survivors, a multiple regression revealed that only paretic hip abduction accuracy made a unique contribution to predicting paretic step width and paretic step period, metrics of gait performance. INTERPRETATION: The present results demonstrate that the ability to accurately abduct the hip is related to post-stroke gait performance, as predicted from a model-based gait stabilization strategy. Therefore, interventions designed to improve lower limb movement accuracy may hold promise for restoring post-stroke gait stability.

The Effects of POWER Training in Young and Older Adults after Stroke.

Background. Approximately 35,000 strokes occur annually in adults below the age of 40, and there is disappointingly little data describing their responses to rehabilitation. The purpose of this analysis was to determine the effects of Poststroke Optimization of Walking using Explosive Resistance (POWER) training in young (<40 years) and older (>60 years) adults and to describe relationships between training-induced improvements in muscular and locomotor function. Methods. Data was analyzed from 16 individuals with chronic stroke who participated in 24 sessions of POWER training. Outcomes included muscle power generation, self-selected walking speed (SSWS), 6-minute walk test, Fugl-Meyer motor assessment, Berg Balance Scale, and Dynamic Gait Index. Results. There were no significant differences between groups at baseline. Within-group comparisons revealed significant improvements in paretic and nonparetic knee extensor muscle power generation in both groups. Additionally, young participants significantly improved SSWS. Improvements in SSWS were more strongly associated with improvements in power generation on both sides in young versus older participants. Conclusions. Younger adults after stroke seem to preferentially benefit from POWER training, particularly when increasing gait speed is a rehabilitation goal. Future research should aim to further understand age-related differences in response to training to provide optimal treatments for all individuals following stroke.

Pilot study of atomoxetine in patients with Parkinson's disease and dopa-unresponsive Freezing of Gait.

BACKGROUND: Freezing of gait (FoG) is a common and debilitating condition in Parkinson's disease (PD) associated with executive dysfunction. A subtype of FoG does not respond to dopaminergic therapy and may be related to noradrenergic deficiency. This pilot study explores the effects of atomoxetine on gait in PD patients with dopa-unresponsive FoG using a novel paradigm for objective gait assessment. FINDINGS: Ten patients with PD and dopa-unresponsive FoG were enrolled in this eight-week open label pilot study. Assessments included an exploratory gait analysis protocol that quantified spatiotemporal parameters during straight-away walking and turning, while performing a dual task. Clinical, and subjective assessments of gait, quality of life, and safety were also administered. The primary outcome was a validated subjective assessment for FoG (FOG-Q). Atomoxetine was well tolerated, however, no significant change was observed in the primary outcome. The gait analysis protocol correlated well with clinical scales, but not with subjective assessments. DBS patients were more likely to increase gait velocity (p = 0.033), and improved in other clinical assessments. CONCLUSIONS: Objective gait analysis protocols assessing gait while dual tasking are feasible and useful for this patient population, and may be superior correlates of FoG severity than subjective measures. These findings can inform future trials in this population.

Lower Extremity Strength Is Correlated with Walking Function After Incomplete SCI.

BACKGROUND: Lower extremity strength has been reported to relate to walking ability, however, the relationship between voluntary lower extremity muscle function as measured by isokinetic dynamometry and walking have not been thoroughly examined in individuals with incomplete spinal cord injury (iSCI). OBJECTIVE: To determine the extent to which measures of maximal voluntary isometric contraction (MVIC) and rate of torque development (RTD) in the knee extensor (KE) and plantar flexor (PF) muscle groups correlate with self-selected overground walking speed and spatiotemporal characteristics of walking. METHODS: Twenty-two subjects with chronic (>6 months) iSCI participated in a cross-sectional study. Values for MVIC and RTD in the KE and PF muscle groups were determined by isokinetic dynamometry. Walking speed and spatiotemporal characteristics of walking were measured during overground walking. RESULTS: MVIC in the KE and PF muscle groups correlated significantly with walking speed. RTD was significantly correlated with walking speed in both muscle groups, the more-involved PF muscle group showing the strongest correlation with walking speed (r = 0.728). RTD in the KE and PF muscle groups of the more-involved limb was significantly correlated with single support time of the more-involved limb. CONCLUSIONS: These data demonstrate that lower extremity strength is associated with walking ability after iSCI. Correlations for the muscle groups of the move-involved side were stronger compared to the less-involved limb. In addition, PF function is highlighted as a potential limiting factor to walking speed along with the importance of RTD.