PEMOCS: theory derivation of a concept for PErsonalized MOtor-Cognitive exergame training in chronic Stroke-a methodological paper with an application example.

Background: Coping with residual cognitive and gait impairments is a prominent unmet need in community-dwelling chronic stroke survivors. Motor-cognitive exergames may be promising to address this unmet need. However, many studies have so far implemented motor-cognitive exergame interventions in an unstructured manner and suitable application protocols remain yet unclear. We, therefore, aimed to summarize existing literature on this topic, and developed a training concept for motor-cognitive exergame interventions in chronic stroke. Methods: The development of the training concept for personalized motor-cognitive exergame training for stroke (PEMOCS) followed Theory Derivation procedures. This comprised (1.1) a thorough (narrative) literature search on long-term stroke rehabilitation; (1.2) a wider literature search beyond the topic of interest to identify analogies, and to induce creativity; (2) the identification of parent theories; (3) the adoption of suitable content or structure of the main parent theory; and (4) the induction of modifications to adapt it to the new field of interest. We also considered several aspects of the "Framework for Developing and Evaluating Complex Interventions" by the Medical Research Council. Specifically, a feasibility study was conducted, and refining actions based on the findings were performed. Results: A training concept for improving cognitive functions and gait in community-dwelling chronic stroke survivors should consider the principles for neuroplasticity, (motor) skill learning, and training. We suggest using a step-based exergame training for at least 12 weeks, 2-3 times a week for approximately 45 min. Gentile's Taxonomy for Motor Learning was identified as suitable fundament for the personalized progression and variability rules, and extended by a third cognitive dimension. Concepts and models from related fields inspired further additions and modifications to the concept. Conclusion: We propose the PEMOCS concept for improving cognitive functioning and gait in community-dwelling chronic stroke survivors, which serves as a guide for structuring and implementing motor-cognitive exergame interventions. Future research should focus on developing objective performance parameters that enable personalized progression independent of the chosen exergame type.

Agreement, Reliability, and Concurrent Validity of an Outdoor, Wearable-Based Walk Ratio Assessment in Healthy Adults and Chronic Stroke Survivors.

Purpose: The walk ratio (WR)-the step-length/cadence relation-is a promising measure for gait control. GPS-running watches deliver clinically relevant outcomes including the WR. The aim of this study was to determine test-retest agreement, reliability and concurrent validity of an outdoor WR assessment using a GPS-running watch. Methods: Healthy adults and moderate-high functioning stroke survivors (≥6 months), performed the 1 km-outdoor walk twice using a GPS-running watch (Garmin Forerunner 35, GFR35) and a Step Activity Monitor (SAM 3). Global cognition was assessed using the Montreal Cognitive Assessment. Test-retest agreement and reliability were assessed using Bland-Altman plots, standard error of measurement (SEM), intraclass correlation coefficients (ICCs) and smallest detectable changes (SDCs). Concurrent validity was determined by the mean difference (MD), standard error (SE), mean absolute percentage errors (MAPEs) and Spearman's Rho between GFR35 and SAM3. WR values of the two groups were compared by a Welch's test. A hierarchical multiple regression was performed with the WR as dependent variable and possible predictors as independent variables. Results: Fifty-one healthy adults [median: 60.0 (47.0, 67.0) years) and 20 stroke survivors [mean: 63.1 (12.4) years, median: 76 (30, 146) months post-stroke] were included. Test-retest agreement and reliability were excellent (SEM% ≤ 2.2, ICCs > 0.9, SDC% ≤ 6.1) and concurrent validity was high (MAPE < 5, ρ > 0.7) for those walking ≥ 1 m/s. Walking < 1 m/s impaired accurate step counting and reduced agreement, reliability, and validity. The WR differed between healthy adults and stroke survivors (t = -2.126, p = 0.045). The hierarchical regression model including stroke and global cognition (Montreal Cognitive Assessment, 0-30) explained 25% of the WR variance (ΔR2 = 0.246, p < 0.001). Stroke had no effect (ß = -0.05, p = 0.682), but global cognition was a predictor for an altered WR (ß = 0.44, p = 0.001). Discussion: The outdoor WR assessment using the GFR35 showed excellent test-retest agreement, reliability and concurrent validity in healthy adults and chronic stroke survivors walking at least 1 m/s. As the WR seems relevant in chronic stroke, future studies should further investigate this parameter.

Motor-cognitive intervention concepts can improve gait in chronic stroke, but their effect on cognitive functions is unclear: A systematic review with meta-analyses.

Motor-cognitive intervention concepts are promising to counteract residual gait and cognitive impairments in chronic stroke. There is, however, considerable variation in motor-cognitive intervention types, which may lead to different effects. This systematic review strived to summarize and compare the effects of different motor-cognitive intervention concepts on gait and cognitive functions in chronic stroke. The systematic search identified twenty-nine articles, which were allocated to three types of motor-cognitive training concepts; SEQUENTIAL, SIMULTANEOUS-ADDITIONAL, and SIMULTANEOUS-INCORPORATED. Random-effects meta-analyses revealed that motor-cognitive interventions may be better than non-combined training approaches for improving gait function in chronic stroke (e.g. gait speed: g = 0.43, 95 % CI [0.22, 0.64], p < 0.0001). SIMULTANEOUS-INCORPORATED motor-cognitive training seems the most promising concept. As very few articles measured both, spatiotemporal gait parameters and cognitive outcomes, future studies are warranted to investigate the effects of motor-cognitive intervention concepts on gait control and cognitive functions in chronic stroke.

Personalized Motor-Cognitive Exergame Training in Chronic Stroke Patients-A Feasibility Study.

Purpose: Exergame training may be beneficial for improving long-term outcome in stroke patients. Personalized training prescription applying progression rules, is missing. We adapted a theory-based taxonomy for a rehabilitation approach using user-centered exergames. The aims were primarily to investigate the feasibility of this rehabilitation approach, and secondarily to evaluate its performance of personalizing training progression, as well as explore the effects on secondary outcomes. Methods: Chronic stroke patients (≥ 18 years) were included, who were able to walk 10 meters and stand for 3 min. The rehabilitation approach was administered twice per week for 8 weeks. As primary outcome, feasibility was evaluated by comparing achieved rates of inclusion, adherence, compliance, attrition, motivation, and satisfaction to pre-defined thresholds for acceptance. Secondary outcomes were (1) perceived motor and cognitive task difficulty throughout the intervention; (2) measures collected during baseline and post-measurements-a gait analysis, the Timed-up-and-go test (TUG), several cognitive tests assessing attentional, executive, and visuospatial functions. Results: Thirteen patients [median: 68.0 (IQR: 49.5-73.5) years, median: 34.5 (IQR: 12.25-90.75) months post-stroke] were included, of whom ten completed the study. Rates for inclusion (57%), adherence (95%), compliance (99%), motivation (77%), and satisfaction (74%) were acceptable, however, the attrition rate was high (23%). The perceived motor and cognitive task difficulty predominantly moved below the targeted range. We found a significant change in the TUG (p = 0.05, r = 0.46) and medium-to-large effect sizes (p > 0.05) for swing time of the affected leg, the asymmetry index, time needed for the Trail-making test (TMT) A and accuracy for the TMT B and the Mental Rotation Test (MRT; 0.26 ≤ r ≤ 0.46). Discussion: The intervention was feasible with minor modifications necessary, which warrants a larger trial investigating the effects of the rehabilitation approach following the adapted taxonomy on mobility, gait and cognitive functions. Two main limitations of the rehabilitation approach were; (1) the taxonomy decoupled motor and cognitive progression, which may be improper as motor and cognitive learning is coupled; (2) separate subjective ratings were used to guide the progression. Future studies should develop an instrument to objectively assess motor-cognitive task difficulty for monitoring the progression of an exergame-based training.

Application of the concept of oxime library screening by mass spectrometry (MS) binding assays to pyrrolidine-3-carboxylic acid derivatives as potential inhibitors of γ-aminobutyric acid transporter 1 (GAT1).

In the present study, the concept of oxime library screening by MS Binding Assays was successfully extended to N-substituted lipophilic pyrrolidine-3-carboxylic acid derivatives in the pursuit of varying the amino acid motif in order to identify new inhibitors for GAT1 and to broaden structure-activity-relationships for this target, the most abundant GABA transporter in the central nervous system. For the screening, 28 different oxime sub-libraries were employed that were generated by simple condensation reaction of an excess of pyrrolidine-3-carboxylic acid derivatives carrying a hydroxylamine functionality with various sub-libraries each assembled of eight aldehydes with broadly varying chemical structures and functionalities. The compounds responsible for the activity of an oxime sub-library were identified by deconvolution experiments performed by employing single oximes. Binding affinities of the oxime hits were confirmed in full-scale competitive MS Binding Assays. Thereby, oxime derivatives with a 1,1'-biphenyl moiety were found as the first inhibitors of mGAT1 comprising a pyrrolidine-3-carboxylic acid motif with affinities in the submicromolar range.

Identification of Pyrrolidine-3-acetic Acid Derived Oximes as Potent Inhibitors of γ-Aminobutyric Acid Transporter†1 through Library Screening with MS Binding Assays.

In this study, pyrrolidine-3-acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ-aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine-3-acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine-3-acetic acid motif were found, of which the most potent oxime, possessing a 2',4'-dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi =7.87±0.01).