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Background: The optimal prescription and precise recommendations of resistance training volume for older adults is unclear in the current literature. In addition, the interactions between resistance training volume and program duration as well as physical health status remain to be determined when assessing physical function, muscle size and hypertrophy and muscle strength adaptations in older adults., Objectives: This study aimed to determine which resistance training volume is the most effective in improving physical function, lean body mass, lower-limb muscle hypertrophy and strength in older adults. Additionally, we examined whether effects were moderated by intervention duration (i.e. short term, < 20 weeks; medium-to-long term, ≥ 20 weeks) and physical health status (i.e. physically healthy, physically impaired, mixed physically healthy and physically impaired; PROSPERO identifier: CRD42023413209)., Methods: CINAHL, Embase, LILACS, PubMed, Scielo, SPORTDiscus and Web of Science databases were searched up to April 2023. Eligible randomised trials examined the effects of supervised resistance training in older adults (i.e. ≥ 60 years). Resistance training programs were categorised as low (LVRT), moderate (MVRT) and high volume (HVRT) on the basis of terciles of prescribed weekly resistance training volume (i.e. product of frequency, number of exercises and number of sets) for full- and lower-body training. The primary outcomes for this review were physical function measured by fast walking speed, timed up and go and 6-min walking tests; lean body mass and lower-body muscle hypertrophy; and lower-body muscle strength measured by knee extension and leg press one-repetition maximum (1-RM), isometric muscle strength and isokinetic torque. A random-effects network meta-analysis was undertaken to examine the effects of different resistance training volumes on the outcomes of interest., Results: We included a total of 161 articles describing 151 trials (n = 6306). LVRT was the most effective for improving timed up and go [- 1.20 standardised mean difference (SMD), 95% confidence interval (95% CI): - 1.57 to - 0.82], 6-min walk test (1.03 SMD, 95% CI: 0.33-1.73), lean body mass (0.25 SMD, 95% CI: 0.10-0.40) and muscle hypertrophy (0.40 SMD, 95% CI: 0.25-0.54). Both MVRT and HVRT were the most effective for improving lower-limb strength, while only HVRT was effective in increasing fast walking speed (0.40 SMD, 95% CI: - 0.57 to 0.14). Regarding the moderators, our results were independent of program duration and mainly observed for healthy older adults, while evidence was limited for those who were physically impaired., Conclusions: A low resistance training volume can substantially improve healthy older adults' physical function and benefits lean mass and muscle size independently of program duration, while a higher volume seems to be necessary for achieving greater improvements in muscle strength. A low volume of resistance training should be recommended in future exercise guidelines, particularly for physically healthy older adults targeting healthy ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The similarity between movement patterns and force-vector specificity of training exercises and the target movement will likely result in the greatest transfer of the practiced skills and physical abilities to the intended sports skill performance. Therefore, this review aimed to investigate whether specific adaptations in athletic performance would be observed following direction specific exercise training., Methodology: The literature search was performed in PubMed, Web of Science, and MEDLINE. Studies comparing acute (post-activation potentiation enhancement) and short-term (>2 weeks) effects of horizontally vs . vertically oriented resistance and plyometric training on athletic performance of recreationally active participants of either sex were included. The effect sizes were determined using a robust variance estimation random-effects model and were reported as Hedge's g ., Results: Twenty-two studies were included. For acute studies ( n = 4), a small non-significant effect favoring horizontal training (HT) for sprint performance improvements (g = -0.19, p = 0.17) was evident. For short-term studies ( n = 18), the results showed non-significant, small to large differences between HT and vertical training (VT) in pooled vertical and horizontal jump improvements (g = 0.06, p = 0.67), vertical (g = 0.21, p = 0.17) and horizontal jump (g = -0.15, p = 0.40), pooled vertical and horizontal maximal strength (g = 0.27, p = 0.42), horizontal (g = -0.83, p = 0.16) and vertical maximal strength (g = 0.78, p = 0.28), pooled short and medium distance sprint (g = -0.23, p = 0.16), short (g = -0.33 [-0.85, 0.19], p = 0.19) and medium (g = -0.12 [-0.37, 0.13], p = 0.28) distance sprint, and COD speed and maneuverability (g = -0.45, p = 0.26)., Conclusions: HT and VT were both equally effective in improving vertically and horizontally athletic performance, potentially refuting the theory of directional specificity of training on athletic performance outcomes., Competing Interests: The authors declare that they have no competing interests., (© 2024 Huang et al.)

We determined beta-band intermuscular (IMC) and corticomuscular coherence (CMC) as a function of age and walking balance difficulty. Younger (n=14, 23y) and older individuals (n=19, 71y) walked 13 m overground, on a 6-cm-wide ribbon overground, and on a 6-cm-wide (5-cm-high) beam. Walking distance as a proxy for walking balance and speed were computed. CMC was estimated between electroencephalographic signal at Cz electrode and surface electromyographic signals of seven leg muscles, while IMC was calculated in four pairs of leg muscles, during stance and swing gait phases. With increasing difficulty, walking balance decreased in old individuals and speed decreased gradually independent of age. Beam walking increased IMC, while age increased IMC in proximal muscle pairs, and decreased IMC in distal muscle pairs. Age and difficulty increased CMC independent of gait phases. Concluding, CMC and IMC increased with walking balance difficulty and age, except for distal muscle pairs, which had lower IMC with age. These findings suggest an age-related increase in corticospinal involvement in the neural control of walking balance. DATA AVAILABILITY: The datasets used in this study are available from the corresponding author upon reasonable request., Competing Interests: Conflict of Interests The authors declare no conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Kettlebell as a sport has gained recognition worldwide. We characterized the physiological responses induced by a simulated kettlebell competition routine in experienced kettlebell athletes (n = 26) in a two-group, pre-post plus short-term follow-up, non-randomized experiment. The experimental group (EXP) included 13 kettlebell athletes, while the control group (CON) consisted of 13 individuals with prior recreational exposure to kettlebell activities. EXP performed a 10-minute-long, long-cycle kettlebell routine, whereas CON engaged in seated rest. Cardiovascular and neuromuscular outcomes were measured at rest, after warm-up, during exercise, at 0 (immediately post), 5 and 15 min into recovery. Group-by-time interactions revealed that the 10-minute-long, long-cycle kettlebell routine increased (P < 0.05) the levels of all outcomes (e.g. heart rate, blood pressure, blood lactate) (range of effect sizes: -0.9-8.9) with many outcomes remaining well above baseline at 5 and 15 min into recovery. A notable exception was a lack of change in maximal squat strength. Kettlebell experience and mass correlated with changes in oxygen uptake (ΔVO2) and in ventilation (ΔVT) (r = -0.70, 0.64, -0.87, and 0.73, respectively, P < 0.05) in EXP. Kettlebell routine evoked significant changes in all physiological variables (respiratory and cardiovascular), out of which the heart rate (HR), diastolic blood pressure (DBP), rate pressure product (RPP), and blood lactate (BL) outlasted the routine for at least 15 min. Future studies should longitudinally examine physiological responses to kettlebell training throughout a season. Long-cycle kettlebell routine adds to the repertoire of evidence-based exercise options for high-intensity exercise.

Emotions have the potential to modulate human voluntary movement by modifying muscle afferent discharge which in turn may affect kinesthetic acuity. We examined if heart rate (HR)-related physiological changes induced by music-elicited emotions would underlie alterations in healthy young adults' ankle joint target-matching strategy quantified by joint position sense (JPS). Participants (n = 40, 19 females, age = 25.9 ± 2.9 years) performed ipsilateral-, and contralateral ankle target-matching tasks with their dominant and non-dominant foot using a custom-made foot platform while listening to classical music pieces deemed to evoke happy, sad, or neutral emotions (each n = 10). Participants in the 4th group received no music during the task. Absolute (ABS), constant (CONST), and variable (VAR) target-matching errors and HR-related data were analyzed. Participants performed the contralateral target-matching task with smaller JPS errors when listening to sad vs. happy music (ABS: p < 0.001, d = 1.6; VAR: p = 0.010, d = 1.2) or neutral (ABS: p < 0.001, d = 1.6; VAR: p < 0.001, d = 1.4) music. The ABS (d = 0.8) and VAR (d = 0.3) JPS errors were lower when participants performed the task with their dominant vs. non-dominant foot. JPS errors were also smaller during the ipsilateral target-matching task when participants (1) listened to sad vs. neutral (ABS: p = 0.007, d = 1.2) music, and (2) performed the target-matching with their dominant vs. non-dominant foot (p < 0.001, d = 0.4). Although emotions also induced changes in some HR-related data during the matching conditions, i.e., participants who listened to happy music had lower HR-related values when matching with their non-dominant vs. dominant foot, these changes did not correlate with JPS errors (all p > 0.05). Overall, our results suggest that music-induced emotions have the potential to affect target-matching strategy and HR-related metrics but the changes in HR-metrics do not underlie the alteration of ankle joint target-matching strategy in response to classical music-elicited emotions., (© 2024. The Author(s).)

Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer's disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways., (© 2024. Crown.)

As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain., (© 2024. The Author(s).)

Background: Various physical fitness qualities such as muscle strength, speed and endurance are related to soccer performance. Accordingly, the combination of strength and endurance training (i.e., concurrent training [CT]) is an often-encountered training regimen in soccer. Less is known about the effects of CT sequencing on performance in young soccer players. The aim of this study was to assess the sequencing effects of strength and intermittent endurance training applied within the same training session (intrasession) on measures of physical fitness and soccer performance in young soccer players., Methods: Fifty male adolescent soccer players volunteered to participate in this study which was conducted in the Netherlands in 2019. Players were randomly assigned to a strength-endurance (SE) or an endurance-strength (ES) group in matched pairs based on their countermovement jump (CMJ) performance at baseline. Both groups completed a 12-weeks in-season training program with two weekly CT sessions. Training sessions consisted of 15 min plyometric exercises and 15 min soccer-specific intermittent endurance training. Both groups performed the same training volumes and the only difference between the groups was the CT intrasession sequencing scheme (SE vs. ES). Pre and post intervention, proxies of muscle power (CMJ, squat jump [SJ]), linear sprint speed (30-m sprint test), agility (Illinois test with / without ball), and soccer performance (ball kicking velocity) were tested., Results: Data from 38 players aged 14.8 ± 1.0 years (body height 172.9 ± 8.1 cm, body mass: 57.0 ± 7.2 kg, soccer experience: 8.8 ± 2.8 years, age from peak-height-velocity [PHV]: +1.2 ± 1.0 years) were included. Significant main time effects were found for CMJ (p = 0.002, d = 0.55), SJ (p = 0.004, d = 0.51), the Illinois agility test with ball (p = 0.016, d = 0.51), and ball kicking velocity (p = 0.016, d = 0.51). Significant group-by-time interactions were observed for 30-m linear sprint speed (p < 0.001, d = 0.76) with ES showing greater improvements (p = 0.006, d = 0.85, Δ-5%)., Conclusions: Both CT-sequencing types improved performance in the tests administered. The intrasession CT sequencing (SE vs. ES) appears not to have a major impact on physical fitness adaptations, except for linear sprint speed which was in favor of ES., (© 2024. The Author(s).)

Background: Beam walking is a new test to estimate dynamic balance. We characterized dynamic balance measured by the distance walked on beams of different widths in five age groups of healthy adults (20, 30, 40, 50, 60 years) and individuals with neurological conditions (i.e., Parkinson, multiple sclerosis, stroke, age: 66.9 years) and determined if beam walking distance predicted prospective falls over 12 months., Methods: Individuals with (n = 97) and without neurological conditions (n = 99, healthy adults, age 20-60) participated in this prospective longitudinal study. Falls analyses over 12 months were conducted. The summed distance walked under single (walking only) and dual-task conditions (walking and serial subtraction by 7 between 300 to 900) on three beams (4, 8, and 12-cm wide) was used in the analyses. Additional functional tests comprised grip strength and the Short Physical Performance Battery., Results: Beam walking distance was unaffected on the 12-cm-wide beam in the healthy adult groups. The distance walked on the 8-cm-wide beam decreased by 0.34 m in the 20-year-old group. This reduction was ~ 3 × greater, 1.1 m, in the 60-year-old group. In patients, beam walking distances decreased sharply by 0.8 m on the 8 versus 12 cm beam and by additional 1.6 m on the 4 versus 8 cm beam. Beam walking distance under single and dual-task conditions was linearly but weakly associated with age (R 2  = 0.21 for single task, R 2  = 0.27 for dual-task). Age, disease, and beam width affected distance walked on the beam. Beam walking distance predicted future falls in the combined population of healthy adults and patients with neurological conditions. Based on receiver operating characteristic curve analyses using data from the entire study population, walking ~ 8.0 of the 12 m maximum on low-lying beams predicted future fallers with reasonable accuracy., Conclusion: Balance beam walking is a new but worthwhile measure of dynamic balance to predict falls in the combined population of healthy adults and patients with neurological conditions. Future studies are needed to evaluate the predictive capability of beam walking separately in more homogenous populations. Clinical Trial Registration Number NCT03532984., (© 2024. The Author(s).)

We conducted a meta-analysis of randomized controlled trials investigating the effects of aerobic exercise training (AET) lasting ≥ 4 weeks on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals. Random-effects robust variance estimation models were used to test differences between AET and controls, while meta-regressions tested associations between CRF and hippocampal volume changes. We included eight studies (N = 554) delivering fully supervised AET for 3 to 12 months (M = 7.8, SD = 4.5) with an average AET volume of 129.85 min/week (SD = 45.5) at moderate-to-vigorous intensity. There were no significant effects of AET on hippocampal volume (SMD = 0.10, 95% CI - 0.01 to 0.21, p = 0.073), but AET moderately improved CRF (SMD = 0.30, 95% CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not associated with changes in hippocampal volume (b SE  = 0.05, SE = 0.51, p = 0.923). From the limited number of studies, AET does not seem to impact hippocampal volume in cognitively unimpaired, healthy older individuals. Notable methodological limitations across investigations might mask the lack of effects., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Previous research has not demonstrated secondary degeneration of the spinal cord (SpC) motoneurons after cerebral infarct. The aim of the present study is to investigate the involvement of the anterior horn cells (AHC) in the early post-stroke period using histomorphological and immunohistochemical methods. Post-mortem analysis of the 6th cervical segment was performed in 7 patients who had total MCA stroke within 1 month before death. Nissl-stained sections were used for morphometry, while CD68 and synaptophysin (SYP) immunohistochemistry to monitor microglial activation and synaptic changes in the anterior horn (AH), respectively. Contralateral to the cerebral lesion (contralesional side), cells were smaller after 3 days and larger after 1 week of stroke, especially regarding the large alpha motoneurons. CD68 density increased mainly on the contralesional Rexed's IX lamina of the SpC. SYP coverage of the large motoneurons was reduced on the contralesional side. Early microglial activation in the AH and electrophysiological signs has suggested the possibility of impairment of anterior horn cells (AHC-s). Our study supported that early microglial activation in the contralesional side of the SpC may primarily affect the area corresponding to the location of large motoneurons, and is accompanied by a transient shrinkage followed by increase in size of the large AHC-s with a reduction of their synaptic coverage. After MCA stroke, early involvement of the SpC motoneurons may be suspected by their morphological and synaptic changes and by the pattern of microglial activation., (© 2023. The Author(s).)

Low-intensity endurance exercise with blood flow restriction (KAATSU) is under consideration for use in cardiac rehabilitation. However, the physiological responses to such exercise have not yet been fully characterized. In an initial effort in healthy males (n = 11, age: 26.3±4.6 y), we compared the physiological responses to low-intensity endurance exercise with and without a thigh KAATSU. Participants performed maximal graded exercise testing using a cycle ergometer with or without KAATSU. We examined responses to cycling exercise at ventilatory threshold (VT) in heart rate (HR), oxygen consumption (VO2), dyspnea, ratings of perceived exertion (RPE), blood pressure (BP), and rectus femoris activation. Participants reached VT at a lower mechanical load, HR, VO2, dyspnea, and double product (HR×systolic BP) with KAATSU vs. no-KAATSU. At VT, RPE, and rectus femoris activity did not differ between the two conditions. These results suggest that KAATSU reduced exercise intensity to reach VT and the physiological responses to exercise at VT without changes in knee extensor muscle activation. Results from this pilot study in healthy males suggest that KAATSU aerobic exercise at VT intensity has the potential to be an effective and low-burden adjuvant to cycling in cardiac rehabilitation., Competing Interests: TN belongs to a donation course supported by KAATSU JAPAN CO., Ltd., but KAATSU JAPAN Co., Ltd., had no role in the design and analysis of the data. The other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2023 Uematsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Magnetic resonance imaging (MRI) has limitations in identifying underlying tissue pathology, which is relevant for neurological diseases such as multiple sclerosis, stroke or brain tumours. However, there are no standardized methods for correlating MRI features with histopathology. Thus, here we aimed to develop and validate a tool that can facilitate the correlation of brain MRI features to corresponding histopathology. For this, we designed the Brainbox, a waterproof and MRI-compatible 3D printed container with an integrated 3D coordinate system. We used the Brainbox to acquire post-mortem ex vivo MRI of eight human brains, fresh and formalin-fixed, and correlated focal imaging features to histopathology using the built-in 3D coordinate system. With its built-in 3D coordinate system, the Brainbox allowed correlation of MRI features to corresponding tissue substrates. The Brainbox was used to correlate different MR image features of interest to the respective tissue substrate, including normal anatomical structures such as the hippocampus or perivascular spaces, as well as a lacunar stroke. Brain volume decreased upon fixation by 7% ( P = 0.01). The Brainbox enabled degassing of specimens before scanning, reducing susceptibility artefacts and minimizing bulk motion during scanning. In conclusion, our proof-of-principle experiments demonstrate the usability of the Brainbox, which can contribute to improving the specificity of MRI and the standardization of the correlation between post-mortem ex vivo human brain MRI and histopathology. Brainboxes are available upon request from our institution., Competing Interests: A patent has been filed for the Brainbox by Wolfgang Faigle, Thomas Ludersdorfer, and Katrin B. M. Frauenknecht. The other authors declare no conflict of interest related to this study., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Age modifies walking balance and neuromuscular control. Cognitive and postural constraints can increase walking balance difficulty and magnify age-related differences. However, how such challenges affect neuromuscular control remains unknown. We determined the effects of age, cognitive task, and arm position on neuromuscular control of walking balance. Young (YA) and older adults (OA) walked on a 6-cm wide beam with and without arm crossing and a cognitive task. Walking balance was quantified by the distance walked on the beam. We also computed step speed, margin of stability, and cognitive errors. Neuromuscular control was determined through muscle synergies extracted from 13 right leg and trunk muscles. We analyzed neuromuscular complexity by the number of synergies and the variance accounted for by the first synergy, coactivity by the number of significantly active muscles in each synergy, and efficiency by the sum of the activation of each significantly active muscle in each synergy. OA vs. YA walked a 14% shorter distance, made 12 times more cognitive errors, and showed less complex and efficient neuromuscular control. Cognitive task reduced walking balance mainly in OA. Decreases in step speed and margin of stability, along with increased muscle synergy coactivity and reduced efficiency were observed in both age groups. Arm-crossing also reduced walking balance mostly in OA, but step speed decreased mainly in YA, in whom the margin of stability increased. Arm-crossing reduced the complexity of synergies. Age, cognitive task, and arm position affect differently muscle synergy recruitment but have similar effects on walking balance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: This study examined the effects of motor-cognitive dual-task exergaming standing balance training on healthy older adults' static, dynamic, and walking balance. Methods: Twenty-four adults older than 70 years (control group: n  = 9, males = 6, balance training group: n  = 15, males = 8) completed the experiment. Dual-tasking standing balance training comprised the accurate control of a ping-pong ball on a tray held with both hands, while standing on one leg (analog training) and three modules of Wii Fit™ exergaming (digital training). The duration of balance training was ∼15 minutes per day, 2 days per week for 8 weeks, in total 16 sessions. We measured one-leg standing time, functional reach distance, walking balance evaluated by the distance walked on a narrow beam (4-cm long, 4-cm wide, and 2-cm high) with single and dual tasking, habitual and maximal walking speed, and muscle strength of the hip extensor, hip abductor, hip adductor, knee extensor, and plantarflexor muscle groups in the right leg at baseline and after 8 weeks. Results: Control group decreased, but balance training group increased one-leg standing time. Only the balance training group improved functional reach distance and hip and knee extensor strength. There was no change in walking speed and walking balance in either group. In the balance training group, changes in maximal speed correlated with changes in dual-tasking walking balance and changes in one-leg standing time correlated with changes in single-tasking walking balance. Conclusion: These results suggest that 16 sessions of motor-cognitive dual-task standing exergaming balance training substantially improved healthy older adults' static and dynamic balance and leg muscle strength but failed to improve walking speed and walking balance. Balance exercises specific to walking balance need to be included in balance training to improve walking balance.

The aim of the present cross-sectional study was to determine if chronic rock climbing and climbing-specific resistance training (RT) would modify the reticulospinal tract (RST) efficacy. Sixteen healthy, elite level climbers (CL; n = 16, 5 F; 29.8 ± 6.7 years) with 12 ± 7 years of climbing and climbing-specific RT experience and 15 healthy recreationally active participants (CON; n = 15, 4 F; 24.6 ± 5.9 years), volunteered for the study. We quantified RST efficacy by comparing the effects of a startle stimulus over reaction time (R time ) and measured rate of force development (RFD) and surface electromyography (sEMG) in representative muscles during powerful hand grip contractions. Both groups performed two R time tasks while performing rapid, powerful gripping with the right hand (Task 1) or during 3-s-long maximal voluntary right hand grip contractions in response to an imperative visual signal alone (V), or combined with a auditory-non startle stimulus (A) or/and startling auditory stimulus (S). We also tested the reproducibility of these responses on two separate days in CON. Intersession reliability ranged from 0.34 to 0.96 for all variables. The CL versus CON was 37% stronger (p = 0.003). The S stimulus decreased R time and increased RFD and sEMG in both groups during both tasks (all p < 0.001). R time was similar between groups in all conditions. However, CL had a greater RFD from 50 to 100 ms compared with CON only after the S stimulus in both tasks (p < 0.05, d = 0.85-0.96). The data tentatively suggest that chronic rock climbing and climbing-specific RT might improve RST efficacy, by increasing RST input to the α-motoneurons., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Abstract: Zecchin, A, Puggina, EF, Hortobágyi, T, and Granacher, U. Association between foundation strength and weightlifting exercises in highly trained weightlifters: support for a general strength component. J Strength Cond Res 37(7): 1375-1381, 2023-In addition to specific weightlifting exercises (i.e., clean and jerk and snatch), foundation strength exercises (i.e., overhead press, front squat, and deadlift) constitute an integral part of the weightlifters' training regime. The unexamined concept behind this training plan is that foundation strength exercises are associated with clean and jerk and snatch performance, implying the existence of a general strength component. We thus determined the relationship between performance in foundation strength exercises (overhead press, front squat, and deadlift) and weightlifting exercises (clean and jerk and snatch) in weightlifters. Well-trained weightlifters ( N = 19, age: 26.8 ± 4.4 years; body mass index: 27.6 ± 2.3 kg·m -2 ; and training history: 4.6 ± 0.8 years) performed 1 repetition maximum tests (1RM) in foundation strength and weightlifting exercises, over 14 days, in a randomized order. We observed significant correlations in 1RM performance between the overhead press and snatch ( r = 0.69), front squat and snatch ( r = 0.73), overhead press and clean and jerk ( r = 0.67), and front squat and clean and jerk ( r = 0.72, all r values: p < 0.01). No significant correlations were found for 1RM performance between the snatch and deadlift or between the clean and jerk and deadlift ( r- range: 0.20-0.58; p > 0.05). Stepwise linear regression revealed that 1RM performance in the overhead press and front squat explained 62% of the variance in snatch 1RM performance ( F = 5.51; p < 0.04). Overhead press and front squat 1RM performance explained 59% of the variance in the clean and jerk 1RM performance ( F = 5.14; p < 0.04). Our results demonstrate the existence of a general strength component between selected foundation strength exercises and weightlifting performance. However, the use of the front squat and overhead press to increase 1RM performance in weightlifting exercises needs to be determined in future research using a different methodological approach (i.e., longitudinal protocols), given that the observed correlations do not necessarily imply causation., (Copyright © 2022 National Strength and Conditioning Association.)

Introduction: Analysing gait in controlled conditions that resemble daily life walking could overcome the limitations associated with gait analysis in uncontrolled real-world conditions. Such analyses could potentially aid the identification of a walking condition that magnifies age-differences in gait. Therefore, the aim of the current study was to determine the effects of age and walking conditions on gait performance., Methods: Trunk accelerations of young (n = 27, age: 21.6) and older adults (n = 26, age: 68.9) were recorded for 3 min in four conditions: walking up and down a university hallway on a track of 10 m; walking on a specified path, including turns, in a university hallway; walking outside on a specified path on a pavement including turns; and walking on a treadmill. Factor analysis was used to reduce 27 computed gait measures to five independent gait domains. A multivariate analysis of variance was used to examine the effects of age and walking condition on these gait domains., Results: Factor analysis yielded 5 gait domains: variability, pace, stability, time & frequency, complexity, explaining 64% of the variance in 27 gait outcomes. Walking conditions affected all gait domains (p < 0.01) but age only affected the time & frequency domain (p < 0.05). Age and walking conditions differently affected the domains variability, stability, time & frequency. The largest age-differences occurred mainly during straight walking in a hallway (variability: 31% higher in older adults), or during treadmill walking (stability: 224% higher, time&frequency: 120% lower in older adults)., Conclusion: Walking conditions affect all domains of gait independent of age. Treadmill walking and walking on a straight path in a hallway, were the most constrained walking conditions in terms of limited possibilities to adjust step characteristics. The age by condition interaction suggests that for the gait domains variability, stability, and time & frequency, the most constrained walking conditions seem to magnify the age-differences in gait., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Gäbler, M, Prieske, O, Elferink-Gemser, MT, Hortobágyi, T, Warnke, T, and Granacher, U. Measures of physical fitness improve prediction of kayak and canoe sprint performance in young kayakers and canoeists. J Strength Cond Res 37(6): 1264-1270, 2023-Markers of talent selection and predictors of performance in canoe and kayak sprint are not yet well defined. We aimed to determine the combination of variables (i.e., demographic, anthropometric, and physical fitness) that most accurately predicts sprint performance (i.e., 500- and 2000-m race time) in semielite, young kayakers and canoeists ( n = 39, age 13 year, 10F). The level of significance was set at p < 0.05. Linear regression analyses identified boat type (i.e., kayak or canoe), skeletal muscle mass, and average power during a 2-minute bench pull test, normalized to body mass, as predictors of 2000-m race time (R 22000 m = 0.69, Akaike information criterion [AIC] = 425) and together with vertical jump height, as predictors of 500-m race time (R 2500 m = 0.87, AIC = 255). This was an improvement over models containing solely demographic variables (R 2500 m = 0.66, AIC = 293; R 22000 m = 0.44, AIC = 446) and over models containing demographic and anthropometric variables (R 2500m = 0.79, AIC = 277; R 22000 m = 0.56, AIC = 437). Race time showed the strongest semipartial correlations with the 2-minute bench pull test (0.7 ≤ r ≤ 0.9). Adding physical fitness data (i.e., 2-minute bench pull test) to demographic and anthropometric data improves the prediction accuracy of race times in young kayak and canoe athletes. The characteristics of physical fitness tests should resemble as much as possible the biomechanical (e.g., prime movers) and metabolic (e.g., duration) demands of the sport., (Copyright © 2023 National Strength and Conditioning Association.)

Purpose: This study aimed to determine the effects of a 2-yr-long maintenance training (MT) exergaming and detraining (DT) on clinical-motor symptoms in subacute ischemic patients with stroke (PwST). The hypothesis was that MT motor rehabilitation program would further increase the effects of the initial rehabilitation., Methods: After high-intensity and high-frequency exergaming twice or once a day, 5 times per week for 5 wk (EX2: 50 sessions; EX1: 25 sessions, results reported previously), 558 PwST were randomized to EX2-MT, EX2-DT, EX1-MT, and EX1-DT. MT exergaming consisted of once a day, 3 times per week for 2 yr, and DT did not train. Outcomes were measured at 6, 12, 18, and 24 months. The data were analyzed using longitudinal linear mixed-effects models and general linear hypotheses testing., Results: Modified Rankin Score (primary outcome), body mass, Mini-Mental State Examination score, Beck Depression Inventory, measures of quality of life, Berg Balance Scale, 6-min walk test, and four measures of center of pressure path tended to retain the initial rehabilitation-induced gains in the MT patients in selected outcomes (especially walking capacity). The scores tended to mildly worsen after DT, partially supporting the hypothesis., Conclusions: MT successfully maintained, but only in selected variables did it further increase the initial exergaming rehabilitation-induced robust improvements. DT modestly reduced the initial exergaming rehabilitation-induced improvements. MT programs might be needed after initial stroke rehabilitation to reduce subsequent losses of quality of life and further improve clinical-motor symptoms., (Copyright © 2022 by the American College of Sports Medicine.)

Changes in old age that contribute to the complex issue of an increased metabolic cost of walking (mass-specific energy cost per unit distance traveled) in older adults appear to center at least in part on changes in gait biomechanics. However, age-related changes in energy metabolism, neuromuscular function and connective tissue properties also likely contribute to this problem, of which the consequences are poor mobility and increased risk of inactivity-related disease and disability. The U.S. National Institute on Aging convened a workshop in September 2021 with an interdisciplinary group of scientists to address the gaps in research related to the mechanisms and consequences of changes in mobility in old age. The goal of the workshop was to identify promising ways to move the field forward toward improving gait performance, decreasing energy cost, and enhancing mobility for older adults. This report summarizes the workshop and brings multidisciplinary insight into the known and potential causes and consequences of age-related changes in gait biomechanics. We highlight how gait mechanics and energy cost change with aging, the potential neuromuscular mechanisms and role of connective tissue in these changes, and cutting-edge interventions and technologies that may be used to measure and improve gait and mobility in older adults. Key gaps in the literature that warrant targeted research in the future are identified and discussed., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

(1) The unilateral countermovement jump is commonly used to examine frontal plane kinetics during unilateral loading and to identify athletes with an increased risk of lower limb injuries. In the present study, we examined the biomechanical mechanisms of knee and pelvis stabilization during unilateral vertical jumps. (2) Healthy males performed jumps on a force plate with the dominant leg. Activity of the dominant-side gluteus medius and the contralateral-side quadratus lumborum and erector spinae muscles was recorded with surface EMG. The EMG data were normalized to the EMG activity recorded during maximal voluntary isometric hip abduction and lateral trunk flexion contractions. During jumps, the propulsive impulse was measured, and the pelvis and thigh segmental orientation angles in the frontal plane were recorded and synchronized with the EMG data. (3) The magnitude of knee valgus during the jump did not correlate with hip abduction force, but negatively correlated with gluteus medius activity. This correlation became stronger when gluteus medius activity was normalized to hip abduction force. Propulsive impulse did not correlate with any neuromechanical measurement. (4) We conclude that hip abduction force itself does not regulate the magnitude of knee valgus during unilateral jumps; rather, the gluteus medius should be highly activated to increase frontal-plane knee joint stability.

Glioblastoma (GBM) is the most aggressive glial tumor, where ion channels, including K Ca 1.1, are candidates for new therapeutic options. Since the auxiliary subunits linked to K Ca 1.1 in GBM are largely unknown we used electrophysiology combined with pharmacology and gene silencing to address the functional expression of K Ca 1.1/β subunits complexes in both primary tumor cells and in the glioblastoma cell line U-87 MG. The pattern of the sensitivity (activation/inhibition) of the whole-cell currents to paxilline, lithocholic acid, arachidonic acid, and iberiotoxin; the presence of inactivation of the whole-cell current along with the loss of the outward rectification upon exposure to the reducing agent DTT collectively argue that K Ca 1.1/β3 complex is expressed in U-87 MG. Similar results were found using human primary glioblastoma cells isolated from patient samples. Silencing the β3 subunit expression inhibited carbachol-induced Ca 2+ transients in U-87 MG thereby indicating the role of the K Ca 1.1/β3 in the Ca 2+ signaling of glioblastoma cells. Functional expression of the K Ca 1.1/β3 complex, on the other hand, lacks cell cycle dependence. We suggest that the K Ca 1.1/β3 complex may have diagnostic and therapeutic potential in glioblastoma in the future., (© 2022. The Author(s).)

Background: We examined changes in autonomic nervous system function, anaerobic power, and fatigue over two days of simulated CrossFit competition in CrossFit athletes. In addition, we determined the relationship between these internal training load variables and variables characterizing two weeks of tapering preceding the competition., Methods: In total, 21 participants (intervention group, N.=10, INT; control group, N.=11, CON) completed the assessments. INT performed the assessments at baseline (pre-day 1), during the competition (post-day 1 and pre-day 2), and after the competition (post-day 2), while CON performed only the baseline assessments., Results: Autonomic nervous system function, anaerobic power, and fatigue did not differ between the beginning of day 1 and day 2. Autonomic nervous system function was impaired at the end of each day. Anaerobic power and fatigue did not change during either day., Conclusions: Finally, the two training weeks preceding the two days of simulated competition were related to anaerobic power but not autonomic nervous system function or fatigue. CrossFit coaches and athletes should be aware of the limited effects of step taper on heart rate variability and fatigue.

Background: Aerobic exercise (AE) may slow age-related cognitive decline. However, such cognition-sparing effects are not uniform across cognitive domains and studies. Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation and is also emerging as a potential alternative to pharmaceutical therapies. Like AE, the effectiveness of tDCS is also inconsistent for reducing cognitive impairment in ageing. The unexplored possibility exists that pairing AE and tDCS could produce synergistic effects and reciprocally augment cognition-improving effects in older individuals with and without cognitive impairments. Previous research found such synergistic effects on cognition when cognitive training is paired with tDCS in older individuals with and without mild cognitive impairment (MCI) or dementia., Aim: The purpose of this systematic review with meta-analysis was to explore if pairing AE with tDCS could augment singular effects of AE and tDCS on global cognition (GC), working memory (WM) and executive function (EF) in older individuals with or without MCI and dementia., Methods: Using a PRISMA-based systematic review, we compiled studies that examined the effects of AE alone, tDCS alone, and AE and tDCS combined on cognitive function in older individuals with and without mild cognitive impairment (MCI) or dementia. Using a PICOS approach, we systematically searched PubMed, Scopus and Web of Science searches up to December 2021, we focused on 'MoCA', 'MMSE', 'Mini-Cog' (measures) and 'cognition', 'cognitive function', 'cognitive', 'cognitive performance', 'executive function', 'executive process', 'attention', 'memory', 'memory performance' (outcome terms). We included only randomized controlled trials (RTC) in humans if available in English full text over the past 20 years, with participants' age over 60. We assessed the methodological quality of the included studies (RTC) by the Physiotherapy Evidence Database (PEDro) scale., Results: Overall, 68 studies were included in the meta-analyses. AE (ES = 0.56 [95% CI: 0.28-0.83], p = 0.01) and tDCS (ES = 0.69 [95% CI: 0.12-1.26], p = 0.02) improved GC in all three groups of older adults combined (healthy, MCI, demented). In healthy population, AE improved GC (ES = 0.46 [95% CI: 0.22-0.69], p = 0.01) and EF (ES = 0.27 [95% CI: 0.05-0.49], p = 0.02). AE improved GC in older adults with MCI (ES = 0.76 [95% CI: 0.21-1.32], p = 0.01). tDCS improved GC (ES = 0.69 [90% CI: 0.12-1.26], p = 0.02), all three cognitive function (GC, WM and EF) combined in older adults with dementia (ES = 1.12 [95% CI: 0.04-2.19], p = 0.04) and improved cognitive function in older adults overall (ES = 0.69 [95% CI: 0.20-1,18], p = 0.01)., Conclusion: Our systematic review with meta-analysis provided evidence that beyond the cardiovascular and fitness benefits of AE, pairing AE with tDCS may have the potential to slow symptom progression of cognitive decline in MCI and dementia. Future studies will examine the hypothesis of this present review that a potentiating effect would incrementally improve cognition with increasing severity of cognitive impairment., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients undergoing unilateral orthopedic or neurological rehabilitation have different levels of impairments in the right- or left-dominant hand. However, how handedness and the complexity of the motor task affect motor skill acquisition and its interlimb transfer remains unknown. In the present study, participants performed finger key presses on a numeric keypad at 4 levels of sequence complexities with each hand in a randomized order. Furthermore, they also performed motor sequence practice with the dominant hand to determine its effect on accuracy, reaction time, and movement time. The NASA-TLX at the end of each block of both testing and practice was used to confirm participants' mental workload related to sequence complexity. Both right- and left-handed participants performed the motor sequence task with faster RT when using their right hand. Although participants had increasing RT with increasing sequence complexity, this association was unrelated to handedness. Motor sequence practice produced motor skill acquisition and interlimb transfer indicated by a decreased RT, however, these changes were independent of handedness. Higher sequence complexity was still associated with longer RT after the practice, moreover, both right- and left-handed participants' RT increased with the same magnitude with the increase in sequence complexity. Similar behavioral pattern was observed in MT as in RT. Overall, our RT results may indicate left-hemisphere specialization for motor sequencing tasks, however, neuroimaging studies are needed to support these findings. On the other hand, handedness did not affect motor skill acquisition by the dominant hand or interlimb transfer to the non-dominant hand regardless of task complexity level., (© 2022. The Author(s).)

Purpose: The aim of this study was to examine the expression pattern of tenascin-C, matrilin-2, and aggrecan in irreversible corneal endothelial pathology such as pseudophakic bullous keratopathy (PBK) and Fuchs’ endothelial corneal dystrophy (FECD), which most frequently require corneal transplantation. Materials and methods: Histological specimens of corneal buttons removed during keratoplasty were investigated in PBK (n = 20) and FECD (n = 9) and compared to healthy control corneas (n = 10). The sections were studied by chromogenic immunohistochemistry (CHR-IHC) and submitted for evaluation by two investigators. Semiquantitative scoring (0 to 3+) was applied according to standardized methods at high magnification (400x). Each layer of the cornea was investigated; in addition, the stroma was subdivided into anterior, middle, and posterior parts for more precise analysis. In case of non-parametric distribution Mann−Whitney test was applied to compare two groups. Kruskal−Wallis and Dunn’s multiple comparisons tests have been applied for comparison of the chromogenic IHC signal intensity among corneal layers within the control and patient groups. Differences of p < 0.05 were considered as significant. Results: Significantly elevated tenascin-C immunopositivity was present in the epithelium and every layer of the stroma in both pathologic conditions as compared to normal controls. In addition, also significantly stronger matrilin-2 positivity was detected in the epithelium; however, weaker reaction was present in the endothelium in PBK cases. Minimal, but significantly elevated immunopositivity could be observed in the anterior and posterior stroma in the FECD group. Additionally, minimally, but significantly higher aggrecan immunoreaction was present in the anterior stroma in PBK and in the posterior stroma in both endothelial disorders. All three antibodies disclosed the strongest reaction in the posterior stroma either in PBK or in FECD cases. Conclusions: These extracellular matrix molecules disclosed up to moderate immunopositivity in the corneal layers in varying extents. Through their networking, bridging, and adhesive abilities these proteins are involved in corneal regeneration and tissue reorganization in endothelial dysfunction.

Objective: To determine the effects of exergaming (EXE) on quality of life (QOL), motor, and clinical symptoms in multiple sclerosis (MS). We compared the effects of EXE, balance (BAL), cycling (CYC), proprioceptive neuromuscular facilitation (PNF), and a standard care wait-listed control group on clinical and motor symptoms and quality of life (QOL) in people with MS (PwMS) and determined the effects of subsequent maintenance programs for 2 years in a hospital setting., Design: A randomized controlled trial, using before-after test design., Setting: University hospital setting., Participants: Of 82 outpatients with MS, 70 were randomized (N=70), and 68 completed the study., Interventions: The initial high-intensity and high-frequency interventions consisted of 25 one-hour sessions over 5 weeks. After the 5-week-long initial intervention, the 2-year-long maintenance programs followed, consisting of 3 sessions per week, each for 1 hour., Main Outcome Measures: The primary outcome: Multiple Sclerosis Impact Scale (MSIS-29)., Secondary Outcomes: Measures 5 aspects of health-related QOL (EuroQol 5-Dimension questionnaire), Beck Depression Inventory, 6-minute walk test (6MWT), Berg Balance Scale (BBS), Tinetti Assessment Tool (TAT), and static BAL (center of pressure)., Results: MSIS-29 improved most in EXE (11 points), BAL (6), and CYC (6) (all P&lt;.05). QOL improved most in EXE (3 points), CYC, and BAL (2) (all P&lt;.05). TAT and BBS improved significantly (P&lt;.05) but similarly (P&gt;.05) in EXE, BAL, and CYC. 6MWT improved most in EXE (57m), BAL (32m), and CYC (19m) (all P&lt;.001). Standing sway did not change. Maintenance programs further increased the initial exercise-induced gains, robustly in EXE., Conclusions: A total of 25 sessions of EXE, BAL, CYC, and PNF, in this order, improved clinical and motor symptoms and QOL, and subsequent 2-year-long thrice weekly maintenance programs further slowed symptom worsening and improved QOL. EXE was the most and PNF was the least effective to improve clinical symptoms, motor function, and QOL in PwMS., (Copyright © 2022 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer's disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8 + pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0-6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8 + cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8 + cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer's disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8 + LC neurons, AT8 + long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8 + processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau., (© 2022. The Author(s).)

We examined the effects of side-dominance on the laterality of standing stability using ground reaction force, motion capture ( MoCap ), and EMG data in healthy young adults. We recruited participants with strong right ( n = 15) and left ( n = 9) hand and leg dominance (side-dominance). They stood on one or two legs on a pair of synchronized force platforms for 50 s with 60 s rest between three randomized stance trials. In addition to 23 CoP -related variables, we also computed six MoCap variables representing each lower-limb joint motion time series. Moreover, 39 time- and frequency-domain features of EMG data from five muscles in three muscle groups were analyzed. Data from the multitude of biosignals converged and revealed concordant patterns: no differences occurred between left- and right-side dominant participants in kinetic, kinematic, or EMG outcomes during bipedal stance. Regarding single leg stance, larger knee but lower ankle joint kinematic values appeared in left vs right-sided participants during non-dominant stance. Left-vs right-sided participants also had lower medial gastrocnemius EMG activation during non-dominant stance. While right-side dominant participants always produced larger values for kinematic data of ankle joint and medial gastrocnemius EMG activation during non-dominant vs dominant unilateral stance, this pattern was the opposite for left-sided participants, showing larger values when standing on their dominant vs non-dominant leg, i.e., participants had a more stable balance when standing on their right leg. Our results suggest that side-dominance affects biomechanical and neuromuscular control strategies during unilateral standing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Négyesi, Petró, Salman, Khandoker, Katona, Wang, Almaazmi, Hortobágyi, Váczi, Rácz, Pálya, Grand, Kiss and Nagatomi.)

Objective: To determine the effects of low- vs. high-intensity aerobic and resistance training on motor and cognitive function, brain activation, brain structure, and neurochemical markers of neuroplasticity and the association thereof in healthy young and older adults and in patients with multiple sclerosis, Parkinson's disease, and stroke., Design: Systematic review and robust variance estimation meta-analysis with meta-regression., Data Sources: Systematic search of MEDLINE, Web of Science, and CINAHL databases., Results: Fifty studies with 60 intervention arms and 2283 in-analyses participants were included. Due to the low number of studies, the three patient groups were combined and analyzed as a single group. Overall, low- (g=0.19, p = 0.024) and high-intensity exercise (g=0.40, p = 0.001) improved neuroplasticity. Exercise intensity scaled with neuroplasticity only in healthy young adults but not in healthy older adults or patient groups. Exercise-induced improvements in neuroplasticity were associated with changes in motor but not cognitive outcomes., Conclusion: Exercise intensity is an important variable to dose and individualize the exercise stimulus for healthy young individuals but not necessarily for healthy older adults and neurological patients. This conclusion warrants caution because studies are needed that directly compare the effects of low- vs. high-intensity exercise on neuroplasticity to determine if such changes are mechanistically and incrementally linked to improved cognition and motor function., (Copyright © 2022. Published by Elsevier B.V.)

Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter-related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine-regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease.

Dry eye disease (DED) is a multifactorial disorder with recognized pathology, but not entirely known pathomechanism. It is suggested to represent a continuum with neuropathic corneal pain with the paradox that DED is a pain-free disease in most cases, although it is regarded as a pain condition. The current paper puts into perspective that one gateway from physiology to pathophysiology could be a Piezo2 channelopathy, opening the pathway to a potentially quad-phasic non-contact injury mechanism on a multifactorial basis and with a heterogeneous clinical picture. The primary non-contact injury phase could be the pain-free microinjury of the Piezo2 ion channel at the corneal somatosensory nerve terminal. The secondary non-contact injury phase involves harsher corneal tissue damage with C-fiber contribution due to the lost or inadequate intimate cross-talk between somatosensory Piezo2 and peripheral Piezo1. The third injury phase of this non-contact injury is the neuronal sensitization process with underlying repeated re-injury of the Piezo2, leading to the proposed chronic channelopathy. Notably, sensitization may evolve in certain cases in the absence of the second injury phase. Finally, the quadric injury phase is the lingering low-grade neuroinflammation associated with aging, called inflammaging. This quadric phase could clinically initiate or augment DED, explaining why increasing age is a risk factor. We highlight the potential role of the NGF-TrkA axis as a signaling mechanism that could further promote the microinjury of the corneal Piezo2 in a stress-derived hyperexcited state. The NGF-TrkA-Piezo2 axis might explain why female sex represents a risk factor for DED., (© 2022. The Author(s).)

Anodal transcranial direct current stimulation (tDCS) can enhance the retention of a previously practiced motor skill. However, the effects of tDCS on the performance of the choice reaction time task are not fully understood. We examined the effects of anodal tDCS over the left primary motor cortex (M1) on the retention of a 4-choice visual-motor reaction time task (4-ChRT). Right-handed healthy participants (n = 100) were randomly assigned to five groups: three groups received anodal tDCS: before (tDCS before ), during (tDCS during ), or after (tDCS after ) motor practice. In addition, there were two control groups: with (CON mp ) and without (CON) motor practice. We evaluated the speed and precision of the 4-ChRT task before (PRE), during, and 24 h (POST) after the interventions. All groups, including the non-stimulation (CON mp ) and non-practice groups (CON), improved (p < 0.05) motor retention (Δ4-ChRT: 35.8 ± 36.0 ms). These findings suggest that the tDCS effects over M1 may differ for serial versus choice RT tasks, perhaps due to the different brain areas involved in each motor task., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Physical fatigue (PF) negatively affects postural control, resulting in impaired balance performance in young and older adults. Similar effects on postural control can be observed for mental fatigue (MF) mainly in older adults. Controversial results exist for young adults. There is a void in the literature on the effects of fatigue on balance and cortical activity. Therefore, this study aimed to examine the acute effects of PF and MF on postural sway and cortical activity. Fifteen healthy young adults aged 28 ± 3 years participated in this study. MF and PF protocols comprising of an all-out repeated sit-to-stand task and a computer-based attention network test, respectively, were applied in random order. Pre and post fatigue, cortical activity and postural sway (i.e., center of pressure displacements [CoP d ], velocity [CoP v ], and CoP variability [CV CoP d , CV CoP v ]) were tested during a challenging bipedal balance board task. Absolute spectral power was calculated for theta (4-7.5 Hz), alpha-2 (10.5-12.5 Hz), beta-1 (13-18 Hz), and beta-2 (18.5-25 Hz) in frontal, central, and parietal regions of interest (ROI) and baseline-normalized. Inference statistics revealed a significant time-by-fatigue interaction for CoP d ( p = 0.009, d = 0.39, Δ 9.2%) and CoP v ( p = 0.009, d = 0.36, Δ 9.2%), and a significant main effect of time for CoP variability (CV CoP d : p = 0.001, d = 0.84; CV CoP v : p = 0.05, d = 0.62). Post hoc analyses showed a significant increase in CoP d ( p = 0.002, d = 1.03) and CoP v ( p = 0.003, d = 1.03) following PF but not MF. For cortical activity, a significant time-by-fatigue interaction was found for relative alpha-2 power in parietal ( p < 0.001, d = 0.06) areas. Post hoc tests indicated larger alpha-2 power increases after PF ( p < 0.001, d = 1.69, Δ 3.9%) compared to MF ( p = 0.001, d = 1.03, Δ 2.5%). In addition, changes in parietal alpha-2 power and measures of postural sway did not correlate significantly, irrespective of the applied fatigue protocol. No significant changes were found for the other frequency bands, irrespective of the fatigue protocol and ROI under investigation. Thus, the applied PF protocol resulted in increased postural sway (CoP d and CoP v ) and CoP variability accompanied by enhanced alpha-2 power in the parietal ROI while MF led to increased CoP variability and alpha-2 power in our sample of young adults. Potential underlying cortical mechanisms responsible for the greater increase in parietal alpha-2 power after PF were discussed but could not be clearly identified as cause. Therefore, further future research is needed to decipher alternative interpretations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gebel, Busch, Stelzel, Hortobágyi and Granacher.)

Cognitive resources contribute to balance control. There is evidence that mental fatigue reduces cognitive resources and impairs balance performance, particularly in older adults and when balance tasks are complex, for example when trying to walk or stand while concurrently performing a secondary cognitive task. We conducted a systematic literature search in PubMed (MEDLINE), Web of Science and Google Scholar to identify eligible studies and performed a random effects meta-analysis to quantify the effects of experimentally induced mental fatigue on balance performance in healthy adults. Subgroup analyses were computed for age (healthy young vs. healthy older adults) and balance task complexity (balance tasks with high complexity vs. balance tasks with low complexity) to examine the moderating effects of these factors on fatigue-mediated balance performance. We identified 7 eligible studies with 9 study groups and 206 participants. Analysis revealed that performing a prolonged cognitive task had a small but significant effect (SMDwm = -0.38) on subsequent balance performance in healthy young and older adults. However, age- and task-related differences in balance responses to fatigue could not be confirmed statistically. Overall, aggregation of the available literature indicates that mental fatigue generally reduces balance in healthy adults. However, interactions between cognitive resource reduction, aging and balance task complexity remain elusive., (Copyright © 2022. Published by Elsevier B.V.)

Detection of changes in dynamic balance could help identify older adults at fall risk. Walking on a narrow beam with its width, cognitive load, and arm position manipulated could be an alternative to current tests. Therefore, we examined additive and interactive effects of beam width, cognitive task (CT), and arm position on dynamic balance during beam walking in older adults. Twenty older adults (69 ± 4y) walked on 6, 8, and 10-cm wide beams (2-cm high, 4-m-long), with and without CT, with three arm positions (free, crossed, akimbo). We determined cognitive errors, distance walked, step speed, root mean square (RMS) of center of mass (COM) displacement and trunk acceleration in the frontal plane. Beam width decrease progressively reduced distance walked and increased trunk acceleration RMS. Step speed decreased on the narrowest beam and with CT. Arm crossing decreased distance walked and step speed. COM displacement RMS and cognitive errors were not affected by any manipulation. In conclusion, distance walked indicated that beam width and arm position, but less so CT, affected dynamic balance, implying that beam walking has the potential to become a test of fall risk. Stability measurements suggested effective trunk adjustments to control COM position and keep dynamic balance during the task., (© 2022. The Author(s).)

Random practice is a form of differential learning and its favorable acute effects on motor performance are well described when visual tasks are practiced. However, no study to date has investigated the acute effects of differential learning using variable proprioceptive stimuli instead of the visual cues. The aim of the present study was to compare the acute effects of randomized versus blocked lower-extremity proprioceptive training stimuli on balance and postural adjustments. In two conditions, healthy young males ( n = 15, age = 23 years) performed 16 one-legged landings on a board tilted in four directions: 1) tilt direction unknown and randomized and 2) tilt direction known with order of presentation blocked. Multi-segmental angular sway while balancing on an unstable surface and postural responses to perturbation stimulus by surface tilts were measured before and 4 min after training. Overall frontal-plane postural sway on the unstable surface decreased ( p < 0.05, η 2 = 0.022) in both conditions, while sagittal-plane postural sway remained unchanged. When the surface was toes-up tilted in the perturbation test, the sagittal-plane shank-thigh-pelvis alignment improved in both conditions ( p < 0.05, η 2 = 0.017), but the direction of the segmental positioning was non-uniform across participants. We conclude that randomization vs. blocking of units of lower-extremity proprioceptive training did not affect balance and postural control in our cohort of healthy young adults but the improvements were test-specific., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ivusza, Hortobágyi, Sebesi, Gáspár, Fésüs, Varga, Malmos and Váczi.)

Background: Walking speed predicts many clinical outcomes in old age. However, a comprehensive assessment of how walking speed affects accelerometer based quantitative and qualitative gait measures in younger and older adults is lacking., Research Question: What is the relationship between walking speed and quantitative and qualitative gait outcomes in younger and older adults?, Methods: Younger (n = 27, age: 21.6) and older participants (n = 27, age: 69.5) completed 340 steps on a treadmill at speeds of 0.70 to a maximum of 1.75 m·s -1 . We used generalized additive mixed models to determine the relationship between walking speed and quantitative (stride length, stride time, stride frequency and their variability) and qualitative (stride regularity, stability, smoothness, symmetry, synchronization, predictability) gait measures extracted from trunk accelerations., Results: The type of relationship between walking speed and the majority of gait measures (quantitative and qualitative) was characterized as logarithmic, with more prominent speed-effects at speeds below 1.20 m·s -1 . Changes in quantitative measures included shorter strides, longer stride times, and a lower stride frequency, with more variability at lower speeds independent of age. For qualitative measures, we found a decrease in gait symmetry, stability and regularity in all directions with decreasing speeds, a decrease in gait predictability (Vertical, V, anterior-posterior, AP) and stronger gait synchronization (AP-mediolateral, ML, AP-V), and direction dependent effects of gait smoothness, which decreased in V direction, but increased in AP and ML directions with decreasing speeds. We found outcome-dependent effects of age on the quantitative and qualitative gait measures, with either no differences between age-groups, age-related differences that existed regardless of speed, and age-related differences in the type of relationship with walking speed., Significance: The relationship between walking speed and quantitative and qualitative gait measures, and the effects of age on this relationship, depends on the type of gait measure studied., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a fatal, multisystem neurodegenerative disease that causes the death of motoneurons (MNs) progressively and eventually leads to paralysis. In contrast, delayed onset muscle soreness (DOMS) is defined as delayed onset soreness, muscle stiffness, loss of force-generating capacity, reduced joint range of motion, and decreased proprioceptive function. Sensory deficits and impaired proprioception are common symptoms of both ALS and DOMS, as impairment at the proprioceptive sensory terminals in the muscle spindle is theorized to occur in both. The important clinical distinction is that extraocular muscles (EOM) are relatively spared in ALS, in contrast to limb skeletal muscles; however, the blink reflex goes through a gradual impairment in a later stage of disease progression. Noteworthy is, that, the stretch of EOM induces the blink reflex. The current authors suggest that the impairment of proprioceptive sensory nerve terminals in the EOM muscle spindles are partially responsible for lower blink reflex, beyond central origin, and implies the critical role of Piezo2 ion channels and Wnt-PIP2 signaling in this pathomechanism. The proposed microinjury of Piezo2 on muscle spindle proprioceptive terminals could provide an explanation for the painless dying-back noncontact injury mechanism theory of ALS., Competing Interests: Conflict of interest: Tibor Hortobágyi is an Editor in Open Medicine, but this fact did not affect the peer-review process., (© 2022 Balázs Sonkodi and Tibor Hortobágyi, published by De Gruyter.)

Background: Age-related changes in muscle properties affect daily functioning, therefore a reliable assessment of such properties is required. We examined the effects of age on reliability, muscle quality and interrelation among muscle architecture (MA) parameters of the gastrocnemius medialis (GM), tibialis anterior (TA), and vastus lateralis (VL) muscles., Methods: Three raters scored ultrasound (US) scans of 12 healthy younger and older adults, on fascicle length (FL), pennation angle (PA) and muscle thickness (MT). Intra- and inter-rater reliability of MA measures in rest and contraction was assessed by intraclass correlation coefficients (ICC) and standard error of measurements (SEM, SEM%). The relationship between MA parameters was examined using Pearson correlation coefficients. Muscle quality (MQ) was examined using mean pixel intensity., Results: Reliability was moderate to excellent for TA in both groups (ICCs: 0.64-0.99, SEM% = 1.6-14.8%), and for VL in the younger group (ICCs: 0.67-0.98, SEM% = 2.0-18.3%). VL reliability was poor to excellent in older adults (ICCs: 0.22-0.99, SEM% = 2.7-36.0%). For GM, ICCs were good to excellent (ICCs: 0.76-0.99) in both groups, but GM SEM% were higher in older adults (SEM% Younger  = 1.5-10.7%, SEM% Older  = 1.6-28.1%). Muscle quality was on average 19.0% lower in older vs. younger adults. In both groups, moderate to strong correlations were found for VL FL and MT (r ≥ 0.54), and TA PA and MT (r ≥ 0.72), while TA FL correlated with MT (r ≥ 0.67) in younger adults only., Conclusions: In conclusion, age- and muscle-specificities were present in the relationships between MT and PA, and MT and FL at rest. Furthermore, the reliability of MA parameters assessed with 2D panoramic US is acceptable. However, the level of reliability varies with age, muscle and MA measure. In older adults notably, the lowest reliability was observed in the VL muscle. Among the MA parameters, MT appears to be the simplest and most easily reproducible parameter in all muscles and age groups., (© 2022. The Author(s).)

Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y 12 -receptor (P2Y 12 R), which is expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y 12 R in PD is unknown. Here we show that MPTP-induced PD symptoms in mice are associated with marked neuroinflammatory changes and P2Y 12 R contribute to the activation of microglia and progression of the disease. Surprisingly, while pharmacological or genetic targeting of the P2Y 12 R augments acute mortality in MPTP-treated mice, these interventions protect against the neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y 12 R regulates ROCK and p38 MAPK activity and control cytokine production. Our principal finding is that the receptor has a dualistic role in PD: functional P2Y 12 Rs are essential to initiate a protective inflammatory response, since the lack of the receptor leads to reduced survival; however, at later stages of neurodegeneration, P2Y 12 Rs are apparently responsible for maintaining the activated state of microglia and stimulating pro-inflammatory cytokine response. Understanding protective and detrimental P2Y 12 R-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD., (Copyright © 2022. Published by Elsevier Ltd.)

To establish the comparative effects of conservative interventions on modifying foot progression angle (FPA) in children and adults with orthopaedic and neurological disease was the main aim of the literature review. Pubmed, Embase, Cinahl, and Web of Science were systematically searched for studies evaluating the effects of conservative interventions on correcting the FPA. The study protocol was registered with PROSPERO (CRD42020143512). Two reviewers independently assessed studies for inclusion and quality. Studies that assessed conservative interventions that could have affected the FPA and objectively measured the FPA were included. Within group Mean Differences (MD) and Standardized Mean Differences (SMDs) of the interventions were calculated for the change in FPA and gait performance (walking speed, stride/step length) and clinical condition (pain). Intervention effects on FPA were synthesized via meta-analysis or qualitatively. 41 studies were identified. For patients with knee osteoarthritis gait training interventions (MD = 6.69° and MD = 16.06°) were significantly more effective than mechanical interventions (MD = 0.44°) in modifying the FPA towards in-toeing (p < 0.00001). Increasing or decreasing the FPA significantly improved pain in patients with medial knee OA. Results were inconclusive for the effectiveness of gait training and mechanical devices in patients with neurological diseases. Gait feedback training is more effective than external devices to produce lasting improvements in FPA, reduce pain, and maintain gait performance in patients with medial knee OA. However, in neurological patients, the effects of external devices on improvements in FPA depends on the interaction between patient-specific impairments and the technical properties of the external device., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Semi-quantitative scoring is a method that is widely used to estimate the quantity of proteins on chromogen-labelled immunohistochemical (IHC) tissue sections. However, it suffers from several disadvantages, including its lack of objectivity and the fact that it is a time-consuming process. Our aim was to test a recently established artificial intelligence (AI)-aided digital image analysis platform, Pathronus, and to compare it to conventional scoring by five observers on chromogenic IHC-stained slides belonging to three experimental groups. Because Pathronus operates on grayscale 0-255 values, we transformed the data to a seven-point scale for use by pathologists and scientists. The accuracy of these methods was evaluated by comparing statistical significance among groups with quantitative fluorescent IHC reference data on subsequent tissue sections. The pairwise inter-rater reliability of the scoring and converted Pathronus data varied from poor to moderate with Cohen's kappa, and overall agreement was poor within every experimental group using Fleiss' kappa. Only the original and converted that were obtained from Pathronus original were able to reproduce the statistical significance among the groups that were determined by the reference method. In this study, we present an AI-aided software that can identify cells of interest, differentiate among organelles, protein specific chromogenic labelling, and nuclear counterstaining after an initial training period, providing a feasible and more accurate alternative to semi-quantitative scoring.