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ObjectivesMagnetic susceptibility changes in brain MRI of Wilson’s disease (WD) patients have been described in subcortical nuclei especially the basal ganglia. The objectives of this study were to investigate its relationship with other microstructural and functional alterations of the subcortical nuclei and the diagnostic utility of these MRI-related metrics.MethodsA total of 22 WD patients and 20 healthy controls (HCs) underwent 3.0T multimodal MRI scanning. Susceptibility, volume, diffusion microstructural indices and whole-brain functional connectivity of the putamen (PU), globus pallidus (GP), caudate nucleus (CN), and thalamus (TH) were analyzed. Receiver operating curve (ROC) was applied to evaluate the diagnostic value of the imaging data. Correlation analysis was performed to explore the connection between susceptibility change and microstructure and functional impairment of WD and screen for neuroimaging biomarkers of disease severity.ResultsWilson’s disease patients demonstrated increased susceptibility in the PU, GP, and TH, and widespread atrophy and microstructural impairments in the PU, GP, CN, and TH. Functional connectivity decreased within the basal ganglia and increased between the PU and cortex. The ROC model showed higher diagnostic value of isotropic volume fraction (ISOVF, in the neurite orientation dispersion and density imaging model) compared with susceptibility. Severity of neurological symptoms was correlated with volume and ISOVF. Susceptibility was positively correlated with ISOVF in GP.ConclusionMicrostructural impairment of the basal ganglia is related to excessive metal accumulation in WD. Brain atrophy and microstructural impairments are useful neuroimaging biomarkers for the neurological impairment of WD.

BackgroundOlder adults oftentimes suffer from the conditions in multiple physiologic systems, interfering with their daily function and thus contributing to physical frailty. The contributions of such multisystem conditions to physical frailty have not been well characterized.MethodsIn this study, 442 (mean age = 71.4 ± 8.1 years, 235 women) participants completed the assessment of frailty syndromes, including unintentional weight loss, exhaustion, slowness, low activity, and weakness, and were categorized into frail (≥3 conditions), pre-frail (1 or 2 conditions), and robust (no condition) status. Multisystem conditions including cardiovascular diseases, vascular function, hypertension, diabetes, sleep disorders, sarcopenia, cognitive impairment, and chronic pain were assessed. Structural equation modeling examined the interrelationships between these conditions and their associations with frailty syndromes.ResultsFifty (11.3%) participants were frail, 212 (48.0%) were pre-frail, and 180 (40.7%) were robust. We observed that worse vascular function was directly associated with higher risk of slowness [standardized coefficient (SC) = −0.419, p < 0.001], weakness (SC = −0.367, p < 0.001), and exhaustion (SC = −0.347, p < 0.001). Sarcopenia was associated with both slowness (SC = 0.132, p = 0.011) and weakness (SC = 0.217, p = 0.001). Chronic pain, poor sleep quality, and cognitive impairment were associated with exhaustion (SC = 0.263, p < 0.001; SC = 0.143, p = 0.016; SC = 0.178, p = 0.004, respectively). The multinomial logistic regression showed that greater number of these conditions were associated with increased probability of being frail (odds ratio>1.23, p < 0.032).ConclusionThese findings in this pilot study provide novel insights into how multisystem conditions are associated with each other and with frailty in older adults. Future longitudinal studies are warranted to explore how the changes in these health conditions alter frailty status.

BackgroundCognitive impairment disrupts postural control, particularly when standing while performing an unrelated cognitive task (i.e., dual-tasking). The temporal dynamics of standing postural sway are “complex,” and such complexity may reflect the capacity of the postural control system to adapt to task demands. We aimed to characterize the impact of cognitive impairment on such sway complexity in older adults.MethodsForty-nine older adult males (Alzheimer’s disease (AD): n = 21; mild cognitive impairment (MCI): n = 13; cognitively-intact: n = 15) completed two 60-s standing trials in each of single-task and visual-search dual-task conditions. In the dual-task condition, participants were instructed to count the frequency of a designated letter in a block of letters projected on screen. The sway complexity of center-of-pressure fluctuations in anterior–posterior (AP) and medial-lateral (ML) direction was quantified using multiscale entropy. The dual-task cost to complexity was obtained by calculating the percent change of complexity from single- to dual-task condition.ResultsRepeated-measures ANOVAs revealed significant main effects of group (F > 4.8, p F = 7.7, p F = 3.7, p = 0.03). The AD group had the lowest dual-task ML complexity, as well as greater dual-task cost to ML (p = 0.03) compared to the other two groups. Visual-search task accuracy was correlated with ML sway complexity in the dual-task condition (r = 0.42, p = 0.007), and the dual-task cost to ML sway complexity (r = 0.39, p = 0.01) across all participants.ConclusionAD-related cognitive impairment was associated with a greater relative reduction in postural sway complexity from single- to dual-tasking. Sway complexity appears to be sensitive to the impact of cognitive impairment on standing postural control.

BackgroundThe pathophysiology of depression in Parkinson’s disease (PD) is not fully understood. Studies based upon functional MRI (fMRI) showed the alterations in the blood-oxygen-level-dependent (BOLD) fluctuations in multiple brain regions pertaining to depression in PD. However, large variance was observed across previous studies. Therefore, we conducted a meta-analysis to quantitatively evaluate the results in previous publications and completed an independent regions-of-interests (ROIs)-based analysis using our own data to validate the results of the meta-analysis.MethodsWe searched PubMed, Embase, and Web of Science to identify fMRI studies in PD patients with depression. Using signed differential mapping (SDM) method, we performed a voxel-based meta-analysis. Then, a validation study by using multiscale entropy (MSE) in 28 PD patients with depression and 25 PD patients without depression was conducted. The fMRI scan was completed in anti-depression-medication-off state. The ROIs of the MSE analysis were the regions identified by the meta-analysis.ResultsA total of 126 PD patients with depression and 153 PD patients without depression were included in meta-analysis. It was observed that the resting-state activities within the posterior cingulate gyrus, supplementary motor area (SMA), and cerebellum were altered in depressed patients. Then, in the validation study, these regions were used as ROIs. PD patients with depression had significantly lower MSE of the BOLD fluctuations in these regions (posterior cingulate gyrus: F = 0.856, p = 0.049; SMA: F = 0.914, p = 0.039; cerebellum: F = 0.227, p = 0.043).ConclusionOur study revealed that the altered BOLD activity in cingulate, SMA, and cerebellum of the brain were pertaining to depression in PD.

ObjectiveThe studies showed the benefits of virtual reality training (VRT) for functional mobility and balance in older adults. However, a large variance in the study design and results is presented. We, thus, completed a systematic review and meta-analysis to quantitatively examine the effects of VRT on functional mobility and balance in healthy older adults.MethodsWe systematically reviewed the publications in five databases. Studies that examine the effects of VRT on the measures of functional mobility and balance in healthy older adults were screened and included if eligible. Subgroup analyses were completed to explore the effects of different metrics of the intervention design (e.g., session time) on those outcomes related to functional mobility and balance.ResultsFifteen studies of 704 participants were included. The quality of these studies was good. Compared to traditional physical therapy (TPT), VRT induced greater improvement in TUG (MD = −0.31 s, 95% CI = −0.57 to −0.05, p = 0.02, I2 = 6.34%) and one-leg stance with open eyes (OLS-O) (MD = 7.28 s, 95% CI = 4.36 to 10.20, p = 0.00, I2 = 36.22%). Subgroup analyses revealed that immersive VRT with more than 800 min of total intervention time over 8 weeks and at least 120 min per week and/or designed by the two motor-learning principles was optimal for functional mobility and balance.ConclusionVirtual reality training can significantly improve functional mobility and balance in healthy older adults compared to TPT, and the findings provided critical knowledge of the optimized design of VRT that can inform future studies with more rigorous designs.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021297085].

Purpose: This systematic review aims to examine the efficacy of transcranial direct current stimulation (tDCS) combined with physical training on the excitability of the motor cortex, physical performance, and motor learning.Methods: A systematic search was performed on PubMed, Web of Science, and EBSCO databases for relevant research published from inception to August 2020. Eligible studies included those that used a randomized controlled design and reported the effects of tDCS combined with physical training to improve motor-evoked potential (MEP), dynamic posture stability index (DPSI), reaction time, and error rate on participants without nervous system diseases. The risk of bias was assessed by the Cochrane risk of bias assessment tool.Results: Twenty-four of an initial yield of 768 studies met the eligibility criteria. The risk of bias was considered low. Results showed that anodal tDCS combined with physical training can significantly increase MEP amplitude, decrease DPSI, increase muscle strength, and decrease reaction time and error rate in motor learning tasks. Moreover, the gain effect is significantly greater than sham tDCS combined with physical training.Conclusion: tDCS combined with physical training can effectively improve the excitability of the motor cortex, physical performance, and motor learning. The reported results encourage further research to understand further the synergistic effects of tDCS combined with physical training.

Background: White matter lesions (WMLs) are highly prevalent in older adults, and hypertension is one of the main contributors to WMLs. The blood pressure (BP) is regulated by complex underlying mechanisms over multiple time scales, thus the continuous beat-to-beat BP fluctuation is complex. The association between WMLs and hypertension may be manifested as diminished complexity of BP fluctuations. The aim of this pilot study is to explore the relationships between hypertension, BP complexity, and WMLs in older adults.Method: Fifty-three older adults with clinically diagnosed hypertension and 47 age-matched older adults without hypertension completed one MRI scan and one BP recording of 10–15 min when sitting quietly. Their cerebral WMLs were assessed by two neurologists using the Fazekas scale based on brain structural MRI of each of their own. Greater score reflected higher WML grade. The complexity of continuous systolic (SBP) and diastolic (DBP) BP series was quantified using multiscale entropy (MSE). Lower MSE reflected lower complexity.Results: Compared to the non-hypertensive group, hypertensives had significantly greater Fazekas scores (F > 5.3, p < 0.02) and lower SBP and DBP complexity (F > 8.6, p < 0.004). Both within each group (β < −0.42, p < 0.01) and across groups (β < −0.47, p < 0.003), those with lower BP complexity had higher Fazekas score. Moreover, complexity of both SBP and DBP mediated the influence of hypertension on WMLs (indirect effects > 0.25, 95% confidence intervals = 0.06 – 0.50).Conclusion: These results suggest that diminished BP complexity is associated with WMLs and may mediate the influence of hypertension on WMLs. Future longitudinal studies are needed to examine the causal relationship between BP complexity and WMLs.

Background: Recently, considerable research has been conducted to study the effects of transcranial direct current stimulation (tDCS) on balance control in older adults. We completed a comprehensive systematic review and meta-analysis to assess the efficacy of tDCS on balance control in this population.Methods: A search strategy based on the PICOS principle was used to find the literatures in the databases of PubMed, EMBASE, EBSCO, Web of Science. The quality and risk of bias in the studies were independently assessed by two researchers.Results: Ten studies were included in the systematic review. A meta-analysis was completed on six of these ten, with a total of 280 participants. As compared to sham (i.e., control), tDCS induced significant improvement with low heterogeneity in balance control in older adults. Specifically, tDCS induced large effects on the performance of the timed-up-and-go test, the Berg balance scale, and standing postural sway (e.g., sway area) and gait (e.g., walking speed) in dual task conditions (standardized mean differences (SMDs) = −0.99~3.41 95% confidence limits (CL): −1.52~4.50, p < 0.006, I2 < 52%). Moderate-to-large effects of tDCS were also observed in the standing posture on a static or movable platform (SMDs = 0.37~1.12 95%CL: −0.09~1.62, p < 0.03, I2 < 62%).Conclusion: Our analysis indicates that tDCS holds promise to promote balance in older adults. These results warrant future studies of larger sample size and rigorous study design and results report, as well as specific research to establish the relationship between the parameter of tDCS and the extent of tDCS-induced improvement in balance control in older adults.

Background/Objectives: Distinguishing between Parkinson's disease (PD) and multiple system atrophy (MSA) is challenging in the clinic because patients with these two conditions present with similar symptoms in motor dysfunction. Here, we aimed to determine whether tremor characteristics can serve as novel markers for distinguishing the two conditions.Methods: Ninety-one subjects with clinically diagnosed PD and 93 subjects with MSA were included. Tremor of the limbs was measured in different conditions (such as resting, postural, and weight-holding) using electromyography (EMG) surface electrodes and accelerometers. The dominant frequency, tremor occurrence rate, and harmonic occurrence rate (HOR) of the tremor were then calculated.Results: Our results demonstrated that the tremor dominant frequency in the upper limbs of the MSA group was significantly higher than that in the PD group across all resting (F = 5.717, p = 0.023), postural (F = 13.409, p < 0.001), and weight-holding conditions (F = 9.491, p < 0.001) and that it was not dependent on the patient's age or disease course. The tremor occurrence rate (75.6 vs. 14.9%, χ2 = 68.487, p < 0.001) and HOR (75.0 vs. 4.5%, χ2 = 46.619, p < 0.001) in the resting condition were significantly lower in the MSA group than in the PD group. The sensitivity of the harmonic for PD diagnosis was 75.0% and the specificity was relatively high, in some cases up to 95.5%. The PPV and NPV were 95.2 and 75.9%, respectively.Conclusion: Our study confirmed that several tremor characteristics, including the dominant tremor frequency and the occurrence rate in different conditions, help detect PD and MSA. The presence of harmonics may serve as a novel marker to help distinguish PD from MSA with high sensitivity and specificity.

On the basis of several recent meta-analyses synthesizing the effects of transcranial direct current stimulation (tDCS) on sport performance (Lattari et al., 2018; Machado et al., 2018; Holgado et al., 2019a), Holgado et al. (2019b) concluded that there is insufficient evidence to support an ergogenic or “brain-doping” effect of tDCS on sport and/or physical performance. The authors also highlighted that the exact neuro-modulatory mechanisms through which tDCS may improve human performance remain largely unclear. We describe here more explicitly several important limitations of the majority of tDCS research to date. We also examine potential mechanisms of action, and provide recommendations that we believe are needed to more robustly study the ergogenic effects of tDCS moving forward.

Foot-sole somatosensory impairment is a main contributor to balance decline and falls in aging and disease. The cortical networks involved in walking-related foot sole somatosensation, however, remain poorly understood. We thus created and tested a novel MRI-compatible device to enable study of the cortical response to pressure stimuli applied to the foot sole that mimic those stimuli experienced when walking. The device consists of a dual-drive stimulator equipped with two pneumatic cylinders, which are separately programed to apply pressure waveforms to the entire foot sole. In a sample of nine healthy younger adults, the pressure curve applied to the foot sole closely correlated with that experienced during over ground walking (r = 0.811 ± 0.043, P < 0.01). MRI compatibility testing indicated that the device has no or negligible impact on MR image quality. Gradient-recalled echo-planar images of nine healthy young adults using a block-designed 3.5-min walking-related stimulation revealed significant activation within the supplementary motor area, supramarginal gyrus, paracingulate gyri, insula, precentral gyrus, middle temporal gyrus, and hippocampus (uncorrected P < 0.001, k ≥ 10). Together, these results indicate that this stimulation system is MRI-compatible and capable of mimicking walking-related pressure waveforms on foot sole. It may thus be used as a research tool to identify cortical targets for interventions (e.g., non-invasive brain stimulation) aimed at enhancing this important source of input to the locomotor control system.

The fatigue in aerobic exercise affects the task performance. In addition to the fatigue in the muscular system, the diminished performance may arise from the altered cerebral blood supply and oxygen extraction. However, the effects of the fatiguing aerobic exercise on the ability of brain to regulate the cerebral blood flow (CBF) and to extract the oxygen are not fully understood. In this pilot study, we aim to quantify such effects via advanced functional MRI techniques. Twenty healthy younger elite athletes were recruited. In the screening visit, one circle ergometer test was used to screen the maximal relative oxygen consumption (VO2max). Eleven eligible participants then completed the next MRI visit after 7 days. These participants completed a 2-min pulsed arterial spin labeling (ASL) using the PICORE/QUIPSS II and 5-min asymmetric spin echo (ASE) scan at baseline and immediately after the aerobic circle ergometer test. The CBF was then measured using the ASL images and the oxygen consumption of the brain was quantified using oxygen extraction fractions (OEF) derived from the ASE images. The test time, VO2max, and anaerobic threshold were also recorded. As compared to baseline, participants had significant reduction of global CBF (p = 0.003). Specifically, the CBF in bilateral striatum, left middle temporal gyrus (MTG) and right inferior frontal gyrus (IFG) decreased significantly (p < 0.005, K > 20). No significant changes of the OEFs were observed. Participants with greater OEF within the right striatum at baseline had longer test time, greater anaerobic threshold and relative VO2max (r2 > 0.51, p < 0.007). Those with longer test time had less reduction of CBF within the right IFG (r2 = 0.55, p = 0.006) and of OEF within the left striatum (r2 = 0.52, p = 0.008). Additionally, greater anaerobic threshold was associated with less reduction of OEF within the left MTG (r2 = 0.49, p = 0.009). This pilot study provided first-of-its-kind evidence suggesting that the fatiguing aerobic exercise alters the cerebral blood supply in the brain, but has no significant effects on the ability of brain to extract oxygenation. Future studies are warranted to further establish the CBF and OEF as novel markers for physical and physiological function to help the assessment in the sports science and clinics.