Biochemical, biomechanical and imaging biomarkers of ischemic stroke: Time for integrative thinking.

Stroke is one of the leading causes of adult disability affecting millions of people worldwide. Post-stroke cognitive and motor impairments diminish quality of life and functional independence. There is an increased risk of having a second stroke and developing secondary conditions with long-term social and economic impacts. With increasing number of stroke incidents, shortage of medical professionals and limited budgets, health services are struggling to provide a care that can break the vicious cycle of stroke. Effective post-stroke recovery hinges on holistic, integrative and personalized care starting from improved diagnosis and treatment in clinics to continuous rehabilitation and support in the community. To improve stroke care pathways, there have been growing efforts in discovering biomarkers that can provide valuable insights into the neural, physiological and biomechanical consequences of stroke and how patients respond to new interventions. In this review paper, we aim to summarize recent biomarker discovery research focusing on three modalities (brain imaging, blood sampling and gait assessments), look at some established and forthcoming biomarkers, and discuss their usefulness and complementarity within the context of comprehensive stroke care. We also emphasize the importance of biomarker guided personalized interventions to enhance stroke treatment and post-stroke recovery.

The motor inhibitory network in patients with asymmetrical Parkinson's disease: An fMRI study.

Recent imaging studies with the stop-signal task in healthy individuals indicate that the subthalamic nucleus, the pre-supplementary motor area and the inferior frontal gyrus are key components of the right hemisphere "inhibitory network". Limited information is available regarding neural substrates of inhibitory processing in patients with asymmetric Parkinson's disease. The aim of the current fMRI study was to identify the neural changes underlying deficient inhibitory processing on the stop-signal task in patients with predominantly left-sided Parkinson's disease. Fourteen patients and 23 healthy controls performed a stop-signal task with the left and right hands. Behaviorally, patients showed delayed response inhibition with either hand compared to controls. We found small imaging differences for the right hand, however for the more affected left hand when behavior was successfully inhibited we found reduced activation of the inferior frontal gyrus bilaterally and the insula. Using the stop-signal delay as regressor, contralateral underactivation in the right dorsolateral prefrontal cortex, inferior frontal and anterior putamen were found in patients. This finding indicates dysfunction of the right inhibitory network in left-sided Parkinson's disease. Functional connectivity analysis of the left subthalamic nucleus showed a significant increase of connectivity with bilateral insula. In contrast, the right subthalamic nucleus showed increased connectivity with visuomotor and sensorimotor regions of the cerebellum. We conclude that altered inhibitory control in left-sided Parkinson's disease is associated with reduced activation in regions dedicated to inhibition in healthy controls, which requires engagement of additional regions, not observed in controls, to successfully stop ongoing actions.

Brain Activity and Functional Connectivity Patterns Associated With Fast and Slow Motor Sequence Learning in Late Middle Adulthood.

The human brain undergoes structural and functional changes across the lifespan. The study of motor sequence learning in elderly subjects is of particularly interest since previous findings in young adults might not replicate during later stages of adulthood. The present functional magnetic resonance imaging (fMRI) study assessed the performance, brain activity and functional connectivity patterns associated with motor sequence learning in late middle adulthood. For this purpose, a total of 25 subjects were evaluated during early stages of learning [i.e., fast learning (FL)]. A subset of these subjects (n = 11) was evaluated after extensive practice of a motor sequence [i.e., slow learning (SL) phase]. As expected, late middle adults improved motor performance from FL to SL. Learning-related brain activity patterns replicated most of the findings reported previously in young subjects except for the lack of hippocampal activity during FL and the involvement of cerebellum during SL. Regarding functional connectivity, precuneus and sensorimotor lobule VI of the cerebellum showed a central role during improvement of novel motor performance. In the sample of subjects evaluated, connectivity between the posterior putamen and parietal and frontal regions was significantly decreased with aging during SL. This age-related connectivity pattern may reflect losses in network efficiency when approaching late adulthood. Altogether, these results may have important applications, for instance, in motor rehabilitation programs.

Kinematic and Kinetic Patterns Related to Free-Walking in Parkinson's Disease.

The aim of this study is to compare the properties of free-walking at a natural pace between mild Parkinson's disease (PD) patients during the ON-clinical status and two control groups. In-shoe pressure-sensitive insoles were used to quantify the temporal and force characteristics of a 5-min free-walking in 11 PD patients, in 16 young healthy controls, and in 12 age-matched healthy controls. Inferential statistics analyses were performed on the kinematic and kinetic parameters to compare groups' performances, whereas feature selection analyses and automatic classification were used to identify the signature of parkinsonian gait and to assess the performance of group classification, respectively. Compared to healthy subjects, the PD patients' gait pattern presented significant differences in kinematic parameters associated with bilateral coordination but not in kinetics. Specifically, patients showed an increased variability in double support time, greater gait asymmetry and phase deviation, and also poorer phase coordination. Feature selection analyses based on the ReliefF algorithm on the differential parameters in PD patients revealed an effect of the clinical status, especially true in double support time variability and gait asymmetry. Automatic classification of PD patients, young and senior subjects confirmed that kinematic predictors produced a slightly better classification performance than kinetic predictors. Overall, classification accuracy of groups with a linear discriminant model which included the whole set of features (i.e., demographics and parameters extracted from the sensors) was 64.1%.

Trade-off between frequency and precision during stepping movements: Kinematic and BOLD brain activation patterns.

The central nervous system has the ability to adapt our locomotor pattern to produce a wide range of gait modalities and velocities. In reacting to external pacing stimuli, deviations from an individual preferred cadence provoke a concurrent decrease in accuracy that suggests the existence of a trade-off between frequency and precision; a compromise that could result from the specialization within the control centers of locomotion to ensure a stable transition and optimal adaptation to changing environment. Here, we explore the neural correlates of such adaptive mechanisms by visually guiding a group of healthy subjects to follow three comfortable stepping frequencies while simultaneously recording their BOLD responses and lower limb kinematics with the use of a custom-built treadmill device. In following the visual stimuli, subjects adopt a common pattern of symmetric and anti-phase movements across pace conditions. However, when increasing the stimulus frequency, an improvement in motor performance (precision and stability) was found, which suggests a change in the control mode from reactive to predictive schemes. Brain activity patterns showed similar BOLD responses across pace conditions though significant differences were observed in parietal and cerebellar regions. Neural correlates of stepping precision were found in the insula, cerebellum, dorsolateral pons and inferior olivary nucleus, whereas neural correlates of stepping stability were found in a distributed network, suggesting a transition in the control strategy across the stimulated range of frequencies: from unstable/reactive at lower paces (i.e., stepping stability managed by subcortical regions) to stable/predictive at higher paces (i.e., stability managed by cortical regions). Hum Brain Mapp 37:1722-1737, 2016. © 2016 Wiley Periodicals, Inc.

Effects of Small-Sided Games vs. Interval Training in Aerobic Fitness and Physical Enjoyment in Young Elite Soccer Players.

The purpose of this study was to compare the effects of Small-Sided Games (SSG) vs. Interval Training (IT) in soccer training on aerobic fitness and physical enjoyment in youth elite soccer players during the last 8 weeks of the season. Seventeen U-16 male soccer players (age = 15.5 ± 0.6 years, and 8.5 years of experience) of a Spanish First Division club academy were randomized to 2 different groups for 6 weeks: SSG group (n = 9) and IT group (n = 8). In addition to the usual technical and tactical sessions and competitive games, the SSG group performed 11 sessions with different SSGs, whereas the IT group performed the same number of sessions of IT. Players were tested before and after the 6-week training intervention with a continuous maximal multistage running field test and the counter movement jump test (CMJ). At the end of the study, players answered the physical activity enjoyment scale (PACES). During the study, heart rate (HR) and session perceived effort (sRPE) were assessed. SSGs were as effective as IT in maintaining the aerobic fitness in elite young soccer players during the last weeks of the season. Players in the SSG group declared a greater physical enjoyment than IT (P = 0.006; ES = 1.86 ± 1.07). Coaches could use SSG training during the last weeks of the season as an option without fear of losing aerobic fitness while promoting high physical enjoyment.

MRI-compatible device for examining brain activation related to stepping.

Repetitive and alternating lower limb movements are a specific component of human gait. Due to technical challenges, the neural mechanisms underlying such movements have not been previously studied with functional magnetic resonance imaging. In this study, we present a novel treadmill device employed to investigate the kinematics and the brain activation patterns involved in alternating and repetitive movements of the lower limbs. Once inside the scanner, 19 healthy subjects were guided by two visual cues and instructed to perform a motor task which involved repetitive and alternating movements of both lower limbs while selecting their individual comfortable amplitude on the treadmill. The device facilitated the performance of coordinated stepping while registering the concurrent lower-limb displacements, which allowed us to quantify some movement primary kinematic features such as amplitude and frequency. During stepping, significant blood oxygen level dependent signal increases were observed bilaterally in primary and secondary sensorimotor cortex, the supplementary motor area, premotor cortex, prefrontal cortex, superior and inferior parietal lobules, putamen and cerebellum, regions that are known to be involved in lower limb motor control. Brain activations related to individual adjustments during motor performance were identified in a right lateralized network including striatal, extrastriatal, and fronto-parietal areas.

Feasibility study of a wearable system based on a wireless body area network for gait assessment in Parkinson's disease patients.

Parkinson's disease (PD) alters the motor performance of affected individuals. The dopaminergic denervation of the striatum, due to substantia nigra neuronal loss, compromises the speed, the automatism and smoothness of movements of PD patients. The development of a reliable tool for long-term monitoring of PD symptoms would allow the accurate assessment of the clinical status during the different PD stages and the evaluation of motor complications. Furthermore, it would be very useful both for routine clinical care as well as for testing novel therapies. Within this context we have validated the feasibility of using a Body Network Area (BAN) of wireless accelerometers to perform continuous at home gait monitoring of PD patients. The analysis addresses the assessment of the system performance working in real environments.

Cortical hypoperfusion in Parkinson's disease assessed using arterial spin labeled perfusion MRI.

Alterations in cerebral perfusion and metabolism in Parkinson's disease have been assessed in several studies, using nuclear imaging techniques and more recently magnetic resonance imaging. However, to date there is no consensus in the literature regarding the extent and the magnitude of these alterations. In this work, arterial spin labeled perfusion MRI was employed to quantify absolute cerebral blood flow in a group of early-to-moderate Parkinson's disease patients and age-matched healthy controls. Perfusion comparisons between the two groups showed that Parkinson's disease is characterized by wide-spread cortical hypoperfusion. Subcortically, hypoperfusion was also found in the caudate nucleus. This pattern of hypoperfusion could be related to cognitive dysfunctions that have been previously observed even at the disease early stages. The present results were obtained by means of whole brain voxel-wise comparisons of absolute perfusion values, using statistical parametric mapping, thus avoiding the potentially biased global mean normalization procedure. In addition, this work demonstrates that between-group comparison of relative perfusion values after global mean normalization, introduced artifactual relative perfusion increases, where absolute perfusion was in fact preserved. This has implications for perfusion studies of other brain disorders.

Reliability of TMS motor evoked potentials in quadriceps of subjects with chronic hemiparesis after stroke.

Transcranial magnetic stimulation (TMS) non-invasively measures excitability of central motor pathways in humans and is used to characterize neuroplasticity after stroke. Using TMS to index lower extremity neuroplasticity after gait rehabilitation requires test-retest reliability. This study assesses the reliability of TMS-derived variables measured at bilateral quadriceps of chronic hemiparetic stroke survivors. Results support using measures of both paretic and nonparetic motor threshold, motor evoked potential (MEP) latencies; and nonparetic MEP amplitudes. Implications for longitudinal research are discussed.

Treadmill exercise activates subcortical neural networks and improves walking after stroke: a randomized controlled trial.

BACKGROUND AND PURPOSE: Stroke often impairs gait thereby reducing mobility and fitness and promoting chronic disability. Gait is a complex sensorimotor function controlled by integrated cortical, subcortical, and spinal networks. The mechanisms of gait recovery after stroke are not well understood. This study examines the hypothesis that progressive task-repetitive treadmill exercise (T-EX) improves fitness and gait function in subjects with chronic hemiparetic stroke by inducing adaptations in the brain (plasticity). METHODS: A randomized controlled trial determined the effects of 6-month T-EX (n=37) versus comparable duration stretching (CON, n=34) on walking, aerobic fitness and in a subset (n=15/17) on brain activation measured by functional MRI. RESULTS: T-EX significantly improved treadmill-walking velocity by 51% and cardiovascular fitness by 18% (11% and -3% for CON, respectively; P<0.05). T-EX but not CON affected brain activation during paretic, but not during nonparetic limb movement, showing 72% increased activation in posterior cerebellar lobe and 18% in midbrain (P<0.005). Exercise-mediated improvements in walking velocity correlated with increased activation in cerebellum and midbrain. CONCLUSIONS: T-EX improves walking, fitness and recruits cerebellum-midbrain circuits, likely reflecting neural network plasticity. This neural recruitment is associated with better walking. These findings demonstrate the effectiveness of T-EX rehabilitation in promoting gait recovery of stroke survivors with long-term mobility impairment and provide evidence of neuroplastic mechanisms that could lead to further refinements in these paradigms to improve functional outcomes.

Intracortical inhibition and facilitation with unilateral dominant, unilateral nondominant and bilateral movement tasks in left- and right-handed adults.

PURPOSE: To investigate intracortical inhibition and facilitation in response to unilateral dominant, nondominant and bilateral biceps activation and short-term upper extremity training in right- and left-handed adults. METHODS: Paired-pulse transcranial magnetic stimulation was used to measure intracortical excitability in motor dominant and nondominant cortices of 26 nondisabled adults. Neural facilitation and inhibition were measured in each hemisphere during unilateral dominant, nondominant and bilateral arm activation and after training in each condition. RESULTS: No differences were seen between right- and left-handed subjects. Intracortical facilitation and decreased inhibition were seen in each hemisphere with unilateral activation/training of contralateral muscles and bilateral muscle activation/training. Persistent intracortical inhibition was seen in each hemisphere with ipsilateral muscle activation/training. Inhibition was greater in the nondominant hemisphere during dominant hemisphere activation (dominant arm contraction). CONCLUSION: Strongly dominant individuals show no difference in intracortical responses given handedness. Intracortical activity with unilateral and bilateral arm activation and short-term training differs based on hemispheric dominance, with the motor dominant hemisphere exerting a larger inhibitory influence over the nondominant hemisphere. Bilateral activation and training have a disinhibitory effect in both dominant and nondominant hemispheres.

Brain activation of lower extremity movement in chronically impaired stroke survivors.

Lower extremity paresis poses significant disability to chronic stroke survivors. Unlike for the upper extremity, cortical adaptations in networks controlling the paretic leg have not been characterized after stroke. Here, the hypotheses are that brain activation associated with unilateral knee movement in chronic stroke survivors is abnormal, depends on lesion location, and is related to walking ability. Functional magnetic resonance imaging of unilateral knee movement was obtained in 31 patients 26.9 months (mean, IQ range: 11.3-68.1) after stroke and in 10 age-matched healthy controls. Strokes were stratified according to lesion location. Locomotor disability (30 ft walking speed) did not differ between patient groups (9 cortical, 12 subcortical, 10 brainstem lesions). Significant differences in brain activation as measured by voxel counts in 10 regions of interest were found between controls and patients with brainstem (P = 0.006) and cortical strokes (P = 0.002), and between subcortical and cortical patients (P = 0.026). Statistical parametric mapping of data per group revealed similar activation patterns in subcortical patients and controls with recruitment of contralateral primary motor cortex (M1), supplementary motor area (SMA), and bilateral somatosensory area 2 (S2). Cortical recruitment was reduced in brainstem and cortical stroke. Better walking was associated with lesser contralateral sensorimotor cortex activation in brainstem, but stronger recruitment of ipsilateral sensorimotor and bilateral somatosensory cortices in subcortical and cortical patients, respectively. A post hoc comparison of brainstem patients with and without mirror movements (50%) revealed lesser recruitment of ipsilateral cerebellum in the latter. Subcortical patients with mirror movements (58%) showed lesser bilateral sensorimotor cortex activation. No cortical patient had mirror movements. The data reveal adaptations in networks controlling unilateral paretic knee movement in chronic stroke survivors. These adaptations depend on lesion location and seem to have functional relevance for locomotion.