Aging effects on electrical and hemodynamic responses in the sensorimotor network during unilateral proximal upper limb functional tasks.

Healthy aging leads to poorer performance in upper limb (UL) daily living movements. Understanding the neural correlates linked with UL functional movements may help to better understand how healthy aging affects motor control. Two non-invasive neuroimaging methods allow for monitoring the movement-related brain activity: functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG), respectively based on the hemodynamic response and electrical activity of brain regions. Coupled, they provide a better spatiotemporal mapping. The aim of this study was to evaluate the effect of healthy aging on the bilateral sensorimotor (SM1) activation patterns of functional proximal UL movements. Twenty-one young and 21 old healthy participants realized two unilateral proximal UL movements during: i) a paced reaching target task and ii) a circular steering task to capture the speed-accuracy trade-off. Combined fNIRS-EEG system was synchronised with movement capture system to record SM1 activation while moving. The circular steering task performance was significantly lower for the older group. The rate of increase in hemodynamic response was longer in the older group with no difference on the amplitude of fNIRS signal for the two tasks. The EEG results showed aging related reduction of the alpha-beta rhythms synchronisation but no desynchronisation modification. In conclusion, this study uncovers the age-related changes in brain electrical and hemodynamic response patterns in the bilateral sensorimotor network during two functional proximal UL movements using two complementary neuroimaging methods. This opens up the possibility to utilise combined fNIRS-EEG for monitoring the movement-related neuroplasticity in clinical practice.

Systematic study of liposomes composition towards efficient delivery of plasmid DNA as potential application of dermal fibroblasts targeting.

The use of non-viral DNA vectors to topically treat skin diseases has demonstrated a high potential. However, vectors applied on the skin face extracellular barriers including the stratum corneum and intracellular barriers such as the endosomal escape and the nuclear targeting of the plasmid DNA. The aim of this study was to develop a formulation suitable for dermal application and effective for delivering plasmid DNA into cells. Different formulations were prepared using different cationic lipids (DOTAP, DC-Chol, DOTMA) and co-lipids (DOPE, DSPE). Lipoplexes were produced by complexing liposomes with plasmid DNA at different pDNA/CL (w/w) ratios. Our results showed that appropriate pDNA/CL ratios allowing total complexation of plasmid DNA differed depending on the structure of the lipid used. The transfection rates showed that (i) higher rates were obtained with DOTMA lipoplexes, (ii) DC-Chol lipoplexes provided a transfection twice as important as DOTAP lipoplexes and (iii) when DSPE was added, the cytotoxicity decreased while transfection rates were similar. We found that formulations composed of DC-Chol:DOPE:DSPE or DOTMA:DOPE were appropriate to complex plasmid DNA and to transfect human primary dermal fibroblasts with efficacy and limited cytotoxicity. Therefore, these formulations are highly promising in the context of gene therapy to treat skin diseases.

In vitro skin penetration enhancement techniques: A combined approach of ethosomes and microneedles.

Dermal administration of different macromolecules, such as nucleic acids, remains a real challenge because of the difficulty of crossing the main skin barrier, the stratum corneum (SC). To overcome this barrier, the use of deformable lipid-based nanovectors were developed to increase topical penetration through the SC and to promote the intercellular delivery of drugs. The purpose of this study is to compare the skin penetration of different liposome formulations according to their composition. In vitro and ex vivo experiments using Franz diffusion cells were performed to highlight the effect of (i) lipid charge, (ii) edge activators (EA) and (iii) ethanol on the diffusion properties of nanovectors. We showed that all formulations were not able to cross the SC. However, on a tape stripped skin, we showed that cationic formulations containing an EA and ethanol improved the skin penetration. The use of microneedles was considered to bypass the SC. We have shown that sodium cholate and ethanol were necessary to ensure an appropriate diffusion of liposomes into the dermis when applied by means of microneedles. This could be a promising approach to further deliver efficiently macromolecules such as genes into the skin.

Kinect-based assessment of proximal arm non-use after a stroke.

BACKGROUND: After a stroke, during seated reaching with their paretic upper limb, many patients spontaneously replace the use of their arm by trunk compensation movements, even though they are able to use their arm when forced to do so. We previously quantified this proximal arm non-use (PANU) with a motion capture system (Zebris, CMS20s). The aim of this study was to validate a low-cost Microsoft Kinect-based system against the CMS20s reference system to diagnose PANU. METHODS: In 19 hemiparetic stroke individuals, the PANU score, reach length, trunk length, and proximal arm use (PAU) were measured during seated reaching simultaneously by the Kinect (v2) and the CMS20s over two testing sessions separated by two hours. RESULTS: Intraclass correlation coefficients (ICC) and linear regression analysis showed that the PANU score (ICC = 0.96, r2 = 0.92), reach length (ICC = 0.81, r2 = 0.68), trunk length (ICC = 0.97, r2 = 0.94) and PAU (ICC = 0.97, r2 = 0.94) measured using the Kinect were strongly related to those measured using the CMS20s. The PANU scores showed good test-retest reliability for both the Kinect (ICC = 0.76) and CMS20s (ICC = 0.72). Bland and Altman plots showed slightly reduced PANU scores in the re-test session for both systems (Kinect: - 4.25 ± 6.76; CMS20s: - 4.71 ± 7.88), which suggests a practice effect. CONCLUSION: We showed that the Kinect could accurately and reliably assess PANU, reach length, trunk length and PAU during seated reaching in post stroke individuals. We conclude that the Kinect can offer a low-cost and widely available solution to clinically assess PANU for individualised rehabilitation and to monitor the progress of paretic arm recovery. TRIAL REGISTRATION: The study was approved by The Ethics Committee of Montpellier, France (N°ID-RCB: 2014-A00395-42) and registered in Clinical Trial (N° NCT02326688, Registered on 15 December 2014, https://clinicaltrials.gov/ct2/show/results/NCT02326688 ).

Proximal arm non-use when reaching after a stroke.

After a stroke, many people "cannot and do not" use their paretic upper limb. With recovery, some people "can but do not" use their paretic upper limb and this non-use should be counteracted with specific rehabilitation. The aim of the study was to quantify one aspect of the non-use: proximal arm non-use when reaching within one's arm length in 45 post-stroke and 45 age matched controls. Arm use refers to the contribution of the shoulder and elbow motion to the hand movement towards the target. Proximal arm non-use is calculated as the ratio of the difference between spontaneous arm use and maximal arm use. We found that proximal arm non-use has very good test-retest reliability, does not depend on time since stroke, increases with impairment (Fugl-Meyer) and loss of function (Box & Block), and most importantly, that 61% of patients with lower impairment (Fugl-Meyer >28/42) exhibit proximal arm non-use. We conclude that quantifying proximal arm non-use in post-stroke individuals provides novel information that complements routine clinical measures. It is likely that proximal arm non-use quantifies one aspect of the motor reserve that therapists can target in patient specific rehabilitation programs.

Kinematics in the brain: unmasking motor control strategies?

In rhythmical movement performance, our brain has to sustain movement while correcting for biological noise-induced variability. Here, we explored the functional anatomy of brain networks during voluntary rhythmical elbow flexion/extension using kinematic movement regressors in fMRI analysis to verify the interest of method to address motor control in a neurological population. We found the expected systematic activation of the primary sensorimotor network that is suggested to generate the rhythmical movement. By adding the kinematic regressors to the model, we demonstrated the potential involvement of cerebellar-frontal circuits as a function of the irregularity of the variability of the movement and the primary sensory cortex in relation to the trajectory length during task execution. We suggested that different functional brain networks were related to two different aspects of rhythmical performance: rhythmicity and error control. Concerning the latter, the partitioning between more automatic control involving cerebellar-frontal circuits versus less automatic control involving the sensory cortex seemed thereby crucial for optimal performance. Our results highlight the potential of using co-registered fine-grained kinematics and fMRI measures to interpret functional MRI activations and to potentially unmask the organisation of neural correlates during motor control.

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition.

The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

Innovative technologies applied to sensorimotor rehabilitation after stroke.

Innovative technologies for sensorimotor rehabilitation after stroke have dramatically increased these past 20 years. Based on a review of the literature on "Medline" and "Web of Science" between 1990 and 2013, we offer an overview of available tools and their current level of validation. Neuromuscular electric stimulation and/or functional electric stimulation are widely used and highly suspected of being effective in upper or lower limb stroke rehabilitation. Robotic rehabilitation has yielded various results in the literature. It seems to have some effect on functional capacities when used for the upper limb. Its effectiveness in gait training is more controversial. Virtual reality is widely used in the rehabilitation of cognitive and motor impairments, as well as posture, with admitted benefits. Non-invasive brain stimulation (rTMS and TDCS) are promising in this indication but clinical evidence of their effectiveness is still lacking. In the same manner, these past five years, neurofeedback techniques based on brain signal recordings have emerged with a special focus on their therapeutic relevance in rehabilitation. Technological devices applied to rehabilitation are revolutionizing our clinical practices. Most of them are based on advances in neurosciences allowing us to better understand the phenomenon of brain plasticity, which underlies the effectiveness of rehabilitation. The acceptation and "real use" of those devices is still an issue since most of them are not easily available in current practice.

Isokinetic muscle strengthening after acquired cerebral damage: a literature review.

OBJECTIVE: Isokinetic strengthening is a rehabilitation technique rarely used in stroke patients. However, the potential benefits of force and endurance training in this population are strongly suspected. METHOD: This literature review synthesizes the results of clinical trials on this topic. The research was conducted on PubMed, using "Stroke", "rehabilitation", "isokinetic", "upper limb" and "training" as keywords. RESULTS: Seventeen studies focusing on the use of isokinetics in assessment or rehabilitation (six studies) following stroke were reviewed. For the lower limb, muscle strength and walking ability improved after isokinetic rehabilitation programs. For the upper limb, the only two studies found in the literature suggest improvement in the strength of the trained muscles, of grip force, of the Fugl-Meyer motor score and of global functional capacities. This review does not reveal any consensus on the protocols to be implemented: type of muscle contraction, velocities…. CONCLUSION: While isokinetic strengthening has not proven its efficiency in rehabilitation of the upper limb following stroke, its interest with regard to rehabilitation of the lower limbs has been recognized. Randomized controlled trials in this field are necessary to confirm its efficiency, especially concerning upper arm rehabilitation.

HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells.

Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic.

A limit-cycle model of leg movements in cross-country skiing and its adjustments with fatigue.

Using dynamical modeling tools, the aim of the study was to establish a minimal model reproducing leg movements in cross-country skiing, and to evaluate the eventual adjustments of this model with fatigue. The participants (N=8) skied on a treadmill at 90% of their maximal oxygen consumption, up to exhaustion, using the diagonal stride technique. Qualitative analysis of leg kinematics portrayed in phase planes, Hooke planes, and velocity profiles suggested the inclusion in the model of a linear stiffness and an asymmetric van der Pol-type nonlinear damping. Quantitative analysis revealed that this model reproduced the observed kinematics patterns of the leg with adequacy, accounting for 87% of the variance. A rising influence of the stiffness term and a dropping influence of the damping terms were also evidenced with fatigue. The meaning of these changes was discussed in the framework of motor control.

Effects of active vs. passive recovery on repeated rugby-specific exercises.

The aim of this study was to determine the effects of active vs. passive recovery on performance of a rugby-specific intermittent test in rugby union players. Seven male rugby players (20.6+/-0.5 yrs; 181.9+/-10.0 cm; 94.5+/-12.8 kg) performed in random order, over two separate sessions, a specific repeated-sprint rugby test, the Narbonne test (6 x 4 consecutive actions: 1, scrummaging; 2, agility sprinting; 3, tackling; 4, straight sprinting) with 30s of passive or active recovery (running at 50% of maximal aerobic speed). The Narbonne tests were completed before (pre-test) and after (post-test) a 30-min rugby match. During the Narbonne test, scrum forces, agility and sprint times, heart rate and rate of perceived exertion were measured. Scrum forces were lower in active (74.9+/-13.4 kg) than in passive recovery (90.4+/-20.9 kg), only during the post-test (p<0.05). Fatigue index (%) (p<0.05) and total sprint time (s) (p<0.01) were significantly greater in active than in passive recovery, both during the pre-test (11.5+/-5.7% vs. 6.7+/-4.5% and 18.1+/-1.3s vs. 16.9+/-0.9s) and the post-test (7.3+/-3.3% vs. 4.3+/-1.5% and 18.3+/-1.6s vs. 16.9+/-1.1s). Consequently, the results indicated that passive recovery enabled better performance during the Narbonne test. However, it is obviously impractical to suggest that players should stand still during and following repeated-sprint bouts: the players have to move to ensure they have taken an optimal position.

Rehabilitation of arm function after stroke. Literature review.

INTRODUCTION: In the recent literature we can find many articles dealing with upper extremity rehabilitation in stroke patients. New techniques, still under evaluation, are becoming the practical applications for the concept of post-stroke brain plasticity. METHODS: This literature review focuses on controlled randomized studies, reviews and meta-analyses published in the English language from 2004 to 2008. The research was conducted in MEDLINE with the following keywords: "upper limb", "stroke", "rehabilitation". RESULTS: We reviewed 66 studies. The main therapeutic strategies are: activation of the ipsilesional motor cortex, inhibition of the contralesional motor cortex and modulation of the sensory afferents. Keeping a cortical representation of the upper limb distal extremity could prevent the learned non-use phenomenon. The modulation of sensory afferents is then proposed: distal cutaneous electrostimulation, anesthesia of the healthy limb, mirror therapy, virtual reality. Intensifying the rehabilitation care means increasing the total hours of rehabilitation dedicated to the paretic limb (proprioceptive stimulation and repetitive movements). This specific rehabilitation is facilitated by robot-aided therapy in the active-assisted mode, neuromuscular electrostimulation and bilateral task training. Intensifying the rehabilitation training program significantly improves the arm function outcome when performed during subacute stroke rehabilitation (< six months). Ipsilesional neurostimulation as well as mental practice optimize the effect of repetitive gestures for slight motor impairments. Contralesional neurostimulation or anesthesia of the healthy hand both improve the paretic hand's dexterity via a decrease of the transcallosal inhibition. This pathophysiological mechanism could also explain the positive impact of constraint-induced movement therapy (CI therapy) in an environmental setting for chronic stroke patients. CONCLUSION: To ensure a positive functional outcome, stroke rehabilitation programs are based on task-oriented repetitive training. This literature review shows that exercising the hemiparetic hand and wrist is essential in all stages of a stroke rehabilitation program. New data stemming from neurosciences suggest that ipsilesional corticospinal excitability should be a priority.

Adaptation of motor behavior to preserve task success in the presence of muscle fatigue.

To achieve task goals in the various contexts of everyday life, the CNS has to adapt to short time scale changes in the properties of the neuromuscular system, such as those induced by fatigue. Here we investigated how humans preserve task success despite fatigue-induced changes within the neuromuscular system, when they have to aim at a target as fast and as accurately as possible. In such a task, subjects generally choose a compromise between speed and accuracy that has been formalized as Fitts's law. We first characterized the effect of fatigue on Fitts's law in an experiment where participants had to perform fast but accurate elbow movements aimed at targets of different sizes, before and after a fatiguing exercise that reduced maximal voluntary force by approximately 30%. We found that movements were slower to guarantee task success in the presence of fatigue. We then used an optimal control model to determine how fatigue-induced changes in variables such as noise in motor commands, muscle contraction and relaxation times, and the gain between neural activation and muscle force may contribute to changes in Fitts's law with fatigue. We concluded that the observed behavior was not due to the lack of available force, but very likely reflected the fact that the CNS uses the same optimal strategy with a fatigued neuromuscular plant that notably exhibits increased signal-dependent noise in motor commands. This strategy appears necessary to preserve task success in the presence of acute changes in the neuromuscular system.

HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.

Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21(WAF1/Cip1)gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.

Non-linear analyses of heart rate variability during heavy exercise and recovery in cyclists.

We investigated the time course of RR interval variability during exercise and subsequent 50 minutes of recovery in seven well-trained male cyclists who performed an exercise with 3 successive 8 min stages at 40 %, 70 % and 90 % of their maximal oxygen uptake. The goal of the study was to check whether the decrease in the amplitude of heart rate variability during heavy exercise was accompanied by changes in the chaotic structure of the fluctuations. Heart rate variability was analysed in the temporal and frequency domain using traditional tools and using non-linear methods (Largest Lyapunov Exponent, Detrended Fluctuation Analysis, Minimum Embedding Dimension). When compared to rest, variability at the heaviest exercise intensity was significantly lower (RR: 0.94 +/- 0.22 vs. 0.34 +/- 0.01 ms; SDRR: 0.11 +/- 0.04 vs. 0.01 +/- 0.00 ms) due to a decrease in both LF (2101 +/- 1450 vs. 0.14 +/- 0.09 ms (2) . Hz (-1)) and HF spectral energy (1148 +/- 1126 vs. 7.88 +/- 9.24 ms (2) . Hz (-1)). Non-linear analyses showed that heart rate variability remained chaotic whatever the exercise intensity (the largest Lyapunov exponent was positive at 90 % of the maximal oxygen uptake), with a fractal organisation that tended towards white noise (DFA value close to 0.5) during heavy exercise. During recovery, temporal and spectral variables came back to their rest values within about 30 minutes following an exponential pattern. Non-linear analyses revealed that heartbeat dynamics were disorganised at the beginning of recovery, and involved more regulating systems than at rest, even after 50 minutes of recovery. We concluded that, during heavy exercise, heart rate variability was mainly influenced by other factors than autonomous nervous system, and suggest that mechanical or neurological couplings between the cardiac, locomotor and respiratory systems could play an important part in the observed changes.

Stability and phase locking in human soccer juggling.

We explored a variant of juggling in which human adults were asked to rhythmically bounce a soccer ball with their dominant foot while standing on the other foot. Eight subjects performed the task at three prescribed heights and one free height condition. Kinematic analyses of foot movement at ball-foot impact showed that, for the smallest height, foot acceleration was positive or zero at impact, which indicates an active stabilization regime. Increasing juggling height resulted in foot acceleration becoming increasingly negative at impact, which is required for a passive dynamical stability regime. These results show that skilled soccer jugglers exploit the passive stability regime afforded by the task, but that similar stability can be achieved with an active stabilization strategy.

Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation.

Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor which is activated by hypoxia and involved in the adaptative response of the cell to oxygen deprivation. During hypoxic stress, HIF-1 triggers the overexpression of genes coding for glycolytic enzymes and angiogenic factors. To be active HIF-1 must be phosphorylated. HIF-1 is a substrate for various kinase pathways including PI-3K and the MAP kinases ERK and p38. Several transduction pathways have been proposed which act downstream of putative oxygen sensors and lead to the activation of these kinases. In this review, we summarize some of the latest advances describing the possible signaling pathways leading to HIF-1 phosphorylation and subsequent activation. The physiological relevance of these regulations is also discussed.

The dynamics of rhythmical aiming in 2D task space: relation between geometry and kinematics under examination.

We explored a two-dimensional task space variant of the classical rhythmical Fitts' task in which participants were asked to sequentially cross four targets arranged around the extreme points of the major axes of an ellipse. Fitts' law was found to adequately describe the changes in movement time with the variations in task difficulty (ID), but the 1/3 power-law relating curvature and tangential velocity of the trajectory did not resist the increase in ID. Kinematic analyses showed that the behavioral adaptation to the ID resulted in an increase in the contribution of non-linear terms to the kinematics along the two axes of task space. Moreover, a limit cycle model (combining Rayleigh damping and Duffing stiffness, as in one-dimensional Fitts' task) captured such a behavior. In such a context, Fitts' law and the 1/3 power law appear as surface relations that emerge from parametric changes in a dynamical structure that captures the nature of Fitts' task.