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.

MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation.

Chronic kidney disease (CKD) is associated with a multifactorial dysregulation of bone and vascular calcification and closely linked to increased cardiovascular mortality and concomitant bone disease. We aimed to investigate specific microRNA (miRNA) signatures in CKD patients to find indicators for vascular calcification and/or bone mineralization changes during CKD and after kidney transplantation (KT). A miRNA array was used to investigate serum miRNA profiles in CKD patients, then selected miRNAs were quantified in a validation cohort comprising 73 patients in CKD stages 3 to 5, 67 CKD patients after KT, and 36 healthy controls. A spectrum of biochemical parameters including markers for kidney function, inflammation, glucose, and mineral metabolism was determined. The relative expression of miR-223-3p and miR-93-5p was down-regulated in patients with CKD stage 4 and 5 compared to healthy controls. This down-regulation disappeared after kidney transplantation even when lower glomerular filtration rates (eGFR) persisted. MiR-223-3p and miR-93-5p were associated with interleukin-6 (IL-6) and eGFR levels, and by trend with interleukin-8 (IL-8), C-peptide, hematocrit, and parathyroid hormone (PTH). This study contributes new knowledge of serum miRNA expression profiles in CKD, potentially reflecting pathophysiological changes of bone and calcification pathways associated with inflammation, vascular calcification, mineral and glucose metabolism. Identified miRNA signatures can contribute to future risk markers or future therapeutic targets in bone and kidney disease.

Direct comparison of regulators of calcification between bone and vessels in humans.

Calcification is not only physiologically present in bone but is a main pathophysiological process in vasculature, favouring cardiovascular diseases. Our aim was to investigate changes in the expression of calcification regulators during vascular calcification in bone and vasculature. Levels of gene expression of osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), osteopontin (OPN), matrix gla protein (MGP), bone sialoprotein (BSP), SMAD6, and runt-related transcription factor 2 (RUNX2) were determined in bone, aorta, and external iliac artery tissue samples of transplant donors. Histological stages of atherosclerosis (AS) in vessels are defined as "no changes", "intima thickening", or "intima calcification". Patients' bone samples were subgrouped accordingly. We demonstrate that in vessels BSP and OPN expression significantly increased during intima thickening and decreased during intima calcification, whereas the expression of regulators of calcification did not significantly change in bone during intima thickening and intima calcification. At the stage of intima thickening, MGP, OPG, and SMAD6 expression and at stage of intima calcification only MGP expression was lower in bone than in vessel. The expression of BSP and RANKL was regulated in opposite ways in bone and vessels, whereas the expression of MGP, OC, RUNX2, and OPN was regulated in a tissue-specific manner. Our study is the first direct comparison of gene expression changes during AS progression in bone and vessels. Our results indicate that changes in the expression of regulators of calcification in the vessel wall as well as in bone occur early in the calcification process, even prior to deposition of calcium/phosphate precipitation.

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.

Osteocalcin is not a strong determinant of serum testosterone and sperm count in men from infertile couples.

Osteocalcin (OC) - released by osteoblasts and known as a marker of bone turnover - has been suggested to influence male fertility in murine models by enhancing testosterone production and sperm count. Results from clinical studies are scarce, however. The aim of this cross-sectional study was to investigate the proposed association of OC, undercarboxylated osteocalcin (ucOC) or carboxylated osteocalcin (cOC) with testosterone and sperm count in a cohort of 159 young male adults from infertile couples. Semen analysis was performed. Testosterone, free testosterone, LH, OC and ucOC were measured in serum samples after an overnight fast. cOC and OC correlated weakly but significantly with testosterone (OC: r = 0.165, p = 0.040, cOC: r = 0.193, p = 0.017), but not after adjusting for age and body mass index (BMI) or waist-hip ratio (WHR). %ucOC (ucOC levels expressed as percentage of total OC) correlated inversely with LH (r = -0.184, p = 0.023) and remained significant after the same adjustment. No significant correlations were observed between OC, cOC, ucOC, %ucOC and sperm count, semen volume and number of vital spermatozoa. In binary logistic regression analyses, none of the parameters of OC were predictors of oligozoospermia after adjusting for age and BMI or WHR. The weak association between %ucOC and LH has marginal clinical importance because of the lack of associations of parameters of OC with testosterone and sperm count. The current data thus cannot support the notion that OC is associated with male fertility in young men from infertile couples.

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, is one of the most common hormonal disorders among premenopausal women and is associated with infertility, obesity, and insulin resistance. Accumulating evidence suggests a role of the blood coagulation factor gene F13A1 in obesity (GeneBank ID: NM_000129.3). The aim of this study was to investigate the association of intronic allelic variants of the F13A1 gene with PCOS susceptibility and metabolic parameters in lean and obese PCOS women. In a case-control study, we determined an intronic F13A1 single nucleotide polymorphism (SNP) (dbSNP ID: rs7766109) in 585 PCOS and 171 control women and tested for PCOS susceptibility and associations with anthropometric, metabolic and hormonal parameters. Genotype frequencies of the F13A1 SNP rs7766109 were equivalent in PCOS and control women. In PCOS women, F13A1 gene variants were significantly associated with body mass index (BMI) (p=0.013), systolic blood pressure (p=0.042), insulin response (AUCins) (p=0.015), triglycerides (TG) (p=0.001), and high density lipoprotein cholesterol (HDL) (p=0.012). In the subgroup of obese PCOS women free androgen index (FAI), free testosterone and sex hormone binding globulin (SHBG) as well as glucose measurements showed a significantly different pattern across F13A1 gene variants (p=0.043; p=0.039 and p=0.013, respectively). We report for the first time an association of the F13A1 SNP rs7766109 with BMI, androgens, and insulin resistance in PCOS women. Further studies are needed to confirm our findings and to evaluate whether F13A1 is causally involved in the pathogenesis of PCOS related metabolic and hormonal disturbances.

Association of genetic variants in the two isoforms of 5α-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome.

OBJECTIVE: Given its role in converting testosterone to dihydrotestosterone and cortisol to dihydrocortisol, 5α-reductase may be important in the pathophysiology of the polycystic ovary syndrome (PCOS). Increased activity of this enzyme has already been demonstrated in ovaries of affected women, and might be caused by genetic alterations. The aim of this study was to analyze representative genetic variants of both isoforms of 5α-reductase with regard to PCOS parameters in lean and obese women. STUDY DESIGN: We analyzed one single nucleotide polymorphism (SNP) (rs523349) of the isoform 2 (SRD5A2) and one haplotype of the isoform 1 (SRD5A1), consisting of the two SNPs rs39848 and rs3797179, in 249 women with PCOS and 226 healthy women using a 5'-exonuclease-assay. The genotypes were associated with anthropometric, metabolic and hormonal as well as functional tests in these women. RESULTS: In the investigated haplotype of SRD5A1, the TA variant was associated with an increased frequency of PCOS (P=0.022) and an increased Ferriman-Gallwey Score (hirsutism) (P=0.016) in women with normal weight. The G allele at the examined position of the SRD5A2 showed a decreased frequency of PCOS (P=0.03) in women with normal weight. CONCLUSION: One of the keys in the development of the PCOS is hyperandrogenism, which might be caused by an increased 5α-reductase activity, as it is often seen in obesity. This mechanism might therefore be of importance in lean PCOS patients and contribute to the clinical findings.

Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome.

OBJECTIVES: Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances, in particular from insulin resistance. Accumulating evidence suggests that vitamin D deficiency may contribute to the development of the metabolic syndrome (MS). Hence, the aim of our study was to investigate the association of 25(OH)D levels and the components of the MS in PCOS women. METHODS: 25(OH)D levels were measured by means of ELISA in 206 women affected by PCOS. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. RESULTS: The prevalence of insufficient 25(OH)D levels (<30 ng/ml) was 72.8% in women with PCOS. PCOS women with the MS had lower 25(OH)D levels than PCOS women without these features (17.3 vs 25.8 ng/ml respectively; P<0.05). In multivariate regression analysis including 25(OH)D, season, body mass index (BMI), and age, 25(OH)D and BMI were independent predictors of homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI; P<0.05 for all). In binary logistic regression analyses, 25(OH)D (OR 0.86, P=0.019) and BMI (OR 1.28, P<0.001) were independent predictors of the MS in PCOS women. We found significantly negative correlations of 25(OH)D levels with BMI, waist circumference, waist-to-hip ratio, systolic and diastolic blood pressure, fasting and stimulated glucose, area under the glucose response curve, fasting insulin, HOMA-IR, HOMA-beta, triglycerides, and quotient total cholesterol/high-density lipoprotein (HDL) and positive correlations of 25(OH)D levels with QUICKI and HDL (P<0.05 for all). CONCLUSION: We demonstrate that low 25(OH)D levels are associated with features of the MS in PCOS women. Large intervention trials are warranted to evaluate the effect of vitamin D supplementation on metabolic disturbances in PCOS women.

Humans can adopt optimal discounting strategy under real-time constraints.

Critical to our many daily choices between larger delayed rewards, and smaller more immediate rewards, are the shape and the steepness of the function that discounts rewards with time. Although research in artificial intelligence favors exponential discounting in uncertain environments, studies with humans and animals have consistently shown hyperbolic discounting. We investigated how humans perform in a reward decision task with temporal constraints, in which each choice affects the time remaining for later trials, and in which the delays vary at each trial. We demonstrated that most of our subjects adopted exponential discounting in this experiment. Further, we confirmed analytically that exponential discounting, with a decay rate comparable to that used by our subjects, maximized the total reward gain in our task. Our results suggest that the particular shape and steepness of temporal discounting is determined by the task that the subject is facing, and question the notion of hyperbolic reward discounting as a universal principle.

Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation.

Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinase-dependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.

Unsupervised learning of granule cell sparse codes enhances cerebellar adaptive control.

Marr [J. Physiol. (1969) 202, 437-470] and Albus [Math. Biosci. (1971) 10, 25-61] hypothesized that cerebellar learning is facilitated by a granule cell sparse code, i.e. a neural code in which the fraction of active neurons is low at any one time. In this paper, we re-examine this hypothesis in light of recent experimental and theoretical findings. We argue that cerebellar motor learning is enhanced by a sparse code that simultaneously maximizes information transfer between mossy fibers and granule cells, minimizes redundancies between granule cell discharges, and re-codes the mossy fiber inputs with an adaptive resolution such that inputs corresponding to large errors are finely encoded. We then propose that a set of biologically plausible unsupervised learning rules can produce such a code. To maintain a low mean firing rate compatible with a sparse code, an activity-dependent homeostatic mechanism sets the cells' thresholds. Then, to maximize information transfer, the mossy fiber--granule cell synapses are adjusted by a Hebbian rule. Furthermore, to minimize redundancies between granule cell discharges, the inhibitory Golgi cell--granule cell synapses are tuned by an anti-Hebbian rule. Finally, to allow adaptive resolution, a performance-based neuromodulator-like signal gates these three plastic processes. We integrate these gated learning rules into a simplified model of the cerebellum for arm movement control, and show that unsupervised learning of granule cell sparse codes greatly improves cerebellar adaptive motor control in comparison to a "fixed" Marr--Albus-type model. Until recently, activity-dependent cerebellar plasticity was thought to be largely confined to the granule cell--Purkinje cell synapses. This static view of the cerebellum is, however, quickly being replaced by an extremely dynamic view in which plasticity is omnipresent. The present theoretical study shows how several forms of plasticity in the granular layer of the cerebellum can produce fast, accurate and stable cerebellar learning.

Diffusion of nitric oxide can facilitate cerebellar learning: A simulation study.

The gaseous second messenger nitric oxide (NO), which readily diffuses in brain tissue, has been implicated in cerebellar long-term depression (LTD), a form of synaptic plasticity thought to be involved in cerebellar learning. Can NO diffusion facilitate cerebellar learning? The inferior olive (IO) cells, which provide the error signals necessary for modifying the granule cell-Purkinje cell (PC) synapses by LTD, fire at ultra-low firing rates in vivo, rarely more than 2-4 spikes within a second. In this paper, we show that NO diffusion can improve the transmission of sporadic IO error signals to PCs within cerebellar cortical functional units, or microzones. To relate NO diffusion to adaptive behavior, we add NO diffusion and a "volumic" LTD learning rule, i.e., a learning rule that depends both on the synaptic activity and on the NO concentration at the synapse, to a cerebellar model for arm movement control. Our results show that biologically plausible diffusion leads to an increase in information transfer of the error signals to the PCs when the IO firing rate is ultra-low. This, in turn, enhances cerebellar learning as shown by improved performance in an arm-reaching task.

Cerebellar learning of accurate predictive control for fast-reaching movements.

Long conduction delays in the nervous system prevent the accurate control of movements by feedback control alone. We present a new, biologically plausible cerebellar model to study how fast arm movements can be executed in spite of these delays. To provide a realistic test-bed of the cerebellar neural model, we embed the cerebellar network in a simulated biological motor system comprising a spinal cord model and a six-muscle two-dimensional arm model. We argue that if the trajectory errors are detected at the spinal cord level, memory traces in the cerebellum can solve the temporal mismatch problem between efferent motor commands and delayed error signals. Moreover, learning is made stable by the inclusion of the cerebello-nucleo-olivary loop in the model. It is shown that the cerebellar network implements a nonlinear predictive regulator by learning part of the inverse dynamics of the plant and spinal circuit. After learning, fast accurate reaching movements can be generated.

Electrophysiological properties of inferior olive neurons: A compartmental model.

As a step in exploring the functions of the inferior olive, we constructed a biophysical model of the olivary neurons to examine their unique electrophysiological properties. The model consists of two compartments to represent the known distribution of ionic currents across the cell membrane, as well as the dendritic location of the gap junctions and synaptic inputs. The somatic compartment includes a low-threshold calcium current (I(Ca_l)), an anomalous inward rectifier current (I(h)), a sodium current (I(Na)), and a delayed rectifier potassium current (I(K_dr)). The dendritic compartment contains a high-threshold calcium current (I(Ca_h)), a calcium-dependent potassium current (I(K_Ca)), and a current flowing into other cells through electrical coupling (I(c)). First, kinetic parameters for these currents were set according to previously reported experimental data. Next, the remaining free parameters were determined to account for both static and spiking properties of single olivary neurons in vitro. We then performed a series of simulated pharmacological experiments using bifurcation analysis and extensive two-parameter searches. Consistent with previous studies, we quantitatively demonstrated the major role of I(Ca_l) in spiking excitability. In addition, I(h) had an important modulatory role in the spike generation and period of oscillations, as previously suggested by Bal and McCormick. Finally, we investigated the role of electrical coupling in two coupled spiking cells. Depending on the coupling strength, the hyperpolarization level, and the I(Ca_l) and I(h) modulation, the coupled cells had four different synchronization modes: the cells could be in-phase, phase-shifted, or anti-phase or could exhibit a complex desynchronized spiking mode. Hence these simulation results support the counterintuitive hypothesis that electrical coupling can desynchronize coupled inferior olive cells.

A model of activity-dependent formation of cerebellar microzones.

According to modern views of the cerebellum in motor control, each cerebellar functional unit, or microzone, learns how to execute predictive and coordinative control, based on long-term depression of the granule cell-Purkinje cell synapses. In the present paper, in light of recent experimental and theoretical studies on synaptic elimination and cerebellar motor learning, a model of the formation of cerebellar microzones by climbing fiber synaptic elimination is proposed. It is shown that competition for an activity-dependent supply of neurotrophic factor can reproduce the spatio-temporal characteristics of climbing fiber synaptic elimination. It is further shown that when this elimination is accurate, motor coordination can be acquired in an arm reaching task. In view of the results of the present study, several predictions are proposed.

Role of the cerebellum in reaching movements in humans. I. Distributed inverse dynamics control.

This study focuses on the role of the motor cortex, the spinal cord and the cerebellum in the dynamics stage of the control of arm movement. Currently, two classes of models have been proposed for the neural control of movements, namely the virtual trajectory control hypothesis and the acquisition of internal models of the motor apparatus hypothesis. In the present study, we expand the virtual trajectory model to whole arm reaching movements. This expanded model accurately reproduced slow movements, but faster reaching movements deviated significantly from the planned trajectories, indicating that for fast movements, this model was not sufficient. These results led us to propose a new distributed functional model consistent with behavioural, anatomical and neurophysiological data, which takes into account arm muscles, spinal cord, motor cortex and cerebellum and is consistent with the view that the central nervous system acquires a distributed inverse dynamics model of the arm. Previous studies indicated that the cerebellum compensates for the interaction forces that arise during reaching movements. We show here how the cerebellum may increase the accuracy of reaching movements by compensating for the interaction torques by learning a portion of an inverse dynamics model that refines a basic inverse model in the motor cortex and spinal cord.

Role of the cerebellum in reaching movements in humans. II. A neural model of the intermediate cerebellum.

The cerebellum is essential for the control of multijoint movements; when the cerebellum is lesioned, the performance error is more than the summed errors produced by single joints. In the companion paper (Schweighofer et al., 1998), a functional anatomical model for visually guided arm movement was proposed. The model comprised a basic feedforward/feedback controller with realistic transmission delays and was connected to a two-link, six-muscle, planar arm. In the present study, we examined the role of the cerebellum in reaching movements by embedding a novel, detailed cerebellar neural network in this functional control model. We could derive realistic cerebellar inputs and the role of the cerebellum in learning to control the arm was assessed. This cerebellar network learned the part of the inverse dynamics of the arm not provided by the basic feedforward/feedback controller. Despite realistically low inferior olive firing rates and noisy mossy fibre inputs, the model could reduce the error between intended and planned movements. The responses of the different cell groups were comparable to those of biological cell groups. In particular, the modelled Purkinje cells exhibited directional tuning after learning and the parallel fibres, due to their length, provide Purkinje cells with the input required for this coordination task. The inferior olive responses contained two different components; the earlier response, locked to movement onset, was always present and the later response disappeared after learning. These results support the theory that the cerebellum is involved in motor learning.

A model of cerebellar metaplasticity.

The term "learning rule" in neural network theory usually refers to a rule for the plasticity of a given synapse, whereas metaplasticity involves a "metalearning algorithm" describing higher level control mechanisms for apportioning plasticity across a population of synapses. We propose here that the cerebellar cortex may use metaplasticity, and we demonstrate this by introducing the Cerebellar Adaptive Rate Learning (CARL) algorithm that concentrates learning on those Purkinje cell synapses whose adaptation is most relevant to learning an overall pattern. Our results show that this biologically plausible metalearning algorithm not only improves significantly the learning capability of the cerebellum but is very robust. Finally, we identify several putative neurochemicals that could be involved in a cascade of events leading to adaptive learning rates in Purkinje cell synapses.

A model of the cerebellum in adaptive control of saccadic gain. I. The model and its biological substrate.

We review data showing that the cerebellum is required for adaptation of saccadic gain to repeated presentations of dual-step visual targets and thus, presumably, for providing adaptive corrections for the brainstem saccade generator in response to any error created by the open-loop saccadic system. We model the adaptability of the system in terms of plasticity of synapses from parallel fibers to Purkinje cells in cerebellar cortex, stressing the integration of cerebellar cortex and nuclei in microzones as the units for correction of motor pattern generators. We propose a model of the inferior olive as an error detector, and use a 'window of eligibility' to insure that error signals that elicit a corrective movement are used to adjust the original movement, not the secondary movement. In a companion paper we simulate this large, realistic network of neural-like units to study the complex spatiotemporal behavior of neuronal subpopulations implicated in the control and adaptation of saccades.

A model of the cerebellum in adaptive control of saccadic gain. II. Simulation results.

A large, realistic cerebellar neural network has been incorporated into a previously developed saccade model. Using this model, in the present paper, we simulate the complex spatiotemporal behavior of the neuronal subpopulations implicated in adaptive saccadic control. Our simulation results are in good agreement with neurophysiological and behavioral data. Furthermore, we suggest several new experiments to test the validity of our predictions on adaptive saccadic control.