Movement-Related EEG Oscillations of Contralesional Hemisphere Discloses Compensation Mechanisms of Severely Affected Motor Chronic Stroke Patients.

Conventional rehabilitation strategies for stroke survivors become difficult when voluntary movements are severely disturbed. Combining passive limb mobilization, robotic devices and EEG-based brain-computer interfaces (BCI) systems might improve treatment and clinical follow-up of these patients, but detailed knowledge of neurophysiological mechanisms involved in functional recovery, which might help for tailoring stroke treatment strategies, is lacking. Movement-related EEG changes (EEG event-related desynchronization (ERD) in [Formula: see text] and [Formula: see text] bands, an indicator of motor cortex activation traditionally used for BCI systems), were evaluated in a group of 23 paralyzed chronic stroke patients in two unilateral motor tasks alternating paretic and healthy hands ((i) passive movement, using a hand exoskeleton, and (ii) voluntary movement), and compared to nine healthy subjects. In tasks using unaffected hand, we observed an increase of contralesional hemisphere activation for stroke patients group. Unexpectedly, when using paralyzed hand, motor cortex activation was reduced or absent in severely affected group of patients, while patients with moderate motor deficit showed an activation greater than control group. Cortical activation was reduced or absent in damaged hemisphere of all the patients in both tasks. Significant differences related to severity of motor deficit were found in the time course of [Formula: see text]-[Formula: see text] bands power ratio in EEG of contralesional hemisphere while moving affected hand. These findings suggest the presence of different compensation mechanisms in contralesional hemisphere of stroke patients related to the grade of motor disability, that might turn quantitative EEG during a movement task, obtained from a BCI system controlling a robotic device included in a rehabilitation task, into a valuable tool for monitoring clinical progression, evaluating recovery, and tailoring treatment of stroke patients.

Respiratory disturbances and high risk of sudden death in the neonatal connexin-36 knockout mouse.

Neural circuits at the brainstem involved in the central generation of the motor patterns of respiration and cardiorespiratory chemoreflexes organize as cell assemblies connected by chemical and electrical synapses. However, the role played by the electrical connectivity mainly mediated by connexin36 (Cx36), which expression reaches peak value during the postnatal period, is still unknown. To address this issue, we analyzed here the respiratory phenotype of a mouse strain devoid constitutively of Cx36 at P14. Male Cx36-knockout mice at rest showed respiratory instability of variable degree, including a periodic Cheyne-Stokes breathing. Moreover, mice lacking Cx36 exhibited exacerbated chemoreflexes to normoxic and hypoxic hypercapnia characterized by a stronger inspiratory/expiratory coupling due to an increased sensitivity to CO2 . Deletion of Cx36 also impaired the generation of the recurrent episodes of transient bradycardia (ETBs) evoked during hypercapnic chemoreflexes; these EBTs constituted a powerful mechanism of cardiorespiratory coupling capable of improving alveolar gaseous exchange under hypoxic hypercapnia conditions. Approximately half of the homo- and heterozygous Cx36KO, but none WT, mice succumbed by respiratory arrest when submitted to hypoxia-hypercapnia, the principal exogenous stressor causing sudden infant death syndrome (SIDS). The early suppression of EBTs, which worsened arterial O2  saturation, and the generation of a paroxysmal generalized clonic-tonic activity, which provoked the transition from eupneic to gasping respiration, were the critical events causing sudden death in the Cx36KO mice. These results indicate that Cx36 expression plays a pivotal role in respiratory control, cardiorespiratory coordination, and protection against SIDS at the postnatal period.

SGK1.1 Reduces Kainic Acid-Induced Seizure Severity and Leads to Rapid Termination of Seizures.

Approaches to control epilepsy, one of the most important idiopathic brain disorders, are of great importance for public health. We have previously shown that in sympathetic neurons the neuronal isoform of the serum and glucocorticoid-regulated kinase (SGK1.1) increases the M-current, a well-known target for seizure control. The effect of SGK1.1 activation on kainate-induced seizures and neuronal excitability was studied in transgenic mice that express a permanently active form of the kinase, using electroencephalogram recordings and electrophysiological measurements in hippocampal brain slices. Our results demonstrate that SGK1.1 activation leads to reduced seizure severity and lower mortality rates following status epilepticus, in an M-current-dependent manner. EEG is characterized by reduced number, shorter duration, and early termination of kainate-induced seizures in the hippocampus and cortex. Hippocampal neurons show decreased excitability associated to increased M-current, without altering basal synaptic transmission or other neuronal properties. Altogether, our results reveal a novel and selective anticonvulsant pathway that promptly terminates seizures, suggesting that SGK1.1 activation can be a potent factor to secure the brain against permanent neuronal damage associated to epilepsy.

User activity recognition system to improve the performance of environmental control interfaces: a pilot study with patients.

BACKGROUND: Assistive technologies aim to increase quality of life, reduce dependence on care giver and on the long term care system. Several studies have demonstrated the effectiveness in the use of assistive technology for environment control and communication systems. The progress of brain-computer interfaces (BCI) research together with exoskeleton enable a person with motor impairment to interact with new elements in the environment. This paper aims to evaluate the environment control interface (ECI) developed under the AIDE project conditions, a multimodal interface able to analyze and extract relevant information from the environments as well as from the identification of residual abilities, behaviors, and intentions of the user. METHODS: This study evaluated the ECI in a simulated scenario using a two screen layout: one with the ECI and the other with a simulated home environment, developed for this purpose. The sensorimotor rhythms and the horizontal oculoversion, acquired through BCI2000, a multipurpose standard BCI platform, were used to online control the ECI after the user training and system calibration. Eight subjects with different neurological diseases and spinal cord injury participated in this study. The subjects performed simulated activities of daily living (ADLs), i.e. actions in the simulated environment as drink, switch on a lamp or raise the bed head, during ten minutes in two different modes, AIDE mode, using a prediction model, to recognize the user intention facilitating the scan, and Manual mode, without a prediction model. RESULTS: The results show that the mean task time spent in the AIDE mode was less than in the Manual, i.e the users were able to perform more tasks in the AIDE mode during the same time. The results showed a statistically significant differences with p<0.001. Regarding the steps, i.e the number of abstraction levels crossed in the ECI to perform an ADL, the users performed one step in the 90% of the tasks using the AIDE mode and three steps, at least, were necessary in the Manual mode. The user's intention prediction was performed through conditional random fields (CRF), with a global accuracy about 87%. CONCLUSIONS: The environment analysis and the identification of the user's behaviors can be used to predict the user intention opening a new paradigm in the design of the ECIs. Although the developed ECI was tested only in a simulated home environment, it can be easily adapted to a real environment increasing the user independence at home.

Synchronization of Slow Cortical Rhythms During Motor Imagery-Based Brain-Machine Interface Control.

Modulation of sensorimotor rhythm (SMR) power, a rhythmic brain oscillation physiologically linked to motor imagery, is a popular Brain-Machine Interface (BMI) paradigm, but its interplay with slower cortical rhythms, also involved in movement preparation and cognitive processing, is not entirely understood. In this study, we evaluated the changes in phase and power of slow cortical activity in delta and theta bands, during a motor imagery task controlled by an SMR-based BMI system. In Experiment I, EEG of 20 right-handed healthy volunteers was recorded performing a motor-imagery task using an SMR-based BMI controlling a visual animation, and during task-free intervals. In Experiment II, 10 subjects were evaluated along five daily sessions, while BMI-controlling same visual animation, a buzzer, and a robotic hand exoskeleton. In both experiments, feedback received from the controlled device was proportional to SMR power (11-14 Hz) detected by a real-time EEG-based system. Synchronization of slow EEG frequencies along the trials was evaluated using inter-trial-phase coherence (ITPC). Results: cortical oscillations of EEG in delta and theta frequencies synchronized at the onset and at the end of both active and task-free trials; ITPC was significantly modulated by feedback sensory modality received during the tasks; and ITPC synchronization progressively increased along the training. These findings suggest that phase-locking of slow rhythms and resetting by sensory afferences might be a functionally relevant mechanism in cortical control of motor function. We propose that analysis of phase synchronization of slow cortical rhythms might also improve identification of temporal edges in BMI tasks and might help to develop physiological markers for identification of context task switching and practice-related changes in brain function, with potentially important implications for design and monitoring of motor imagery-based BMI systems, an emerging tool in neurorehabilitation of stroke.

Human arm joints reconstruction algorithm in rehabilitation therapies assisted by end-effector robotic devices.

BACKGROUND: End-effector robots are commonly used in robot-assisted neuro-rehabilitation therapies for upper limbs where the patient's hand can be easily attached to a splint. Nevertheless, they are not able to estimate and control the kinematic configuration of the upper limb during the therapy. However, the Range of Motion (ROM) together with the clinical assessment scales offers a comprehensive assessment to the therapist. Our aim is to present a robust and stable kinematic reconstruction algorithm to accurately measure the upper limb joints using only an accelerometer placed onto the upper arm. METHODS: The proposed algorithm is based on the inverse of the augmented Jaciobian as the algorithm (Papaleo, et al., Med Biol Eng Comput 53(9):815-28, 2015). However, the estimation of the elbow joint location is performed through the computation of the rotation measured by the accelerometer during the arm movement, making the algorithm more robust against shoulder movements. Furthermore, we present a method to compute the initial configuration of the upper limb necessary to start the integration method, a protocol to manually measure the upper arm and forearm lengths, and a shoulder position estimation. An optoelectronic system was used to test the accuracy of the proposed algorithm whilst healthy subjects were performing upper limb movements holding the end effector of the seven Degrees of Freedom (DoF) robot. In addition, the previous and the proposed algorithms were studied during a neuro-rehabilitation therapy assisted by the 'PUPArm' planar robot with three post-stroke patients. RESULTS: The proposed algorithm reports a Root Mean Square Error (RMSE) of 2.13cm in the elbow joint location and 1.89cm in the wrist joint location with high correlation. These errors lead to a RMSE about 3.5 degrees (mean of the seven joints) with high correlation in all the joints with respect to the real upper limb acquired through the optoelectronic system. Then, the estimation of the upper limb joints through both algorithms reveal an instability on the previous when shoulder movement appear due to the inevitable trunk compensation in post-stroke patients. CONCLUSIONS: The proposed algorithm is able to accurately estimate the human upper limb joints during a neuro-rehabilitation therapy assisted by end-effector robots. In addition, the implemented protocol can be followed in a clinical environment without optoelectronic systems using only one accelerometer attached in the upper arm. Thus, the ROM can be perfectly determined and could become an objective assessment parameter for a comprehensive assessment.

A four-state Markov model of sleep-wakefulness dynamics along light/dark cycle in mice.

Behavioral states alternate between wakefulness (wk), rapid eye movement (rem) and non-rem (nrem) sleep at time scale of hours i.e., light and dark cycle rhythms and from several tens of minutes to seconds (i.e., brief awakenings during sleep). Using statistical analysis of bout duration, Markov chains of sleep-wk dynamics and quantitative EEG analysis, we evaluated the influence of light/dark (ld) changes on brain function along the sleep-wk cycle. Bout duration (bd) histograms and Kaplan-Meier (km) survival curves of wk showed a bimodal statistical distribution, suggesting that two types of wk do exist: brief-wk (wkb) and long-wk (wkl). Light changes modulated specifically wkl bouts, increasing its duration during active/dark period. In contrast, wkb, nrem and rem bd histograms and km curves did not change significantly along ld cycle. Hippocampal eeg of both types of wk were different: in comparison wkb showed a lower spectral power in fast gamma and fast theta bands and less emg tone. After fitting a four-states Markov chain to mice hypnograms, moreover in states transition probabilities matrix was found that: in dark/active period, state-maintenance probability of wkl increased, and probability of wkl to nrem transition decreased; the opposite was found in light period, favoring the hypothesis of the participation of brief wk into nrem-rem intrinsic sleep cycle, and the role of wkl in SWS homeostasis. In conclusion, we propose an extended Markov model of sleep using four stages (wkl, nrem, rem, wkb) as a fully adequate model accounting for both modulation of sleep-wake dynamics based on the differential regulation of long-wk (high gamma/theta) epochs during dark and light phases.

Safety and tolerability of silk fibroin hydrogels implanted into the mouse brain.

At present, effective therapies to repair the central nervous system do not exist. Biomaterials might represent a new frontier for the development of neurorestorative therapies after brain injury and degeneration. In this study, an in situ gelling silk fibroin hydrogel was developed via the sonication-induced gelation of regenerated silk fibroin solutions. An adequate timeframe for the integration of the biomaterial into the brain tissue was obtained by controlling the intensity and time of sonication. After the intrastriatal injection of silk fibroin the inflammation and cell death in the implantation area were transient. We did not detect considerable cognitive or sensorimotor deficits, either as examined by different behavioral tests or an electrophysiological analysis. The sleep and wakefulness states studied by chronic electroencephalogram recordings and the fitness of thalamocortical projections and the somatosensory cortex explored by evoked potentials were in the range of normality. The methodology used in this study might serve to assess the biological safety of other biomaterials implanted into the rodent brain. Our study highlights the biocompatibility of native silk with brain tissue and extends the current dogma of the innocuousness of this biomaterial for therapeutic applications, which has repercussion in regenerative neuroscience. STATEMENT OF SIGNIFICANCE: The increasingly use of sophisticated biomaterials to encapsulate stem cells has changed the comprehensive overview of potential strategies for repairing the nervous system. Silk fibroin (SF) meets with most of the standards of a biomaterial suitable to enhance stem cell survival and function. However, a proof-of-principle of the in vivo safety and tolerability of SF implanted into the brain tissue is needed. In this study we have examined the tissue bioresponse and brain function after implantation of SF hydrogels. We have demonstrated the benign coexistence of silk with the complex neuronal circuitry that governs sensorimotor coordination and mechanisms such as learning and memory. Our results have repercussion in the development of advances strategies using this biomaterial in regenerative neuroscience.

Long-term dynamics of somatosensory activity in a stroke model of distal middle cerebral artery oclussion.

A constant challenge in experimental stroke is the use of appropriate tests to identify signs of recovery and adverse effects linked to a particular therapy. In this study, we used a long-term longitudinal approach to examine the functional brain changes associated with cortical infarction in a mouse model induced by permanent ligation of the middle cerebral artery (MCA). Sensorimotor function and somatosensory cortical activity were evaluated with fault-foot and forelimb asymmetry tests in combination with somatosensory evoked potentials. The stroke mice exhibited both long-term deficits in the functional tests and impaired responses in the infarcted and intact hemispheres after contralateral and ipsilateral forepaw stimulation. In the infarcted hemisphere, reductions in the amplitudes of evoked responses were detected after contralateral and ipsilateral stimulation. In the intact hemisphere, and similar to cortical stroke patients, a gradual hyperexcitability was observed after contralateral stimulation but no parallel evidence of a response was detected after ipsilateral stimulation. Our results suggest the existence of profound and persistent changes in the somatosensory cortex in this specific mouse cortical stroke model. The study of evoked potentials constitutes a feasible and excellent tool for evaluating the fitness of the somatosensory cortex in relation to functional recovery after preclinical therapeutic intervention.

Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations.

Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.