The combined action of a passive exoskeleton and an EMG-controlled neuroprosthesis for upper limb stroke rehabilitation: First results of the RETRAINER project.

The combined use of Functional Electrical Stimulation (FES) and robotic technologies is advocated to improve rehabilitation outcomes after stroke. This work describes an arm rehabilitation system developed within the European project RETRAINER. The system consists of a passive 4-degrees-of-freedom exoskeleton equipped with springs to provide gravity compensation and electromagnetic brakes to hold target positions. FES is integrated in the system to provide additional support to the most impaired muscles. FES is triggered based on the volitional EMG signal of the same stimulated muscle; in order to encourage the active involvement of the patient the volitional EMG is also monitored throughout the task execution and based on it a happy or sad emoji is visualized at the end of each task. The control interface control of the system provides a GUI and multiple software tools to organize rehabilitation exercises and monitor rehabilitation progress. The functionality and the usability of the system was evaluated on four stroke patients. All patients were able to use the system and judged positively its wearability and the provided support. They were able to trigger the stimulation based on their residual muscle activity and provided different levels of active involvement in the exercise, in agreement with their level of impairment. A randomized controlled trial aimed at evaluating the effectiveness of the RETRAINER system to improve arm function after stroke is currently ongoing.

Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age.

The optimization of the targeting of a defined cortical region is a challenge in the current practice of transcranial magnetic stimulation (TMS). The dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) are among the most usual TMS targets, particularly in its "therapeutic" application. This study describes a practical algorithm to determine the anatomical location of the DLPFC and M1 using a three-dimensional (3D) brain reconstruction provided by a TMS-dedicated navigation system from individual magnetic resonance imaging (MRI) data. The coordinates of the right and left DLPFC and M1 were determined in 50 normal brains (100 hemispheres) by five different investigators using a standardized procedure. Inter-rater reliability was good, with 95% limits of agreement ranging between 7 and 16 mm for the different coordinates. As expressed in the Talairach space and compared with anatomical or imaging data from the literature, the coordinates of the DLPFC defined by our algorithm corresponded to the junction between BA9 and BA46, while M1 coordinates corresponded to the posterior border of hand representation. Finally, we found an influence of gender and possibly of age on some coordinates on both rostrocaudal and dorsoventral axes. Our algorithm only requires a short training and can be used to provide a reliable targeting of DLPFC and M1 between various TMS investigators. This method, based on an image-guided navigation system using individual MRI data, should be helpful to a variety of TMS studies, especially to standardize the procedure of stimulation in multicenter "therapeutic" studies.

Intraoperative ultrasound in malformations of cortical development.

PURPOSE: Malformations of cortical development (MCD) are a common cause of medically refractory focal epilepsy. However, the intraoperative definition of MCD can be challenging. In this study we assess the feasibility of intraoperative ultrasound (IOUS) for the intraoperative localization of MCD. MATERIALS AND METHODS: Five epilepsy patients with at least one suspected lesion of MCD were operated with the aid of IOUS. IOUS was compared to preoperative MRI and histopathology. RESULTS: In three cases of focal cortical dysplasia (FCD) type IIB and one case of periventricular heterotopia, the lesions could be delineated well on IOUS and the configuration of the lesion corresponded to the appearance on MRI. However, only one of two FCD type I lesions could be detected on IOUS. CONCLUSION: IOUS can be helpful in defining FCD IIB as well as periventricular heterotopia intraoperatively, but this seems to be more difficult in FCD type I.

Men and women are different: diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum.

INTRODUCTION: Numerous magnetic resonance imaging (MRI) studies have addressed the question of morphological differences of the brain of men and women, reporting conflicting results regarding brain size and the ratio of gray and white matter. In the present study, we used diffusion tensor imaging (DTI) to delineate sex differences of brain white matter. METHODS: We investigated brain microstructure in 25 male and 25 female healthy subjects using a 3T MRI scanner. Whole-head DTI scans were analyzed without a-priori hypothesis using Tract-Based Spatial Statistics (TBSS) calculating maps of fractional anisotropy (FA), radial diffusivity (RD, a potential marker of glial alteration and changes in myelination) and axial diffusivity (AD, a potential marker of axonal changes). RESULTS: DTI revealed regional microstructural differences between the brains of male and female subjects. Those were prominent in the thalamus, corpus callosum and cingulum. Men showed significantly (p<0.0001) higher values of fractional anisotropy and lower radial diffusivity in these areas, suggesting that the observed differences are mainly due to differences in myelination. DISCUSSION: As a novel finding we showed widespread differences in thalamic microstructure that have not been described previously. Additionally, the present study confirmed earlier DTI studies focusing on sexual dimorphism in the corpus callosum and cingulum. All changes appear to be based on differences in myelination. The sex differences in thalamic microstructure call for further studies on the underlying cause and the behavioral correlates of this sexual dimorphism. Future DTI group studies may carefully control for gender to avoid confounding.

Sleep quality in a family with hereditary parkinsonism (PARK6).

OBJECTIVES: The autosomal recessive disorder PARK6 manifests as early-onset Parkinson's disease (PD) with a particularly mild progression. PARK6 is of particular scientific interest, since it is caused by loss-of-function mutations in the mitochondrial protein kinase PINK1 and may thus serve as a model for oxidative damage in PD and in other basal ganglia disorders. Sleep disturbances are very common in PD but have not yet been reported for PARK6 patients. The present study reports on sleep of a Spanish family with PARK6. Of the 5 siblings, 3 were homozygous and severely affected, and 2 were heterozygous and clinically asymptomatic. Research questions concerned possible differences in sleep recordings between homozygote and heterozygote siblings and similarities between PARK6 and sporadic PD sleep profiles. METHOD: The data from detailed clinical interviews of the patients and their bedpartners are reported and compared with polysomnographic data from second-night recordings. CONCLUSIONS: All siblings had good subjective and objective sleep quality. Restless legs syndrome and rapid eye movement (REM) sleep behaviour disorder (RBD) were not observed, suggesting that sleep disturbances are not commonly found in PARK6 patients. Good sleep quality and the absence of RBD might be a useful diagnostic guide in the differential diagnosis of sporadic PD versus PARK6.

Topiramate in add-on therapy: results from an open-label, observational study.

An open-label, observational prospective study assessed the effectiveness of topiramate (TPM) as add-on therapy. A total of 450 patients aged 12 and above with a diagnosis of epilepsy and at least one epileptic seizure during the 12-week retrospective baseline were to be documented. After baseline evaluation, topiramate was added. Ninety-five percent of patients had at least one baseline AED, most commonly Carbamazepine (53%) or Valproate (34%). In 5% TPM was started in monotherapy. Topiramate dose titration and target dose was determined by clinical response and side effect profile. Patients were intended to be followed for a total of 1 year which included 6 visits during which seizure frequency, adverse events, weight as well as clinical global impression were recorded. During the 12 weeks retrospective baseline, a median of 2.8 seizures per month were recorded which reduced significantly to 0.7 per month during the complete treatment phase (p < 0.0001). Seventy-two percent of patients had a > or =50% seizure reduction. Ten percent of patients were seizure free during the study. The most commonly reported adverse events were difficulties with memory (4.2%), somnolence (3.6%), and dizziness (2.7%). Overall, topiramate was well tolerated, and only 5% of patients discontinued treatment due to an adverse event. Retention in the study was higher than previously reported during randomized, dose controlled studies and is likely due to individualized doses as well as slower titration used.

Stages of sleep pathology in spinocerebellar ataxia type 2 (SCA2).

BACKGROUND: Autosomal dominant spinocerebellar ataxia type 2 (SCA2) bears clinical and neuropathologic similarities to sporadic multisystem atrophy (MSA) or Parkinson disease, in which sleep pathology is well documented. However, those clinical entities have a marked variability of the reported sleep disturbances, and their etiology is heterogeneous. In contrast, the study of SCA2 provides an opportunity to examine a molecularly homogeneous patient group, in which disease stages can be defined not only based on disease duration and ataxia scores, but also with regard to modulatory effects of mutation size. OBJECTIVE: To examine the presence and progression of sleep pathology in SCA2. METHODS: We analyzed eight patients with disease durations of 3 to 31 years, all with medium size SCA2 expansions (CAG 38 to 49), using clinical scores, sleep interviews, and video-polysomnography (VPSG) recordings. RESULTS: Almost all patients reported good subjective sleep quality and negated incidents of REM behavior disorder (RBD). At early disease stages, however, REM without atonia in four patients' VPSG suggested subclinical RBD. This was accompanied by a consistent reduction of REM density. In three patients at later SCA2 stages, REM sleep was undetectable, whereas slow wave sleep (SWS) was markedly increased at the cost of light sleep. Periodic leg movements, apnea, or hypopnea were not prominent. CONCLUSIONS: Progressive loss of dream recall in spinocerebellar ataxia type 2 was found and correlated with stages of REM more than non-REM pathology in video-polysomnography. These stages correspond to the progressive atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus.

Where the BOLD signal goes when alpha EEG leaves.

Previous studies using simultaneous EEG and fMRI recordings have yielded discrepant results regarding the topography of brain activity in relation to spontaneous power fluctuations in the alpha band of the EEG during eyes-closed rest. Here, we explore several possible explanations for this discrepancy by re-analyzing in detail our previously reported data. Using single subject analyses as a starting point, we found that alpha power decreases are associated with fMRI signal increases that mostly follow two distinct patterns: either 'visual' areas in the occipital lobe or 'attentional' areas in the frontal and parietal lobe. On examination of the EEG spectra corresponding to these two fMRI patterns, we found greater relative theta power in sessions yielding the 'visual' fMRI pattern during alpha desynchronization and greater relative beta power in sessions yielding the 'attentional' fMRI pattern. The few sessions that fell into neither pattern featured the overall lowest theta and highest beta power. We conclude that the pattern of brain activation observed during spontaneous power reduction in the alpha band depends on the general level of brain activity as indexed over a broader spectral range in the EEG. Finally, we relate these findings to the concepts of 'resting state' and 'default mode' and discuss how - as for sleep - EEG-based criteria might be used for staging brain activity during wakefulness.

Right hemispheric language dominance in a right-handed male with a right frontal tumor shown by functional transcranial Doppler sonography.

BACKGROUND: A 38-year-old, right-handed man with late-onset right frontal epilepsy due to a ganglioglioma and atypical right hemispheric language dominance is described. METHODS: Language dominance was investigated with functional transcranial Doppler sonography (fTCD), and language localization with functional magnetic resonance imaging (fMRI). RESULTS: During a word generation task, fTCD showed atypical right hemispheric language dominance, which was confirmed by fMRI using a semantic word comparison and a word stem completion task. This information helped to guide the resective procedure, which left the patient seizure-free and did not induce new deficits. CONCLUSION: Functional TCD appears to be a useful and reliable screening tool for determining hemispheric language dominance, even in patients with atypical language representation. Functional MRI may be used to confirm fTCD results and further localize eloquent cortex.

Electroencephalographic signatures of attentional and cognitive default modes in spontaneous brain activity fluctuations at rest.

We assessed the relation between hemodynamic and electrical indices of brain function by performing simultaneous functional MRI (fMRI) and electroencephalography (EEG) in awake subjects at rest with eyes closed. Spontaneous power fluctuations of electrical rhythms were determined for multiple discrete frequency bands, and associated fMRI signal modulations were mapped on a voxel-by-voxel basis. There was little positive correlation of localized brain activity with alpha power (8-12 Hz), but strong and widespread negative correlation in lateral frontal and parietal cortices that are known to support attentional processes. Power in a 17-23 Hz range of beta activity was positively correlated with activity in retrosplenial, temporo-parietal, and dorsomedial prefrontal cortices. This set of areas has previously been characterized by high but coupled metabolism and blood flow at rest that decrease whenever subjects engage in explicit perception or action. The distributed patterns of fMRI activity that were correlated with power in different EEG bands overlapped strongly with those of functional connectivity, i.e., intrinsic covariations of regional activity at rest. This result indicates that, during resting wakefulness, and hence the absence of a task, these areas constitute separable and dynamic functional networks, and that activity in these networks is associated with distinct EEG signatures. Taken together with studies that have explicitly characterized the response properties of these distributed cortical systems, our findings may suggest that alpha oscillations signal a neural baseline with "inattention" whereas beta rhythms index spontaneous cognitive operations during conscious rest.

EEG-correlated fMRI of human alpha activity.

Electroencephalography-correlated functional magnetic resonance imaging (EEG/fMRI) can be used to identify blood oxygen level-dependent (BOLD) signal changes associated with both physiological and pathological EEG events. Here, we implemented continuous and simultaneous EEG/fMRI to identify BOLD signal changes related to spontaneous power fluctuations in the alpha rhythm (8-12 Hz), the dominant EEG pattern during relaxed wakefulness. Thirty-two channels of EEG were recorded in 10 subjects during eyes-closed rest inside a 1.5-T magnet resonance (MR) scanner using an MR-compatible EEG recording system. Functional scanning by echoplanar imaging covered almost the entire cerebrum every 4 s. Off-line MRI artifact subtraction software was applied to obtain continuous EEG data during fMRI acquisition. The average alpha power over 1-s epochs was derived at several electrode positions using a Fast Fourier Transform. The power time course was then convolved with a canonical hemodynamic response function, down-sampled, and used for statistical parametric mapping of associated signal changes in the image time series. At all electrode positions studied, a strong negative correlation of parietal and frontal cortical activity with alpha power was found. Conversely, only sparse and nonsystematic positive correlation was detected. The relevance of these findings is discussed in view of the current theories on the generation and significance of the alpha rhythm and the related functional neuroimaging findings.

[Diffusion-weighted MRI of spinal cord infarction. Description of two cases and review of the literature]. / Diffusionsgewichtete MRT bei spinalen Infarkten Darstellung von zwei Fällen und Literaturübersicht.

Spinal cord infarctions occur rarely and are due to various aetiologies. In an emergency setting with acute spinal cord symptoms, magnetic resonance imaging (MRI) is used to exclude space-occupying lesions which require neurosurgical intervention. We report on two patients presenting with an anterior spinal artery syndrome caused by infarction of the thoracolumbar spinal cord including the conus medullaris. While T2-weighted images 4 h and 28 h after onset of clinical symptoms showed only slight unspecific signal changes, diffusion-weighted imaging revealed clear infarction and detected spinal cord ischaemia in an early stage, showing signal intensity conversion comparable to that in acute cerebral stroke.

Cerebellar volumes in newly diagnosed and chronic epilepsy.

Cerebellar atrophy is assumed to be a common finding in patients suffering from epilepsy. Anticonvulsants as well as seizure activity itself have been considered to be responsible for it but many studies have addressed these questions in specialised centres for epilepsy thus having a referral bias towards patients with severe epileptic syndromes. The purpose of this study was: 1. To develop a quantitative method on 3D-MRI data to achieve volume or planimetric measurements (of cerebrum, cerebellum and cerebellar substructures). 2. To investigate the prevalence of cerebellar atrophy (and substructure atrophy) in a prospectively investigated population-based cohort of patients with newly diagnosed and chronic epilepsy. 3. To quantify cerebellar atrophy in clinic-based patients, who had had atrophy previously diagnosed on routine visual MRI assessment. 4. To correlate the measures of atrophy with clinical features in both patient groups. A total of 57 patients with either newly diagnosed or chronic active epilepsy and 36 control subjects were investigated with a newly developed semiautomated method for cerebral as well as cerebellar volume measurements and substructure planimetry, corrected for intracranial volume. We did not find any significant atrophy in the population-based cohort of patients with newly diagnosed epilepsy or with chronic epilepsy. Visually diagnosed cerebellar atrophy was mostly confirmed and quantified by volumetric analysis. The clinical data suggested a correlation between cerebellar atrophy and the duration of the seizure disorder and also the total number of lifetime seizures experienced and the frequency of generalised tonic-clonic seizures per year. Volumetry on 3D-MRI yields reliable quantitative data which shows that cerebellar atrophy might be common in severe and/or longstanding epilepsy but not necessarily in unselected patient groups. The results do not support the proposition that cerebellar atrophy is a predisposing factor for epilepsy but rather are consistent with the view that cerebellar atrophy is the aftermath of epileptic seizures or anticonvulsant medication.

Comparison of spike-triggered functional MRI BOLD activation and EEG dipole model localization.

We studied six patients with localization-related epilepsy, frequent interictal epileptiform discharges, and positive spike-triggered blood oxygen level-dependent functional MRI (BOLD-fMRI) findings. EEG source analysis solutions based on 64-channel EEG recorded in a separate session outside the scanner were obtained using dipole models and compared to the BOLD localization. The BOLD and structural images were coregistered, allowing the measurement of distances between the generator models and BOLD activation(s) and structural lesion when present. In all cases dipole models could be found that explained a sufficient amount of the data and that were anatomically concordant with the BOLD localization. In the five cases with structural abnormality visible on T1 scans, the BOLD activation overlapped or was in close proximity to the abnormality. The overall mean distance between the main moving dipole and the center of the nearest BOLD activation was 3.5 and 2.2 cm for the negative and positive peaks, respectively, including one case of a deep BOLD activation, in which the distance was 5 cm. In conclusion, the degree of agreement between the BOLD and EEG source localization indicates that the combination of these two noninvasive techniques offers the possibility of advancing the study of the generators of epileptiform electrical activity.

Event-related fMRI with simultaneous and continuous EEG: description of the method and initial case report.

We report on the initial imaging findings with a new technique for the simultaneous and continuous acquisition of functional MRI data and EEG recording. Thirty-seven stereotyped interictal epileptiform discharges (spikes) were identified on EEG recorded continuously during the fMRI acquisition on a patient with epilepsy. Localization of the BOLD activation associated with the EEG events was consistent with previous findings and EEG source modeling. The time course of activation was comparable with the physiological hemodynamic response function (HRF). The new methodology could lead to novel and important applications in many areas of neuroscience.

Spatio-temporal imaging of focal interictal epileptiform activity using EEG-triggered functional MRI.

EEG-triggered, blood oxygen level-dependent functional MRI (BOLD-fMRI) was used in 24 patients with localization-related epilepsy and frequent interictal epileptiform discharges (spikes) to identify those brain areas involved in generating the spikes, and to study the evolution of the BOLD signal change over time. The location of the fMRI activation was compared with the scalp EEG spike focus and the structural MR abnormality. Twelve patients (50%) had an fMRI activation concordant with the EEG focus and structural brain abnormalities where present (n = 7). In 2 other patients, the fMRI activation was non-concordant with electroclinical findings. The remaining 10 patients (41.7%) showed no significant fMRI activation. These patients had significantly lower mean spike amplitudes compared to those with positive fMRI results (p = 0.03). The time course of the BOLD response was studied in 3 patients and this revealed a maximum signal change 1.5 to 7.5 sec after the spike. In conclusion, EEG-triggered fMRI can directly identify the generators of interictal epileptiform activity, with high spatial resolution, in selected patients with frequent spikes. The superior spatial resolution obtainable through EEG-triggered fMRI may provide an additional non-invasive tool in the presurgical evaluation of patients with intractable focal seizures.

Long-term continuation of levetiracetam in patients with refractory epilepsy.

The long-term continuation (retention) rate, efficacy, and safety data of the new antiepileptic drug levetiracetam (LEV) was evaluated in all patients with epilepsy exposed to the drug during its developmental program (n = 1,422). The retention rate was estimated to be 60% after 1 year and 32% after 5 years. Thirty-nine percent (512/1,325) of patients had a seizure reduction of > or =50%, and 13% (183/1,422) became seizure-free for at least 6 months. LEV seems an effective and well tolerated new antiepileptic drug.

Combined functional magnetic resonance imaging and diffusion tensor imaging demonstrate widespread modified organisation in malformation of cortical development.

A patient with a mild left hemiparesis and a malformation of cortical development in the right hemisphere was investigated with fMRI (functional magnetic resonance imaging) and DTI (diffusion tensor imaging). The motor cortex was studied using a finger tapping fMRI experiment. The fibre orientation was studied by displaying the principal eigenvector of the diffusion tensor in the spatially normalised brain of the patient and of control subjects. In addition, the anisotropy (directionality) of water diffusion of the patient was statistically compared with control subjects. The malformation was located in the right central region in the expected position of the motor cortex. fMRI showed activation anterior and posterior to the malformation. DTI disclosed that fibres with rostrocaudal orientation, presumably representing the pyramidal tract, were deviating from their normal orientation and passing around the malformation. There were widespread regions of reduced anisotropy affecting both hemispheres. In conclusion, fMRI and DTI provided concordant information showing widespread modified functional and structural organisation including regions which appeared normal on standard imaging.

Functional MRI activation of individual interictal epileptiform spikes.

We used spike-triggered functional MRI in a patient with localization-related epilepsy to determine whether individual (as opposed to averaged) focal interictal epileptiform discharges (spikes) were associated with hemodynamic changes detectable with blood oxygen level-dependent functional MRI (fMRI). It was found that 15 of 43 spikes (34.9%) were associated with significant focal fMRI activation. Single event-related fMRI of interictal spikes is feasible in selected patients, giving complementary information to that provided by averaged fMRI data.

[Reversible bilateral cortical MRI changes as sequelae of status epilepticus]. / Reversible bilaterale kortikale MRT-Veränderungen infolge einer Anfallsserie.

Neuroimaging may detect structural and functional changes following seizures. Magnetic resonance imaging (MRI) studies showed increased signal intensities in T2- and diffusion-weighted images, especially in the temporal cortex. We report a patient with reversible symmetrical signal abnormalities of the insular cortex after seizures. In addition, the frontal paramedian cortex and the central region were involved. There was no leptomeningeal or parenchymal enhancement on contrast-enhanced T1-weighted images, suggesting an intact blood-brain barrier. Upon follow-up examination 12 days later, the signal abnormalities resolved completely. Reversible hyperintensities on T2-weighted images are due to different causes leading to increased water content, such as demyelinisation or edema. According to published data, cytotoxic edema caused by excessive glutamate concentration and other noxious substances is assumed to be the most probable cause for these findings.