The novel PSEN1 M84V mutation associated to frontal dysexecutive syndrome, spastic paraparesis, and cerebellar atrophy in a dominant Alzheimer's disease family.

We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.

Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease.

The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar-motor cortex connectivity, likely via cerebellar-thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions.

Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands.

Cerebellar ataxias represent a very heterogeneous group of disabling disorders for which we lack effective symptomatic therapies in most cases. There is currently an intense interest in the use of non-invasive transcranial DC stimulation (tDCS) to modulate the activity of the cerebellum in ataxic disorders. We performed a detailed laboratory assessment of the effects of transcranial cerebello-cerebral DC stimulation (tCCDCS, including a sham procedure) on upper limb tremor and dysmetria in 2 patients presenting a dominant spinocerebellar ataxia (SCA) type 2, one of the most common SCAs encountered during practice. Both patients had a very similar triplet expansion size in the ATXN2 gene (respectively, 39 and 40 triplets). tCCDCS reduced both postural tremor and action tremor, as confirmed by spectral analysis. Quadratical PSD (power spectral density) of postural tremor dropped to 38.63 and 41.42% of baseline values in patient 1 and 2, respectively. The integral of the subband 4-20 Hz dropped to 46.9 and 62.3% of baseline values, respectively. Remarkably, tCCDCS canceled hypermetria and reduced dramatically the onset latency of the antagonist EMG activity associated with fast goal-directed movements toward 3 aimed targets (0.2, 0.3, and 0.4 rad). Following tCCDCS, the latency dropped from 108-98 to 63-57 ms in patient 1, and from 74-87 to 41-46 ms in patient 2 (mean control values ± SD: 36 ± 8 to 45 ± 11 ms), corresponding to a major drop of z scores for the 2 patients from 7.12 ± 0.69 to 1.28 ± 1.27 (sham procedure: 6.79 ± 0.71). This is the first demonstration that tCCDCS improves upper limb tremor and hypermetria in SCA type 2. In particular, this is the first report of a favorable effect on the onset latency of the antagonist EMG activity, a neurophysiological marker of the defect in programming of timing of motor commands. Our results indicate that tCCDCS should be considered in the symptomatic management of upper limb motor deficits in cerebellar ataxias. Future studies addressing a tDCS-based neuromodulation to improve motor control of upper limbs are required (a) in a large group of cerebellar disorders, and (b) in different subgroups of ataxic patients. The anatomical location of the cerebellum below the skull is particularly well suited for such studies.

Functional impacts of exoskeleton-based rehabilitation in chronic stroke: multi-joint versus single-joint robotic training.

Stroke is a major cause of disability in the world. The activities of upper limb segments are often compromised following a stroke, impairing most daily tasks. Robotic training is now considered amongst the rehabilitation methods applied to promote functional recovery. However, the implementation of robotic devices remains a major challenge for the bioengineering and clinical community. Latest exoskeletons with multiple degrees of freedom (DOF) may become particularly attractive, because of their low apparent inertia, the multiple actuators generating large torques, and the fact that patients can move the arm in the normal wide workspace. A recent study published in JNER by Milot and colleagues underlines that training with a 6-DOF exoskeleton impacts positively on motor function in patients being in stable phase of recovery after a stroke. Also, multi-joint robotic training was not found to be superior to single-joint robotic training. Although it is often considered that rehabilitation should start from simple movements to complex functional movements as the recovery evolves, this study challenges this widespread notion whose scientific basis has remained uncertain.

Is essential tremor a Purkinjopathy? The role of the cerebellar cortex in its pathogenesis.

Essential tremor (ET) encompasses a group of progressive neurological diseases in which the primary clinical feature is kinetic tremor of the arms. There is accumulating evidence to suggest that the cerebellum is involved in the pathogenesis of ET; the clinical presentation, neurophysiological data, and functional and metabolic abnormalities revealed by neuroimaging studies all point toward the dysregulation of cerebellar circuits. Recent neuropathological findings at postmortem demonstrate that Purkinje neurons, and some brainstem neurons, play an integral role in the pathogenesis of this common neurological disorder. The assessment of Purkinje cell linear density shows that Purkinje density is abnormal in ET brains. Specific efforts need be devoted to understanding the molecular and cellular events occurring in the Purkinje neurons of the cerebellar cortex, which are emerging as being of particular importance in the pathogenesis of ET in a subgroup of patients.

Augmented visual feedback counteracts the effects of surface muscular functional electrical stimulation on physiological tremor.

BACKGROUND: Recent studies suggest that surface muscular functional electrical stimulation (FES) might suppress neurological upper limb tremor. We assessed its effects on upper limb physiological tremor, which is mainly driven by mechanical-reflex oscillations. We investigated the interaction between FES and augmented visual feedback, since (a) most daily activities are performed using visual cues, and (b) augmented visual feedback exacerbates upper limb tremor. METHODS: 10 healthy subjects (23.4 ± 7.7 years) performed 2 postural tasks with combinations of FES (4 sites; frequency of stimulation: 30 Hz; pulse width: 300 microsec; range of current delivered 10-34 mAmp) and augmented visual feedback. RESULTS: Spectral analysis of tremor showed a decrease of power spectral density to 62.18% (p = 0.01), of the integral in the 8-12 Hz frequency band to 57.67% (p = 0.003), and of tremor root mean square (RMS) to 57.16% (p = 0.002) during FES, without any changes in tremor frequency. Augmented visual feedback blocked the beneficial effect of FES, as confirmed by power spectral analysis (p = 0.01). We found a statistically significant interaction between augmented visual feedback and electrical stimulation (p = 0.039). CONCLUSIONS: Augmented visual feedback antagonizes the effects of FES on physiological tremor. The absence of changes of peak frequency argues against an effect of FES on mechanical properties of the upper limb.

Anodal transcranial direct current stimulation (tDCS) decreases the amplitudes of long-latency stretch reflexes in cerebellar ataxia.

Recent studies suggest that the neuromodulation of the cerebellum using transcranial direct current stimulation (tDCS) could represent a new therapeutic strategy for the management of cerebellar disorders. Anodal tDCS of the cerebellum increases the excitability of the cerebellar cortex. We tested the effects of anodal tDCS applied over the cerebellum in ataxic patients. We studied (a) stretch reflexes (SR) in upper limb (SLSR: short-latency stretch reflexes; LLSR: long-latency stretch reflexes), (b) a coordination functional task in upper limbs based on mechanical counters (MCT: mechanical counter test), and (c) computerized posturography. tDCS did not change the amplitude of SLSR, but reduced significantly the amplitudes of LLSR. tDCS did not improve the MCT scores and did not modify posture. We suggest that anodal tDCS of the cerebellum reduces the amplitudes of LLSR by increasing the inhibitory effect exerted by the cerebellar cortex upon cerebellar nuclei. The absence of effect upon upper limb coordination and posture suggests that the cerebello-cerebral networks subserving these functions are less responsive to anodal tDCS of the cerebellum. Anodal tDCS of the cerebellum represents a novel experimental tool to investigate the effects of the cerebellar cortex on the modulation of the amplitudes of LLSR.

Quality parameters for a multimodal EEG/EMG/kinematic brain-computer interface (BCI) aiming to suppress neurological tremor in upper limbs.

Tremor is the most common movement disorder encountered during daily neurological practice. Tremor in the upper limbs causes functional disability and social inconvenience, impairing daily life activities. The response of tremor to pharmacotherapy is variable. Therefore, a combination of drugs is often required. Surgery is considered when the response to medications is not sufficient. However, about one third of patients are refractory to current treatments. New bioengineering therapies are emerging as possible alternatives. Our study was carried out in the framework of the European project "Tremor" (ICT-2007-224051). The main purpose of this challenging project was to develop and validate a new treatment for upper limb tremor based on the combination of functional electrical stimulation (FES; which has been shown to reduce upper limb tremor) with a brain-computer interface (BCI). A BCI-driven detection of voluntary movement is used to trigger FES in a closed-loop approach. Neurological tremor is detected using a matrix of EMG electrodes and inertial sensors embedded in a wearable textile. The identification of the intentionality of movement is a critical aspect to optimize this complex system. We propose a multimodal detection of the intentionality of movement by fusing signals from EEG, EMG and kinematic sensors (gyroscopes and accelerometry). Parameters of prediction of movement are extracted in order to provide global prediction plots and trigger FES properly. In particular, quality parameters (QPs) for the EEG signals, corticomuscular coherence and event-related desynchronization/synchronization (ERD/ERS) parameters are combined in an original algorithm which takes into account the refractoriness/responsiveness of tremor. A simulation study of the relationship between the threshold of ERD/ERS of artificial EEG traces and the QPs is also provided. Very interestingly, values of QPs were much greater than those obtained for the corticomuscular module alone.

Topography of cerebellar deficits in humans.

The cerebellum is a key-piece for information processing and is involved in numerous motor and nonmotor activities, thanks to the anatomical characteristics of the circuitry, the enormous computational capabilities and the high connectivity to other brain areas. Despite its uniform cytoarchitecture, cerebellar circuitry is segregated into functional zones. This functional parcellation is driven by the connectivity and the anatomo-functional heterogeneity of the numerous extra-cerebellar structures linked to the cerebellum, principally brain cortices, precerebellar nuclei and spinal cord. Major insights into cerebellar functions have been gained with a detailed analysis of the cerebellar outputs, with the evidence that fundamental aspects of cerebrocerebellar operations are the closed-loop circuit and the predictions of future states. Cerebellar diseases result in disturbances of accuracy of movements and lack of coordination. The cerebellar syndrome includes combinations of oculomotor disturbances, dysarthria and other speech deficits, ataxia of limbs, ataxia of stance and gait, as well as often more subtle cognitive/behavioral impairments. Our understanding of the corresponding anatomo-functional maps for the human cerebellum is continuously improving. We summarize the topography of the clinical deficits observed in cerebellar patients and the growing evidence of a regional subdivision into motor, sensory, sensorimotor, cognitive and affective domains. The recently described topographic dichotomy motor versus nonmotor cerebellum based upon anatomical, functional and neuropsychological studies is also discussed.

A new myohaptic instrument to assess wrist motion dynamically.

The pathophysiological assessment of joint properties and voluntary motion in neurological patients remains a challenge. This is typically the case in cerebellar patients, who exhibit dysmetric movements due to the dysfunction of cerebellar circuitry. Several tools have been developed, but so far most of these tools have remained confined to laboratories, with a lack of standardization. We report on a new device which combines the use of electromyographic (EMG) sensors with haptic technology for the dynamic investigation of wrist properties. The instrument is composed of a drivetrain, a haptic controller and a signal acquisition unit. Angular accuracy is 0.00611 rad, nominal torque is 6 N·m, maximal rotation velocity is 34.907 rad/sec, with a range of motion of -1.0472 to +1.0472 rad. The inertia of the motor and handgrip is 0.004 kg·m2. This is the first standardized myohaptic instrument allowing the dynamic characterization of wrist properties, including under the condition of artificial damping. We show that cerebellar patients are unable to adapt EMG activities when faced with an increase in damping while performing fast reversal movements. The instrument allows the extraction of an electrophysiological signature of a cerebellar deficit.

Neurological tremor: sensors, signal processing and emerging applications.

Neurological tremor is the most common movement disorder, affecting more than 4% of elderly people. Tremor is a non linear and non stationary phenomenon, which is increasingly recognized. The issue of selection of sensors is central in the characterization of tremor. This paper reviews the state-of-the-art instrumentation and methods of signal processing for tremor occurring in humans. We describe the advantages and disadvantages of the most commonly used sensors, as well as the emerging wearable sensors being developed to assess tremor instantaneously. We discuss the current limitations and the future applications such as the integration of tremor sensors in BCIs (brain-computer interfaces) and the need for sensor fusion approaches for wearable solutions.