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Deep brain stimulation (DBS) is an established clinical therapy, and directional DBS electrode designs are now commonly used in clinical practice. Directional DBS leads have the ability to increase the therapeutic window of stimulation, but they also increase the complexity of clinical programming. Therefore, computational models of DBS have become available in clinical software tools that are designed to assist in the identification of therapeutic settings. However, the details of how the DBS model is implemented can influence the predictions of the software. The goal of this study was to compare different methods for representing directional DBS electrodes within finite element volume conductor (VC) models. We evaluated 15 different DBS VC model variants and quantified how their differences influenced estimates on the spatial extent of axonal activation from DBS. Each DBS VC model included the same representation of the brain and head, but the details of the current source and electrode contact were different for each model variant. The more complex VC models explicitly represented the DBS electrode contacts, while the more simple VC models used boundary condition approximations. The more complex VC models required 2–3 times longer to mesh, build, and solve for the DBS voltage distribution than the more simple VC models. Differences in individual axonal activation thresholds across the VC model variants were substantial (-24% to +47%). However, when comparing total activation of an axon population, or estimates of an activation volume, the differences between model variants decreased (-7% to +8%). Nonetheless, the technical details of how the electrode contact and current source are represented in the DBS VC model can directly affect estimates of the voltage distribution and electric field in the brain tissue.

Current developments towards multipin, dry electrodes in electroencephalography (EEG) are promising for applications in non-laboratory environments. Dry electrodes do not require the application of conductive gel, which mostly confines the use of gel EEG systems to the laboratory environment. The aim of this study is to validate soft, multipin, dry EEG electrodes by comparing their performance to conventional gel EEG electrodes. Fifteen healthy volunteers performed three tasks, with a 32-channel gel EEG system and a 32-channel dry EEG system: the 40 Hz Auditory Steady-State Response (ASSR), the checkerboard paradigm, and an eyes open/closed task. Within-subject analyses were performed to compare the signal quality in the time, frequency, and spatial domains. The results showed strong similarities between the two systems in the time and frequency domains, with strong correlations of the visual (ρ = 0.89) and auditory evoked potential (ρ = 0.81), and moderate to strong correlations for the alpha band during eye closure (ρ = 0.81–0.86) and the 40 Hz-ASSR power (ρ = 0.66–0.72), respectively. However, delta and theta band power was significantly increased, and the signal-to-noise ratio was significantly decreased for the dry EEG system. Topographical distributions were comparable for both systems. Moreover, the application time of the dry EEG system was significantly shorter (8 min). It can be concluded that the soft, multipin dry EEG system can be used in brain activity research with similar accuracy as conventional gel electrodes.

Objective. Elucidating how cueing alleviates freezing of gait (FOG) in Parkinson’s disease (PD) would enable the development of more effective, personalized cueing strategies. Here, we aimed to validate a visual cueing virtual environment (VE) paradigm for future use in e.g. neuroimaging studies and behavioral studies on motor timing and scaling in PD patients with FOG. Approach. We included 20 PD patients with FOG and 16 age-matched healthy control subjects. Supine participants were confronted with a VE displaying either no cues, bars or staircases. They navigated forward using alternate suppression of foot pedals. Motor arrests (as proxy for FOG), and measures of motor timing and scaling were compared across the three VE conditions for both groups.Main results. VE cues (bars and staircases) did not reduce motor arrests in PD patients and healthy control subjects. The VE cues did reduce pedal amplitude in healthy control subjects, without effects on other motor parameters. Conclusion. We could not validate a visual cueing VE paradigm to study FOG. The VE cues possibly failed to convey the necessary spatial and temporal information to support motor timing and scaling. We discuss avenues for future research.

The most frequently used method for evaluating tremor in Parkinson’s disease (PD) is currently the internationally standardized Movement Disorder Society—Unified PD Rating Scale (MDS-UPDRS). However, the MDS-UPDRS is associated with limitations, such as its inherent subjectivity and reliance on experienced raters. Objective motor measurements using accelerometry may overcome the shortcomings of visually scored scales. Therefore, the current study focuses on translating the MDS-UPDRS tremor tests into an objective scoring method using 3D accelerometry. An algorithm to measure and classify tremor according to MDS-UPDRS criteria is proposed. For this study, 28 PD patients undergoing neurosurgical treatment and 26 healthy control subjects were included. Both groups underwent MDS-UPDRS tests to rate tremor severity, while accelerometric measurements were performed at the index fingers. All measurements were performed in an off-medication state. Quantitative measures were calculated from the 3D acceleration data, such as tremor amplitude and area-under-the-curve of power in the 4–6 Hz range. Agreement between MDS-UPDRS tremor scores and objective accelerometric scores was investigated. The trends were consistent with the logarithmic relationship between tremor amplitude and MDS-UPDRS score reported in previous studies. The accelerometric scores showed a substantial concordance (>69.6%) with the MDS-UPDRS ratings. However, accelerometric kinetic tremor measures poorly associated with the given MDS-UPDRS scores (R2 < 0.3), mainly due to the noise between 4 and 6 Hz found in the healthy controls. This study shows that MDS-UDPRS tremor tests can be translated to objective accelerometric measurements. However, discrepancies were found between accelerometric kinetic tremor measures and MDS-UDPRS ratings. This technology has the potential to reduce rater dependency of MDS-UPDRS measurements and allow more objective intraoperative monitoring of tremor.

Cortical involvement in essential tremor, an involuntary action tremor supposedly of subcortical origin, is uncertain. Conflicting results of corticomuscular coherence studies in essential tremor suggest an intermittent corticomuscular coupling. On the basis of the literature, we hypothesized that corticomuscular coupling is influenced by bilateral motor synchronization and “cognitive states” such as awareness of tremor. In the present study, we investigated 1) the existence of intermittent corticomuscular coherence (CMC) in essential tremor and 2) factors that influence CMC strength. In 18 essential tremor patients and 18 healthy controls, who mimicked tremor, we simultaneously recorded 64-channel EEG and 6-channel bipolar surface EMG from right and left wrist extensors and flexors. Right-sided (mimicked) hand tremor was recorded with and without a cognitive arithmetic task and with left-sided (mimicked) hand tremor. CMC values per task were compared within and between groups. Changes in CMC strength during tasks were calculated. Our main findings are 1) significant CMC around the (mimicked) tremor frequency across all tasks in both groups; 2) significant differences in CMC between unilateral tasks, with the highest values during the cognitive task only in the essential tremor group; and 3) significant fluctuations of CMC strength over time, independent of the tremor intensity, only in the essential tremor group. Our results suggest a limited role, and certainly not a continuous steering role, of sensorimotor cortical neurons in the generation of tremor. In clinical practice, these findings might help to standardize tremor registration and the interpretation of the analysis. NEW & NOTEWORTHY The part of the motor cortex involved in essential tremor is uncertain. The current electrophysiological study is the first to assess corticomuscular coherence systematically. The study shows a dynamic nature of corticomuscular coherence and a possible influence of cognitive states. The results elucidate the involvement of the motor cortex in tremor and help interpret the varying results in the literature. In clinical practice, the findings may guide in standardizing tremor registration and its interpretation.

The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the "hyperdirect'' pathway. The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented. Using extracellular electrophysiological approaches, we investigated to what degree the motor and non-motor regions in the STN are segregated in control and dopamine (DA) depleted rats. We performed electrical stimulation of different cortical areas and recorded STN neuronal responses. We showed that motor and non-motor cortico-subthalamic pathways are not fully segregated, but partially integrated in the rat. This integration was mostly present through the indirect pathway. The spatial distribution and response latencies were the same in sham and 6-hydroxydopamine lesioned animals. The inhibitory phase was, however, less apparent in the lesioned animals. In conclusion, this study provides the first evidence that motor and non-motor cortico-subthalamic pathways in the rat are not fully segregated, but partially integrated. This integration was mostly present through the indirect pathway. We also show that the inhibitory phase induced by GABAergic inputs from the external segment of the globus pallidus is reduced in the DA-depleted animals.

BackgroundThe development of treatments for freezing of gait (FOG) in Parkinson's disease (PD) requires experimental study set-ups in which FOG is likely to occur, and is amenable to therapeutic interventions. We explore whether the 'Auditory Stroop Task' (AST) can be used to increase cognitive load (and thereby elicit FOG), simultaneously with visual cues (as a therapeutic intervention for FOG). We additionally examined how these two contrasting effects might interact in affecting gait and FOG parameters.ObjectivesWe investigated whether: (1) the 'Auditory Stroop Task' (AST) influences gait in healthy elderly and persons with PD who experience FOG, and increases the frequency of FOG events among PD patients; (2) the AST and visual cues interact; and (3) different versions of the AST exert different cognitive loads.MethodsIn 'Experiment 1', 19 healthy elderly subjects performed a walking task while performing a high and low load version of the AST. Walking with a random numbers task, and walking without cognitive load served as control conditions. In 'Experiment 2', 20 PD patients with FOG and 18 healthy controls performed a walking task with the AST, and no additional cognitive load as control condition. Both experiments were performed with and without visual cues. Velocity, cadence, stride length, and stride time were measured in all subjects. FOG severity was measured in patients.ResultsCompared to the control conditions, the AST negatively affected all gait parameters in both patients and controls. The AST did not increase the occurrence of FOG in patients. Visual cues reduced the decline in stride length induced by cognitive load in both groups. Both versions of the AST exerted similar effects on gait parameters in controls.ConclusionsThe AST is well-suited to simulate the effects of cognitive load on gait parameters, but not FOG severity, in gait experiments in persons with PD and FOG.

Background: In deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson’s Disease (PD), often microelectrode recordings (MER) are used for STN identification. However, for advanced target identification of the sensorimotor STN, it may be relevant to use local field potential (LFP) recordings. Then, it is important to assure that the measured oscillations are coming from the close proximity of the electrode. New method: Through multiple simultaneous recordings of LFP and neuronal spiking, we investigated the temporal relationship between local neuronal spiking and more global LFP. We analyzed the local oscillations in the LFP by calculating power only over specific frequencies that show a significant coherence between LFP and neuronal spiking. Using this ‘coherence method’, we investigated how well measurements in the sensorimotor STN could be discriminated from measurements elsewhere in the STN. Results/comparison with existing methods: The ‘sensorimotor power index’ (SMPI) of beta frequencies, representing the ability to discriminate sensorimotor STN measurements based on the beta power, was significantly larger using the ‘coherence method’ for LFP spectral analysis compared to other methods where either the complete LFP beta spectrum or only the prominent peaks in the LFP beta spectrum were used to calculate beta power. Conclusions: The results suggest that due to volume conduction of beta frequency oscillations, proper localization of the sensorimotor STN with only LFP recordings is difficult. However, combining recordings of LFP and neuronal spiking and calculating beta power over the coherent parts of the LFP spectrum can be beneficial in discriminating the sensorimotor STN.

Objective: The aim of the study is to test whether the PowerGlove (PG), an instrumented glove which consists of inertial (accelerometers and gyroscopes) and magnetic sensors, is a valid and reliable instrument to measure different degrees of hand motor impairments in patients with Parkinson’s disease (PD). Background: Assessment of hand movements is an important part of the motor function section of the Unified PD Rating Scale (UPDRS). Unfortunately, the assessment often varies per physician and is highly dependent on experience. This subjective nature sometimes makes it hard to interpret the UPDRS correctly. Recently, the University of Twente developed the PG which enables accurate and ambulant measurement of hand and finger movements (Fig. 1A)[1]. Application of the PG during the clinical scoring will enable more accurate observation of hand function and quantification of the PD motor symptoms. Methods: We plan to include 35 PD patients. We will assess the hand movements of the patients in medication on/off state with the PG during 7 UPDRS items, i.e. tremor at rest, action and postural tremor, finger tapping, rapid opening/closing of the hand, pro/supination of the hand, and wrist rigidity. Sensor units of the PG are attached to the dorsal side of the left hand and on the finger segments of the thumb, index and middle finger. One additional PG sensor is attached to the forearm to measure the wrist angle. A force sensor is used to measure the force which is applied to passively flex the wrist of the patient. Prior to measurement, an anatomical calibration procedure is performed to determine the sensor-to-segment coordinate systems. Results: Visual inspection of preliminary results showed there were notable differences in the recorded data within a patient in medication on/off state. Conclusions: The results indicate that the PG enables to quantitatively detect differences in the clinical state of the patient. In the next phase of this study, parameters need to be found which describe the performance of UPDRS tasks and include these in the group analyses of the 35 PD patients.

Objective: To investigate variability of spatial and temporal performance of Parkinson’s disease (PD) patients and healthy elderly subjects during spirography tasks.Background: A total of 105 subje ...

Contains fulltext : 174851.pdf (Publisher’s version ) (Open Access) External cueing is a potentially effective strategy to reduce freezing of gait (FOG) in persons with Parkinson's disease (PD). Case reports suggest that three-dimensional (3D) cues might be more effective in reducing FOG than two-dimensional cues. We investigate the usability of 3D augmented reality visual cues delivered by smart glasses in comparison to conventional 3D transverse bars on the floor and auditory cueing via a metronome in reducing FOG and improving gait parameters. In laboratory experiments, 25 persons with PD and FOG performed walking tasks while wearing custom-made smart glasses under five conditions, at the end-of-dose. For two conditions, augmented visual cues (bars/staircase) were displayed via the smart glasses. The control conditions involved conventional 3D transverse bars on the floor, auditory cueing via a metronome, and no cueing. The number of FOG episodes and percentage of time spent on FOG were rated from video recordings. The stride length and its variability, cycle time and its variability, cadence, and speed were calculated from motion data collected with a motion capture suit equipped with 17 inertial measurement units. A total of 300 FOG episodes occurred in 19 out of 25 participants. There were no statistically significant differences in number of FOG episodes and percentage of time spent on FOG across the five conditions. The conventional bars increased stride length, cycle time, and stride length variability, while decreasing cadence and speed. No effects for the other conditions were found. Participants preferred the metronome most, and the augmented staircase least. They suggested to improve the comfort, esthetics, usability, field of view, and stability of the smart glasses on the head and to reduce their weight and size. In their current form, augmented visual cues delivered by smart glasses are not beneficial for persons with PD and FOG. This could be attributable to distraction, blockage of visual feedback, insufficient familiarization with the smart glasses, or display of the visual cues in the central rather than peripheral visual field. Future smart glasses are required to be more lightweight, comfortable, and user friendly to avoid distraction and blockage of sensory feedback, thus increasing usability.

Objective Patients with Parkinson’s disease often experience difficulties in adapting movements and learning alternative movements to compensate for symptoms. Since observation of movement has been demonstrated to lead to the formation of a lasting specific motor memory that resembled that elicited by physical training we hypothesize that mu-rhythm desynchronization in response to movement observation is impaired in Parkinson’s disease. Method In a pilot study with nine patients with Parkinson’s disease at a Hoehn and Yahr stage of I or II and eleven age-matched controls, we tested this hypothesis by comparing the event related desynchronization (ERD) patterns from the EEG recorded during the observation of hand action and baseline videos. Results Healthy subjects showed normal bilateral ERD of the mu-rhythm. In patients with Parkinson’s disease this distinct ERD pattern was lacking. Conclusion The results of this study suggest that event-related mu-rhythm desynchronization is impaired in Parkinson’s disease, even at early stages of the disease. Significance Studying event-related mu-rhythm desynchronization dysfunction in Parkinson’s disease patients may enhance our understanding of symptoms as impaired motor learning.

The nucleus accumbens is selected as a surgical target in deep brain stimulation for treating refractory obsessive-compulsive disorder (OCD). One of the therapeutic benefits of this procedure is that the abnormal hyper-functioning prefrontal cortex of patients with OCD is restored during stimulation. One hypothesis regarding the mechanism of deep brain stimulation is that the neuronal electrophysiological properties are directly altered by electrical stimulation; another hypothesis assumes that the stimulation induces selective neuron transmitter release, such as γ-aminobutyric acid (GABA). In this study, we used multi-electrode arrays with electrode size of 40 × 40 μm to record electrophysiological signals from the large nucleus accumbens neurons in acute rat brain slices while applying electrical stimulation simultaneously. We revealed that high-frequency stimulation (HFS, 140 Hz) suppressed the spontaneous neuronal firing rate significantly, whereas low-frequency stimulation (LFS, 10 Hz) did not. Both HFS and LFS have no effect on neuronal firing pattern or on neuronal oscillation synchrony. GABAB receptor antagonism reversed the HFS-provoked neuronal inhibition, whereas GABAA receptor blockade failed to affect it. The recorded neurons were pharmacologically identified to be cholinergic interneurons. We propose that HFS has a direct suppressive effect on the identified accumbal acetylcholine (ACh) interneurons by enhancing GABA release in the stimulated region. Potentially, suppressed ACh interneurons decrease the disinhibiting function of medium-sized spiny neurons in the striato-thalamo-cortical circuit. This finding might give an indication of the mechanism of the therapeutic effect of HFS in nucleus accumbens on restoring the abnormal hyperactive prefrontal cortex status in OCD.

Background: Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinson’s disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation-induced behavioral side effects, by using motor cortex stimulation. Methods: We describe the results of subthalamic nucleus neuronal responses to stimulation of the hand area of the motor cortex and evaluate the safety of this novel technique. Results: Responses differed between regions within the subthalamic nucleus. In the anterior and lateral electrode at dorsal levels of the subthalamic nucleus, an early excitation (~5–45 ms) and subsequent inhibition (45–105 ms) were seen. The lateral electrode also showed a late excitation (~125–160 ms). Focal seizures were observed following motor cortex stimulation. Conclusions: To prevent seizures the current density should be lowered, so that motor cortex stimulationevoked responses can be safely used during deep brain stimulation surgery.

In this computational study, we investigated (i) the functional importance of correlated basal ganglia (BG) activity associated with Parkinson's disease (PD) motor symptoms by analysing the effects of globus pallidus internum (GPi) bursting frequency and synchrony on a thalamocortical (TC) relay neuron, which received GABAergic projections from this nucleus; (ii) the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on the response of the TC relay neuron to synchronized GPi oscillations; and (iii) the functional basis of the inverse relationship that has been reported between DBS frequency and stimulus amplitude, required to alleviate PD motor symptoms [A. L. Benabid et al. (1991)Lancet, 337, 403–406]. The TC relay neuron selectively responded to and relayed synchronized GPi inputs bursting at a frequency located in the range 2–25 Hz. Input selectivity of the TC relay neuron is dictated by low-threshold calcium current dynamics and passive membrane properties of the neuron. STN-DBS prevented the TC relay neuron from relaying synchronized GPi oscillations to cortex. Our model indicates that DBS alters BG output and input selectivity of the TC relay neuron, providing an explanation for the clinically observed inverse relationship between DBS frequency and stimulus amplitude.

Objectives: Essential tremor (ET), the most prevalent hyperkinetic movement disorder, is characterized by an action tremor (4-7 Hz). The role of the sensorimotor cortex in tremor generation is uncertain. Previous corticomuscular coupling studies in ET showed either a cortical drive, an afferent input, or both. In contrast, familial cortical myoclonic tremor with epilepsy (FCMTE) with tremulous movements, clinically resembling ET, is characterized by a cortical drive around 15-20Hz. Methods: Corticomuscular directionality was investigated with renormalized partial directed coherence (rPDC) in ET (n=16), FCMTE (n=7), and healthy controls (HC; n=16). EEG-EMG was recorded during 2 minutes of postural tremor (ET and FCMTE right arm outstretched; HC mimicking tremor ±5Hz), and 1 minute of self-paced slow movements

Introduction: Patients with medically refractory epilepsy treated with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) vary highly in their therapy response. Proper positioning of the DBS lead is crucial to maximize efficacy and minimize side effects. For a correct implantation, the ANT is anatomically located using pre-operative 3T MRI and perioperative microelectrode recordings (MER). Neurons in the ANT have highly variable, yet characteristic patterns of firing in bursts. During DBS lead implantation, we noted differences among patients’ characteristic burst patterns along the electrode trajectory. In this study, we investigate whether electrophysiological characteristics of the target region could predict therapy response to DBS and could thus be used to improve ANT targeting during DBS surgery. Objectives: To determine whether perioperative neurophysiological characteristics relate to therapy response in DBS for patients with medically refractory epilepsy. Patients and methods: We included ten consecutive epilepsy patients planned for DBS surgery at Maastricht University Medical Center. All patients were diagnosed with medically refractory epilepsy and had incapacitating seizures. Patients failed trials of at least two reasonably tolerated and adequately chosen antiepileptic drug schedules. Using pre-operative 3T MRI, we planned an extraventricular approach to target. The ANT was defined as a grey matter structure at the top of the mamillothalamic tract. Along this trajectory, we performed stereotactic single cell MERs. The anatomical location of the recordings were verified using preoperative 3T MR images. We compared characteristics of the neural signals at different depths along the trajectory between DBS responders and non-responders. Responders were defined as patients with a seizure frequency reduction of more than 50% at one year follow-up. Results: Using MER data from 19 electrode trajectories of ten patients (one unilateral and nine bilateral trajectories), we found high-amplitude neuronal bursts around the target area or ANT. Responders to DBS (n = 5) had higher normalized mean firing rates and mean burst rates near the target area compared to non-responders (n = 5), with a clearer delineation between the target region and surroundings. Electrode trajectories and lead localization did not differ between responders and non-responders. Conclusion: Single cell firing patterns in the ANT relate to therapy response in DBS for patients with medically refractory epilepsy. Analysis of single cell firing patterns using MER may guide targeting or contribute to predicting therapy response to ANT DBS. Further exploration into the use of electrophysiological recordings is warranted to improve targeting or predict outcome in DBS for epilepsy patients.

Recent advances in smart glasses, wearable computers in the form of glasses, bring new therapeutic and monitoring possibilities for people with Parkinson's disease (PD). For example, it can provide visual and auditory cues during activities of daily living that have long been used to improve gait disturbances. Furthermore, smart glasses can personalize therapies based on the state of the user and/or the user environment in real-time using object recognition and motion tracking. To provide guidelines for developers in creating new PD applications for smart glasses, a self-reported questionnaire was designed to survey the requirements, constraints, and attitudes of people with PD with respect to this new technology. The survey was advertised online over an 11 month period on the website of the Parkinson Vereninging. The results were derived from 62 participants (54.8% men and 45.2% women, average age of 65.7 +/- 9.1), representing a response rate of 79.5% . The participants were overall very enthusiastic about smart glasses as an assistive technology to facilitate daily living activities, especially its potential to self-manage motor problems and provide navigational guidance, thereby restoring their confidence and independence. The reported level of usage of mobile technologies like tablets and smartphones suggests that smart glasses could be adopted relatively easily, especially by younger people with PD. However, the respondents were concerned about the cost, appearance, efficacy, and potential side effects of smart glasses. To accommodate a wide range of symptoms, personal preferences, and comfort level with technology, smart glasses should be designed to allow simple operation and personalization.

By application of dielectrophoresis neuronal cells can be trapped successfully. Several trapping experiments have been performed using a quadrupole electrode structure at different amplitudes (1, 3, and 5?Vpp) and frequencies (10-50?MHz). Due to the high conductivity of the suspending medium negative dielectrophoretic forces are created. The dielectrophoretic force is determined by the gradient of the electric field. However, the electrode-liquid interfaces are responsible for decreased electric field strengths, and thus decreased field gradients, inside the medium, especially at lower frequencies. Circuit modelling is used to determine the frequency-dependent electric field inside the medium. The creation of an electric field in high conductivity of the medium results in local heating, which in turn induces fluid flow. This flow also drives the neurons and was found to enhance the trapping effect of the dielectrophoretic force. With the use of finite element modelling, this aspect was investigated. The results show that the dielectrophoretic force is dominating just above the substrate. When the upward dielectrophoretic force is large enough to levitate the cells, they may be dragged along with the fluid flow. The result is that more cells may be trapped than expected on the basis of dielectrophoresis alone.

Negative dielectrophoretic forces can effectively be used to trap cortical rat neurons. The creation of dielectrophoretic forces requires electric fields of high non-uniformity. High electric field strengths, however, can cause excessive membrane potentials by which cells may unrecoverably be changed or it may lead to cell death. In a previous study it was found that cells trapped at 3 Vtt/14 MHz did not change morphologically as compared to cells that were not exposed to the electric field. This study investigates the viability of fetal cortical rat neurons after being trapped by negative dielectrophoretic forces at frequencies up to 1 MHz. A planar quadrupole micro-electrode structure was used for the creation of a non-uniform electric field. The sinusoidal input signal was varied in amplitude (3 and 5 Vtt) and frequency (10 kHz-1 MHz). The results presented in this paper show that the viability of dielectrophoretically trapped postnatal cortical rat cells was greatly frequency dependent. To preserve viability frequencies above 100 kHz (at 3 Vtt) or 1 MHz (5 Vtt) must be used.

Objective: Identifying specifically motor related activation patterns in essential tremor by manipulation of the sensorimotor loop to separate motor activity from sensory feedback during functional magnetic resonance imaging (fMRI) applying a haptic wrist manipulator. Background: Essential tremor is a high prevalent movement disorder with yet unclear pathophysiology and overlapping clinical features with other tremor disorders. In essential tremor efferent motor activity and afferent sensory activity are intermingled, thereby hampering identification of truly tremor related brain areas (efferent drive) in neuroimaging studies1. With help of novel quantitative fMRI approach we manipulate both motor and sensory input to gain insight in the sensorimotor closed loop. Methods: Seven essential tremor patients, diagnosed according to the criteria of the Tremor Investigation Group2(four men; mean age 66±16) with bilateral postural arm tremor, were studied off medication. Subjects performed a motor task with the right hand using a haptic manipulator during fMRI. Tasks included an active isometric motor task (exerting a static torque to the handle) and a passive movement task (going along with a continuous (multi)sinusoidal perturbations). Results were derived from a conventional block-design with random effects analysis of the group comparing active motor tasks and passive motor conditions, with the tasks and the movement parameters used as regressors (FWE corrected, p

Background Parkinson’s disease (PD) patients show a higher ability to perform repetitive movements when they are cued by external stimuli, suggesting that rhythmic synchronization with an auditory timekeeper can be achieved in the absence of intact basal ganglia function. Deep brain stimulation (DBS) is another therapeutic method that improves movement performance in PD and may suppress or enhance action tremor. However, the combined effect of these therapies on action tremor has not been studied yet. In this pilot study, we thus test the effect of both DBS in the subthalamic nucleus (STN) and auditory cueing on movement performance and action tremor. Methods 7 PD patients treated with (bilateral) STN DBS were asked to move one hand or foot between two dots, separated by 30 cm as indicated on the table or the floor. The movement frequency was dictated by a metronome with a frequency in the range of 1.6 to 4.8 Hz. Each test was repeated three times for each extremity, with different stimulation settings applied during each repetition. The power spectral density patterns of recorded movements were studied. Tremor intermittency was taken into account by classifying each 2-second window of the recorded angular velocity signals as a tremor or non-tremor window. By determining the phase locking value it was tested whether movement or tremor was synchronized with the auditory cue. Results While action tremor presence or absence did not affect the level of synchronization of the movement signal with the auditory cue for the different metronome frequencies, the number of extremities showing action tremor was significantly reduced under external cueing conditions in combination with DBS. In this respect the cueing frequencies of 1.6 and 4.8 Hz showed similar effects, suggesting that the frequency of the cueing signal is not that critical. Conclusion The combination of deep brain stimulation and auditory cueing, which both are proposed to involve the activation of cerebellar circuits, shows an enhanced action tremor reduction in Parkinson’s disease. Electronic supplementary material The online version of this article (doi:10.1186/1743-0003-11-135) contains supplementary material, which is available to authorized users.

Contains fulltext : 135149.pdf (Publisher’s version ) (Open Access) Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin-36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin-36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin-36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin-36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia.

The aim of this pilot study is to test whether the combination of DBS and auditory cueing has an enhanced effect on tremor reduction. Therefore, in a group of seven PD patients receiving STN-DBS, tremor occurrence in both hands and both feet was sequentially tested while performing repetitive movements cued by an auditory signal.

Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN) is widely used in advanced stages of Parkinson's disease(PD) and has proven to be an effective treatment of the various motor symptoms. The therapy involves implanting a lead consisting of multiple electrodes in the STN through which continues high frequency electric pulses are delivered. The clinical outcome highly depends on the location of the electrodes within the STN. However, despite careful planning

Objectives: Pathological oscillations in the beta frequencies (8-30Hz) have been found in the local field potentials of Parkinson's disease (PD) patients and non-human primate models of PD1. In particular, these synchronizations appear in the subthalamic nucleus (STN), a common target for deep brain stimulation (DBS) for medically intractable PD2. DBS and dopamine replacement therapy have been shown to reduce these oscillations and ameliorate the motor symptoms of PD. To better understand the origin and mechanisms of these synchronizations, we performed in vitro multielectrode recordings from the rat basal ganglia that support the detection of synchronous activity from numerous neurons. Methods: 300-400 μm basal ganglia slices were obtained from Wistar rats (postnatal days 15-60) using a vibratome and warmed up to room temperature in a holding chamber. The slices were transferred onto a 3D multielectrode array (Ayanda Systems) for recording and continuously perfused with carbogenated artificial cerebral spinal fluid at 36 °C. Neural signals were measured and filtered with a 60 channel amplifier (Multichannel Systems GmbH) and visualized in LabView. Action potentials were detected from the extracellular signal using a 5 standard deviation voltage threshold and sorted into different neuronal units using principal component analysis. Further signal analysis was performed in Matlab to analyze the neuronal firing patterns and measure the extent of synchronous firing. Results: Our preliminary results identified three distinct firing patterns in the STN and substantia nigra. Most neurons exhibited regular spike trains (60%) while others were random (30%) or bursty (10%). The addition of dopamine however reduced the percentage of cells with bursty and random firing patterns. Additionally, we found a very low incidence of synchronizations. Taken together, these results form the basis with which to compare firing patterns in an animal model of PD. Conclusions: Multi-electrode array recordings from the basal ganglia can reveal changes in their neurophysiological properties and measure the amount of synchronization between different neurons. We intend to use this technique to investigate pathological firing patterns in the basal ganglia in a rotenone rat model of PD. Using a combination of chemical and electrical stimulation, we will explore contributions from different nuclei of the basal ganglia to the network behavior. This would allow us to build more realistic models of the basal ganglia and lead to better therapies for PD.

Background Observation of the signals recorded from the extremities of Parkinson’s disease patients showing rest and/or action tremor reveal a distinct high power resonance peak in the frequency band corresponding to tremor. The aim of the study was to investigate, using quantitative measures, how clinically effective and less effective deep brain stimulation protocols redistribute movement power over the frequency bands associated with movement, pathological and physiological tremor, and whether normal physiological tremor may reappear during those periods that tremor is absent. Methods The power spectral density patterns of rest and action tremor were studied in 7 Parkinson’s disease patients treated with (bilateral) deep brain stimulation of the subthalamic nucleus. Two tests were carried out: 1) the patient was sitting at rest; 2) the patient performed a hand or foot tapping movement. Each test was repeated four times for each extremity with different stimulation settings applied during each repetition. Tremor intermittency was taken into account by classifying each 3-second window of the recorded angular velocity signals as a tremor or non-tremor window. Results The distribution of power over the low frequency band (7.5 Hz – normal physiological tremor) revealed that rest and action tremor show a similar power-frequency shift related to tremor absence and presence: when tremor is present most power is contained in the tremor frequency band; when tremor is absent lower frequencies dominate. Even under resting conditions a relatively large low frequency component became prominent, which seemed to compensate for tremor. Tremor absence did not result in the reappearance of normal physiological tremor. Conclusion Parkinson’s disease patients continuously balance between tremor and tremor suppression or compensation expressed by power shifts between the low frequency band and the tremor frequency band during rest and voluntary motor actions. This balance shows that the pathological tremor is either on or off, with the latter state not resembling that of a healthy subject. Deep brain stimulation can reverse the balance thereby either switching tremor on or off.

Methods: Using immunohistochemistry and confocal imaging, we reconstructed the distribution of Cx36, the major neural connexin, in human post-mortem tissue of the STN, GPe and GPi. Our preliminary analysis included tissue from 6 subjects (2x STN control, 2x STN PD, 1x GPi/e control, 1x GPi/e PD). Assuming that at least a part of the detected Cx36 indicates functional gap junctions, we implemented gap junctions in an existing computational model of the basal ganglia, the Rubin-Terman model including the STN, GPe and GPi. Results: Control tissue from the GPe/i showed punctuate Cx36 labeling, which was absent in a negative control leaving out the primary antibody. PD tissue additionally showed clusters of cells highly expressing Cx36. In the STN, only few spots of Cx36 were visible in control tissues. Their occurrence did not significantly increase in PD tissue. In the Rubin-Terman model (2002/2004) including STN, GPe and GPi, homogeneous gap junction coupling between nearest neighbors inside the GPe/i only slightly influenced the network behavior, unless the gap junction conductance was very high. However, clusters of cells in the GPi/e coupled via gap junctions led to bursting and synchronization, even if the gap junction conductance was comparably low. Conclusions: Clusters of cells coupled via gap junctions seen in the GPi/e of the PD patient could explain the occurrence of bursting and synchronization in the basal ganglia. The modulation of gap junctions by dopamine might be a candidate for the remodeling of neural activity. Our experiments do not provide evidence for the functionality of the detected gap junctions.

Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in Parkinson’s disease (PD) patients. However, in a substantial number of patients the beneficial effects of STN DBS are overshadowed by psychiatric side effects. We hypothesize that stimulation of the STN motor area will provide the optimal effect on the motor symptoms without inducing these side effects, and expect that motor cortex stimulation (MCS) evokes a spatially specific response within the STN, which identifies the STN motor area. We previously showed that MCS evokes responses in the unit activity specifically within certain areas of the STN. Unit activity is generally considered a measure of the output activity. To gain more insight into the neuronal input into the STN, we describe the results of cortically evoked subthalamic local field potentials (LFPs). We show that the cortically evoked LFPs follow a certain temporal and spatial pattern. The significant peaks of the evoked LFPs coincide with the timing of some of the inhibitions and excitations present in the unit responses. The spatial resolution of responses measured in the LFP to MCS is not high enough to identify the STN motor region. However, we believe that optimizing targeting techniques and the development of novel DBS electrodes will improve STN DBS therapy for PD patients.

The subthalamic nucleus (STN) is a major player in the input and output of the basal ganglia motor circuitry. The neuronal regular firing pattern of the STN changes into a pathological bursting mode in both advanced Parkinson's disease (PD) and in PD animals models with severe dopamine depletion. One of the current hypothesis, based on clinical and experimental evidence, is that this typical burst activity is responsible for some of the principal motor symptoms. In the current study we tested whether mild DA depletion, mimicking early stages of PD, induced deficits in motor behaviour and changes in STN neuronal activity. The present study demonstrated that rats with a mild lesion (20–40% loss of DA neurons) and a slowed motor response, but without gross motor abnormalities already have an increased number of bursty STN neurons under urethane anaesthesia. These findings indicate that the early increase in STN burst activity is a compensatory mechanism to maintain the dopamine homeostasis in the basal ganglia.

Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinson's disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation-induced behavioral side effects, by using motor cortex stimulation.We describe the results of subthalamic nucleus neuronal responses to stimulation of the hand area of the motor cortex and evaluate the safety of this novel technique.Responses differed between regions within the subthalamic nucleus. In the anterior and lateral electrode at dorsal levels of the subthalamic nucleus, an early excitation (∼5-45 ms) and subsequent inhibition (45-105 ms) were seen. The lateral electrode also showed a late excitation (∼125-160 ms). Focal seizures were observed following motor cortex stimulation.To prevent seizures the current density should be lowered, so that motor cortex stimulation-evoked responses can be safely used during deep brain stimulation surgery.