The olivo-cerebellar circuit is thought to play a crucial role in the pathophysiology of essential tremor (ET). Whether olivo-cerebellar circuit dysfunction is also present at rest, in the absence of clinical tremor and linked voluntary movement, remains unclear. Assessing this network in detail with fMRI is challenging, considering the brainstem is close to major arteries and pulsatile cerebrospinal fluid-filled spaces obscuring signals of interest. Here, we used methods tailored to the analysis of infratentorial structures. We hypothesize that the olivo-cerebellar circuit shows altered intra-network connectivity at rest and decreased functional coupling with other parts of the motor network in ET. In 17 ET patients and 19 healthy controls, we investigated using resting state fMRI intracerebellar functional and effective connectivity on a dedicated cerebellar atlas. With independent component analysis, we investigated data-driven cerebellar motor network activations during rest. Finally, whole-brain connectivity of cerebellar motor structures was investigated using identified components. In ET, olivo-cerebellar pathways show decreased functional connectivity compared with healthy controls. Effective connectivity analysis showed an increased inhibitory influence of the dentate nucleus towards the inferior olive. Cerebellar independent component analyses showed motor resting state networks are less strongly connected to the cerebral cortex compared to controls. Our results indicate the olivo-cerebellar circuit to be affected at rest. Also, the cerebellum is "disconnected" from the rest of the motor network. Aberrant activity, generated within the olivo-cerebellar circuit could, during action, spread towards other parts of the motor circuit and potentially underlie the characteristic tremor of this patient group.

Background Parkinson’s disease (PD) and essential tremor (ET) are neurodegenerative diseases characterized by movement deficits. Especially in PD, maintaining cyclic movement can be significantly disturbed due to pathological changes in the basal ganglia and the cerebellum. Providing external cues improves timing of these movements in PD and also affects ET. The aim of this study is to determine differences in cortical activation patterns in PD and ET patients during externally and internally cued movements. Methods Eleven PD patients, twelve ET patients, OFF tremor suppressing medication, and nineteen age-matched healthy controls (HC) were included and asked to perform a bimanual tapping task at two predefined cue frequencies. The auditory cue, a metronome sound presented at 2 or 4 Hz, was alternately switched on and off every 30 s. Tapping at two different frequencies were used since it is expected that different brain networks are involved at different frequencies as has been shown in previous studies. Cortical activity was recorded using a 64-channel EEG cap. To establish the cortical activation pattern in each group, the task related power (TRP) was calculated for each subject. For inter-groups analysis, EEG electrodes for divided into 5 different areas. Results Inter-group analysis revealed significant differences in areas responsible for motor planning, organization and regulation and involved in initiation, maintenance, coordination and planning of complex sequences of movements. Within the area of the primary motor cortex the ET group showed a significantly lower TRP than the HC group. In the area responsible for combining somatosensory, auditory and visual information both patient groups had a higher TRP than the HC group. Conclusions Different neurological networks are involved during cued and non-cued movements in ET, PD and HC. Distinct cortical activation patterns were revealed using task related power calculations. Different activation patterns were revealed during the 2 and 4 Hz tapping task indicating different strategies to execute movements at these rates. The results suggest that a including a cued/non-cued tapping task during clinical decision making could be a valuable tool in an objective diagnostic protocol.

BackgroundThe basal ganglia and cerebellum are brain structures involved in movement initiation, execution and termination. They are thought to be involved in the tremor generation and movement deficits in Parkinson's disease (PD) and essential tremor (ET). Especially in PD, maintaining cyclic movement, such as walking or tapping can be significantly disturbed. Providing external cues improves timing of these movements in PD but its effect on ET has not yet been studied in depth. The aim of this study is to evaluate the usefulness of a bimanual tapping task as a tool during clinical decision making.MethodHand movements and tremor was recorded using accelerometers and EMG (m. extensor carpi ulnaris) from PD and ET patients and healthy controls during a bimanual tapping task as a way to distinguish PD from ET. All subjects performed the tapping task at two different frequencies, 2Hz and 4 Hz, with and without the presence of auditory cues.ResultsNo significant intra-group differences were found in the patient groups. Acceleration data revealed significantly less accurate tapping and more variable tapping in PD than in ET and healthy controls. ET subjects tapped less accurate and with a greater variability than healthy controls during the 4Hz tapping task. Most interestingly the tapping accuracy improved in PD patients when kinetic tremor was recorded with EMG during the task.ConclusionProviding ET and PD patients with an external cue results in different tapping performances between patient groups and healthy controls. Furthermore, the findings suggest that kinetic tremor in PD enables patients to perform the task with a greater accuracy. So far this has not been shown in other studies.

Motor improvement after deep brain stimulation (DBS) in the subthalamic nucleus (STN) may vary substantially between Parkinson’s disease (PD) patients. Research into the relation between improvement and active contact location requires a correction for anatomical variation. We studied the relation between active contact location relative to the neurophysiological STN, estimated by the intraoperative microelectrode recordings (MER-based STN), and contralateral motor improvement after one year. A generic STN shape was transformed to fit onto the stereotactically defined MER sites. The location of 43 electrodes (26 patients), derived from MRI-fused CT images, was expressed relative to this patient-specific MER-based STN. Using regression analyses, the relation between contact location and motor improvement was studied. The regression model that predicts motor improvement based on levodopa effect alone was significantly improved by adding the one-year active contact coordinates (R2 change = 0.176, p = 0.014). In the combined prediction model (adjusted R2 = 0.389, p < 0.001), the largest contribution was made by the mediolateral location of the active contact (standardized beta = 0.490, p = 0.002). With the MER-based STN as a reference, we were able to find a significant relation between active contact location and motor improvement. MER-based STN modeling can be used to complement imaging-based STN models in the application of DBS.

There is no objective gold standard to detect tremors. This concerns not only the choice of the algorithm and sensors, but methods are often designed to detect tremors in one specific group of patients during the performance of a specific task. Therefore, the aim of this study is twofold. First, an objective quantitative method to detect tremor windows (TWs) in accelerometer and electromyography recordings is introduced. Second, the tremor stability index (TSI) is determined to indicate the advantage of detecting TWs prior to analysis. Ten Parkinson’s disease (PD) patients, ten essential tremor (ET) patients, and ten healthy controls (HC) performed a resting, postural and movement task. Data was split into 3-s windows, and the power spectral density was calculated for each window. The relative power around the peak frequency with respect to the power in the tremor band was used to classify the windows as either tremor or non-tremor. The method yielded a specificity of 96.45%, sensitivity of 84.84%, and accuracy of 90.80% of tremor detection. During tremors, significant differences were found between groups in all three parameters. The results suggest that the introduced method could be used to determine under which conditions and to which extent undiagnosed patients exhibit tremors.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising treatment for patients with refractory epilepsy. However, therapy response varies and precise positioning of the DBS lead is potentially essential for maximizing therapeutic efficacy. We investigate if single-cell recordings acquired by microelectrode recordings can aid targeting of the ANT during surgery and hypothesize that the neuronal firing properties of the target region relate to clinical outcome. We prospectively included 10 refractory epilepsy patients and performed microelectrode recordings under general anesthesia to identify the change in neuronal signals when approaching and transecting the ANT. The neuronal firing properties of the target region, anatomical locations of microelectrode recordings and active contact positions of the DBS lead along the recorded trajectory were compared between responders and nonresponders to DBS. We obtained 19 sets of recordings from 10 patients (five responders and five nonresponders). Amongst the 403 neurons detected, 365 (90.6%) were classified as bursty. Entry into the ANT was characterized by an increase in firing rate while exit of the ANT was characterized by a decrease in firing rate. Comparing the trajectories of responders to nonresponders, we found differences neither in the neuronal firing properties themselves nor in their locations relative to the position of the active contact. Single-cell firing rate acquired by microelectrode recordings under general anesthesia can thus aid targeting of the ANT during surgery, but is not related to clinical outcome in DBS for patients with refractory epilepsy.

Tremor, characterized by involuntary and rhythmical movements, is the most common movement disorder. Tremor can have peripheral and central oscillatory components which properly assessed may improve diagnostics. A magnetic resonance (MR)-safe haptic wrist manipulator enables simultaneous measurement of proprioceptive reflexes (peripheral components) and brain activations (central components) through functional magnetic resonance imaging (fMRI). The presented design for an MR-safe haptic wrist manipulator has electrohydraulic closed-circuit actuation, optical position and force sensing, and consists of exclusively nonconductive and magnetically compatible materials inside the MR-environment (Zone IV). The MR-safe hydraulic actuator, a custom-made plastic vane motor, is connected to the magnetic parts and electronics located in the shielded control room (Zone III) via hydraulic hoses and optical fibers. Deliberate internal leakage provides backdriveability, damping, and circumvents friction. The manipulator is completely MR-safe and therefore operates safely in any MR-environment while ensuring fMRI imaging quality. Undesired external leakage in the actuator prevented the use of prepressure, limiting the control bandwidth. The compact end effector design fits in the MR-scanner, is easily setup, and can be clamped to the MR-scanner bed. This enables use of the manipulator with the subject at the optimal fMRI location and allows it to be setup quickly, saving costly MR-scanner time. The actuation and sensor solutions performed well inside the MR-environment and did not deteriorate image quality, which allows for various motor control experiments. Enabling prepressure by carrying out the recommendations on fabrication and sealing should improve the bandwidth and fulfill the requirements for proprioceptive reflex identification.

OBJECTIVE:Novel deep brain stimulation (DBS) lead designs are currently entering the market, which are hypothesized to provide a way to steer the stimulation field away from neural populations responsible for side effects and towards populations responsible for beneficial effects. The objective of this study is to assess the performances of a new eight channel steering-DBS lead and compare this with a conventional cylindrical contact (CC) lead.APPROACH:The two leads were evaluated in a finite element electric field model combined with multicompartment neuron and axon models, representing the internal capsule (IC) fibers and subthalamic nucleus (STN) cells. We defined the optimal stimulation setting as the configuration that activated the highest percentage of STN cells, without activating any IC fibers. With this criterion, we compared monopolar stimulation using a single contact of the steering-DBS lead and CC lead, on three locations and four orientations of the lead. In addition, we performed a current steering test case by dividing the current over two contacts with the steering-DBS lead in its worst-case orientation.MAIN RESULTS:In most cases, the steering-DBS lead is able to stimulate a significantly higher percentage of STN cells compared to the CC lead using single contact stimulation or using a two contact current steering protocol when there is approximately a 1 mm displacement of the CC lead. The results also show that correct placement and orientation of the lead in the target remains an important aspect in achieving the optimal stimulation outcome.SIGNIFICANCE:Currently, clinical trials are set up in Europe with a similar design as the steering-DBS lead. Our results illustrate the importance of the orientation of the new steering-DBS lead in avoiding side effects induced by stimulation of IC fibers. Therefore, in clinical trials sufficient attention should be paid to implanting the steering DBS-lead in the most effective orientation.

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.

This proof-of-principle study describes the methodology and explores and demonstrates the applicability of a system, existing of miniature inertial sensors on the hand and a separate force sensor, to objectively quantify hand motor symptoms in patients with Parkinson’s disease (PD) in a clinical setting (off- and on-medication condition). Four PD patients were measured in off- and on- dopaminergic medication condition. Finger tapping, rapid hand opening/closing, hand pro/supination, tremor during rest, mental task and kinetic task, and wrist rigidity movements were measured with the system (called the PowerGlove). To demonstrate applicability, various outcome parameters of measured hand motor symptoms of the patients in off- vs. on-medication condition are presented. The methodology described and results presented show applicability of the PowerGlove in a clinical research setting, to objectively quantify hand bradykinesia, tremor and rigidity in PD patients, using a single system. The PowerGlove measured a difference in off- vs. on-medication condition in all tasks in the presented patients with most of its outcome parameters. Further study into the validity and reliability of the outcome parameters is required in a larger cohort of patients, to arrive at an optimal set of parameters that can assist in clinical evaluation and decision-making.

Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted torque, were designed to target activation of the CBL and BG in healthy subjects during functional magnetic resonance imaging (fMRI). Selective activation of the cerebellum (CBL) and basal ganglia (BG), often implicated in movement disorders such as tremor and dystonia, may help identify pathological changes and expedite diagnosis. A prototyped MR-compatible wrist torque measurement device, free of magnetic and conductive materials, allowed safe execution of tasks during fMRI without causing artifacts. A significant increase of activity in CBL and BG was found in healthy volunteers during a constant torque task with visual feedback compared to a constant torque task without visual feedback. This study shows that specific pairs of motor tasks using MR-compatible equipment at the wrist allow for targeted activation of CBL and BG, paving a new way for research into the pathophysiology of movement disorders.

Background Multi-directional electrodes in STN-DBS give the possibility to steer the high frequency current into the direction for clinical improvement and moreover recording of multi-array local field potential recordings (LFPs) give the possibility to determine the spatiotemporal distribution of oscillatory power across the STN that is related to the symptomatology in PD patients. Ultimately this information can be used as a feedback to optimize the stimulation parameters. Methods Eight PD patients were included in the study. After micro-electrode recording (MER), to determine the boundaries of the STN, temporarily a prototype of a new 32-contact DBS lead was inserted during the DBS procedure. Different modes of current steering were employed to improve motor symptoms and patients were scored on beneficial and adverse effects. Prior to and immediately after stimulation the distribution of spectral power was recorded by LFPs and spatiotemporal changes were evaluated with Fourier analysis. Results Thresholds of the effects of spherical stimulation were comparable to thresholds of stimulation through the conventional electrode at the same location in 89% of the cases. In eight of fourteen side effects, steering stimulation current increased the threshold for side effects by ⩾ 1 mA compared to spherical stimulation. The size of the therapeutic window could be widened in patient 6, 7 and 8 by steering stimulation in the posterior, posterior and anterior direction, respectively. LFP recordings prior to stimulation yielded the boundaries of the STN by showing increased spectral power particularly in the 13–40 Hz range. Recordings across all directions showed distinct spatiotemporal patterns of neuronal activity, which were related to the pattern of stimulation and the PD symptoms of the patient. Conclusions With a new DBS lead it is possible to steer stimulation current in STN-DBS such that it leads to a larger therapeutic window than with conventional spherical stimulation. Simultaneous LFP recordings across the entire STN provide spatial information about the location of the STN and its disease-related electrical activity. This may potentially be of benefit in predicting how to steer the current towards the sensorimotor part, while avoiding adverse effects.

Objective. The correspondence between the anatomical STN and the STN observed in T2-weigthed MRI images used for deep brain stimulation (DBS) targeting remains unclear. Using a new method, we compared the STN borders seen on MRI images with those estimated by intraoperative microelectrode recordings (MER). Approach. We developed a method to automatically generate a detailed estimation of STN shape and the location of its borders, based on multiple-channel MER measurements. In 33 STNs of 19 Parkinson patients, we quantitatively compared the dorsal and lateral borders of this MER-based STN model with the STN borders visualized by 1.5 T (n = 14), 3.0 T (n = 10) and 7.0 T (n = 9) T2-weighted MRI. Main results. The dorsal border was identified more dorsally on coronal T2 MRI than by the MER-based STN model, with a significant difference in the 3.0 T (range 0.97-1.19 mm) and 7.0 T (range 1.23-1.25 mm) groups. The lateral border was significantly more medial on 1.5 T (mean: 1.97 mm) and 3.0 T (mean: 2.49 mm) MRI than in the MER-based STN; a difference that was not found in the 7.0 T group. Significance. The STN extends further in the dorsal direction on coronal T2 MRI images than is measured by MER. Increasing MRI field strength to 3.0 T or 7.0 T yields similar discrepancies between MER and MRI at the dorsal STN border. In contrast, increasing MRI field strength to 7.0 T may be useful for identification of the lateral STN border and thereby improve DBS targeting.

Steering DBS, adaptive DBS and coordinated reset neuromodulation the last fifteen years have been proposed as new techniques to improve the effect of DBS. Application of these techniques strongly depends on the design of the electronic devices. Why has the design of conventional pulse generators not changed up till now? Steering DBS opens the possibility to steer the DBS current into a specific direction after implantation. A special high-density DBS lead and a multichannel programmable device is required. Adaptive DBS has the advantage of the adjustment of the stimulation amplitude depending on local field potential parameters. This requires a sensing possibility of the DBS equipment. Coordinated reset neuromodulation includes a different stimulation protocol with independent asynchronous stimulation on different contact points. All three new techniques have been tested experimentally per-operatively or shortly after neurosurgery. However, data on chronic stimulation are lacking since appropriate implantable pulse generators are missing. But also there is still uncertainty about how to implement these new techniques. More studies are needed on the advantage of steering DBS, on which local field potential parameters are most suitable for feedback (Fig. 1) and on what is the best protocol to take optimum advantage of coordinated reset. Very promising new techniques for DBS therapy are under development which have the potential of making DBS more efficient, leading to much smaller batteries and giving more possibilities on automatic adjustment of temporal and spatial stimulus parameters ([Contarino et al., 2014], [Bour et al., 2015], [Lourens et al., 2015], [Adamchic et al., 2014], [Little et al., 2015]).

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.

Objective. The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STNDBS) as a treatment for Parkinson's disease are sensitive to the location of the DBS lead within the STN. New high density (HD) lead designs have been created which are hypothesized to provide additional degrees of freedom in shaping the stimulating electric field. The objective of this study is to compare the performances of a new HD lead with a conventional cylindrical contact (CC) lead. Approach. A computational model, consisting of a finite element electric field model combined with multi-compartment neuron and axon models representing different neural populations in the subthalamic region, was used to evaluate the two leads. We compared ringmode and steering-mode stimulation with the HD lead to single contact stimulation with the CC lead. These stimulation modes were tested for the lead: (1) positioned in the centroid of the STN, (2) shifted 1 mm towards the internal capsule (IC), and (3) shifted 2 mm towards the IC. Under these conditions, we quantified the number of STN neurons that were activated without activating IC fibers, which are known to cause side-effects. Main results. The modeling results show that the HD lead is able to mimic the stimulation effect of the CC lead. Additionally, in steering-mode stimulation there was a significant increase of activated STN neurons compared to the CC mode. Significance. From the model simulations we conclude that the HD lead in steering-mode with optimized stimulation parameter selection can stimulate more STN cells. Next, the clinical impact of the increased number of activated STN cells should be tested and balanced across the increased complexity of identifying the optimized stimulation parameter settings for the HD lead.

Objectives: STN-DBS could be improved by specifically targeting the dorsolateral part of the STN. However, the correspondence between the location of the STN on T2 MRI images used for targeting and the location of the neurophysiological STN remains unclear. In this study, we compared the STN borders on T2 MRI images with the STN borders identified by microelectrode recordings (MER), measured during DBS surgery.

OBJECTIVES:To explore sensory gating deficits in subjects at Ultra High Risk (UHR) for psychosis before and after transition to a first psychotic episode.METHODS:Sensory gating was assessed with the paired click paradigm in 61 UHR subjects, of whom 18 (30%) made a transition to psychosis (UHR + T) over a 3-year follow-up period and 28 matched healthy controls. Subjects were assessed at inclusion and again after approximately 18 months. P50, N100 (N1) and P200 (P2) sensory gating was established using the amplitude on the first (S1) and second (S2) click, the ratio- (S2/S1) and the difference score (S1-S2). Psychopathology was also assessed.RESULTS:At baseline, UHR + T subjects presented smaller N1 difference scores compared to UHR + NT subjects and controls. The N1 difference score contributed modestly to the prediction of a first psychotic episode. Repeated measure analyses revealed smaller N1 and P2 S1 amplitudes, smaller P2 difference scores and larger P2 ratio's at follow-up compared to baseline in UHR + T subjects.CONCLUSION:The N1 difference score may be helpful in predicting a first psychosis. N1 and P2 sensory gating measures also showed alterations between the prodromal phase and the first psychosis, suggesting that these changes may relate to the onset of a frank psychotic episode.