Closing the loop: Novel quantitative fMRI approach for manipulation of the sensorimotor loop in tremor.

Tremor is thought to be an effect of oscillatory activity within the sensorimotor network. To date, the underlying pathological brain networks are not fully understood. Disentangling tremor activity from voluntary motor output and sensorimotor feedback systems is challenging. To better understand the intrinsic sensorimotor fingerprint underlying tremor, we aimed to disentangle the sensorimotor system into driving (motor) and feedback/compensatory (sensory) neuronal involvement, and aimed to pinpoint tremor activity in essential tremor (ET) and tremor-dominant Parkinson's disease (PD) with a novel closed-loop approach. Eighteen ET patients, 14 tremor-dominant PD patients, and 18 healthy controls were included. An MR-compatible wrist manipulator was employed during functional MRI (fMRI) while muscle activity during (in)voluntary movements was concurrently recorded using electromyography (EMG). Tremor was quantified based on EMG and correlated to brain activity. Participants performed three tasks: an active wrist motor task, a passive wrist movement task, and rest (no wrist movement). The results in healthy controls proved that our experimental paradigm activated the expected motor and sensory networks separately using the active (motor) and passive (sensory) task. ET patients showed similar patterns of activation within the motor and sensory networks. PD patients had less activity during the active motor task in the cerebellum and basal ganglia compared to ET and healthy controls. EMG showed that in ET, tremor fluctuations correlated positively with activity in the inferior olive region, and that in PD tremor fluctuations correlated positively with cerebellar activity. Our novel approach with an MR-compatible wrist manipulator, allowed to investigate the involvement of the motor and sensory networks separately, and as such to better understand tremor pathophysiology. In ET sensorimotor network function did not differ from healthy controls. PD showed less motor-related activity. Focusing on tremor, our results indicate involvement of the inferior olive in ET tremor modulation, and cerebellar involvement in PD tremor modulation.

Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor-a Voxel-Based Morphometry Study.

Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements.

A comparison of methods to suppress electrocardiographic artifacts in local field potential recordings.

OBJECTIVE: Local field potential (LFP) recordings from deep brain stimulation (DBS) electrodes are often contaminated with electrocardiographic (ECG) artifacts that hinder the detection of disease-specific electrical brain activity. METHODS: Three ECG suppression methods were evaluated: (1) QRS interpolation of the Perceive toolbox, (2) template subtraction, and (3) singular value decomposition (SVD). LFPs were recorded with the Medtronic PerceptTM PC system in nine Parkinson's disease patients with stimulation OFF ("OFF-DBS"; anode disconnected) and ON at 0 mA ("ON-DBS 0 mA"; anode connected). Findings were verified with simulated ECG-contaminated time series. RESULTS: ECG artifacts were present in 10 out of 18 ON-DBS 0 mA recordings. All ECG suppression methods drastically reduced artifact-induced beta band (13-35 Hz) power and at least partly recovered the beta peak and beta burst dynamics. Using external ECG recordings and lengthening artifact epoch length improved the performance of the suppression methods. Increasing epoch length, however, elevated the risk of flattening the beta peak and losing beta burst dynamics. CONCLUSIONS: The SVD method formed the preferred trade-off between artifact cleaning and signal loss, as long as its parameter settings are adequately chosen. SIGNIFICANCE: ECG suppression methods enable analysis of disease-specific neural activity from signals affected by ECG artifacts.

Thalamic local field potentials recorded using the deep brain stimulation pulse generator.

Background: Essential tremor (ET) is one of the most common movement disorders, and continuous deep brain stimulation (DBS) is an established treatment for medication-refractory cases. However, the need for increasing stimulation intensities, with unpleasant side effects, and DBS tolerance over time can be problematic. The advent of novel DBS devices now provides the opportunity to longitudinally record LFPs using the implanted pulse generator, which opens up possibilities to implement adaptive DBS algorithms in a real-life setting. Methods: Here we report a case of thalamic LFP activity recorded using a commercially available sensing-enabled DBS pulse generator (Medtronic Percept PC). Results: In the OFF-stimulation condition, a peak tremor frequency of 3.8 Hz was identified during tremor evoking movements as assessed by video and accelerometers. Activity at the same and supraharmonic frequency was seen in the frequency spectrum of the LFP data from the left vim nucleus during motor tasks. Coherence analysis showed that peripherally recorded tremor was coherent with the LFP signal at the tremor frequency and supraharmonic frequency. Conclusion: This is the first report of recorded tremor-related thalamic activity using the electrodes and pulse generator of an implanted DBS system. Larger studies are needed to evaluate the clinical potential of these fully implantable systems, and ultimately pulse generators with sensing-coupled algorithms driving stimulation, to really close the loop.

Limited correlations between clinician-based and patient-based measures of essential tremor severity.

INTRODUCTION: We investigated the relation between changes in clinician-based and patient-based measures of tremor severity, within the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and Visual Analogue Scale (VAS) in essential tremor patients. METHODS: Thirty-seven patients were assessed twice: on- and off-medication. Clinician-based, objective TRS assessments, consisting of part A (postures/movements) and part B (tremor-inducing tasks) were conducted by a blinded assessor using video-tapes. Patients completed TRS part C (limitations in activities of daily life) and indicated subjective tremor severity using VAS. RESULTS: Patients' total TRS and VAS scores improved on-medication (both p < 0.001). Mean improvement was 6.3 (sd 5.4) points on the total TRS and 2.3 (sd 2.3) points on the VAS score. Within the TRS, we found moderate correlations between changes in clinician-based TRS-B and patient-based TRS-C scores (ρ = 0.387, p = 0.011), but not between changes in clinician-based TRS-A and TRS-C scores (ρ = 0.128, p = 0.232). Moreover, changes in subjective VAS scores correlated with changes in total TRS (ρ = 0.422, p = 0.007), changes in TRS-C scores (ρ = 0.367, p = 0.015) and, more weakly, with changes in TRS-B scores (ρ = 0.281, p = 0.049), but again: not with changes in TRS-A scores (ρ = -0.008, p = 0.482). DISCUSSION: We found no correlation between changes in clinician-based TRS-A, and patient-based measures TRS-C or VAS scores, and a weak correlation between clinician-based TRS-B and VAS scores. The limited correlations between changes in clinician-based and patient-based measures of tremor severity suggest that the different scales measure different aspects of tremor severity and support the additional use of subjective patient-based assessments in clinical practice and clinical trials.

Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor.

INTRODUCTION: Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. METHODS: Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. RESULTS: In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. CONCLUSION: The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor.

Reporting of medical research costs. Improving transparency and reproducibility of medical research.

Increasing numbers of research reporting guidelines are being published. These guidelines facilitate rigorous and complete reporting, and presentation of published studies. However, current reporting guidelines do not address issues related to costs of research methods. We propose to publish costs of research in order to increase transparency, efficiency, quality and ultimately reproducibility of scientific studies.

How to tackle tremor - systematic review of the literature and diagnostic work-up.

BACKGROUND: Tremor is the most prevalent movement disorder in clinical practice. It is defined as involuntary, rhythmic, oscillatory movements. The diagnostic process of patients with tremor can be laborious and challenging, and a clear, systematic overview of available diagnostic techniques is lacking. Tremor can be a symptom of many diseases, but can also represent a distinct disease entity. OBJECTIVE: The objective of this review is to give a clear, systematic and step-wise overview of the diagnostic work-up of a patient with tremor. The clinical relevance and value of available laboratory tests in patients with tremor will be explored. METHODS: We systematically searched through EMBASE. The retrieved articles were supplemented by articles containing relevant data or provided important background information. Studies that were included investigated the value and/or usability of diagnostic tests for tremor. RESULTS: In most patients, history and clinical examination by an experienced movement disorders neurologist are sufficient to establish a correct diagnosis, and further ancillary examinations will not be needed. Ancillary investigation should always be guided by tremor type(s) present and other associated signs and symptoms. The main ancillary examination techniques currently are electromyography and SPECT imaging. Unfortunately, many techniques have not been studied in large prospective, diagnostic studies to be able to determine important variables like sensitivity and specificity. CONCLUSION: When encountering a patient with tremor, history, and careful clinical examination should guide the diagnostic process. Adherence to the diagnostic work-up provided in this review will help the diagnostic process of these patients.