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.

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.

Objective: A role of the motor cortex in tremor generation in essential tremor (ET) is assumed, yet the directionality of corticomuscular coupling is unknown. Our aim is to clarify the role of the motor cortex. To this end we also study 'familial cortical myoclonic tremor with epilepsy' (FCMTE) and slow repetitive voluntary movements with a known cortical drive. Methods: Directionality of corticomuscular coupling (EEG-EMG) was studied with renormalized partial directed coherence (rPDC) during tremor in 25 ET patients, 25 healthy controls (mimicked) and in seven FCMTE patients; and during a self-paced 2 Hz task in eight ET patients and seven healthy controls. Results: Efferent coupling around tremor frequency was seen in 33% of ET patients, 45.5% of healthy controls, all FCMTE patients, and, around 2 Hz, in all ET patients and all healthy controls. Ascending coupling, seen in the majority of all participants, was weaker in ET than in healthy controls around 5-6 Hz. Conclusions: Possible explanations are that tremor in ET results from faulty subcortical output bypassing the motor cortex; rate-dependent transmission similar to generation of rhythmic movements; and/or faulty feedforward mechanism resulting from decreased afferent (sensory) coupling. Significance: A linear cortical drive is lacking in the majority of ET patients. (C) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.

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.

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.

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.

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: Movement disorders, including Parkinson's disease (PD) and essential tremor (ET), have overlapping symptoms, which hamper diagnostics. To improve diagnostics, objective parameters may help to differentiate PD from ET. Therefore, this study aims at differentiating between PD, ET and healthy controls (HC) by comparing α(8-13Hz) and β-band (13-40Hz) scalp EEG power during rest and arm movements.

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 <0.05). Results: The active motor task versus the passive movement in essential tremor was associated with activation in bilateral cerebellum, bilateral basal ganglia, thalamus, SMA and motor cortex (fig 1). The reversed contrast did not show any activations in motor networks. Conclusions: Our preliminary findings show accurate identification of motor network activity including the cerebellum, thalamus, basal ganglia and motor cortex during isometric contraction versus passive movement. By manipulation of the sensorimotor loop with a wrist manipulator we are able to reveal specific motor network activations. This novel quantitative approach is a promising new technique to study pathophysiological mechanisms in hyperkinetic movement disorders, and potentially lead to new diagnostic approaches.

Objective: To develop fMRI-based tools in tremor diagnostics and to demonstrate their clinical applicability. Background: Due to overlapping features of tremor disorders, clinical diagnostic tools are limited. Although seldomly used in diagnostic assessment of tremor, fMRI of pathological brain networks underlying tremor could aid accurate and early diagnosis. fMRI of the closed loop behaviour of the sensorimotor system may manifest itself differently with different tremor disorders and has not been fully explored yet in diagnostics. Methods: Following a literature review that we performed on neuroimaging studies in essential tremor (ET), we developed a novel fMRI setup to investigate pathological brain networks related to tremor. An MR-compatible wrist manipulator, to perturb the sensorimotor loop, is combined with movement measures. Results: Our review showed that current findings are consistent with the hypothesis that the cerebellothalamo-cortical network is involved in ET with a major role for the cerebellum. To date, imaging techniques roughly are divided into structural (n=11) and functional methods (n=24). Limitations include heterogeneity of ET symptoms, spatial resolution and inability to directly relate tremor to functional images. The typical nature of a sensorimotor loop is generally not taken into account. We have developed a high-end novel experimental setup within the MR-environment including artifact-free movement measures (EMG, accelerometry) and a MR-compatible wrist manipulator to apply perturbations. Perturbations applied close to pathological tremor frequencies provide sensory input in passive conditions and manipulate motor action in active conditions. Conclusions: We introduce a multimodal fMRI set-up manipulating the sensorimotor loop to identify faulty brain circuitries. This system can potentially lead to a novel quantitative diagnostic tool for differentiating tremor and other movement disorders.

AIM:Systemic sclerosis (SSc) is a generalized connective tissue disease that affects smooth muscle cells. Patients with SSc often have faecal incontinence caused by fibrotic degeneration of the internal anal sphincter (IAS). The functional lumen imaging probe (FLIP) is a novel method that allows the segmental biomechanical properties of the anal canal to be dynamically evaluated. The aim of the present study was to compare the segmental biomechanical properties of the anal canal in incontinent SSc patients and healthy controls. We hypothesized that the FLIP would reveal weaknesses of the IAS in the SSc patients. METHOD:We performed FLIP distensions, endoanal ultrasonography and standard anal manometry on 14 incontinent SSc patients [11 women, median age 60 years (range 35-80)] and 15 healthy volunteers [12 women, median age 54 years (range 33-67)]. The anal canal was divided into three parts for the biomechanical analysis: upper (surrounded by the IAS and the puborectalis), middle (IAS and external anal sphincter) and lower (external sphincter only). RESULTS:The middle anal canal was the segment most resistant to distension in all of the subjects, but it was less resistant in the SSc patients than in the controls (P < 0.01). Correspondingly, the endoanal ultrasonography showed that the IAS of the SSc patients was thinner than normal (P < 0.05), and the anal resting and squeeze pressures were lower (P < 0.05). Only minor distensibility differences were found in the upper anal canal. No changes were found in the lower anal canal. CONCLUSION:Faecal incontinence in SSc patients is associated with poor IAS function, causing increased distensibility of the middle anal canal.

The muscle structures surrounding the anal canal are of major importance in maintaining continence but their anatomy and function vary along its length. Standard manometry does not provide detailed information about mechanical properties of the anal canal. A new functional luminal imaging probe (FLIP) has been developed for this purpose. The aim of our study was to investigate whether FLIP allows detailed evaluation of dynamic biomechanical properties along the length of the anal canal.The in vitro validity and reproducibility of the FLIP system were tested. Fifteen healthy volunteers (age 32-65 years, mean 51 years), of whom 12 were females, were investigated. The integrity and dimensions of the anal sphincter apparatus were evaluated with endoanal ultrasonography and standard anal manometry. During standardized distensions with the FLIP, 16 cross-sectional areas of the anal canal were measured at 5-mm intervals. Distensibility of the following three segments was evaluated: upper anal canal (surrounded by the internal anal sphincter and the puborectalis muscle), mid-anal canal (surrounded by the internal anal sphincter and the external anal sphincter) and lower anal canal (surrounded by the external anal sphincter). Color contour plots were generated from the FLIP-based dynamic recordings of serial cross-sections.In vitro tests confirmed the validity and reproducibility of the FLIP system. The luminal geometry during distension and the biomechanical properties of the anal canal differed at the three levels. Both at rest and during squeeze the mid-anal canal was significantly less distensible than the upper (p < 0.01) and the lower (p < 0.05) anal canal.FLIP is a promising method for evaluation of the nonhomogeneous biomechanical properties along the length of the anal canal.