Sarvi Sharifi

Neuroimaging essentials in essential tremor: A systematic review

Background Essential tremor is regarded to be a disease of the central nervous system. Neuroimaging is a rapidly growing field with potential benefits to both diagnostics and research. The exact role of imaging techniques with respect to essential tremor in research and clinical practice is not clear. A systematic review of the different imaging techniques in essential tremor is lacking in the literature. Methods We performed a systematic literature search combining the terms essential tremor and familial tremor with the following keywords: imaging, MRI, VBM, DWI, fMRI, PET and SPECT, both in abbreviated form as well as in full form. We summarize and discuss the quality and the external validity of each study and place the results in the context of existing knowledge regarding the pathophysiology of essential tremor. Results A total of 48 neuroimaging studies met our search criteria, roughly divided into 19 structural and 29 functional and metabolic studies. The quality of the studies varied, especially concerning inclusion criteria. Functional imaging studies indicated cerebellar hyperactivity during rest and during tremor. The studies also pointed to the involvement of the thalamus, the inferior olive and the red nucleus. Structural studies showed less consistent results. Discussion and conclusion Neuroimaging techniques in essential tremor give insight into the pathophysiology of essential tremor indicating the involvement of the cerebellum as the most consistent finding. GABAergic dysfunction might be a major premise in the pathophysiological hypotheses. Inconsistencies between studies can be partly explained by the inclusion of heterogeneous patient groups. Improvement of scientific research requires more stringent inclusion criteria and application of advanced analysis techniques. Also, the use of multimodal neuroimaging techniques is a promising development in movement disorders research. Currently, the role of imaging techniques in essential tremor in daily clinical practice is limited.

Motor network disruption in essential tremor: a functional and effective connectivity study

Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations during a motor task. Twenty-two essential tremor patients and 22 healthy controls were analysed. For the effective connectivity analysis, a network of tremor-signal related regions was constructed, consisting of the left primary motor cortex, premotor cortex, supplementary motor area, left thalamus, and right cerebellar motor regions lobule V and lobule VIII. A measure of variation in tremor severity over time, derived from the electromyogram, was included as modulatory input on intrinsic connections and on the extrinsic cerebello-thalamic connections, giving a total of 128 models. Bayesian model selection and random effects Bayesian model averaging were used. Separate seed-based functional connectivity analyses for the left primary motor cortex, left supplementary motor area and right cerebellar lobules IV, V, VI and VIII were performed. We report two novel findings that support an important role for the cerebellar system in the pathophysiology of essential tremor. First, in the effective connectivity analysis, tremor variation during the motor task has an excitatory effect on both the extrinsic connection from cerebellar lobule V to the thalamus, and the intrinsic activity of cerebellar lobule V and thalamus. Second, the functional integrity of the motor network is affected in essential tremor, with a decrease in functional connectivity between cortical and cerebellar motor regions. This decrease in functional connectivity, related to the motor task, correlates with an increase in clinical tremor severity. Interestingly, increased functional connectivity between right cerebellar lobules I-IV and the left thalamus correlates with an increase in clinical tremor severity. In conclusion, our findings suggest that cerebello-dentato-thalamic activity and cerebello-cortical connectivity is disturbed in essential tremor, supporting previous evidence of functional cerebellar changes in essential tremor.

Familial cortical myoclonic tremor with epilepsy and cerebellar changes: description of a new pathology case and review of the literature.

Background Over 60 Asian and European families with cortical myoclonic tremor and epilepsy have been reported under various names. Cerebellar changes may be part of the syndrome. In this study, we report the neuropathology findings in a new Dutch familial cortical myoclonic tremor with epilepsy case and review the literature on this syndrome. Methods Neuropathological investigations were performed for a third case of the Dutch pedigree. In addition, we searched the literature for pedigrees meeting the criteria for benign familial myoclonic tremor and epilepsy. Results Our third Dutch case showed cerebellar Purkinje cell changes and a normal cerebral cortex. The pedigrees described show phenotypical differences, cerebellar symptoms and cerebellar atrophy to a variable degree. Japanese pedigrees with linkage to chromosome 8q have been reported with milder disease features than members of Italian pedigrees with linkage to chromosome 2p. French pedigrees (5p) possibly show even more severe and progressive disease, including cognitive changes and cerebellar features. Discussion Currently, familial cortical myoclonic tremor is not listed by the International League Against Epilepsy, although it can be differentiated from other epileptic syndromes. Genetic heterogeneity and phenotypical differences between pedigrees exist. Cerebellar changes seem to be part of the syndrome in at least a number of pedigrees.

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.

Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review

Background Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings. Methods We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria. Results Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A “benign” phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam. Several genes have been identified, which differ in potential pathogenicity. Discussion Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes.

PET and SPECT Imaging in Hyperkinetic Movement Disorders

Movement disorders can be classified into hypokinetic (e.g., Parkinson’s disease; PD) and hyperkinetic disorders (e.g., dystonia, chorea, tremor, tics, myoclonus, and restless legs syndrome). In this chapter, we will discuss results from PET and SPECT imaging studies in patients with tremor, tics, myoclonus, and restless legs syndrome.

Differentiation of tremor disorders with fMRI: A novel quantitative approach

Objective:To define and evaluate a Computer-Vision (CV) method for scoring Paced Finger-Tapping (PFT) in Parkinsons disease (PD) using quantitative motion analysis of index-fingers and to compare the obtained scores to the UPDRS (Unified Parkinsons Disease Rating Scale) finger-taps (FT).Background:The naked-eye evaluation of PFT in clinical practice results in coarse resolution to determine PD status. Besides, sensor mechanisms for PFT evaluation may cause patients discomfort. In order to avoid cost and effort of applying wearable sensors, a CV system for non-invasive PFT evaluation is introduced.Methods:A database of 221 PFT videos from 6 PD patients was processed. The subjects were instructed to position their hands above their shoulders besides the face and tap the index-finger against the thumb consistently with speed. They were facing towards a pivoted camera during recording. The videos were rated by two clinicians between symptom levels 0-to-3 using UPDRS-FT.The CV method incorporates a motion analyzer and a face detector. The method detects the face of testee in each video-frame. The frame is split into two images from face-rectangle center. Two regions of interest are located in each image to detect index-finger motion of left and right hands respectively. The tracking of opening and closing phases of dominant hand index-finger produces a tapping time-series. This time-series is normalized by the face height. The normalization calibrates the amplitude in tapping signal which is affected by the varying distance between camera and subject (farther the camera, lesser the amplitude). A total of 15 features were classified using K-nearest neighbor (KNN) classifier to characterize the symptoms levels in UPDRS-FT. The target ratings provided by the raters were averaged.Results:A 10-fold cross validation in KNN classified 221 videos between 3 symptom levels with 75% accuracy. An area under the receiver operating characteristic curves of 82.6% supports feasibility of the obtained features to replicate clinical assessments.Conclusions:The system is able to track index-finger motion to estimate tapping symptoms in PD. It has certain advantages compared to other technologies (e.g. magnetic sensors, accelerometers etc.) for PFT evaluation to improve and automate the ratingsObjective: To compare the efficacy of botulinum toxin type A (BTX-A) treatment for patients with primary versus secondary blepharospasm (BS) associated with Parkinson’s disease (PD), with or without deep brain stimulation (DBS). Background: BS, a focal eyelid dystonia, can be idiopathic (primary) or secondary to other disorders such as PD. Furthermore eyelid-opening disorders are common in patients with PD undergoing deep brain stimulation (DBS). BTX-A is the treatment of choice for these conditions. Methods: 27 patients [15 males, age: 65.11 6 13.66 years, disease duration 7.7 6 8.2], newly or routinely treated with BTX-A were recruited including patients with primary BS (N 5 10), secondary BS associated with PD (N 5 6), PD1DBS (N 5 5), and other various types of BS (N 5 6). Patients were evaluated before and 4 weeks following BTX-A injections, using the Blepharospam Disability Scale (BDS), the Blepharospasm Disability Index (BDI), the Jankovic Rating Scale (JRS), the Blepharospasm Movement Scale (BMS), and the Clinical Global Impression of improvement (CGI-I). Additionally all were recorded on a 5-minute videotape and scored by a blinded rater. Results: Following BTX-A injections, our sample as a whole showed a statistically significant improvement in Severity of Illness (2.34 6 1.05 vs. 1.74 6 1.27, p 5 0.013), JRS severity scale (1.96 6 1.22 vs. 1.37 6 1.04, p 5 0.002), BMS severity scale (5.04 6 1.79 vs. 4 6 2.35, p 5 0.04), and the severity rating scale (1.61 6 0.8 vs. 1.19 6 0.84, p 5 0.013). When efficacy was compared by diagnosis group, the best effect was evident in patients with BS secondary to PD and was maximal for the PD patients without DBS who demonstrated significant improvement in Severity of Illness compared to the other two groups. Conclusions: In this study BTX-A was an effective treatment for BS. Patients with PD associated BS showed a better response than those with primary BS.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.