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Background MR-guided focused ultrasound (MRgFUS) is an effective treatment for essential tremor (ET). However, the optimal intracranial target sites remain to be determined. Objective To assess MRgFUS induced sequential lesions in (anterior-VIM/VOP nuclei) the thalamus and then posterior subthalamic area (PSA) performed during the same procedure for alleviating ET. Methods 14 patients had unilateral MRgFUS lesions placed in anterior-VIM/VOP then PSA. Bain-Findley Spirals were collected during MRgFUS from the treated arm (BFS-TA) and throughout the study from the treated (BFS-TA) and non-treated (BFS-NTA) arms and scored by blinded assessors. Although, the primary outcome was change in the BFS-TA from baseline to 12 months we have highlighted the 24-month data. Secondary outcomes included the Clinical Rating Scale for Tremor (CRST), Quality of Life for ET (QUEST) and PHQ-9 depression scores. Results The mean improvement in the BFS-TA from baseline to 24 months was 41.1% (p

This chapter concerns orthostatic tremor (OT), a form of tremor that characteristically affects the legs during stance. The clinical features of OT are described in detail, including the findings obtained from the history and examination of patients with OT, along with its associations, social consequences and effects on mood, cognitive function, and quality of life. The investigation of patients with OT using blood tests, MR imaging, single-photon emission tomography (SPECT) dopamine transporter imaging, transcranial sonography, and functional imaging are detailed. The processes involved in differentiating the three subtypes of orthostatic tremor, namely primary orthostatic tremor, orthostatic tremor plus, and pseudo-orthostatic tremor, are discussed, along with a scheme for distinguishing these forms of OT from orthostatic myoclonus. The management of OT by simple measures medical therapy, deep brain stimulation, and chronic spinal cord stimulation, are detailed. The advances in understanding of the pathophysiology of OT are reported.

Background: The relationship between essential tremor (ET) and dystonia has been long debated and the boundaries between these disorders remain unclear. Here, we highlight the diagnostic uncertainty that can arise when observing dystonic postures in patients who have received ET diagnoses. Methods: An international panel of seven movement disorders neurologists from five countries reviewed the clinical history and videotaped neurological examinations of five individuals diagnosed with ET who also had various features of dystonia on neurological examination. Experts were instructed to assign diagnoses and provide their rationale for diagnostic assignments. Results: The five cases each exhibited a variety of abnormal postures. These were observed by all experts, and interpreted as dystonic postures by six experts. According to six of seven experts, all five cases had ET. One expert classified all cases as dystonic tremor rather than ET. One case had cervical dystonia, and five of seven experts assigned dual diagnoses of ET and dystonia in that case. The assignment of dystonia diagnoses was variable among the other four cases, with two to three experts assigning this diagnosis in each case, underscoring differences in diagnostic interpretation of dystonic postures on examination. Conclusions: This study draws attention to some of the differences between experts in assigning diagnoses of ET or dystonia to individuals with ET and abnormal postures. The goal here was not necessarily to build consensus, but to raise issues, highlight areas of uncertainty, and identify areas of common vs. differentiated thought. Several questions for additional research were also raised.

Background: Programming deep brain stimulation (DBS) settings in patients with Parkinson disease (PD) is challenging and time consuming because of the vast number of possible parameter combinations. This results in long sessions that can be exhausting for the patients and physicians. GUIDE (Boston Scientific) is a 3-dimensional neuroanatomic visual software that precisely visualizes the location of the DBS electrode in the subthalamic nucleus (STN). The objective of this paper is to compare the duration and clinical effects of traditional trial and error versus GUIDE-assisted DBS programming in 10 patients with PD treated with STN DBS. Methods: For each patient, neurostimulation parameters were selected with GUIDE to create a stimulation field encompassing the dorsal part of the STN. On programming day, each patient was assessed with both traditional and GUIDE approaches using a crossover design. For GUIDE-assisted sessions, the patients were programmed directly with the DBS settings obtained with the stimulated field model, and if necessary, parameters were adjusted to achieve optimal clinical response. Clinical improvement was assessed with Unified Parkinson's Disease Rating Scale scores for limb bradykinesia, tremor, and rigidity. Results: In 7 patients, DBS settings obtained with GUIDE led to suboptimal clinical improvement and mild adjustments were required. After these adjustments, the magnitude of clinical improvement with the 2 approaches was comparable (P = 0.8219). Programming time with GUIDE was significantly shorter than with the traditional programming approach (P < 0.0001). Conclusions: Visualization of stimulation fields with GUIDE provides useful information to achieve a clinical improvement comparable with that obtained with the traditional trial and error approach, but with shorter and more efficient programming sessions.

BACKGROUND Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been explored as a target to treat axial motor symptoms of advanced Parkinson disease (PD). The aim of this study was to consider relative effects of bilateral subthalamic nucleus (STN) and PPN DBS on both initiation and inhibition of saccades in advanced PD. METHODS Five patients with advanced PD performed 2 different oculomotor tasks off stimulation, with bilateral STN DBS, with bilateral PPN DBS, and with simultaneous bilateral STN and PPN DBS. The first task involved visually guided saccades, and the second task involved antisaccades (ASs). Saccadic latency, accuracy, and velocity were recorded for both the visually guided saccade and AS tasks, and prosaccades were measured for the AS task alone. Control subjects included patients with advanced PD without DBS, age-matched healthy subjects, and young healthy subjects (n = 12 in each group). RESULTS Simultaneous bilateral STN and PPN DBS produced the greatest improvement in mean latencies, velocities, and accuracies for visually guided saccades and ASs compared with DBS off (P < 0.001). Bilateral STN and PPN DBS caused a significant additional improvement compared with STN DBS alone by reducing the number of prosaccades (P < 0.01). CONCLUSIONS It is known that the frontal lobe is involved in saccadic inhibition during AS tasks. Hence, our novel finding of an improvement in the AS task suggests an ascending, frontally mediated effect of PPN DBS. This implies that there may be PPN-to-frontal lobe connections that may partly explain the benefits of PPN DBS in axial motor function.

Introduction: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. Results: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03). Conclusion: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.

Introduction: Magnetic Resonance guided Focused UltraSound (MRgFUS) is an emerging technique that utilizes multiple high-energy low-frequency ultrasound beams generated from a multi-element transducer focused onto a single site to cause thermal ablation of the target tissue. The ExAblate Neuro 4000 system is the leading MRgFUS brain system, performing targeted thermal ablation on specific nuclei in the brain. Its precision targeting opens up new and exciting possibilities for future treatments of a wide range of neurological diseases. Areas covered: This article aims to introduce the non-expert reader (clinician and non-clinicians) to the role of the ExAblate Neuro 4000 System in brain MRgFUS. The current clinical uses of the ExAblate system in the brain are explored with a particular focus on Essential Tremor, where internationally there is most experience, this includes reference to current literature. The safety and efficacy of MRgFUS treatments are explored and the challenges the ExAblate system must overcome to balance these juxtaposed outcomes.Expert opinion: We describe the hopes for future clinical uses of the ExAblate Neuro 4000 system to treat neurological disease and consider further advancements in MRgFUS transducer technology that may open up new exciting frontiers within the brain.

ObjectiveThe mechanisms contributing to the pathogenesis of tremor and/or dysmetria in multiple sclerosis (MS) are poorly understood. Abnormal oscillations within the olivo-cerebello-thalamo-cortical networks are believed to play an important part in tremor aetiology, but could also contribute to intention dysmetria due to disruptions in motor timing. Conversely, delayed central motor conduction times are a common feature of ataxias, but could also contribute to the expression of dysmetria in MS. This study examined the roles of central conduction delays in the manifestation of tremor and/or dysmetria in MS.MethodsTwenty-three individuals with MS participated: 8 with no movement disorder, 6 with tremor, 4 with pure dysmetria and 5 with both tremor and dysmetria. Median nerve somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) over the motor cortex and cervical spine, stretch reflexes were used assess sensory and motor conduction times.ResultsCentral, but not peripheral, sensory conductions time were significantly delayed in participants with dysmetria, regardless of the presence of tremor. Similarly, the TMS evoked muscles responses and the long-latency component of stretch reflexes were significantly delayed in those with dysmetria, but not pure tremor.ConclusionDysmetria in MS is associated with delays in central conduction of sensory or motor pathways, or both, likely leading to disruption of muscle activation timing and terminal oscillations that contribute to dysmetria.SignificanceThe presence of dysmetria in MS is associated with decreased conduction velocities in central sensory and/or motor pathways likely reflects greater demyelination of these axons compared to those with no movement disorder or pure tremor.

BackgroundMR-guided focused ultrasound (MRgFUS) is an effective treatment for essential tremor (ET). However, the optimal intracranial target sites remain to be determined.ObjectiveTo assess MRgFUS induced sequential lesions in (anterior-VIM/VOP nuclei) the thalamus and then posterior subthalamic area (PSA) performed during the same procedure for alleviating ET.Methods14 patients had unilateral MRgFUS lesions placed in anterior-VIM/VOP then PSA. Bain-Findley Spirals were collected during MRgFUS from the treated arm (BFS-TA) and throughout the study from the treated (BFS-TA) and non-treated (BFS-NTA) arms and scored by blinded assessors. Although, the primary outcome was change in the BFS-TA from baseline to 12 months we have highlighted the 24 month data.Secondary outcomes included the Clinical Rating Scale for Tremor (CRST), Quality of Life for ET (QUEST) and PHQ-9 depression scores.ResultsThe mean improvement in the BFS-TA from baseline to 24 months was 41.1% (pMean improvements at 24 month follow-up in the CRST-parts A, B and C were 60.7%, 30.4% and 65.6% respectively and 37.8% in QUEST-tremor score (all pConclusionUnilateral anterior-VIM/VOP and PSA MRgFUS significantly diminished contralateral arm tremor with improvements in arm function, tremor related disability and quality of life, with an acceptable adverse event profile.

The Consensus Statement on the Classification of Tremors, from the Task Force of the International Parkinson's and Movement Disorder Society was published in 2018 in response to advances in the understanding of essential tremor (ET), tremor associated with dystonia and other monosymptomatic and indeterminate tremors. This was a revision of the previous 1998 Consensus Statement. A number of problems arise from this classification and, in this manuscript, we highlight several of these. These problems relate to the definition of tremor, the definition of ET, the proposal of the term 'essential tremor plus', issues related to orthostatic tremor (OT) including the proposal of the term 'orthostatic tremor plus', and the absence of a hierarchy of terms used to classify tremor. Among the proposals we make is that the definition of tremor should acknowledge that tremor is a symptom, ET should be redefined, severity is an important characteristic for classifying and diagnosing tremor, the terms 'essential tremor plus' and 'orthostatic tremor plus' should be abandoned, and classification of tremor requires rules for creating a hierarchy of terminology. "This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh".

Objective:To investigate the relationship between hypothalamic D3 dopamine receptor availability and severity of sleep problems in Parkinson disease (PD).Methods:Twelve patients were assessed with PET and the high-affinity dopamine D3 receptor radioligand [11C]-propyl-hexahydro-naphtho-oxazin ([11C]-PHNO). Severity of sleep problems was rated with appropriate subitems of the Unified Parkinson's Disease Rating Scale part I (patient questionnaire) and the Epworth Sleepiness Scale.Results:We found that lower dopamine D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of excessive daytime sleepiness but not with problems of falling asleep or insomnia.Conclusion:In our cohort of patients with PD, the occurrence of excessive daytime sleepiness was linked to reductions in hypothalamic dopamine D3 receptor availability. If these preliminary findings are confirmed in larger cohorts of patients with polysomnographic characterization, selective pharmacologic modulation of the dopaminergic D3 system could be used to increase daytime alertness in patients with PD.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Tremor is a rhythmic involuntary oscillatory movement of a body part, most commonly affecting the hands and arms but other body parts can also be affected including the legs, head, jaw, chin, palate, voice, and trunk. This chapter covers the differential diagnosis of tremor, the approach to diagnosis (including key diagnostic tests), therapies, and prognosis.

Background This article proposes an International Parkinson and Movement Disorder Society (MDS)-UPDRS tremor-based scale and describes its measurement properties, with a view to developing an improved scale for assessing tremor in Parkinson's disease (PD). Methods This was a cross-sectional, multicenter study of 435 PD patients. Rasch analysis was performed on the 11 MDS-UPDRS tremor items. Construct validity, precision, and test-retest reliability were also analyzed. Results After some modifications, which included removal of an item owing to redundancy, the obtained MDS-UPDRS tremor scale showed moderate reliability, unidimensionality, absence of differential item functioning, satisfactory convergent validity with medication, and better precision than the raw sum score. However, the scale displayed a floor effect and a need for more items measuring lower levels of tremor. Conclusions The MDS-UPDRS tremor scale provides linear scores that can be used to assess tremor in PD in a valid, reliable way. The scale might benefit from modifications and studies that analyze its responsiveness. © 2015 International Parkinson and Movement Disorder Society

The Movement Disorder Society established a task force to review rating scales for the assessment of tremor. Screening instruments used in identifying patients with tremor were also reviewed. Seven tremor severity scales, six activities of daily living (ADL)/disability scales, four quality-of-life scales, and five screening instruments were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and sensitivity to change were reviewed for each scale; and each scale was classified as recommended, suggested or listed based on whether 3, 2, or 1 of the following criteria were met: (1) used in the assessment of tremor (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no). Five tremor severity scales (the Fahn-Tolosa-Marin Tremor Rating Scale, the Bain and Findley Clinical Tremor Rating Scale, the Bain and Findley Spirography Scale, the Washington Heights-Inwood Genetic Study of Essential Tremor Rating Scale, and the Tremor Research Group Essential Tremor Rating Assessment Scale), one ADL/disability scale (the Bain and Findley Tremor ADL Scale), one quality-of-life scale (the Quality of Life in Essential Tremor Questionnaire), and one screening instrument (the Washington Heights-Inwood Genetic Study of Essential Tremor Rating Scale, version 1) are recommended using these criteria. However, all scales need a more comprehensive analysis of sensitivity to change in order to judge their utility in clinical trials and individual patient assessments. The task force recommends that further work with existing recommended scales be performed as opposed to the development of new tremor scales. (c) 2013 International Parkinson and Movement Disorder Society.

Despite that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favored intervention for patients with medically intractable dystonia, the pathophysiological mechanisms of dystonia are largely unclear. In eight patients with primary dystonia who were treated with bilateral chronic pallidal stimulation, we correlated symptom-related electromyogram (EMG) activity of the most affected muscles with the local field potentials (LFPs) recorded from the globus pallidus electrodes. In 5 dystonic patients with mobile involuntary movements, rhythmic EMG bursts in the contralateral muscles were coherent with the oscillations in the pallidal LFPs at the burst frequency. In contrast, no significant coherence was seen between EMG and LFPs either for the sustained activity separated out from the compound EMGs in those 5 cases, or in the EMGs in 3 other cases without mobile involuntary movements and rhythmic EMG bursts. In comparison with the resting condition, in both active and passive movements, significant modulation in the GPi LFPs was seen in the range of 8-16 Hz. The finding of significant coherence between GPi oscillations and rhythmic EMG bursts but not sustained tonic EMG activity suggests that the synchronized pallidal activity may be directly related to the rhythmic involuntary movements. In contrast, the sustained hypertonic muscle activity may be represented by less synchronized activity in the pallidum. Thus, the pallidum may play different roles in generating different components of the dystonic symptom complex.

With the rapid increase in provision of deep brain stimulation for Parkinson's disease, the efficacy of pallidotomy in symptom alleviation appears to be increasingly ignored. We demonstrate that lesional surgery is effective with benefit over a significant period of time with very significant societal cost savings. Such studies are essential for future planning of services so that maximum numbers of patients can benefit from surgery, both lesional and neuromodulation, as deemed appropriate.

Objective To differentiate physiological from harmonic components in coherence analysis of the tremor-related neural and muscular signals by comparing power, cross-power and coherence spectra. Methods Influences of waveform, burst-width and additional noise on generating harmonic peaks in the power, cross-power and coherence spectra were studied using simulated signals. The local field potentials (LFPs) of the subthalamic nucleus (STN) and the EMGs of the contralateral forearm muscles in PD patients with rest tremor were analysed. Results (1) Waveform had significant effect on generating harmonics; (2) noise significantly decreased the coherence values in a frequency-dependent fashion; and (3) cross-spectrum showed high resistance to harmonics. Among six examples of paired LFP–EMG signals, significant coherence appeared at the tremor frequency only, both the tremor and double tremor frequencies and the double-tremor frequency only. Conclusions In coherence analysis of neural and muscular signals, distortion in waveform generates significant harmonic peaks in the coherence spectra and the coherence values of both physiological and harmonic components are modulated by extra noise or non-tremor related activity. Significance The physiological or harmonic nature of a coherence peak at the double tremor frequency may be differentiated when the coherence spectra are compared with the power and in particular the cross-power spectra.

The effect of stereotactic lesional surgery for the treatment of tremor in multiple sclerosis was examined in a prospective case-controlled study. Surgery was not undertaken in 33 patients (72% of 46 cases referred for stereotactic surgery), two of whom died within 4 months of referral. Twenty-four multiple sclerosis patients were included in the study; 13 underwent surgery and were matched against 11 controls on the basis of age, sex, expanded disability system scores (EDSS) and disease duration. Assessments were carried out at baseline/preoperatively, and then 3 and 12 months later; these included accelerometric and clinical ratings of tremor, spirography, handwriting, a finger-tapping test, nine-hole peg test, tremor-related disability, general neurological examination, Barthel Activities of Daily Living (ADL) Index of general disability, EDSS, a 0-4 ataxia scale, Mini-Mental State (MMS) examination, speech and swallowing assessments and grip strength. Postoperative MRI scans demonstrated that tremor could be attenuated by lesions centred on the thalamus in seven cases, on the zona incerta in five cases and in the subthalamic nucleus in one case. Two patients developed hemiparesis and in two cases epilepsy recurred. Two surgical patients and one control patient died between the 3 and 6 months assessments. Both groups had a significant deterioration in EDSS but not Barthel ADL Index scores at 1 year, but the difference between the groups was not significant. Similarly, no differences between the groups' rates of deterioration of speech or swallowing or MMS were found. Significant improvements in contralateral upper limb postural (P2) and kinetic tremors, spiral scores and head tremor were detected at 3 and 12 months after surgery (but not handwriting or nine-hole peg test performance). Tremor-related disability and finger-tapping speed were also significantly better 12 months after surgery, the latter having significantly worsened for the control group. A 3 Hz 'filter' for postural (P2) upper limb tremor was detected by accelerometry/spectral analysis above which tremor was always abolished and at or below which some residual tremor invariably remained. Criteria for selecting multiple sclerosis patients for this form of surgery are discussed.

The assessment of the extent of involvement of the distal and proximal joints in a complex arm tremor is important clinically, as tremor generated around the distal and proximal arm joints can be differentially alleviated by surgical intervention to the thalamic and subthalamic targets, respectively. We observed that the tremor present in spiral drawings shows a diagonal directional preference. We hypothesized that the directional preference of tremor within spiral drawings could be related to the involvement of different arm joints. In this study, we tested this hypothesis by: (1) studying simulated tremulous drawings performed by healthy subjects with the joints selectively restrained; (2) recording surface EMGs from the forearm extensor and deltoid muscles during drawing; and (3) mathematical modelling the kinematics of the arm in 2D drawings. Our data showed that a "main diagonal" axis of orientation of the tremor along the orientation of the forearm indicates a predominantly proximal tremor driven by the shoulder, and a "cross diagonal" axis of orientation of tremor (i.e. perpendicular to the forearm) indicates that the tremor is predominantly distal and driven by the elbow or wrist. We conclude that the spiral drawing task can be used as an objective and quantitative method for differentiating the involvement of the proximal and distal arm joints in complex arm tremors.

Lesioning or chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius results in abolition of tremor in the contralateral limbs in Parkinson's disease (PD) and also in essential tremor. Recently, chronic DBS of the subthalamic nucleus has also proved to be very effective in reducing contralateral limb tremor in PD. These targets have been less effective in controlling the complex limb tremor often seen in multiple sclerosis (MS). Consequently, other targets have been sought in cases of MS with tremor. We describe a patient with MS with disabling proximal and distal involuntary arm movements in whom we were able to obtain sustained control of contralateral arm tremor and achieve functional improvement of the affected arm by chronic DBS of the region of the zona incerta. We also highlight the important role played by local field potentials recorded from the brain, with simultaneous recording of corresponding EMGs, in target localisation. © 2002 Harcourt Publishers Ltd.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

Tremor in multiple sclerosis is considered to be a persistent and progressive sign. We describe five patients with multiple sclerosis in whom upper limb tremor severity gradually decreased over a period of several years after deep brain stimulation. In every case this attenuation of tremor was accompanied by increasing pyramidal weakness in the relevant upper limb. In two patients this attenuation of tremor remained after stimulation was permanently switched off. In one other patient, where upper limb strength remained normal, tremor severity gradually worsened in spite of continuing stimulation. There was a highly significant difference (p = 0.0007) between the changes in intention tremor severities when the arms with increasing pyramidal weakness (n = 9) were compared to those in which normal strength was retained throughout follow-up period (n = 3); intention tremor decreased in the former and increased in the latter by means of -3.66 and +4.0 points of a 0-10 tremor scale respectively. There was also a significant correlation (0.699; p = 0.0359) between decreasing upper limb strength and decreasing intention tremor severity for the upper limbs of patients that had undergone contralateral DBS.

Deep brain stimulation (DBS) is a successful surgical therapy used to treat the disabling symptoms of movement disorders such as Parkinson’s disease. It involves the chronic stimulation of disorder-specific nuclei. However, the mechanisms that lead to clinical improvements remain unclear. Consequently, this slows the optimization of present-day DBS therapy and hinders its future development and application. We used a computational model to calculate the distribution of electric potential induced by DBS and study the effect of stimulation on the spiking activity of a subthalamic nucleus (STN) projection neuron. We previously showed that such a model can reveal detailed spatial effects of stimulation in the vicinity of the electrode. However, this multi-compartmental STN neuron model can fire in either a burst or tonic mode and, in this study, we hypothesized that the firing mode of the cell will have a major impact on the DBS-induced effects. Our simulations showed that the bursting model exhibits behaviour observed in studies of high-frequency stimulation of STN neurons, such as the presence of a silent period at stimulation offset and frequency-dependent stimulation effects. We validated the model by simulating the clinical parameter settings used for a Parkinsonian patient and showed, in a patient-specific anatomical model, that the region of affected tissue is consistent with clinical observations of the optimal DBS site. Our results demonstrated a method of quantitatively assessing neuronal changes induced by DBS, to maximize therapeutic benefit and minimize unwanted side effects.

We investigated whether turning problems in Parkinson's disease may be the result of abnormal horizontal multisegmental angular coordination. Ten mildly affected patients and controls stood upright and voluntarily reoriented eyes and body to illuminated targets of eccentricities up to ±180 degrees. The effects of target location, visibility, and predictability on movement parameters were evaluated. Patients' latencies were normal. Control subjects foveated large eccentricity targets with a single gaze shift in approximately 30% of predictable trials. Patients rarely did so (10% of predictable trials) because of reduced head-in-space and trunk velocity. This resulted in massive foveation delays in patients-an average of half a second for displacements of 180 degrees. The covariation of eye, head, and trunk rotations was quantified statistically by means of principal components analysis. In both groups, the combined movement was initially stereotyped and two principal components accounted for nearly all data variance-the original three mechanical degrees of freedom (i.e., eye-head-trunk) are reduced to two kinematic degrees of freedom. However, in patients, the eye contributed more, and the head and trunk less, to the gaze shift than in control subjects. Although the eye-to-foot turning synergy is preserved in early-stage parkinsonism, quantitative differences are prominent, particularly a larger ocular (and smaller head-trunk) contribution in patients. Turning problems in Parkinson's disease do not result from inability to assemble multisegmental movements, as patients' ability to control numerous degrees of freedom is preserved. However, trunk bradykinesia reduces the frequency of single-step gaze shifts, thus prolonging target acquisition time. Preserved eye motion compensates for trunk slowness.

Background: Previous studies have compared the accuracy of spiral analysis in distinguishing essential tremor (ET) from PD. In this study, we have used this technique to distinguish cases of tremulous PD (TDPD) (N = 24) from tremulous parkinsonian subjects without evidence of dopaminergic deficit (N = 41). Methods: All patients were characterized on clinical and 123I-N-ω-fluoro-propyl-2s-carbomethoxy-3s-(4-iodophenyl) nortropane ([123I] FP-CIT) SPECT scan data, which were concordant in every case. All analyses were carried out by observers blinded to the clinical details and supplied with just the spiral drawings, from which tremor severity (TS), 3-turn spiral diameter (3TD), and spiral density (SD) were measured. Results: The spirals drawn by TDPD cases had significantly smaller 3TD (P = 0.029) and greater SD (P = 0.0082) than those with normal FP-CIT scans. There was no significant difference in the TS between the two groups (P = 0.11). The sensitivity and specificity of TS were 62.5% and 65.0%, 3TD were 75% and 56.7%, and SD were 30.4% and 82.5%, respectively, in predicting the correct classification. Further analyses combining these factors into pairs, showed that the respective sensitivities and specificities of (1) TS × 3TD were 75.0% and 40.0%, (2) TS/SD were 56% and 70.0%, and (3) 3TD/SD were 87.0% and 40.0%. Discussion: There are significant differences in the 3TD and SD of spirals drawn by tremulous patients with normal versus abnormal FP-CIT scans. Spiral analysis may have some clinical value in helping to distinguish tremulous parkinsonian patients with normal presynaptic dopaminergic imaging from tremulous PD patients, providing results similar to those reported for expert movement disorder neurologists using standardized videotaped examinations. © 2011 Movement Disorder Society

Patients suffering from Parkinson's disease (PD) will typically experience a range of motor and nonmotor symptoms during the course of their illness, each of which will affect a particular individual to varying degrees. However, patients' perceptions of troublesome symptoms often differ from the clinician's view, and these discrepancies can hamper effective management of PD. In this study, we have assessed 265 consecutive PD patients by asking them to rank their three most troublesome symptoms in the last 6 months, so to gain further insight from the impact of illness on patients' quality of life. Patients were divided into early ( /=6 years) from symptom onset. The division at 6 years was based on the mean time from symptom onset to the development of motor complications. In the early PD group, the 5 most prevalent complaints (ranked in descending order) are slowness, tremor, stiffness, pain, and loss of smell and/or taste. In the advanced PD group, fluctuating response to their medication (most common: wearing-off phenomenon followed by dyskinesia), mood changes, drooling, sleep problems (most common: middle and late night insomnia followed by daytime sleepiness), and tremor were the top 5. Our findings provide further evidence for the diversity of experience in PD and suggest that as the disease advances the most troublesome issues that patients perceive are the lack of response to medication and the nonmotor aspects of the disease, highlighting the importance of assessment and patient-centered management in the follow-up of these patients.

Deep brain stimulation (DBS) is an effective surgical treatment used to alleviate the symptoms of neurological disorders, most commonly movement disorders. However, the mechanism of how the applied stimulus pulses interact with the surrounding neuronal elements is not yet clearly understood, slowing progress and development of this promising therapeutic technology. To extend previous approaches of using isolated, myelinated axon models used to estimate the effect of DBS, we propose that taking into account entire neurons will reveal stimulation induced effects overlooked by previous studies. We compared the DBS induced volume of tissue activated (VTA) using arrays of whole cell models of subthalamic nucleus (STN) excitatory neurons consisting of a cell body and an anatomically accurate dendritic tree, to the common models of axon arrays. Our results demonstrate that STN neurons have a higher excitation threshold than axons, as stimulus amplitudes 10 times as large elicit a VTA range a fifth of the distance from the electrode surface. However, the STN neurons do show a change in background firing rate in response to stimulation, even when they are classified as sub-threshold by the VTA definition. Furthermore the whole neuron models are sensitive to regions of high current density, as the distribution of firing is centred on the electrode contact edges These results demonstrate the importance of accurate neuron models for fully appreciating the spatial effects of DBS on the immediate surrounding brain volume within small distances of the electrode, which are overlooked by previous models of isolated axons and individual neurons.

The role for neuroimaging in the management of patients with tremor is gradually increasing, particularly with respect to stereotactic neurosurgery and deep brain stimulation where less than 2-mm tolerance is required for accurate electrode placement. The routine use of single photon emission CT technology to image the nigrostriatal dopaminergic system is proving helpful in distinguishing essential and dystonic tremors from neurodegenerative forms of parkinsonism and in improving our understanding of the pathophysiology of rarer tremors.

We measured reaction times during a stop-signal task while patients with Parkinson's disease were on and off unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). While reaction times to a “go” stimulus improved, there was no change in reaction times to the “stop” stimulus (SSRTs). However, changes in SSRTs induced by DBS were highly dependent on baseline SSRTs (measured off stimulation), with the greatest improvements being achieved by those with particularly slow reaction times. We therefore selected only those patients whose baseline SSRTs were within the limits of a control sample (N = 10). In this group, SSRTs became slower when DBS was on. This finding suggests a role for the STN in response inhibition, which can be interrupted by DBS, observable only when more general improvements in Parkinson's function are minimised. We also compared the effects of unilateral left and right sided stimulation. We found a greater increase in SSRTs after DBS of the left STN.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Ciguatera is a form of poisoning that occurs after eating tropical and subtropical ciguatoxic fish. The ciguatoxins are a family of heat stable, lipid soluble cyclic polyether compounds that bind to and open voltage-sensitive Na(+) channels at resting membrane potential, resulting in neural hyperexcitability, as well as swelling of the nodes of Ranvier. The authors describe a 45-year-old man who developed acute gastrointestinal symptoms in Antigua soon after eating red snapper and grouper, potentially "ciguatoxic fish". This was followed by neurological symptoms 24-48 hours later, including temperature reversal (paradoxical dysaesthesia), intense pruritus and increased nociception as a result of a small fibre peripheral neuropathy. The patient's symptoms and small fibre neuropathy improved over a period of 10 months.

For almost one hundred years, the exact role of human brain structures controlling the cardiorespiratory response to exercise (‘central command’) has been sought. Animal experiments and functional imaging studies have provided clues, but the underlying electrophysiological activity of proposed relevant neural sites in humans has never been measured. In this study, local field potentials were directly recorded in a number of ‘deep’ brain nuclei during an exercise task designed to dissociate the exercise from peripheral feedback mechanisms. Several patient groups had electrodes implanted sterotaxically for the treatment of movement disorder or chronic pain. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Anticipation of exercise resulted in increases in heart rate, blood pressure and ventilation. The greatest neural changes were found in the periaqueductal grey area (PAG) where anticipation of exercise was accompanied by an increase of 43% in the power of the 12–25 Hz frequency band (P = 0.007). Exercise increased the activity by 87% compared to rest (P = 0.006). Changes were also seen in the 60–90 Hz band when anticipation or exercise increased power by 32% (P = 0.006) and 109% (P < 0.001), respectively. In the subthalamic nucleus there was a reduction in the power of the beta frequency during both anticipation (7.6 ± 0.68% P = 0.001) and exercise (17.3 ± 0.96% P < 0.001), whereas an increase was seen with exercise only at higher frequencies (93 ± 1.8% P = 0.007). No significant changes were seen in the globus pallidus during anticipation of exercise. We provide direct electrophysiological evidence highlighting the PAG as an important subcortical area in the neural circuitry of the cardiorespiratory response to exercise, since stimulation of this structure is known to alter blood pressure in awake humans.

Tremor, a rhythmical involuntary oscillatory movement, is the most common movement disorder to afflict man. It is classified on both phenomenonological and aetiological grounds and can be measured using clinical rating scales or physiological techniques. Investigation of tremor is guided by the clinical scenario but where appropriate may include neurophysiological tests, imaging the nigro-striatal dopaminergic system with SPECT or PET, cerebral MR imaging and also genetic testing. Treatment of tremor depends on the severity and cause of tremor and includes medical therapy and stereotactic surgery including deep brain stimulation.

Deep brain stimulation (DBS) is a surgical treatment used for a number of movement disorders, involving the chronic implantation of electrodes into disorder specific regions in the brain. For essential tremor (ET) the targeted brain structure is the ventralis intermedius (ViM) nucleus of the thalamus. ET is a common movement disorder, which affects as many as 4 out of 100 adults over 40 years of age. While the cause of this disorder is unknown, DBS works well, achieving up to 90% improvement in symptoms [1,2]. However, the mechanisms by which the therapeutic effect is obtained are not fully understood, which in turn slows the process of finding the optimal parameter settings which suppress symptoms and minimise unwanted side effects. DBS additionally provides an opportunity to record the pathological neural activity via intraoperative recordings from the implanted electrodes in the form of local field potentials (LFP) whilst simultaneously recording muscle activity from the affected limbs (EMG). Here, we present data which shows peaks in the EMG-LFP cross spectra within the tremor frequency band (4-12 Hz). To understand the effects of a DBS input on such pathological neural activity, we adopt a computational modelling approach using a population representation of the network hypothesised to underlie ET, namely cortex, cerebellum and thalamus (Figure 1 A) and is based on previous descriptions of the essential tremor network [3]. The model is implemented using the Wilson-Cowan approach [4], and was simulated by exploring the parameter space to uncover regions which produced oscillatory thalamic activity and we found that the network exhibited oscillatory behaviour within the tremor frequency range (Figure 1B). By applying an input to the thalamus simulating the effect of DBS (e.g. 150Hz square pulse), we found that these oscillations are suppressed. Therefore, this study shows that the dynamics of the ET network are able to support oscillations at the tremor frequency. Furthermore, the application of a DBS-like input to such a network disrupts synchronous activity, which could explain one mechanism by which DBS achieves therapeutic benefit. Figure 1 The structure of the model is shown schematically (A), and consists of the cortex, the ViM nucleus and the reticular nucleus (nRT) of the thalamus, and the deep cerebellar nuclei (DCN). The baseline oscillatory activity of the thalamic population is within ...

Background and purpose Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) reduces the number of falls in patients with Parkinson's disease (PD). It was hypothesized that enhanced sensory processing contributes to this PPN‐mediated gait improvement. Methods Four PD patients (and eight matched controls) with implanted bilateral PPN and subthalamic nucleus DBS electrodes were assessed on postural (with/without vision) and vestibular perceptual threshold tasks. Results Pedunculopontine nucleus ON stimulation (compared to OFF) lowered vestibular perceptual thresholds but there was a disproportionate increase in the normal sway increase on going from light to dark. Conclusions The disproportionate increased sway with PPN stimulation in the dark may paradoxically improve balance function since mechanoreceptor signals rapidly adapt to continuous pressure stimulation from postural akinesia. Additionally, the PPN‐mediated vestibular signal enhancement also improves the monitoring of postural sway. Overall, PPN stimulation may improve sensory feedback and hence balance performance.

The periaqueductal grey matter is known to play a role in cardiovascular control in animals. Cardiovascular responses to electrical stimulation of the periventricular/periaqueductal grey matter were measured in 15 awake human study participants following implantation of deep brain stimulating electrodes for treatment of chronic pain. We found that stimulation of the ventral periventricular/periaqueductal grey matter caused a mean reduction in systolic blood pressure of 14.2+/-3.6 mmHg in seven patients and stimulation of the dorsal periventricular/periaqueductal grey matter caused a mean increase of 16.7+/-5.9 mmHg in six patients. A comparison between ventral and dorsal electrodes demonstrated significant differences (P

This study examined the relative anti-Parkinson's disease (PD) tremor potencies of pergolide and pramipexole in people with PD, using a 3-month double-blind cross-over design. Patients were randomly assigned to receive either pergolide and then pramipexole (n = 9) or vice versa (n = 8). The dose of the respective dopamine agonist was increased according to a titration schedule up to a maximum 1.5 mg t.d.s., with cross-over at 10 weeks. Assessments were performed at baseline, 4, 8 and 12 weeks. The primary outcome measures were the differences in the clinical (rest and postural) tremor scores on pergolide versus pramipexole. Seventeen PD patients (11 females and six males) with a mean age 68.4 years (range: 55-84 years) and a mean disease duration of 3.9 years (range: 2 months to 13 years) participated in the study. Twelve of the patients were taking other anti-parkinsonian medications. Two patients dropped out of the study whilst on pergolide. Fifteen of 16 patients were able to cross-over from one dopamine agonist to the other, without major retitration. There were no significant differences between the effects of the two drugs on the primary outcome measures, suggesting that the anti-PD tremor efficacies of dopaminergic medications are not dependent on differential affinities for dopamine receptor types.

We compared the antitremor effect of pramipexole, pergolide, or placebo in Parkinson's disease (PD). A double-blind, randomly controlled, parallel protocol was deployed to examine the effects of placebo, pergolide, and pramipexole [doses escalated to 1.5 mg three times daily (t.i.d.) over 3 months] on a compound Tremor Index (TI) and Unified Parkinson's Disease Rating Scale (UPDRS) part III. Thirty PD patients (19 men, 11 women; mean age 69 years, range 54-80 years; mean disease duration 3.9 years, range, 0.5-10 years) participated in the study, with 10 patients in each arm. Six subjects failed to complete the study (4 on pergolide and 2 on placebo). Analysis of covariance demonstrated strong evidence for a treatment effect on both TI and UPDRS III. There was no significant difference between the active treatments on either TI or UPDRS III. Both pergolide and pramipexole were significantly better than placebo. The results indicate that pergolide and pramipexole (1.5 mg t.i.d.) have similar anti-PD tremor and UPDRS III actions that are significantly superior to placebo. Patients on pergolide were more likely to drop out because of adverse events than those on pramipexole.

In the current era of functional surgery for movement disorders, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favoured intervention for patients with dystonia. Here we report our results in 20 patients with medically intractable dystonia treated with GPi stimulation. The series comprised 14 patients with generalized dystonia and six with spasmodic torticollis. Although comparisons were limited by differences in their respective neurological rating scales, chronic DBS clearly benefited both patient groups. Data conveying the rate of change in neurological function following intervention are also presented, demonstrating the gradual but progressive and sustained nature of improvement following stimulation of the GPi in dystonic patients.

The selection of patients with movement disorders for deep brain stimulation is becoming a common neurological and neurosurgical task. Deep brain stimulation is suitable for different forms of tremor, which can often not be treated with medication. This suitability applies for essential tremor, monosymptomatic tremor at rest, cerebellar or multiple sclerosis tremor, Holmes' tremor, primary writing tremor or tremor in neuropathies. The appropriate selection of patients is critical for the outcome of surgical relief of tremors. Considering the risks of any stereotactic intervention, the following must apply: (1) motor symptoms lead to a relevant disability in activities of daily living, despite optimal medical treatment; (2) biological age of the patient; (3) neurosurgical contraindications; (4) the patient is neither demented nor severely depressed. If these conditions are fulfilled, the individual chances of improvement of the target symptoms need to be checked, based on the following guidelines: (1) the kind of tremor, (2) the natural course of the tremor, (3) the chances for medical treatment in a particular patient, (4) the outcome of surgery in a specific condition, (5) the individual risks for a patient to suffer from complications. The outcome of surgery for tremor depends on the clinical type and distribution. Distal limb tremors are easier to treat than proximal limb tremors. Intention tremor is more difficult to treat than rest or postural tremor. The indication for surgical treatment depends on the analysis of the individual risk-benefit ratio, which also has to take into account the patients' social, professional, and familial background. The patient needs to be well informed about his individual risk-benefit ratio and of alternative treatments, before undergoing stereotactic surgery.

We assessed the impact of surgical treatment of Parkinson's disease on quality of life using generic quality of life instruments and utility scores. The Medical Outcomes Study short form health survey SF-36 and Parkinson's Disease Questionnaire PDQ-39 were used before and 3-6 months after surgery to assess quality of life, and the results were converted into utility valuations. Ninety-seven patients were studied; 33 underwent unilateral thalamotomy, 33 unilateral pallidotomy, 20 bilateral pallidotomy, six subthalamic nucleus (STN) lesions, four mixed lesions, and in one case bilateral STN stimulation. All dimensions of the SF-36 except role mental and mental health showed statistically significant improvement following surgery. The PDQ-39 recorded significant improvements in the mobility, stigma, and bodily discomfort dimensions. The rating scale and time trade-off scales showed statistically significant gains in utility of 8% and 3%, respectively. Gains were particularly marked in the bilateral pallidotomy group. Differences in patient characteristics and selection made direct comparisons between procedures unreliable. Quality of life in patients with advanced Parkinson's disease is amenable to measurement; such measurement provides tentative evidence of significant gains in quality of life following some neurosurgical procedures.

Three patients with spasmodic torticollis (ST) obtained substantial benefit from bilateral globus pallidus internus (GPi) stimulation. Progressive improvement in ST occurred over several months but residual cervical dystonia remained. These results corroborate those obtained by Krauss et al. on three patients with ST.