The pathophysiology of essential tremor (ET) is not clearly understood but is thought to involve multiple brain regions. The purpose of this study was to describe in greater detail head tremor in ET and to investigate the possible relationship between head and hand tremor. Ten ET subjects were recruited (1 male, 9 female) and compared to three control subjects (1 male, 2 female). Head and hand tremors were recorded simultaneously with surface electromyography (EMG) of the wrist extensors and various neck muscles, laser displacement sensors (hand tremor), a load cell (hand tremor) and an accelerometer (head tremor). While seated, subjects performed four tasks: 1) constant force (10% maximum) wrist extensions (with and without visual feedback); maintenance of the hands in a horizontal posture against gravity while 2) seated upright in a chair, 3) seated in a reclined chair (20° backward, head not supported); and 4) seated upright in a chair and producing steady submaximal hip adduction forces. Head tremor spectral peaks were found between 3.5 and 7 Hz in neck muscle EMG and the accelerometer signal. Wrist tremor (EMG and kinematic data) was slightly higher in frequency with a range of 4 -10 Hz. Of the ten ET subjects recruited for this study, 60% (n = 6) demonstrated significant levels of coherence (p < 0.05) in at least one neck-wrist muscle comparison at the fundamental frequency of their tremor. The results demonstrated an obvious bias of the trapezius descendens (TD) muscles over the more axial neck muscles to demonstrate significant coherence with the extensor carpi radialis (ECR) muscles. Of the six neck muscles investigated, the SPLs and the SCMs were commonly driven at the same frequencies (change in frequency < 0.5), although this seldom resulted in coherence. There is indication that the oscillatory activity driving more distal muscles is different from that in the SPL and the SCM. Due to the multifunctional nature of the TD, it may be the recipient of two descending neural commands. These commands may each be of a different oscillatory frequency originating from different central oscillators. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2008-10-29 10:03:22.354

<div> <p> Essential tremor (ET) is one of the most common movement disorders, characterized by kinetic tremor in the upper extremities with additional cranial tremor often present in the neck or jaw. While it is well established that ET is primarily a cerebellar disorder, recent investigations have shown more widespread pathological effects throughout the brain. Furthermore, the neurodegenerative nature of ET is still disputed and requires additional investigation. Additionally, the link between ET and Parkinson’s disease (PD) is of special interest, as it can be challenging to clinically differentiate these diseases.</p> <p> While post-mortem studies have helped to further the pathological understanding of these diseases, non-invasive in-vivo techniques allow for more accurate diagnosis in the clinic. With a more accurate diagnosis comes a more targeted treatment, and hopefully an improved remediation of the disease. My thesis seeks to further investigate the neurodegenerative hypothesis of ET as well as explore magnetic resonance imaging (MRI) biomarkers for potential differences in ET and PD. </p> <p>These aims will be accomplished in three steps. First, gray matter volume loss in the cerebellum was investigated using voxel-based morphometry and the Spatially Unbiased Infra-Tentorial Template (SUIT) atlas on a lobule level. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls. The cerebellum was segmented into 34 lobules using the SUIT atlas. Percent gray matter was calculated as the ratio of lobule gray matter volume divided by total lobule volume. No significant differences were identified between ET cases and controls in any of the 34 lobules. However, nine lobules had significantly decreased percent gray matter in ET cases with head or jaw tremor (n = 27) compared to controls. Also, 11 lobules had significantly decreased percent gray matter in ET cases with voice tremor (n = 22) compared to controls. This result confirms, with increased regional accuracy, gray matter volume loss in the cerebellum of ET cases.</p> <p>Second, gray matter volume loss beyond the cerebellum, in the cerebrum, was investigated using voxel-based morphometry. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls for processing in SPM12. The processing steps of SPM12 were updated to include a higher resolution atlas and set of tissue probability maps to optimize the segmentation and normalization of each subject image. After segmentation, normalization, and smoothing, a voxel-wise statistical analysis was performed to identify clusters of gray matter volume in ET cases compared to controls. ET cases showed decreased gray matter volume in the bilateral superior temporal region and the anterior and posterior cingulate cortex. These results, in combination with previous work provide support of wide-spread neurodegeneration in ET using optimized methodology.</p> <p>Third, we applied T2* mapping to determine relative iron concentrations in the substantia nigra (SN) and globus pallidus (GP) in ET and PD cases. Three separate studies were independently investigated to validate the reproducibility and detectability of group differences using T2* mapping. The first study (ET study) acquired T2* maps on 21 ET cases and 12 matched controls, the second study (PD study 1) acquired T2* maps on 10 PD cases and 7 controls, and the third study (PD study 2) acquired T2* maps on 21 PD cases and 17 controls. Regions of interest (ROIs) were manually placed in the SN and GP for each subject and group differences were calculated independently for each study using a linear regression model with age and sex as covariates. A significant decrease in T2* was found in PD study 1 and PD study 2 in the right SN in PD cases compared to their respective controls, indicating increased iron deposition. No significant difference was found in the ET group compared to their respective controls in the SN. No significant differences were found in any of the three studies in the GP. These results provide evidence for a difference in brain iron regulation in the pathology of ET and PD.</p> <p>Together, these thesis aims provide additional evidence in support of the neurodegenerative hypothesis of ET using updated methodology and present a quantitative imaging difference between groups of ET and PD cases. </p> </div> <br>

Background The last decade has witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders, especially advanced Parkinson’s disease (PD), essential tremor (ET) and dystonia. Ablative lesions such as thalamotomy and pallidotomy have been gradually replaced by the technique of chronic deep brain stimulation (DBS) applied to targets in the basal ganglia and thalamus, and assumed to be more lenient to the brain than stereotactic radiofrequency lesions. Since the aim of functional neurosurgery is to alleviate symptoms of these chronic, progressive, non-fatal diseases, and to improve life quality of the patients, it is imperative that the surgical procedures remain safe and do not result in complications mitigating any anticipated positive effect of the surgery on the symptoms of the disease. Aim The aim of this thesis is to evaluate, compare and analyse the safety of various surgical procedures used to treat patients with movement disorders, and to document side effects and complications both peri operatively and in a long term follow-up. Further to compare the effects of pallidotomy and pallidal DBS, and to evaluate the longterm efficacy of Vim-DBS. Method 256 consecutive surgical procedures, 129 DBS and 127 stereotactic lesions, were reviewed with respect to complications in 197 treated patients. In a series of 119 patients operated on with DBS during a 10 year period, the occurrence of hardware related complications (infection, breakage, erosion etc) was documented and analysed. Additionally, the interference of external magnetic field with the stimulation was documented. In one patient operated on with subthalamic nucleus DBS, a highly unusual and unexpected psychiatric side effect was carefully analysed. In 5 patients operated on with both methods (lesion and DBS) on each hemisphere, respectively, the effect and side effects of each method were compared. The long term effect and side effects of thalamic DBS was analysed in a series of patients with ET followed for 7 years. Results There were no deaths and few severe neurological complications in this material. Unilateral ablative lesions in the pallidum were well tolerated by patients with advanced PD, while for tremor, thalamic DBS was much safer than thalamotomy, even if its effect on certain aspects of tremor could show some decrease of efficacy over time. Some of the side effects of lesioning are transient while most but not all side effects of DBS are reversible. Hardware-related complications were not uncommon especially in the early “learning curve” period, and the DBS technique, being a life-long therapy, will necessitate a life long follow up of patients. Provided safety protocols are followed and provided patient’s and carer’s education and awareness, external electromagnetic interference should not constitute a risk for patients with DBS. PD patients undergoing STN DBS should be carefully selected to avoid psychiatric or cognitive side effects, due to this brain target´s proximity to, and involvment in, non-motor associative and limbic circuitry. Conclusions In terms of mortality and morbidity, modern stereotactic neurosurgery for movement disorders, both ablation and DBS, is a safe procedure even in advanced stages of disease. Symptoms of PD, ET and dystonia can be alleviated mainly with DBS and even unilaterally with pallidal lesions, at the expense of, in most cases, minor side-effects.

Although tremor is the most common movement disorder, there exist few effective tremor-suppressing devices, in part because the characteristics of tremor throughout the upper limb are unknown. To clarify, optimally suppressing tremor requires a knowledge of the mechanical origin, propagation, and distribution of tremor throughout the upper limb. Here we present the first systematic investigation of how tremor propagates between the shoulder, elbow, forearm, and wrist. We simulated tremor propagation using a linear, time-invariant, lumped-parameter musculoskeletal model relating joint torques and the resulting joint displacements. The model focused on the seven main degrees of freedom (DOF) from the shoulder to the wrist and included coupled joint inertia, damping, and stiffness. We deliberately implemented a simple model to focus first on the most basic effects. Simulating tremorogenic joint torque as a sinusoidal input, we used the model to establish fundamental principles describing how input parameters (torque location and frequency) and joint impedance (inertia, damping, and stiffness) affect tremor propagation. We expect that the methods and principles presented here will serve as the groundwork for future refining studies to understand the origin, propagation, and distribution of tremor throughout the upper limb in order to enable the future development of optimal tremor-suppressing devices.

Background: The birth of stereotactic functional neurosurgery in 1947 was to a great extent dependent on the development of ventriculography. The last decades have witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders. Initially, these procedures were largely based on the same imaging technique that had been used since the birth of this technique, and that is still used in some centers. The introduction of new imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provided new potentials, but also new challenges for accurate identification and visualisation of the targets in the basal ganglia and the thalamus with an urge to thoroughly evaluate and optimize the stereotactic targeting technique, as well as evaluate accurately in stereotactic space the location and extent of stereotactic Radiofrequency (RF) lesions and the position of deep brain stimulation (DBS) electrodes. Aims: To study the differences between CT and MRI regarding indirect atlas coordinates in thalamic and pallidal procedures and to evaluate and validate visualisation of the pallidum and the subthalamic nucleus in view of direct targeting irrespective of atlas-derived coordinates. Furthermore, to evaluate the contribution of RF parameters on the size of stereotactic lesions, as well as the impact of size and location on clinical outcome. Method: The coordinates in relation to the landmarks of the 3rd ventricle of the targets in the pallidum and ventrolateral thalamus were compared between CT and MRI in 34 patients. In another 48 patients direct visualization  of the pallidum was evaluated and compared to indirect atlas based targeting. The possibility and versatility of visualizing the Subthalamic Nucleus (STN) on short acquisition MRI were evaluated in a multicentre study, and the use of alternative landmarks in identification of the STN was demonstrated in another study. In 46 patients CT and MRI were compared regarding the volume of the visible RF lesions. The volume was analysed with regard to coagulation parameters, and the location and size of the lesions were further evaluated concerning the clinical outcome. Results:Minor deviations were seen between MRI and  CT coordinates of brain targets. The rostro-caudal direction of these deviations were such that they would be easily accounted for during surgery, why MRI can obviate the need for CT in these procedures. MRI using a proton density sequence provided detailed images of the pallidal structures, which demonstrated considerable inter-individual variations in relation to the landmarks of the 3rd ventricle. By using a direct visualization of the target, each patient will act as his or her own atlas, avoiding the uncertainties of atlas-based targeting. The STN could be visualized on various brands of MRI machines in 8 centers in 6 countries with good discrimination and with a short acquisition time, allowing direct visual targeting. The same scanning technique could be used for postoperative localization of the implanted electrodes. In cases where the lateral and inferior borders of the STN cannot be easily distinguished on MRI the Sukeroku sign and the dent internal-capsule-sign signs might be useful. The volume of a stereotactic RF lesion could be as accurately assessed by CT as by MRI. The lesion´s size was most strongly influenced by the temperature used for coagulation. The lesions´ volumes were however rather scattered and difficult to predict in the individual patient based solely on the coagulation parameters. For thalamotomy, the results on tremor was not related to the lesion´s volume. For pallidotomy, larger and more posterior-ventral lesions had better effect on akinesia while effects on tremor and dyskinesias were not related to size or location of the lesions. Conclusions: The minor deviations of MRI from CT coordinates can be accounted for during surgery, why MRI can obviate the need of CT in these procedures. Direct visualized targeting on MRI of the pallidum is superior to atlas based targeting. The targets in the pallidum and the STN, as well as the location of the electrodes, can be well visualized with short acquisition MRI. When borders of the STN are poorly defined on MRI the Sukeroku sign and the dent internal-capsule-sign signs proved to be useful. The volumes of RF lesions can be accurately assessed by both stereotactic thin slice CT and MRI. The size of these lesions is most strongly influenced by the temperature of coagulation, but difficult to predict in the individual patient based on the coagulation parameters. Within certain limits, there were no clear relationships between lesions´ volume and location and clinical effects of thalamotomies and pallidotomies.

Modulation of voice is a result of physiologic oscillation within one or more components of the vocal system including the breathing apparatus (i.e., pressure supply), the larynx (i.e. sound source), and the vocal tract (i.e., sound filter). These oscillations may be caused by pathological tremor associated with neurological disorders like essential tremor or by volitional production of vibrato in singers. Because the acoustical characteristics of voice modulation specific to each component of the vocal system and the effect of these characteristics on perception are not well-understood, it is difficult to assess individuals with vocal tremor and to determine the most effective interventions for reducing the perceptual severity of the disorder. The purpose of the present studies was to determine how the acoustical characteristics associated with laryngeal-based vocal tremor affect the perception of the magnitude of voice modulation, and to determine if adjustments could be made to the voice source and vocal tract filter to alter the acoustic output and reduce the perception of modulation. This research was carried out using both a computational model of speech production and trained singers producing vibrato to simulate laryngeal-based vocal tremor with different voice source characteristics (i.e., vocal fold length and degree of vocal fold adduction) and different vocal tract filter characteristics (i.e., vowel shapes). It was expected that, by making adjustments to the voice source and vocal tract filter that reduce the amplitude of the higher harmonics, the perception of magnitude of voice modulation would be reduced. The results of this study revealed that listeners' perception of the magnitude of modulation of voice was affected by the degree of vocal fold adduction and the vocal tract shape with the computational model, but only by the vocal quality (corresponding to the degree of vocal fold adduction) with the female singer. Based on regression analyses, listeners' judgments were predicted by modulation information in both low and high frequency bands. The findings from these studies indicate that production of a breathy vocal quality might be a useful compensatory strategy for reducing the perceptual severity of modulation of voice for individuals with tremor affecting the larynx.

Objectives: Determine the effect of contraction type and intensity, inertial loading, and visual feedback on various measures of hand tremor in subjects with essential tremor. Methods: Study 1. Twenty-three ET subjects and 22 controls held their hand in an outstretched position while supporting various submaximal loads (no-load, 5%, 15% and 25% 1-repetition maximum). Hand postural tremor and wrist extensor neuromuscular activity (EMG) were recorded. Study 2. Twenty-one ET subjects and 22 controls applied isometric wrist extension contractions with and without visual feedback. Various submaximal contraction intensities were evaluated (5%, 10%, 20% and 30% MVC). Force production and EMG were recorded. Study 3. Twenty-one ET subjects and 22 healthy controls performed slow wrist extension-flexion movements while supporting various submaximal loads (no-load, 5%, 15% and 25% 1-repetition maximum). Angular displacement and EMG were recorded. Results: Study 1. Inertial loading resulted in a reduction in postural tremor in ET subjects. The largest reduction in tremor amplitude occurred at the 15% load, which was associated with spectral separation of the mechanical reflex and central tremor component. Despite an increase in overall neuromuscular activity with inertial loading, EMG tremor power did not increase with loading. Study 2. Higher contraction intensities were associated with larger amplitude force fluctuations and greater EMG amplitudes. Tremor spectral power of force and EMG remained constant at all target intensities, resulting in a reduction in relative tremor power at higher contraction intensities. Visual feedback affected subjects in the control and ET groups similarly. Study 3. Subjects with more pronounced tremor spectral peaks had larger amplitude kinetic tremor, which was reduced with inertial loading. Despite an increase in overall neuromuscular activity with inertial loading, EMG tremor spectral power was only slightly increased with loading, which resulted in a large reduction in relative EMG tremor power. Conclusions: The effect of inertial loading on postural and kinetic tremor amplitude appears to be mediated in large part by its effect on the interaction between the mechanical reflex and central tremor components. The level of motor unit entrainment remains relatively constant in subjects with ET despite increasing contraction intensities. / Thesis (Ph.D, Rehabilitation Science) -- Queen's University, 2008-10-24 11:18:57.537

The work presented in this thesis investigates novel modalities to guide Transcranial Magnetic Resonance guided Focused Ultrasound (TcMRgFUS). TcMRgFUS is an emerging and promising non-invasive technique for the treatment of neurological disorders, such as essential tremor or Parkinsonian tremor. A novel Magnetic Resonance Acoustic Radiation Force Imaging (MRARFI) has been used to image the location of the ultrasonic beam produced by a preclinical prototype: an accelerated 2D spin-echo MR ARFI pulse sequence has been introduced to generate undistorted ultrasound-induced displacement maps in ex vivo veal brains with minimum energy deposition. We then investigated direct effects of the ultrasonic beam on brain activity by conducting in vivo ultrasonic neuromodulation, similarly to what is currently achieved with transcranial magnetic stimulation (TMS) but with the millimetric targeting capabilities of the ultrasound. Experiments have been first conducted in an anesthetized rat model to investigate the motor threshold. Numerical simulations have shown that the acoustic pattern in the rat head is affected by reverberations and that special care must be taken when relating acoustic parameters to neurostimulation effects, especially at a low frequency and for small animals. Finally, for the first time, we used low intensity FUS stimulation to causally modulate behavior in an awake nonhuman primate brain. We showed that the latency of an anti-saccade task was delayed significantly in the presence of ultrasonic beam focused in the Frontal Eye Field. Sham experiments did not show any significant change in the latencies.

Sammanfattning Bakgrund: Deep brain stimulation (DBS) i nucleus ventralis intermedius i thalamus (VIM) eller caudala zona incerta (cZi) ger goda effekter på tremorsymptomen för patienter med essentiell tremor. Patienterna som behandlats med DBS kan få bieffekter som i vissa fall leder till talpåverkan, så kallad stimuleringsinducerad dysartri. Huruvida det finns risk för bieffekter som drabbar röstens funktion hos patienter med essentiell tremor saknas studier kring men man vet att grundsjukdomen kan påverka rösten akustiskt samt att vissa patienter utvecklar rösttremor. Att drabbas av en bieffekt efter DBS kan ha en inverkan på hur patienten subjektivt upplever resultatet av behandlingen.     Mål: Att undersöka om patienter med essentiell tremor som genomgått DBS subjektivt upplever någon form av röst- eller talbesvär jämfört med en frisk, ålders- och könsmatchad kontrollgrupp.   Metod: I studien deltog sammanlagt 42 deltagare varav 21 tillhörde en patientgrupp med essentiell tremor som genomgått DBS i cZi och de övriga 21 tillhörde en frisk, ålders- och könsmatchad kontrollgrupp. Deltagarna i de båda grupperna fick fylla i två formulär, RHI som berör röstens funktion och SOFT som berör talets funktion. Deltagarna som tillhörde patientgruppen fick också svara på fem fördjupande frågor om deras subjektiva upplevelse. Den statistiska signifikanstestningen genomfördes med avseende på om det fanns en skillnad i självskattningen mellan de båda grupperna.   Resultat: Resultaten i denna studie visade att patienterna med essentiell tremor s0m är behandlade med DBS skattar en signifikant större del subjektiva svårigheter av sin egen röst- och talfunktion jämfört med den friska kontrollgruppen.   Slutsats: Resultaten visade att det på gruppnivå finns signifikant större andel upplevda svårigheter relaterade till tal- och röstfunktionen hos patienter med essentiell tremor behandlade med DBS jämfört med en frisk kontrollgrupp. Resultaten visar även en stor individuell variation av den subjektiva upplevelsen av tal och röstpåverkan vilket är viktig information att delge patienter som ska genomgå DBS. Ett preoperativt samtal med logoped för information om möjliga bieffekter vid DBS och hur detta kan påverka patienten subjektivt är nödvändigt. De patienter som subjektivt upplever besvär med talet eller rösten bör erbjudas kontakt med logoped. / Abstract Background: Deep brain stimulation (DBS) of ventralis intermedius nucleus of thalamus (VIM) or caudala zona incerta (cZi) have been shown to be efficient in supressing tremor symptoms in patients with essential tremor. Patients who has been treated with DBS may acquire certain side effects of which in some cases results in an impact on the patients speech, known as stimulation- induced dysarthria. There is a lack of studies that investigate if there is a risk of side effects that is affecting voice functioning in patients with essential tremor. Previous studies have claimed that the disease itself may have an effect on the voice acoustics and that some patients develop voice tremor. The occurrence of a side effect caused by DBS may have an impact on the patients subjective experience of the treatment result.   Aim: To investigate whether patients with essential tremor treated with DBS are subjectively experiencing any form of voice or speech disability compared to a healthy, age and sex matched control group.   Method: The study included 42 participants all together whereof 21 was part of a patient group with essential tremor treated with DBS in cZi and the other 21 participants was part of a healthy, age and sex matched control group. The participants of both groups filled out two different forms, VHI (RHI) which affects voice function and SOFT which affects speech function. The participants in the patient group also answered five profound questions about their subjective experience. The test of statistical significance was performed with regard of if a difference was to be found in the self-ratings between the two groups.   Results: The results of the study show that patients with essential tremor whom have been treated with DBS rates a significantly greater amount of subjective difficulties related to the voice and speech functioning compared to the healthy control group.   Conclusion: The results show that the DBS-treated patients with essential tremor experience a significantly greater amount of subjective difficulties related to voice and speech functioning compared to a healthy control group. The results also show a great individual variety in the subjective experience of speech and voice function which is important information to notify patients who are due to undergo DBS-treatment. A preoperative meeting with a speech and language pathologist to be informed of possible side effects caused by the DBS and in what ways this can effect the patient subjectively is required. Patients who postoperatively experience a negative effect on speech or voice functioning should be offered contact with a speech and language pathologist. / Tal- och rösteffekter av djup hjärnstimulering hos patienter med ärftlig tremor

The movement disorder essential tremor can be treated with deep brain stimulation (DBS), where electric current is delivered to deep brain structures through permanently implanted electrodes. In this study, brain activity during working memory performance was measured with functional magnetic resonance imaging in thirteen essential tremor patients with DBS in caudal Zona incerta, a diencephalic nucleus. With active stimulation less exertion of certain working memory areas was required to achieve the same level of performance in a manipulation and a maintenance-type working memory task. At the same time, a relatively higher activation was reached for the more demanding manipulation task. These results indicate that DBS can make the brains of tremor patients more efficient in working memory tasks, in accordance with the “efficiency hypothesis” proposed by Nyberg et al. (2014). / Rörelsestörningen essentiell tremor kan behandlas med djup hjärnstimulering (DBS), vid vilken elektrisk ström tillförs djupa hjärnstrukturer genom permanent inopererade elektroder. I den här studien mättes hjärnaktivering under arbetsminnesbelastning med funktionell magnetresonans-tomografi hos tretton essentiell tremor-patienter med DBS i kaudala Zona incerta, en kärna i mellanhjärnan. Med stimuleringen påslagen krävdes en lägre hjärnaktivering i arbetsminnes-relaterade områden för att nå samma resultat i två arbetsminnesuppgifter där den enda krävde manipulation och den andra enbart kvarhållande av information. Samtidigt kunde en relativt sett högre aktiveringsnivå uppnås för den mer krävande manipulationsuppgiften. De här resultaten tyder på att DBS kan göra tremorpatienters hjärna mer effektiv i arbetsminnesuppgifter, i enlighet med den “effektivitetshypotes” som lagts fram av Nyberg m fl (2014).