Illusions of Self-Motion during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor.

OBJECTIVE: Brain networks mediating vestibular perception of self-motion overlap with those mediating balance. A systematic mapping of vestibular perceptual pathways in the thalamus may reveal new brain modulation targets for improving balance in neurological conditions. METHODS: Here, we systematically report how magnetic resonance-guided focused ultrasound surgery of the nucleus ventralis intermedius of the thalamus commonly evokes transient patient-reported illusions of self-motion. In 46 consecutive patients, we linked the descriptions of self-motion to sonication power and 3-dimensional (3D) coordinates of sonication targets. Target coordinates were normalized using a standard atlas, and a 3D model of the nucleus ventralis intermedius and adjacent structures was created to link sonication target to the illusion. RESULTS: A total of 63% of patients reported illusions of self-motion, which were more likely with increased sonication power and with targets located more inferiorly along the rostrocaudal axis. Higher power and more inferiorly targeted sonications increased the likelihood of experiencing illusions of self-motion by 4 and 2 times, respectively (odds ratios = 4.03 for power, 2.098 for location). INTERPRETATION: The phenomenon of magnetic vestibular stimulation is the most plausible explanation for these illusions of self-motion. Temporary unilateral modulation of vestibular pathways (via magnetic resonance-guided focused ultrasound) unveils the central adaptation to the magnetic field-induced peripheral vestibular bias, leading to an explicable illusion of motion. Consequently, systematic mapping of vestibular perceptual pathways via magnetic resonance-guided focused ultrasound may reveal new intracerebral targets for improving balance in neurological conditions. ANN NEUROL 2024;96:121-132.

The evolution of ventral intermediate nucleus targeting in MRI-guided focused ultrasound thalamotomy for essential tremor: an international multi-center evaluation.

Background: The ventral intermediate nucleus (VIM) is the premiere target in magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for tremor; however, there is no consensus on the optimal coordinates for ablation. This study aims to ascertain the various international VIM targeting approaches (VIM-TA) and any evolution in practice. Methods: International MRgFUS centers were invited to share VIM-TAs in 2019 and 2021. Analyses of any modification in practice and of anatomical markers and/or tractography in use were carried out. Each VIM-TA was mapped in relation to the mid-commissural point onto a 3D thalamic nucleus model created from the Schaltenbrand-Wahren atlas. Results: Of the 39 centers invited, 30 participated across the study period, providing VIM-TAs from 26 centers in 2019 and 23 in 2021. The results are reported as percentages of the number of participating centers in that year. In 2019 and 2021, respectively, 96.2% (n = 25) and 95.7% (n = 22) of centers based their targeting on anatomical landmarks rather than tractography. Increased adoption of tractography in clinical practice and/or for research was noted, changing from 34.6% to 78.3%. There was a statistically significant change in VIM-TAs in the superior-inferior plane across the study period; the percentage of VIM-TAs positioned 2 mm above the intercommissural line (ICL) increased from 16.0% in 2019 to 40.9% in 2021 (WRST, p < 0.05). This position is mapped at the center of VIM on the 3D thalamic model created based on the Schaltenbrand-Wahren atlas. In contrast, the VIM-TA medial-lateral and anterior-posterior positions remained stable. In 2022, 63.3% of participating centers provided the rationale for their VIM-TAs and key demographics. The centers were more likely to target 2 mm above the ICL if they had increased experience (more than 100 treatments) and/or if they were North American. Conclusion: Across the study period, FUS centers have evolved their VIM targeting superiorly to target the center of the VIM (2 mm above the ICL) and increased the adoption of tractography to aid VIM localization. This phenomenon is observed across autonomous international centers, suggesting that it is a more optimal site for FUS thalamotomy in tremors.

'Am I fixed, am I better now?': undergoing MR-guided focused ultrasound for essential tremor: an interpretative phenomenological analysis.

Introduction: Essential tremor (ET) is characterised by postural and intentional tremor typically affecting the upper limbs, which can negatively impact functionality and quality of life. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is a novel and promising non-invasive treatment for ET which offers instantaneous results. Methods: Using interpretative phenomenological analysis we explored the experience of undergoing MRgFUS in six ET patients as well as their experiences pre- and post-procedure. Results: One-time, retrospective semi-structured interviews were conducted and six themes emerged: Life pre-treatment: "It's everyday tasks that get you down" and "Most people who understand, they are okay. Some people aren't"; MRgFUS: Treatment day: "Going into the unknown" and "There's no way I was going to press that button"; and Life post-treatment: "One is good. Two is better" and "Am I fixed, am I better now?." Discussion: The findings point to a significant period of adjustment associated with living with ET and the effects of undergoing ET MRgFUS treatment. As ET progressed, participants struggled to cope with increasing symptoms and had to develop coping strategies to manage life with ET. The procedure itself was perceived as strange and extraordinary and despite some immediate adverse effects participants were determined to go through with it. Post procedure, all participants reported tremor suppression which was life changing. While some participants still felt burdened by ET, others expressed it took them a while to psychologically adjust to what essentially was their new body. This study has highlighted the need for patients to be supported at all stages of their ET journey.

The cost-effectiveness of unilateral magnetic resonance-guided focused ultrasound in comparison with unilateral deep brain stimulation for the treatment of medically refractory essential tremor in England.

OBJECTIVES: This study aims to ascertain the cost-effectiveness of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of medically refractory Essential Tremor (mrET) in England. Essential Tremor (ET) is the most common movement disorder affecting approximately 1 million in the UK causing considerable societal impact affecting patients, carers and the wider healthservice. Medical treatment has mixed efficacy, with approximately 25-55% of ET medication refractory. Deep brain stimulation (DBS) is a proven neurosurgical treatment; however, the risks of surgery and anaesthesia mean some patients are ineligible. MRgFUS is an emerging noninvasive technique that causes tremor suppression by thermal ablation of tremor-sensitive brain tissue. Several international clinical trials have demonstrated MRgFUS is safe and clinically effective; however, to-date no cost-effectiveness study has been performed in Europe. METHODS: A Markov model was used to assess two subpopulations of mrET - those eligible and those ineligible for neurosurgery - in the context specific to England and its healthcare system. For those eligible for neurosurgery, MRgFUS was compared to DBS, the current standard treatment. For those ineligible for neurosurgery, MRgFUS was compared to treatment with medication alone. The model calculated the Incremental cost-effectiveness ratio (ICER) with appropriate sensitivity and scenario analyses. RESULTS: For those eligible for neurosurgery: In the model base case, the MRgFUS was economically dominant compared to DBS; MRgFUS was less costly (£19,779 vs £62,348) and more effective generating 0.03 additional quality-adjusted life-years (QALYs) per patient (3.71 vs 3.68) over the 5-year time horizon.For those ineligible for neurosurgery: In the model base case, MRgFUS cost over £16,000 per patient more than medication alone (£19,779 vs £62,348) but yielded 0.77 additional QALYs per patient(3.71 vs 2.95), producing an incremental cost-effectiveness ratio (ICER) of £20,851 per QALY. This ICER of £20,851 per QALY falls within the National Institute for Clinical Excellence's (NICE) willingness to pay threshold (WTP) of 20,000-30,000 demonstrating the cost-effectiveness profile of MRgFUS. CONCLUSION: This study demonstrates the favourable cost-effectiveness profile of MRgFUS for the treatment of mrET in England; in both patients suitable and not suitable for neurosurgery. ADVANCES IN KNOWLEDGE: The introduction of MRgFUS as a widely available ET treatment in UK is currently undergoing the necessary stages of regulatory approval. As the first European study, these favourable cost-effectiveness outcomes (notably the model base case ICER falling within NICE's WTP) can provide a basis for future commissioning of brain MRgFUS treatments in the UK, Europe and globally.

The Conundrum of Dystonia in Essential Tremor Patients: How does One Classify these Cases?

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.

Problems and controversies in tremor classification.

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".

Double lesion MRgFUS treatment of essential tremor targeting the thalamus and posterior sub-thalamic area: preliminary study with two year follow-up.

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 < 0.001) whilst BFS-NTA worsened by 8.8% (p < 0.001). Intra-operative BFS scores from the targeted arm showed a mean 27.9% (p < 0.001) decrease after anterior-VIM/VOP ablation and an additional 30.1% (p < 0.001) reduction from post anterior-VIM/VOP to post-PSA ablation. Mean 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 p < 0.05). Unilateral tremor severity scores decreased in the treated arm (UETTS-TA) 72.9% (p = 0.001) and non-treated arm (UETTS-NTA) 30.5% (p = 0.003). At 24 months residual adverse effects were slight unsteadiness (n = 1) and mild hemi-chorea (n = 1). CONCLUSION: Unilateral 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.

Tremor and Dysmetria in Multiple Sclerosis: A Neurophysiological Study.

Objective: The 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. Methods: Twenty-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. Results: Central, 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. Conclusion: Dysmetria 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. Significance: The 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.

Device profile of exAblate Neuro 4000, the leading system for brain magnetic resonance guided focused ultrasound technology: an overview of its safety and efficacy in the treatment of medically refractory essential tremor.

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.

Using bioanalytical tools to detect and track organic micropollutants in the Ganga River near two major cities.

Major rivers in India are subject to ongoing impacts from urban drain discharges, most of which contain high levels of domestic and industrial wastewater and stormwater. The aim of the present study was to determine the levels of bioactive organic micropollutants at the discharge points of major urban drains in comparison to upstream and downstream sites. To achieve this, we employed a panel of in vitro bioanalytical tools to quantify estrogenic, androgenic, progestogenic, glucocorticoid and peroxisome proliferator-like activity in water extracts collected from two Indian cities in the Ganga Basin. Cytotoxicity of the water extracts in a human-derived cell line and the potential to cause oxidative stress in a fish cell line were also investigated. We found high levels of activity for all endpoints in samples directly receiving urban drain discharge and low levels at sites upstream from drain discharges. Estrogenicity was detected at levels equivalent to 10 ng/L 17ß-estradiol, representing a high likelihood of biomarker effects in fish. Sites located downstream from drain discharges exhibited low to intermediate activity in all assays. This study demonstrates the importance of managing urban drain discharges and the utility of applying bioanalytical tools to assess water quality.

A Population Model of Deep Brain Stimulation in Movement Disorders From Circuits to Cells.

For more than 30 years, deep brain stimulation (DBS) has been used to target the symptoms of a number of neurological disorders and in particular movement disorders such as Parkinson's disease (PD) and essential tremor (ET). It is known that the loss of dopaminergic neurons in the substantia nigra leads to PD, while the exact impact of this on the brain dynamics is not fully understood, the presence of beta-band oscillatory activity is thought to be pathological. The cause of ET, however, remains uncertain, however pathological oscillations in the thalamocortical-cerebellar network have been linked to tremor. Both of these movement disorders are treated with DBS, which entails the surgical implantation of electrodes into a patient's brain. While DBS leads to an improvement in symptoms for many patients, the mechanisms underlying this improvement is not clearly understood, and computational modeling has been used extensively to improve this. Many of the models used to study DBS and its effect on the human brain have mainly utilized single neuron and single axon biophysical models. We have previously shown in separate models however, that the use of population models can shed much light on the mechanisms of the underlying pathological neural activity in PD and ET in turn, and on the mechanisms underlying DBS. Together, this work suggested that the dynamics of the cerebellar-basal ganglia thalamocortical network support oscillations at frequency range relevant to movement disorders. Here, we propose a new combined model of this network and present new results that demonstrate that both Parkinsonian oscillations in the beta band and oscillations in the tremor frequency range arise from the dynamics of such a network. We find regions in the parameter space demonstrating the different dynamics and go on to examine the transition from one oscillatory regime to another as well as the impact of DBS on these different types of pathological activity. This work will allow us to better understand the changes in brain activity induced by DBS, and allow us to optimize this clinical therapy, particularly in terms of target selection and parameter setting.

Traditional Trial and Error versus Neuroanatomic 3-Dimensional Image Software-Assisted Deep Brain Stimulation Programming in Patients with Parkinson Disease.

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.

Pedunculopontine and Subthalamic Nucleus Stimulation Effect on Saccades in Parkinson Disease.

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.

The Toxicogenome of Hyalella azteca: A Model for Sediment Ecotoxicology and Evolutionary Toxicology.

Hyalella azteca is a cryptic species complex of epibenthic amphipods of interest to ecotoxicology and evolutionary biology. It is the primary crustacean used in North America for sediment toxicity testing and an emerging model for molecular ecotoxicology. To provide molecular resources for sediment quality assessments and evolutionary studies, we sequenced, assembled, and annotated the genome of the H. azteca U.S. Lab Strain. The genome quality and completeness is comparable with other ecotoxicological model species. Through targeted investigation and use of gene expression data sets of H. azteca exposed to pesticides, metals, and other emerging contaminants, we annotated and characterized the major gene families involved in sequestration, detoxification, oxidative stress, and toxicant response. Our results revealed gene loss related to light sensing, but a large expansion in chemoreceptors, likely underlying sensory shifts necessary in their low light habitats. Gene family expansions were also noted for cytochrome P450 genes, cuticle proteins, ion transporters, and include recent gene duplications in the metal sequestration protein, metallothionein. Mapping of differentially expressed transcripts to the genome significantly increased the ability to functionally annotate toxicant responsive genes. The H. azteca genome will greatly facilitate development of genomic tools for environmental assessments and promote an understanding of how evolution shapes toxicological pathways with implications for environmental and human health.

In vitro nuclear receptor inhibition and cytotoxicity of hydraulic fracturing chemicals and their binary mixtures.

The widespread use of hydraulic fracturing (HF) in oil and gas extraction operations has led to concern over environmental risks posed by chemicals used in HF fluids. Here we employed a suite of stable luciferase reporter gene assays to investigate the potential for selected HF chemicals or geogenics to activate or antagonise nuclear receptor signalling. We screened three biocides (bronopol [BP], glutaraldehyde [GA], and tetrakis(hydroxymethyl)phosphonium sulfate [THPS]), a surfactant (2-butoxyethanol), a friction reducer (polyacrylamide), and a coal seam geogenic (o-cresol) for their potential to act as agonists or antagonists of the estrogen receptor, androgen receptor, progesterone receptor (PR), glucocorticoid receptor or peroxisome proliferator-activated receptor gamma (PPARγ). None of the chemicals induced luciferase activity in any of assays used in the study. In antagonistic mode, BP, GA and THPS caused reductions in luciferase activity in the reporter assays at higher concentrations (50-100 µM), while at low concentrations (2-10 µM) GA and THPS enhanced luciferase activity in some assays relative to controls. None of the other tested chemicals exhibited antagonism in the selected assays. In most cases, altered receptor signalling only occurred at concentrations exhibiting cytotoxicity. However, PPARγ activity, and to a lesser extent PR activity, were inhibited by THPS at sub-cytotoxic concentrations. The majority of binary combinations tested exhibited significantly less-than-additive cytotoxicity, and none of the combinations exhibited synergistic cytotoxicity. In summary, the results of the present study indicate that the selected chemicals are not likely to function as direct agonists of the nuclear receptors tested, and only one chemical, THPS was an apparent partial antagonist of two nuclear receptors.

Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society.

BACKGROUND: Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary. OBJECTIVES: Convene an international panel of experienced investigators to review the definition and classification of tremor. METHODS: Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: "tremor", "tremor disorders", "essential tremor", "dystonic tremor", and "classification" limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews. RESULTS: Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1-clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2-etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes. CONCLUSIONS: This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society.

Environmental pollution affects molecular and biochemical responses during gonadal maturation of Astyanax fasciatus (Teleostei: Characiformes: Characidae).

Endocrine disrupting compounds (EDCs) have the potential to alter fish reproduction at various levels of organization. The aim of this study was to assess the impact of a natural environment with heavily anthropogenic influence on the physiological processes involved in reproduction in the freshwater fish lambari (Astyanax fasciatus) using different biomarkers. Adult males and females were collected in different seasons from two distinct sites in the same watershed: Ponte Nova Reservoir (PN) considered a pristine or small anthropogenic influence reference point; and Billings Reservoir (Bil), subjected to a large anthropogenic impact. Biological indices, such as hepatosomatic index and gonadosomatic index (GSI), gonadal histomorphology, fecundity, and biomarkers such as plasma levels of estradiol (E2) as well as hepatic gene expression of its alfa nuclear receptor (ERα), were analyzed. Hepatic vitellogenin (VTG) gene expression was evaluated in both sexes, as an indicator of xenoestrogen exposure. Females collected at PN presented a typical annual variation reflected in GSI, whereas for those sampled at Bil the index did not change through the seasons. The higher concentration of E2 in males collected at Bil during spring/2013, together with the detection of VTG gene expression, suggest the presence of EDCs in the water. These EDCs may have also influenced fecundity of females from Bil, which was higher during winter and spring/2013. Gene expression of ERα and ovarian morphology did not differ between fish from both sites. Water conditions from Bil reservoir impacted by anthropic activity clearly interfered mainly with biomarkers of biological effect such as plasma E2 levels and absolute and relative fecundity, but also altered biomarkers of exposure as VTG gene expression. These facts support the notion that waterborne EDCs are capable of causing estrogenic activity in A. fasciatus.

Biased numerical cognition impairs economic decision-making in Parkinson's disease.

OBJECTIVE: Previous findings suggest a context-dependent bihemispheric allocation of numerical magnitude. Accordingly, we predicted that lateralized motor symptoms in Parkinson's disease (PD), which reflect hemispheric asymmetries, would induce systematic lateralized biases in numerical cognition and have a subsequent influence on decision-making. METHODS: In 20 PD patients and matched healthy controls we assessed numerical cognition using a number-pair bisection and random number generation task. Decision-making was assessed using both the dictator game and a validated questionnaire. RESULTS: PD patients with predominant right-sided motor symptoms exhibited pathological biases toward smaller numerical magnitudes and formulated less favorable prosocial choices during a neuroeconomics task (i.e., dictator game). Conversely, patients with left-sided motor symptoms exhibited pathological biases toward larger numerical magnitudes and formulated more generous prosocial choices. Our account of context-dependent hemispheric allocation of numerical magnitude in PD was corroborated by applying our data to a pre-existing computational model and observing significant concordance. Notably, both numerical biasing and impaired decision-making were correlated with motor asymmetry. INTERPRETATION: Accordingly, motor asymmetry and functional impairment of cognitive processes in PD can be functionally intertwined. To conclude, our findings demonstrate context-dependent hemispheric allocation and encoding of numerical magnitude in PD and how biases in numerical magnitude allocation in Parkinsonian patients can correspondingly impair economic decision-making.

A Network Model of Local Field Potential Activity in Essential Tremor and the Impact of Deep Brain Stimulation.

Essential tremor (ET), a movement disorder characterised by an uncontrollable shaking of the affected body part, is often professed to be the most common movement disorder, affecting up to one percent of adults over 40 years of age. The precise cause of ET is unknown, however pathological oscillations of a network of a number of brain regions are implicated in leading to the disorder. Deep brain stimulation (DBS) is a clinical therapy used to alleviate the symptoms of a number of movement disorders. DBS involves the surgical implantation of electrodes into specific nuclei in the brain. For ET the targeted region is the ventralis intermedius (Vim) nucleus of the thalamus. Though DBS is effective for treating ET, the mechanism through which the therapeutic effect is obtained is not understood. To elucidate the mechanism underlying the pathological network activity and the effect of DBS on such activity, we take a computational modelling approach combined with electrophysiological data. The pathological brain activity was recorded intra-operatively via implanted DBS electrodes, whilst simultaneously recording muscle activity of the affected limbs. We modelled the network hypothesised to underlie ET using the Wilson-Cowan approach. The modelled network exhibited oscillatory behaviour within the tremor frequency range, as did our electrophysiological data. By applying a DBS-like input we suppressed these oscillations. This study shows that the dynamics of the ET network support oscillations at the tremor frequency and the application of a DBS-like input disrupts this activity, which could be one mechanism underlying the therapeutic benefit.

Effects of antiandrogenic progestins, chlormadinone and cyproterone acetate, and the estrogen 17α-ethinylestradiol (EE2), and their mixtures: Transactivation with human and rainbowfish hormone receptors and transcriptional effects in zebrafish (Danio rerio) eleuthero-embryos.

Synthetic progestins act as endocrine disrupters in fish but their risk to the environment is not sufficiently known. Here, we focused on an unexplored antiandrogenic progestin, chlormadinone acetate (CMA), and the antiandrogenic progestin cyproterone acetate (CPA). The aim was to evaluate whether their in vitro interaction with human and rainbowfish (Melanotaenia fluviatilis) sex hormone receptors is similar. Furthermore, we investigated their activity in zebrafish (Danio rerio) eleuthero-embryos. First, we studied agonistic and antagonistic activities of CMA, CPA, and 17α-ethinylestradiol (EE2), in recombinant yeast expressing either the human progesterone (PGR), androgen (AR), or estrogen receptor. The same compounds were also investigated in vitro in a stable transfection cell system expressing rainbowfish nuclear steroid receptors. For human receptors, both progestins exhibited progestogenic, androgenic and antiestrogenic activity with no antiandrogenic or estrogenic activity. In contrast, interactions with rainbowfish receptors showed no progestogenic, but antiandrogenic, antiglucocorticoid, and some antiestrogenic activity. Thus, interaction with and transactivation of human and rainbowfish PGR and AR were distinctly different. Second, we analyzed transcriptional alterations in zebrafish eleuthero-embryos at 96 and 144h post fertilization after exposure to CPA, CMA, EE2, and binary mixtures of CMA and CPA with EE2, mimicking the use in oral contraceptives. CMA led to slight down-regulation of the ar transcript, while CPA down-regulated ar and pgr transcripts. EE2 exposure resulted in significant transcriptional alterations of several genes, including esr1, pgr, vtg1, cyp19b, and gonadotropins (fshb, lhb). The mixture activity of CMA and EE2 followed the independent action model, while CPA and EE2 mixtures showed additive action in transcriptional alterations. Third, we analyzed the interactions of binary mixtures of CMA and CPA, and of CMA and EE2 for their joint activity in vitro and in eleuthero-embryos. Both mixtures behaved according to the concentration addition model in their in vitro interaction with human and rainbowfish receptors, often showing antagonism. In zebrafish eleuthero-embryos, binary mixtures of CMA and EE2 showed the same expression patterns as EE2 alone, indicating an independent action in vivo. Our study demonstrates that CMA and CPA interact distinctly with human and rainbowfish receptors, suggesting that activities of these and possibly additional environmental steroids determined with yeast expressing human receptors cannot simply be translated to fish. The lack of agonistic activities of both progestins to rainbowfish PGR and AR is the probable reason for the low activity found in zebrafish eleuthero-embryos.