Endemic parkinsonism: clusters, biology and clinical features.

The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Tremor associated with similar structural networks in Parkinson's disease and essential tremor.

INTRODUCTION: Despite substantial clinical and pathophysiological differences, the characteristics of tremor in Parkinson's disease (PD) and essential tremor (ET) patients bear certain similarities. The presented study delineates tremor-related structural networks in these two disorders. METHODS: 42 non-advanced PD patients (18 tremor-dominant, 24 without substantial tremor), 17 ET, and 45 healthy controls underwent high-angular resolution diffusion-weighted imaging acquisition to reconstruct their structural motor connectomes as a proxy of the anatomical interconnections between motor network regions, implementing state-of-the-art globally optimised probabilistic tractography. RESULTS: When compared to healthy controls, ET patients exhibited higher structural connectivity in the cerebello-thalamo-cortical network. Interestingly, the comparison of tremor-dominant PD patients and PD patients without tremor yielded very similar results - higher structural connectivity in tremor-dominant PD sharing multiple nodes with the tremor network detected in ET, despite the generally lower structural connectivity between basal ganglia and frontal cortex in the whole PD group when compared to healthy controls. CONCLUSION: The higher structural connectivity of the cerebello-thalamo-cortical network seems to be the dominant tremor driver in both PD and ET. While it appears to be the only tremor-related network in ET, its combination with large scale hypoconnectivity in the frontal cortico-subcortical network in PD may explain different clinical features of tremor in these two disorders.

Infantile status epilepticus disrupts myelin development.

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.

Alterations in Sensorimotor and Mesiotemporal Cortices and Diffuse White Matter Changes in Primary Progressive Multiple Sclerosis Detected by Adiabatic Relaxometry.

Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced magnetic resonance imaging (MRI) protocols. Objective: The presented cross-sectional study evaluated the utility of four different MRI relaxation metrics and diffusion-weighted imaging in PPMS. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ in combination with diffusion-weighted parameters were acquired in 13 PPMS patients and 13 age- and sex-matched controls. Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, the sensorimotor cortex, and the cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus an indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols outperformed both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches, methods previously used in the MRI research of PPMS. Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical gray matter, cerebellar, and white matter alterations in PPMS invisible to other in vivo biomarkers.

Corrigendum: RAFF-4, Magnetization Transfer and Diffusion Tensor MRI of Lysophosphatidylcholine Induced Demyelination and Remyelination in Rats.

[This corrects the article DOI: 10.3389/fnins.2021.625167.].

Neurostimulation Methods in the Treatment of Depression: A Comparison of rTMS, tDCS, and Venlafaxine Using a Pooled Analysis of Two Studies.

BACKGROUND: There are no head-to-head studies comparing the antidepressant effect of transcranial direct current stimulation (tDCS) with repetitive transcranial magnetic stimulation (rTMS). This pooled analysis compared indirectly the antidepressant efficacy and acceptability of rTMS, tDCS, and the antidepressant venlafaxine (VNF) extended-release. METHODS: The analysis (n=117, both patients with treatment-resistant depression (TRD) and non-TRD were included) examined pooled data from two 4-week, single-centered, two-armed, double-blind, randomized studies (EUDRACT n. 2005-000826-22 and EUDRACT n. 2015-001639-19). The antidepressant efficacy of right-sided low-frequency rTMS (n=29) vs VNF (n=31) and left-sided anodal tDCS (n=29) vs VNF (n=28) was evaluated. The primary outcome was a change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to the treatment endpoint at week 4. The response was defined as a ≥50% reduction in the MADRS score and remission as the MADRS score ≤10 points, both were calculated for the primary treatment endpoint at week 4. RESULTS: Mean change in total MADRS scores from baseline to week 4 was 7.0 (95% CI, 4.8-9.1) points in the rTMS group, 7.6 (95% CI, 5.5-9.8) in the tDCS group, and 8.9 (95% CI, 7.4-10.4) among patients in the VNF group, a non-significant difference (F(2111)=0.62, p=0.54). Similarly, neither the response rates nor remission rates for rTMS (response 31%; remission 17%), tDCS (24%, 17%), or VNF (41%; 27%) significantly differed among treatment groups (χ 2=2.59, p=0.28; χ 2=1.66, p=0.44). Twenty patients (17%) dropped out of the studies in a similar proportion across groups (rTMS 3/29, tDCS 6/29, VNF 11/59, χ 2=1.41, p=0.52). CONCLUSION: Our current analysis found a comparable efficacy and acceptability in all three treatment modalities (rTMS, tDCS, and VNF) and clinical relevance for the acute treatment of major depressive disorder.

RAFF-4, Magnetization Transfer and Diffusion Tensor MRI of Lysophosphatidylcholine Induced Demyelination and Remyelination in Rats.

Remyelination is a naturally occurring response to demyelination and has a central role in the pathophysiology of multiple sclerosis and traumatic brain injury. Recently we demonstrated that a novel MRI technique entitled Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n (RAFFn) achieved exceptional sensitivity in detecting the demyelination processes induced by lysophosphatidylcholine (LPC) in rat brain. In the present work, our aim was to test whether RAFF4, along with magnetization transfer (MT) and diffusion tensor imaging (DTI), would be capable of detecting the changes in the myelin content and microstructure caused by modifications of myelin sheets around axons or by gliosis during the remyelination phase after LPC-induced demyelination in the corpus callosum of rats. We collected MRI data with RAFF4, MT and DTI at 3 days after injection (demyelination stage) and at 38 days after injection (remyelination stage) of LPC (n = 12) or vehicle (n = 9). Cell density and myelin content were assessed by histology. All MRI metrics detected differences between LPC-injected and control groups of animals in the demyelination stage, on day 3. In the remyelination phase (day 38), RAFF4, MT parameters, fractional anisotropy, and axial diffusivity detected signs of a partial recovery consistent with the remyelination evident in histology. Radial diffusivity had undergone a further increase from day 3 to 38 and mean diffusivity revealed a complete recovery correlating with the histological assessment of cell density attributed to gliosis. The combination of RAFF4, MT and DTI has the potential to differentiate between normal, demyelinated and remyelinated axons and gliosis and thus it may be able to provide a more detailed assessment of white matter pathologies in several neurological diseases.

Contemporary clinical neurophysiology applications in dystonia.

The complex phenomenological understanding of dystonia has transcended from the clinics to genetics, imaging and neurophysiology. One way in which electrophysiology will impact into the clinics are cases wherein a dystonic clinical presentation may not be typical or a "forme fruste" of the disorder. Indeed, the physiological imprints of dystonia are present regardless of its clinical manifestation. Underpinnings in the understanding of dystonia span from the peripheral, segmental and suprasegmental levels to the cortex, and various electrophysiological tests have been applied in the course of time to elucidate the origin of dystonia pathophysiology. While loss of inhibition remains to be the key finding in this regard, intricacies and variabilities exist, thus leading to a notion that perhaps dystonia should best be gleaned as network disorder. Interestingly, the complex process has now spanned towards the understanding in terms of networks related to the cerebellar circuitry and the neuroplasticity. What is evolving towards a better and cohesive view will be neurophysiology attributes combined with structural dynamic imaging. Such a sound approach will significantly lead to better therapeutic modalities in the future.

Individual differences in interoceptive accuracy and prediction error in motor functional neurological disorders: A DTI study.

In motor functional neurological disorders (mFND), relationships between interoception (a construct of high theoretical relevance to its pathophysiology) and neuroanatomy have not been previously investigated. This study characterized white matter in mFND patients compared to healthy controls (HCs), and investigated associations between fiber bundle integrity and cardiac interoception. Voxel-based analysis and tractography quantified fractional anisotropy (FA) in 38 mFND patients compared to 38 HCs. Secondary analyses compared functional seizures (FND-seiz; n = 21) or functional movement disorders (n = 17) to HCs. Network lesion mapping identified gray matter origins of implicated fiber bundles. Within-group mFND analyses investigated relationships between FA, heartbeat tracking accuracy and interoceptive trait prediction error (discrepancies between interoceptive accuracy and self-reported bodily awareness). Results were corrected for multiple comparisons, and all findings were adjusted for depression and trait anxiety. mFND and HCs did not show any between-group interoceptive accuracy or FA differences. However, the FND-seiz subgroup compared to HCs showed decreased integrity in right-lateralized tracts: extreme capsule/inferior fronto-occipital fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, and thalamic/striatum to occipital cortex projections. These alterations originated predominantly from the right temporoparietal junction and inferior temporal gyrus. In mFND patients, individual differences in interoceptive accuracy and interoceptive trait prediction error correlated with fiber bundle integrity originating from the insula, temporoparietal junction, putamen and thalamus among other regions. In this first study investigating brain-interoception relationships in mFND, individual differences in interoceptive accuracy and trait prediction error mapped onto multimodal integration-related fiber bundles. Right-lateralized limbic and associative tract disruptions distinguished FND-seiz from HCs.

Processing of emotionally ambiguous stimuli in eating disorders: an fMRI pilot study.

PURPOSE: People with eating disorders (EDs) have difficulties understanding their own emotions and recognizing the emotions of others, especially in ambiguous settings. We examined the neuronal mechanisms underlying the emotion processing of ambiguous interpersonal stimuli in EDs and healthy controls (HCs). METHODS: The fMRI data were acquired by a blocked experimental design with 28 women (14 EDs) during the visual presentation of a modified Thematic Apperception Test. RESULTS: EDs showed very strong associations between experienced and inferred emotions evoked by the stimuli; no such relationship was found in HCs. HCs displayed elevated left anterior insula activity during the mentalizing condition; EDs showed increased activity in the right supramarginal gyrus and medial prefrontal cortex. CONCLUSION: The two groups seem to apply different strategies for judging emotionally ambiguous stimuli, albeit resulting in equivalent judgments. We assume that activity in the supramarginal gyrus and insula in EDs is linked with suppressing their own perspective while considering emotional states, probably due to alexithymia and the lack of awareness of their own mental states. We hypothesize that the strong correlation between experienced and inferred emotions in EDs could reflect their tendency to use others as a reference point for perceiving themselves and gaining information about their affective state. LEVEL OF EVIDENCE: No level of evidence, this is a basic science study.

Differential diagnosis of tremor syndromes using MRI relaxometry.

Differential diagnosis of the most common tremor syndromes - essential tremor (ET) and Parkinson's disease (PD) is burdened with high error rate. However, diagnostic MRI biomarkers applicable in this clinically highly relevant scenario remain an unfulfilled objective. The presented study was designed in search for possible candidate MRI protocols relevant for differential diagnostic process in tremor syndromes.10 non-advanced tremor-dominant PD patients meeting diagnostic criteria for clinically established PD, 12 isolated ET patients and 16 healthy controls were enrolled into this study. The study focused on relaxation MRI protocols - T1, T2, adiabatic T1ρ and adiabatic T2ρ due to their relatively low post-processing requirements enabling implementation into routine clinical practice. Compared to ET, PD patients had significantly longer T2 relaxation times in striata with dominant findings in the putamen contralateral to the clinically more affected body side. This difference was driven by alterations in the PD group as confirmed in the complementary comparison with healthy controls. According to the receiver operating characteristic analysis, this region provided a reasonable sensitivity of 0.91 and specificity of 0.89 in the differential diagnosis of PD and ET. In PD patients, we further found prolonged T1ρ in the substantia nigra compared to ET and healthy controls, and shorter T2 and T2ρ in the cerebellum compared to healthy controls. T2 relaxation time in the putamen contralateral to the clinically more affected body side is a plausible candidate diagnostic marker for the differentiation of PD and ET.

Predicting Sex From EEG: Validity and Generalizability of Deep-Learning-Based Interpretable Classifier.

Explainable artificial intelligence holds a great promise for neuroscience and plays an important role in the hypothesis generation process. We follow-up a recent machine learning-oriented study that constructed a deep convolutional neural network to automatically identify biological sex from EEG recordings in healthy individuals and highlighted the discriminative role of beta-band power. If generalizing, this finding would be relevant not only theoretically by pointing to some specific neurobiological sexual dimorphisms, but potentially also as a relevant confound in quantitative EEG diagnostic practice. To put this finding to test, we assess whether the automatic identification of biological sex generalizes to another dataset, particularly in the presence of a psychiatric disease, by testing the hypothesis of higher beta power in women compared to men on 134 patients suffering from Major Depressive Disorder. Moreover, we construct ROC curves and compare the performance of the classifiers in determining sex both before and after the antidepressant treatment. We replicate the observation of a significant difference in beta-band power between men and women, providing classification accuracy of nearly 77%. The difference was consistent across the majority of electrodes, however multivariate classification models did not generally improve the performance. Similar results were observed also after the antidepressant treatment (classification accuracy above 70%), further supporting the robustness of the initial finding.

Associated factors of REM sleep without atonia in younger (≤ 50 years) hospitalized psychiatric patients.

BACKGROUND: Isolated REM sleep without atonia (RSWA) as a main polysomnograhic feature of REM sleep behaviour disorder (RBD) is thought to be a prodromal or subclinical state of the disease. RSWA/RBD occurence in psychiatric population is much more frequent than in general population but its associated factors are still not known. METHODS: We invited 88 psychiatry in-patients to undervent video-polysomnography. The visual scoring was focused on RSWA in submentales and flexores digitales superficiales muscles. This parametr was subsequently correlated mainly with age/gender, their medication and mental status. RESULTS: The RWSA was mostly still in normal range despite the fact, that selected psychiatry patients (≤ 50 years) were taking several classes of psychoactive medication. 3,6% had convincingly RBD, although 35.7% reported rare lifetime occurence of dream-enacting behaviour and 62.8% sporadic nightmares. We found correlation between RSWA and SNRI medication class (p = 0.015), specifically venlafaxine (p = 0.029) as well as quetiapine (p = 0.030). Another significant associated factors were current anxiety (p < 0.001) and depressive symptoms (p = 0.05), but we found no relation between RSWA and given diagnosis. CONLUCIONS: Isolated RSWA in younger psychiatry patients might be a result of multiple factors, including medication and current mental status but these factors are in most cases not sufficient to manifest RBD.

Baseline Difference in Quantitative Electroencephalography Variables Between Responders and Non-Responders to Low-Frequency Repetitive Transcranial Magnetic Stimulation in Depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depressive disorder, with outcomes approaching 45-55% response and 30-40% remission. Eligible predictors of treatment outcome, however, are still lacking. Few studies have investigated quantitative electroencephalography (QEEG) parameters as predictors of rTMS treatment outcome and none of them have addressed the source localization techniques to predict the response to low-frequency rTMS (LF rTMS). We investigated electrophysiological differences based on scalp EEG data and inverse solution method, exact low-resolution brain electromagnetic tomography (eLORETA), between responders and non-responders to LF rTMS in resting brain activity recorded prior to the treatment. Twenty-five unmedicated depressive patients (mean age of 45.7 years, 20 females) received a 4-week treatment of LF rTMS (1 Hz; 20 sessions per 600 pulses; 100% of the motor threshold) over the right dorsolateral prefrontal cortex. Comparisons between responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale score) and non-responders were made at baseline for measures of eLORETA current density, spectral absolute power, and inter-hemispheric and intra-hemispheric EEG asymmetry. Responders were found to have lower current source densities in the alpha-2 and beta-1 frequency bands bilaterally (with predominance on the left side) in the inferior, medial, and middle frontal gyrus, precentral gyrus, cingulate gyrus, anterior cingulate, and insula. The most pronounced difference was found in the left middle frontal gyrus for alpha-2 and beta-1 bands (p < 0.05). Using a spectral absolute power analysis, we found a negative correlation between the absolute power in beta and theta frequency bands on the left frontal electrode F7 and the change in depressive symptomatology. None of the selected asymmetries significantly differentiated responders from non-responders in any frequency band. Pre-treatment reduction of alpha-2 and beta-1 sources, but not QEEG asymmetry, was found in patients with major depressive disorder who responded to LF rTMS treatment. Prospective trials with larger groups of subjects are needed to further validate these findings.

Quantitative but Not Qualitative Performance Changes in Predictive Motor Timing as a Result of Overtraining.

The possibilities of substantial long-term improvement of predictive timing might be sometimes seen as limited, with scanty information of neural substrates underlying the potential learning process. To address this issue, we have investigated the performance of 21 baseball professionals and 21 matched controls in a predictive motor timing task previously shown to engage the cerebellum. Baseball players, hypothesized as a model of overtraining of the prediction of future state of the surroundings, showed significantly higher quantitative performance than nonathletic controls, with a substantial part of the baseball players reaching levels far beyond the range observed in common population. Furthermore, the qualitative performance profile of baseball players under various conditions as target speed and acceleration modes did not differ from the profile of healthy controls. Our results suggest that regular exigent training has the potential to vastly improve predictive motor timing. Moreover, the quantitative but not qualitative difference in the performance profile allows us to hypothesize that the selective honing of the same cerebellar processes and networks as in non-trained individuals is the substrate for the quantitative performance improvement, without substantial engagement of further neural nodes.

Impulsivity in patients with borderline personality disorder: a comprehensive profile compared with healthy people and patients with ADHD.

BACKGROUND: Impulsivity is a core symptom of borderline personality disorder (BPD). Impulsivity is a heterogeneous concept, and a comprehensive evaluation of impulsivity dimensions is lacking in the literature. Moreover, it is unclear whether BPD patients manifest impaired cognitive functioning that might be associated with impulsivity in another patient group, such as ADHD, a frequent comorbidity of BPD. METHODS: We tested 39 patients with BPD without major psychiatric comorbidities and ADHD, 25 patients with ADHD, and 55 healthy controls (HC) using a test battery consisting of a self-report measure of impulsivity (UPPS-P questionnaire), behavioral measures of impulsivity - impulsive action (Go/NoGo task, stop signal task) and impulsive choice (delay discounting task, Iowa gambling task), and standardized measures of attention (d2 test), working memory (digit span), and executive functioning (Tower of London). RESULTS: Patients with BPD and ADHD, as compared with HC, manifested increased self-reported impulsivity except sensation seeking and increased impulsive choice; patients with ADHD but not BPD showed increased impulsive action and deficits in cognitive functioning. Negative urgency was increased in BPD as compared to both HC and ADHD groups and correlated with BPD severity. CONCLUSIONS: Patients with BPD without ADHD comorbidity had increased self-reported impulsivity and impulsive choice, but intact impulsive action and cognitive functioning. Controlling for ADHD comorbidity in BPD samples is necessary. Negative urgency is the most diagnostically specific impulsivity dimension in BPD.

Essential tremor-plus: a controversial new concept.

In addition to redefining essential tremor (ET), the 2018 consensus statement of the Movement Disorder Society on tremor coined a new term: essential tremor-plus (ET-plus). This term is uncertainly defined as tremor with the characteristics of ET, with additional neurological signs of uncertain clinical significance. If ET-plus had been defined on the basis of a difference in underlying pathology or an appreciable difference in prognosis, it would have a valid, scientific rationale, as does the term Parkinson-plus. However, there is no such evidence, so the basis for the term is questionable. In fact, ET-plus might only represent a state condition (ie, patients with ET might develop these additional clinical features when the disease is at a more advanced stage). We caution against coining new terms that are not supported by a firm scientific basis and encourage research into the creation of essential tremor subsets that are defined with respect to differences in underlying causes or pathophysiology.