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Abstract Parkinson’s disease (PD) and multiple system atrophy (MSA) can be preceded by isolated REM sleep behavior disorder (iRBD). As excessive sighing during wakefulness is a red flag for MSA in individuals with parkinsonism, we measured sighing during slow wave sleep (N3) and REM sleep as potential biomarkers in 73 participants with MSA, 111 with iRBD, 257 with PD, and 115 controls. The number of sighs/hour of N3 (index) was higher in the MSA group than in the other groups. Sighs were rarer in REM sleep than in N3 sleep. A sigh index greater than 3.4/h of N3 was 95% sensitive in discriminating participants with MSA from controls, and a sigh index greater than 0.8 sigh/h of REM sleep was 87% specific in discriminating participants with MSA from controls. MSA participants with (vs. without) sigh were younger, had a lower apnea-hypopnea index (but no more stridor), and had no other difference in motor, autonomic, cognitive, and sensory symptoms. The sigh index could be used for screening for MSA in the millions of middle-aged persons who receive polysomnography for other purposes. Whether sighing in iRBD predicts preferential conversion towards MSA should be measured in a longitudinal study.

Abstract Psychiatric symptoms are common in neurodevelopmental movement disorders, including some types of dystonia. However, research has mainly focused on motor manifestations and underlying circuits. Myoclonus-dystonia is a rare and homogeneous neurodevelopmental condition serving as an illustrative paradigm of childhood-onset dystonias, associated with psychiatric symptoms. Here, we assessed the prevalence of psychiatric disorders and the severity of depressive symptoms in patients with myoclonus-dystonia and healthy volunteers (HV). Using resting-state functional neuroimaging, we compared the effective connectivity within and among non-motor and motor brain networks between patients and HV. We further explored the hierarchical organization of these networks and examined the relationship between their connectivity and the depressive symptoms. Comparing 19 patients to 25 HV, we found a higher prevalence of anxiety disorders and more depressive symptoms in the patient group. Patients exhibited abnormal modulation of the cerebellum on the cerebral cortex in the sensorimotor, dorsal attention, salience, and default mode networks. Moreover, the salience network activity was directed by the cerebellum in patients and was related to depressive symptoms. Altogether, our findings highlight the role of the cerebellar drive on both motor and non-motor cortical areas in this disorder, suggesting cerebellar involvement in the complex phenotype of such neurodevelopmental movement disorders.

Background: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. Objective: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. Methods: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. Results: VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. Conclusions: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

Abstract Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p

Abstract In Parkinson’s disease (PD), it remains unclear whether sleep disorders including insomnia, REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), restless legs syndrome (RLS) and sleep-disordered breathing (SDB), are isolated or combined, interact with each other and are associated with clinical factors. We sought to determine the prevalence and combinations of the main sleep disorders, and their clinical and polysomnographic associations in early stage PD. Sleep disorders were systematically diagnosed after medical interview and video-polysomnography in 162 participants with early stage PD and 58 healthy controls from the baseline of the longitudinal ICEBERG cohort. Demographic, clinical (motor, cognitive, autonomic, psychological and sensory tests), therapeutic and polysomnographic associations of sleep disorders were investigated. Sleep disorders were frequent (71%) and combined in half of the patients. The number of sleep disorders increased with disease duration and dysautonomia. Insomnia was the most common (41%), followed by definite RBD (25%), EDS (25%), and RLS (16%). These disorders were more frequent than in controls whereas SDB was rare, moderate and similar in both groups. In patients, insomnia (mainly difficulties maintaining sleep) was associated with female gender, shorter sleep time and RLS, but not with motor or psychological symptoms. RBD was associated with dysautonomia and advanced age, but not with motor and cognitive measures. EDS was associated with psychiatric and motor symptoms as well as the sedative effects of dopamine agonists but not with other sleep disturbances. Sleep disturbances are frequent and combined in early patients with PD. Their determinants and markers are more organic than psychological.

The Dystonia Medical Research Foundation organized an expert virtual workshop in March 2023 to review the evidence on non-motor symptoms across the spectrum of dystonia, discuss existing assessment methods, need for their harmonisation and roadmap to achieve this, and evaluate potential treatment approaches. Albeit the most investigated non-motor domains, experts highlighted the need to identify the most accurate screening procedure for depression and anxiety, clarify their mechanistic origin and quantify their response to already available therapies. Future exploration of sleep disruption in dystonia should include determining the accuracy and feasibility of wearable devices, understanding the contribution of psychotropic medication to its occurrence, and defining the interaction between maladaptive plasticity and abnormal sleep patterns. Despite recent advances in the assessment of pain in dystonia, more research is needed to elucidate the relative importance of different mechanisms called into play to explain this impactful sensory feature and the most appropriate treatments. Amongst the different non-motor features investigated in dystonia, cognitive dysfunction and fatigue require an in-depth observation to evaluate their functional impact, their clinical profile and assessment methods and, in the case of cognition, whether impairment represents a prodrome of dementia. Finally, experts identified the development and field validation of a self-rated screening tool encompassing the full spectrum of non-motor symptoms as the most urgent step towards incorporating the management of these features into routine clinical practice.

Parkinson’s disease (PD) is the second most common neurodegenerative disease clinically characterized by classical motor symptoms and a range of associated non-motor symptoms. Due to the heterogeneity of symptoms and variability in patient prognosis, the discovery of blood biomarkers is of utmost importance to identify the biological mechanisms underlying the different clinical manifestations of PD, monitor its progression and develop personalized treatment strategies. Whereas studies often rely on motor symptoms alone or composite scores, our study focused on finding relevant molecular markers associated with three clinical models describing either motor, cognitive or emotional symptoms. An integrative multiblock approach was performed using regularized generalized canonical correlation analysis to determine specific associations between lipidomics, transcriptomics and clinical data in 48 PD patients. We identified omics signatures confirming that clinical manifestations of PD in our cohort could be classified according to motor, cognition or emotion models. We found that immune-related genes and triglycerides were well-correlated with motor variables, while cognitive variables were linked to triglycerides as well as genes involved in neuronal growth, synaptic plasticity and mitochondrial fatty acid oxidation. Furthermore, emotion variables were associated with phosphatidylcholines, cholesteryl esters and genes related to endoplasmic reticulum stress and cell regulation.

Abstract Growing evidence suggests that sleep plays a key role in regulating emotions. Rapid eye movements (REMs) in REM sleep could be associated with dreams emotions, but supporting evidence is indirect. To highlight this association, we studied the REM sleep during video-polysomnography of 20 subjects with REM sleep behaviour disorder (RBD), a model of enacted dreams offering direct access to the emotional content of the sleeper (face expression, speeches, behaviour). Video and the electro-oculography recordings were divided into 3 s time intervals and classified as non-behavioural, or behavioural (neutral, positive or negative emotions), and as containing no eye movements (EMs), slow eye movements (SEMs) or REMs (isolated or bursts). Compared to the absence of EMs, neutral behaviours successively increased in the presence of SEMs (odd ratio, OR = 1.4), then isolated REMs (OR = 2.8) and then REM bursts (OR = 4.6). Positive behaviours increased with SEMs (OR = 2.8) but did not increase further with isolated REMs (OR = 2.8) and REM bursts (OR = 3). Negative behaviours were absent with SEMs, increased with isolated REMs (OR = 2.6) and further with REM bursts (OR = 10.1). These results support an association between REMs and SEMs, and dream emotions.

Abstract Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson’s disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson’s disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.

Background: Parkinson’s disease (PD) demonstrates neurodegenerative changes in the substantia nigra pars compacta (SNc) using neuromelanin-sensitive (NM)-MRI. As SNc manual segmentation is prone to substantial inter-individual variability across raters, development of a robust automatic segmentation framework is necessary to facilitate nigral neuromelanin quantification. Artificial intelligence (AI) is gaining traction in the neuroimaging community for automated brain region segmentation tasks using MRI. Objective: Developing and validating AI-based NigraNet, a fully automatic SNc segmentation framework allowing nigral neuromelanin quantification in patients with PD using NM-MRI. Methods: We prospectively included 199 participants comprising 144 early-stage idiopathic PD patients (disease duration = 1.5 ± 1.0 years) and 55 healthy volunteers (HV) scanned using a 3 Tesla MRI including whole brain T1-weighted anatomical imaging and NM-MRI. The regions of interest (ROI) were delineated in all participants automatically using NigraNet, a modified U-net, and compared to manual segmentations performed by two experienced raters. The SNc volumes (Vol), volumes corrected by total intracranial volume (Cvol), normalized signal intensity (NSI) and contrast-to-noise ratio (CNR) were computed. One-way GLM-ANCOVA was performed while adjusting for age and sex as covariates. Diagnostic performance measurement was assessed using the receiver operating characteristic (ROC) analysis. Inter and intra-observer variability were estimated using Dice similarity coefficient (DSC). The agreements between methods were tested using intraclass correlation coefficient (ICC) based on a mean-rating, two-way, mixed-effects model estimates for absolute agreement. Cronbach’s alpha and Bland-Altman plots were estimated to assess inter-method consistency. Results: Using both methods, Vol, Cvol, NSI and CNR measurements differed between PD and HV with an effect of sex for Cvol and CNR. ICC values between the methods demonstrated optimal agreement for Cvol and CNR (ICC > 0.9) and high reproducibility (DSC: 0.80) was also obtained. The SNc measurements also showed good to excellent consistency values (Cronbach's alpha > 0.87). Bland-Altman plots of agreement demonstrated no association of SNc ROI measurement differences between the methods and ROI average measurements while confirming that 95 % of the data points were ranging between the limits of mean difference (d ± 1.96xSD). Percentage changes between PD and HV were −27.4 % and −17.7 % for Vol, −30.0 % and –22.2 % for Cvol, −15.8 % and −14.4 % for NSI, −17.1 % and −16.0 % for CNR for automatic and manual measurements respectively. Using automatic method, in the entire dataset, we obtained the areas under the ROC curve (AUC) of 0.83 for Vol, 0.85 for Cvol, 0.79 for NSI and 0.77 for CNR whereas in the training dataset of 0.96 for Vol, 0.95 for Cvol, 0.85 for NSI and 0.85 for CNR. Disease duration correlated negatively with NSI of the patients for both the automatic and manual measurements. Conclusions: We presented an AI-based NigraNet framework that utilizes a small MRI training dataset to fully automatize the SNc segmentation procedure with an increased precision and more reproducible results. Considering the consistency, accuracy and speed of our approach, this study could be a crucial step towards the implementation of a time-saving non-rater dependent fully automatic method for studying neuromelanin changes in clinical settings and large-scale neuroimaging studies.

Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson’s disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson’s disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson’s disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality.The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody.As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference.R2∗ values significantly increased in Parkinson’s disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning.In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27).We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power.These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis.Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers.Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology.Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

Many articles have used voice analysis to detect Parkinson's disease (PD), but few have focused on the early stages of the disease and the gender effect. In this article, we have adapted the latest speaker recognition system, called x-vectors, in order to detect PD at an early stage using voice analysis. X-vectors are embeddings extracted from Deep Neural Networks (DNNs), which provide robust speaker representations and improve speaker recognition when large amounts of training data are used. Our goal was to assess whether, in the context of early PD detection, this technique would outperform the more standard classifier MFCC-GMM (Mel-Frequency Cepstral Coefficients—Gaussian Mixture Model) and, if so, under which conditions. We recorded 221 French speakers (recently diagnosed PD subjects and healthy controls) with a high-quality microphone and via the telephone network. Men and women were analyzed separately in order to have more precise models and to assess a possible gender effect. Several experimental and methodological aspects were tested in order to analyze their impacts on classification performance. We assessed the impact of the audio segment durations, data augmentation, type of dataset used for the neural network training, kind of speech tasks, and back-end analyses. X-vectors technique provided better classification performances than MFCC-GMM for the text-independent tasks, and seemed to be particularly suited for the early detection of PD in women (7–15% improvement). This result was observed for both recording types (high-quality microphone and telephone).

LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2–2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0–2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

The EARLYSTIM Study compared deep brain stimulation (DBS) with best medical treatment (BMT) over 2-years, showing a between-group difference of 8.0 from baseline in favor of DBS in health-related quality of life (HRQoL), measured with the PDQ-39 SI (summary index). This study obtained complementary information about the importance of the change in HRQoL as measured by the PDQ-39, using anchor-based (Patient Global Impression of Change, PGIC) and distribution-based techniques (magnitude of change, effect size, thresholds, distribution of benefit) applied to the EARLYSTIM study data. Anchor-based techniques showed a difference follow-up-baseline for patients who reported "minimal improvement" of -5.8 [-9.9, -1.6] (mean [95%CI]) in the DBS group vs -2.9 [-9.0, 3.1] in the BMT group. As the vast majority (80.8%) of DBS patients reported "much or very much improvement", this difference was explored for the latter group and amounted to -8.7 for the DBS group and -6.5 in the BMT group. Distribution-based techniques that analyzed the relative change and treatment effect size showed a moderate benefit of the DBS on the HRQoL, whereas a slight worsening was observed in the BMT group. The change in the DBS group (-7.8) was higher than the MIC (Minimally Important Change) estimated value (-5.8 by the anchor; -6.3 by triangulation of thresholds), but not in the BMT (0.2 vs. -3.0 to -5.4, respectively). Almost 90% of the patients in the DBS group declared some improvement (58.3% and 56.7% beyond the estimated MIC), which was significantly different from the BMT group whose proportions were 32.0% and 30.3%, respectively. The number needed to treat to improve ≥1 MIC by DBS vs BMT was 3.8. Change in depression, disability and pain influenced the improvement of the DBS group. DBS improved HRQoL in a high proportion of patients to a significant and moderate degree, at 2 years follow-up.

Objective To report demographic data from a large cohort of patients with oromandibular dystonia (OMD). Methods This is a retrospective review of patients with OMD referred to our institution between 1989 and 2015. Demographic (age of onset, gender, and familial history of dystonia) and clinical (type of OMD, associated dystonia, and etiology of dystonia) data were collected from a cohort of 240 individuals. Results The mean age of onset of OMD was 51.6 years old, with a female predominance (2:1). A family history of dystonia was found in 6 patients (2.5%). One hundred and forty-nine patients (62.1%) had the jaw-opening type of OMD, 48 patients (20.0%) had the jaw-closing type, and 43 patients (17.9%) had a mixed form of OMD. Lingual dystonia was also present in 64 (26.7%) of these patients. Eighty-two patients (34.2%) had a focal dystonia, 131 patients (54.6%) had a segmental dystonia, and 27 patients (11.3%) had a generalized dystonia. One hundred and seventy-one patients (71.3%) had idiopathic OMD. Conclusion OMD is a chronic and disabling focal dystonia. Our study found a prevalence of female patients, an onset in middle age and a predominantly idiopathic etiology. Unlike other studies, jaw-opening was found to be the most frequent clinical type of OMD.

Abstract Background Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Methods We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. Results In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. Conclusions Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. Trial registration The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.

Abstract DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. Humans with heterozygous DCC mutations have congenital mirror movements (CMM). As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human. Here, we investigated the role of DCC in CST midline crossing both in human and mice. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline.

BackgroundPrimary orthostatic tremor (POT) is a movement disorder characterized by unsteadiness upon standing still due to a tremor affecting the legs. It is a gradually progressive condition with limited treatment options. Impairments in health-related quality of life (HQoL) seem to far exceed the physical disability associated with the condition.MethodsA multi-center, mixed-methodology study was undertaken to investigate 40 consecutive patients presenting with POT to four movement disorder centers in France. HQoL was investigated using eight quantitative scales and a qualitative study which employed semi-structured interviews. Qualitative data were analyzed with a combination of grounded-theory approach.ResultsOur results confirm that HQoL in POT is severely affected. Fear of falling was identified as the main predictor of HQoL. The qualitative arm of our study explored our initial results in greater depth and uncovered themes not identified by the quantitative approach.ConclusionOur results illustrate the huge potential of mixed methodology in identifying issues influencing HQoL in POT. Our work paves the way for enhanced patient care and improved HQoL in POT and is paradigmatic of this modern approach for investigating HQoL issues in chronic neurological disorders.

IntroductionRecent studies suggest that repeated transcranial magnetic stimulation (TMS) improves functional movement disorders (FMDs), but the underlying mechanisms are unclear. The objective was to determine whether the beneficial action of TMS in patients with FMDs is due to cortical neuromodulation or rather to a cognitive-behavioral effect.MethodConsecutive patients with FMDs underwent repeated low-frequency (0.25 Hz) magnetic stimulation over the cortex contralateral to the symptoms or over the spinal roots [root magnetic stimulation (RMS)] homolateral to the symptoms. The patients were randomized into two groups: group 1 received RMS on day 1 and TMS on day 2, while group 2 received the same treatments in reverse order. We blindly assessed the severity of movement disorders before and after each stimulation session.ResultsWe studied 33 patients with FMDs (dystonia, tremor, myoclonus, Parkinsonism, or stereotypies). The median symptom duration was 2.9 years. The magnetic stimulation sessions led to a significant improvement (>50%) in 22 patients (66%). We found no difference between TMS and RMS.ConclusionWe suggest that the therapeutic benefit of TMS in patients with FMDs is due more to a cognitive-behavioral effect than to cortical neuromodulation.

BACKGROUND:Focal dystonia has been associated with deficient processing of sense of effort cues. However, corresponding studies are lacking in cervical dystonia (CD). We hypothesized that dystonic muscle activity would perturb neck force control based on sense of effort cues. METHODS:Neck extension force control was investigated in 18 CD patients with different clinical features (7 with and 11 without retrocollis) and in 19 control subjects. Subjects performed force-matching and force-maintaining tasks at 5% and 20% of maximum voluntary contraction (MVC). Three task conditions were tested: i) with visual force feedback, ii) without visual feedback (requiring use of sense of effort), iii) without visual feedback, but with neck extensor muscle vibration (modifying muscle afferent cues). Trapezius muscle activity was recorded using electromyography (EMG). RESULTS:CD patients did not differ in task performance from healthy subjects when using visual feedback (ANOVA, p>0.7). In contrast, when relying on sense of effort cues (without visual feedback, 5% MVC), force control was impaired in patients without retrocollis (p = 0.006), but not in patients with retrocollis (p>0.2). Compared to controls, muscle vibration without visual feedback significantly affected performance in patients with retrocollis (p

Background: Glucose transporter type 1 deficiency syndrome is due to de novo mutations in the SLC2A1 gene encoding the glucose transporter type 1. Phenomenology Shown: Paroxysmal motor manifestations induced by exercise or fasting may be the main manifestations of glucose transporter type 1 deficiency syndrome. Educational Value: Proper identification of the paroxysmal events and early diagnosis is important since the disease is potentially treatable.

In the present study, we examined the potential symptomatic and/or disease-modifying effects of monthly bee venom injections compared to placebo in moderatly affected Parkinson disease patients. We conducted a prospective, randomized double-blind study in 40 Parkinson disease patients at Hoehn & Yahr stages 1.5 to 3 who were either assigned to monthly bee venom injections or equivalent volumes of saline (treatment/placebo group: n = 20/20). The primary objective of this study was to assess a potential symptomatic effect of s.c. bee venom injections (100 μg) compared to placebo 11 months after initiation of therapy on United Parkinson’s Disease Rating Scale (UPDRS) III scores in the « off » condition pre-and post-injection at a 60 minute interval. Secondary objectives included the evolution of UPDRS III scores over the study period and [123I]-FP-CIT scans to evaluate disease progression. Finally, safety was assessed by monitoring specific IgE against bee venom and skin tests when necessary. After an 11 month period of monthly administration, bee venom did not significantly decrease UPDRS III scores in the « off » condition. Also, UPDRS III scores over the study course, and nuclear imaging, did not differ significantly between treatment groups. Four patients were excluded during the trial due to positive skin tests but no systemic allergic reaction was recorded. After an initial increase, specific IgE against bee venom decreased in all patients completing the trial. This study did not evidence any clear symptomatic or disease-modifying effects of monthly bee venom injections over an 11 month period compared to placebo using a standard bee venom allergy desensitization protocol in Parkinson disease patients. However, bee venom administration appeared safe in non-allergic subjects. Thus, we suggest that higher administration frequency and possibly higher individual doses of bee venom may reveal its potency in treating Parkinson disease.ClinicalTrials.gov NCT01341431.

BACKGROUND:Abnormalities in the cognitive processing of movement have been demonstrated in patients with dystonia. The sense of agency, which is the experience of initiating and controlling one's own actions, has never before been studied in these patients. OBJECTIVES:We investigated whether the sense of agency is altered in patients with cervical dystonia. METHODS:We used an explicit metacognitive agency task in which participants had to catch targets with a cursor by moving a computer's mouse. The task included several conditions in which the control over the cursor could be disrupted by adding a spatial or a temporal discrepancy between the mouse and the cursor's movements. Participants had to acknowledge these discrepancies and reflect them in metacognitive judgements of agency. RESULTS:Twenty cervical dystonia patients and 20 matched controls were included in the study. Despite performing equally well as the matched controls, cervical dystonia patients did not fully recognize alterations of agency when a temporal lag was added between their movement and the visual feedback. Moreover, they relied predominantly on their perceived performance to provide judgements of agency and less on their objective degree of controls. There was no correlation between agency scores and clinical severity of dystonia measured by the Toronto Western Spasmodic Torticollis Rating Scale. CONCLUSION:We demonstrated an abnormal processing of agency in cervical dystonia patients, even for motor actions not affected by dystonia. The exact contribution of abnormal agency to dystonia pathophysiology remains to be clarified.

[This corrects the article DOI: 10.1371/journal.pone.0158235.].

To date, the most frequently used Parkinson’s disease (PD) biomarkers are the brain imaging measures of dopaminergic dysfunction using positron emission tomography and single photon emission computed tomography. However, major advances have occurred in the development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade. Although conventional structural imaging remains normal in PD, advanced techniques have shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques such as tractography and resting state functional connectivity give access to anatomical and functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to metabolites concentrations. However, to date these techniques are not yet fully validated and standardized quantitative metrics for PD are still lacking. This review presents an overview of new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use in PD and their potential applications to improve the clinical diagnosis of Parkinsonian syndromes and the quality of clinical trials.

Mirror movements correspond to involuntary movements observed in the limb contralateral to the one performing voluntary movement. They can be observed in Parkinson's disease (PD) but their pathophysiology remains unclear. The present study aims at identifying their neural correlates in PD using functional magnetic resonance imaging. Ten control subjects and 14-off drug patients with asymmetrical right-sided PD were included (8 with left-sided mirror movements during right-hand movements, and 6 without mirror movements). Between-group comparisons of BOLD signal were performed during right-hand movements and at rest (p

Progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTD) are two clinicohistological entities that share a severe prefrontal syndrome. To what extent do the cognitive syndrome and the location of the underlying brain atrophy unify or segregate these entities? Here, we examined the clinical and radiological patterns of frontal involvement and the neural bases of the cognitive dysfunctions observed in the Richardson form of PSP and the behavioral variant of FTD (bvFTD). The cognitive profile and grey and white matter volume of PSP (n = 19) and bvFTD (n = 16) patients and control participants (n = 18) were compared using a standard battery of neuropsychological tests and voxel-based morphometry (VBM), respectively. Analyses of correlations between neuropsychological and morphometric data were additionally performed. The severity and qualitative pattern of cognitive dysfunction was globally similar between the two patient groups. Grey matter volume was decreased in widespread frontal areas and in the temporal uncus in bvFTD, while it was decreased in the frontal and temporal lobes as well as in the thalamus in PSP. We also found an unexpected involvement of the frontal rectal gyrus in PSP patients compared to controls. Correlation analyses yielded different results in the two groups, with no area showing significant correlations in PSP patients, while several frontal and some temporal areas did so in bvFTD patients. In spite of minor neuropsychological and morphological differences, this study shows that the patterns of cognitive dysfunction and atrophy are very similar in PSP and bvFTD. However, executive dysfunction in these diseases may stem from partially divergent cortical and subcortical neural circuits.

Nonmotor symptoms (NMSs) of Parkinson’s disease (PD) are common, but they are often underrecognized in clinical practice, because of the lack of spontaneous complaints by the patients, and partly because of the absence of systematic questioning by the consulting physician. However, valid specific instruments for identification and assessment of these symptoms are available in 2012. The administration of the self-completed screening tool, NMSQuest, associated with questioning during the consultation, improves the diagnosis of NMSs. NMSs play a large role in degradation of quality of life. More relevant NMSs are described in this review, mood disorders, impulse control disorders, cognitive deficits, hallucinations, pain, sleep disorders, and dysautonomia.

Animal studies have shown that sequenced patterns of neuronal activity may be replayed during sleep. However, the existence of such replay in humans has not yet been directly demonstrated. Here we studied patients who exhibit overt behaviors during sleep to test whether sequences of movements trained during the day may be spontaneously reenacted by the patients during sleep. We recruited 19 sleepwalkers (who displayed complex and purposeful behaviors emerging from non REM sleep), 20 patients with REM sleep behavior disorder (who enacted their dreams in REM sleep) and 18 healthy controls. Continuous video sleep recordings were performed during sleep following intensive training on a sequence of large movements (learned during a variant of the serial reaction time task). Both patient groups showed learning of the intensively trained motor sequence after sleep. We report the re-enactment of a fragment of the recently trained motor behavior during one sleepwalking episode. This study provides, to our knowledge, the first evidence of a temporally-structured replay of a learned behavior during sleep in humans. Our observation also suggests that the study of such sleep disorders may provide unique and critical information about cognitive functions operating during sleep.

BackgroundRepetitive behaviours (RB) in patients with Gilles de la Tourette syndrome (GTS) are frequent. However, a controversy persists whether they are manifestations of obsessive-compulsive disorder (OCD) or correspond to complex tics.Methods166 consecutive patients with GTS aged 15-68 years were recruited and submitted to extensive neurological, psychiatric and psychological evaluations. RB were evaluated by the YBOCS symptom checklist and Mini International Neuropsychiatric Interview (M.I.N.I), and classified on the basis of a semi-directive psychiatric interview as compulsions or tics.ResultsRB were present in 64.4% of patients with GTS (107/166) and categorised into 3 major groups: a 'tic-like' group (24.3%-40/166) characterised by RB such as touching, counting, 'just right' and symmetry searching; an 'OCD-like' group (20.5%-34/166) with washing and checking rituals; and a 'mixed' group (13.2%-22/166) with both 'tics-like' and 'OCD-like' types of RB present in the same patient. In 6.3% of patients, RB could not be classified into any of these groups and were thus considered 'undetermined'.ConclusionsThe results confirm the phenomenological heterogeneity of RB in GTS patients and allows to distinguish two types: tic-like behaviours which are very likely an integral part of GTS; and OCD-like behaviours, which can be considered as a comorbid condition of GTS and were correlated with higher score of complex tics, neuroleptic and SSRIs treatment frequency and less successful socio-professional adaptation. We suggest that a meticulous semiological analysis of RB in GTS patients will help to tailor treatment and allow to better classify patients for future pathophysiologic studies.Trial registrationClinicalTrials.gov NCT00169351.