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Background: Functional neurological disorder (FND) is a common cause of neurological disability. Despite recent advances in pathophysiological understanding and treatments, application of this knowledge to clinical practice is variable and limited., Objective: Our aim was to provide an expert overview of the state of affairs of FND practice across Europe, focusing on education and training, access to specialized care, reimbursement and disability policies, and academic and patient-led representation of people with FND., Methods: We conducted a survey across Europe, featuring one expert per country. We asked experts to compare training and services for people with FND to those provided to people with multiple sclerosis (MS)., Results: Responses from 25 countries revealed that only five included FND as a mandatory part of neurological training, while teaching about MS was uniformly included. FND was part of final neurology examinations in 3/17 countries, unlike MS that was included in all 17. Seventeen countries reported neurologists with an interest in FND but the estimated mean ratio of FND-interested neurologists to MS neurologists was 1:20. FND coding varied, with psychiatric coding for FND impacting treatment access and disability benefits in the majority of countries. Twenty countries reported services refusing to see FND patients. Eight countries reported an FND special interest group or network; 11 reported patient-led organizations., Conclusions: FND is largely a marginal topic within European neurology training and there is limited access to specialized care and disability benefits for people with FND across Europe. We discuss how this issue can be addressed at an academic, healthcare and patient organization level., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: The role of inflammation and neuroimmune mechanisms, which have been documented in various neuropsychiatric disorders including the seizure subtype of functional neurological disorder, remains unclear in functional movement disorders (FMD). To explore these mechanisms, we analyzed selected inflammatory markers in cerebrospinal fluid (CSF) in patients with FMD., Methods: We compared CSF markers in 26 patients with clinically established FMD (20 females; mean [SD] age = 43.3 [10.9], disease duration = 3.9 [3], range = 0.1-11 years; mean follow-up after lumbar puncture = 4.3 [2] years, range = 0.5-7 years) and 26 sex- and age-matched clinical controls with noninflammatory nonneurodegenerative neurological disorders, mostly sleep disorders., Results: Sixty-five percent of FMD patients versus 15% of controls showed cytological abnormalities (i.e., increased white blood cells [WBC] count, signs of WBC activation, or both; odds ratio [OR] = 9.85, 95% confidence interval = 2.37-52.00, p < .01, corrected), with a significantly higher frequency of an isolated lymphocytic activation, 35% versus 0% (OR = ∞, 95% confidence interval = 2.53-∞, p < .05, corrected). There were no differences in CSF protein and albumin levels, quotient albumin, IgG index, and oligoclonal bands. CSF abnormalities were not associated with more severe motor symptoms or a higher frequency of depression in FMD., Conclusions: Our results suggest a possible involvement of immune mechanisms in the pathophysiology of (at least a subtype of) FMD that deserves further investigation., (Copyright © 2024 by the American Psychosomatic Society.)

Sleep symptoms, including excessive sleepiness, are frequently reported by patients with functional motor disorders (FMD). We aimed to classify the comorbid sleep disorders in FMD, and to investigate the relationship between subjective sleepiness and objective measures of hypersomnia, comparing them with data from people with central hypersomnia. A total of 37 patients (mean [SD] age 46.4 [11.2] years) with clinically definite FMD, and 17 patients (mean [SD] age 41.1 [11.6] years) with central hypersomnia underwent structured medical and sleep history, neurological examination, polysomnography, multiple sleep latency test (MSLT), and questionnaires assessing sleepiness, fatigue, and depression. In all, 23 patients with FMD (62%) reported excessive daytime sleepiness. Evidence of specific sleep disorders was identified in our cohort, with 35% having restless legs syndrome; 49% obstructive sleep apnea; and 8% periodic limb movements in sleep; however, the presence of these disorders was not correlated with subjective sleepiness. Patients with FMD with self-reported sleepiness reported higher fatigue (p = 0.002), depression (p = 0.002), and had longer sleep latencies in the MSLT (p < 0.001) compared to the patients with central hypersomnia. No correlation was found between subjective and objective sleepiness in either group. Fatigue positively correlated with self-reported sleepiness in patients with FMD (p < 0.001). This study did not find objective correlates of increased sleepiness in patients with FMD. While sleep abnormalities were found to be common in FMD, they were not correlated with self-reports of excessive sleepiness. Positive correlations between self-reported sleepiness and fatigue support the current unified model of non-motor symptoms in FMD., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

The blink reflex (BR) is integrated at the brainstem; however, it is modulated by inputs from various structures such as the striatum, globus pallidus, substantia nigra, and nucleus raphe magnus but also from afferent input from the peripheral nervous system. Therefore, it provides information about the pathophysiology of numerous peripheral and central nervous system disorders. The BR is a valuable tool for studying the integrity of the trigemino-facial system, the relevant brainstem nuclei, and circuits. At the same time, some neurophysiological techniques applying the BR may indicate abnormalities involving structures rostral to the brainstem that modulate or control the BR circuits. This is a state-of-the-art review of the clinical application of BR modulation; physiology is reviewed in part 1. In this review, we aim to present the role of the BR and techniques related to its modulation in understanding pathophysiological mechanisms of motor control and pain disorders, in which these techniques are diagnostically helpful. Furthermore, some BR techniques may have a predictive value or serve as a basis for follow-up evaluation. BR testing may benefit in the diagnosis of hemifacial spasm, dystonia, functional movement disorders, migraine, orofacial pain, and psychiatric disorders. Although the abnormalities in the integrity of the BR pathway itself may provide information about trigeminal or facial nerve disorders, alterations in BR excitability are found in several disease conditions. BR excitability studies are suitable for understanding the common pathophysiological mechanisms behind various clinical entities, elucidating alterations in top-down inhibitory systems, and allowing for follow-up and quantitation of many neurological syndromes., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Aim of Study: We aimed to compare knowledge, opinions, and clinical experiences among Czech, Slovak, and Italian neurologists to identify potential educational gaps and unify understanding., Clinical Rationale for Study: Functional neurological disorder (FND) is a disabling condition characterised by motor, sensory, or cognitive symptoms which are incompatible with other neurological disorders. Novel diagnostic and treatment approaches have improved FND management. However, the extent of their adoption, and any differences or similarities across European communities, remain to be established., Material and Methods: Members of the Czech and Slovak Neurological Societies were invited via e-mail to participate in a 14- -item web-based survey investigating their approach to FND. This data was compared to results from a previous study involving 492 Italian neurologists., Results: 232 questionnaires were completed by Czech and Slovak neurologists (CZ-SK). Similarities were found between CZ- -SK and Italian neurologists in their preference for the term 'FND' over other psychological-related terms and in explaining symptoms as due to abnormal functioning of the nervous system rather than attributing them to mental illness. However, only fewer than 5% in both groups thought that simulation was highly unlikely. Both groups reported relying on positive signs (e.g. inconsistency, distractibility) according to the current diagnostic criteria, but also a tendency to perform additional tests to exclude other causes. However, some differences were observed: Italian neurologists placed a greater emphasis on psychological factors including litigation. CZ-SK neurologists were more likely to suggest physiotherapy as a treatment option and to provide educational intervention for patients and their relatives., Conclusions: Overall, our findings suggest that although Czech, Slovak, and Italian neurologists have adopted some new developments in the field of FND, significant gaps still exist in their understanding and common practices regarding conceptualisation, diagnosis, and treatment., Clinical Implications: Our results suggest that promoting knowledge through postgraduate curricula and teaching courses for neurologists is necessary to optimise patient management in various European countries.

Functional movement disorder (FMD) is a common, potentially reversible source of disability in neurology. Over the last two decades, there have been major advances in our understanding of the clinical picture, diagnosis, and management of this condition. Motor presentation is heterogeneous and several non-motor symptoms (e.g., pain, fatigue) are part of the clinical spectrum. The diagnosis should be made by neurologists or neuropsychiatrists based on the presence of positive signs of inconsistency and incongruence with neurological diseases. Promising evidence has accumulated for the efficacy of physiotherapy, psychotherapy, or both in the management of FMD, for a majority of patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Functional movement disorders (FMD) are associated with a high prevalence of psychiatric comorbidities., Objective: To assess the frequency of obsessive-compulsive symptoms (OCS) in FMD., Methods: A total of 167 consecutive patients with clinically definite FMD (mean age = 44.4 years, standard deviation [SD] = 12.0, 119 females) and 145 healthy controls (mean age = 43.2 years, SD = 11.8, 103 females) completed the Obsessive-Compulsive Inventory-Revised (OCI-R), which is a widely used tool for assessing OCS. The cutoff score ≥21 is indicative of clinically significant obsessive-compulsive disorder (OCD). Motor symptom severity was assessed using the Simplified FMD Rating Scale (S-FMDRS). All subjects completed questionnaires for depression, anxiety, pain, fatigue, cognitive complaints, health-related quality of life, and childhood trauma. Personality traits were assessed using the Big Five questionnaire., Results: FMD patients had higher mean OCI-R score and higher proportion of individuals with OCI-R ≥ 21 42%, 95% confidence interval (CI) = (30.2, 54.6) versus 16%, 95% CI = (8.2, 28.2) in controls, P  < 0.001. Patients had higher scores in three domains: checking, ordering, and obsessing ( P  < 0.001). FMD patients with OCI-R score ≥21 had higher depression, anxiety, cognitive complaints, and lower quality of life compared to those with score <21 ( P  < 0.001). No correlation between OCI-R and S-FMDRS scores was found., Conclusions: FMD patients reported higher rates of OCS compared to controls, along with higher rates of non-motor symptoms and lower quality of life. This finding may have clinical implications and raises the possibility of shared risk factors and common pathophysiological mechanisms in FMD and OCD., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Patients with functional neurological disorders (FND) often present with multiple motor, sensory, psychological and cognitive symptoms. In order to explore the relationship between these common symptoms, we performed a detailed clinical assessment of motor, non-motor symptoms, health-related quality of life (HRQoL) and disability in a large cohort of patients with motor FND. To understand the clinical heterogeneity, cluster analysis was used to search for subgroups within the cohort., Methods: One hundred fifty-two patients with a clinically established diagnosis of motor FND were assessed for motor symptom severity using the Simplified Functional Movement Disorder Rating Scale (S-FMDRS), the number of different motor phenotypes (i.e. tremor, dystonia, gait disorder, myoclonus, and weakness), gait severity and postural instability. All patients then evaluated each motor symptom type severity on a Likert scale and completed questionnaires for depression, anxiety, pain, fatigue, cognitive complaints and HRQoL., Results: Significant correlations were found among the self-reported and all objective motor symptoms severity measures. All self-reported measures including HRQoL correlated strongly with each other. S-FMDRS weakly correlated with HRQoL. Hierarchical cluster analysis supplemented with gap statistics revealed a homogenous patient sample which could not be separated into subgroups., Conclusions: We interpret the lack of evidence of clusters along with a high degree of correlation between all self-reported and objective measures of motor or non-motor symptoms and HRQoL within current neurobiological models as evidence to support a unified pathophysiology of 'functional' symptoms. Our results support the unification of functional and somatic syndromes in classification schemes and for future mechanistic and therapeutic research.

Oxidative stress supposedly plays a role in the pathogenesis of Parkinson's disease (PD). Uric acid (UA), a powerful antioxidant, is lowered in PD while allantoin, the oxidation product of UA and known biomarker of oxidative stress, was not systematically studied in PD. We aim to compare serum and cerebrospinal fluid (CSF) levels of UA, allantoin, and allantoin/UA ratio in de novo PD patients and controls, and evaluate their associations with clinical severity and the degree of substantia nigra degeneration in PD. We measured serum and CSF levels of UA, allantoin, and allantoin/UA ratio in 86 PD patients (33 females, mean age 57.9 (SD 12.6) years; CSF levels were assessed in 51 patients) and in 40 controls (19 females, 56.7 (14.1) years). PD patients were examined using Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson Disease-Autonomic (SCOPA-AUT), the University of Pennsylvania Smell Identification Test (UPSIT), one-night video-polysomnography, and dopamine transporter single-photon emission computed tomography (DAT-SPECT). Serum allantoin and allantoin/UA ratio were significantly increased in the PD group compared to controls (p < 0.001 and p = 0.002, respectively). Allantoin/UA ratios in serum and CSF were positively associated with the SCOPA-AUT score (p = 0.005 and 0.031, respectively) and RBD presence (p = 0.044 and 0.028, respectively). In conclusion, serum allantoin and allantoin/UA ratio are elevated in patients with de novo PD. Allantoin/UA ratio in serum and CSF is associated with autonomic dysfunction and RBD presence, indicating that higher systemic oxidative stress occurs in PD patients with more diffuse neurodegenerative changes., (© 2023. The Author(s).)

Objective: Our objective was to assess cognitive functioning across multiple cognitive domains using a standardised neuropsychological battery in patients with motor functional neurological disorders (mFND)., Methods: Thirty patients with clinically established mFND and 30 age-, sex- and education-matched control subjects underwent a thorough neuropsychological assessment evaluating (1) attention including processing speed, (2) executive functions including working memory, (3) short-term memory, (4) speech and language and (5) visuospatial functions. Performance validity tests (PVT) and self-report measures of depression, anxiety and cognitive complaints were included in the assessment. Only patients with valid test performance were included in the analysis., Results: Three patients scored below the cut-off scores in PVT. Patients performed significantly worse than controls in the following areas: (1) the attention domain which included a slow processing speed (p = 0.005, Cohen's d = 0.89), (2) executive functions (p = 0.01, Cohen's d = 0.88) and (3) speech and language domains (p = 0.025, Cohen's d = 0.77). Patients with mFND showed greater intra-individual variability in cognitive performance (p = 0.005, Cohen's d = 0.94). Cognitive impairments were independent of depressive symptoms, which were higher in mFND patients., Conclusion: This study revealed both subjective and objective cognitive impairment in patients with mFND. The neuropsychological profile in mFND was characterised primarily by attentional impairment including a slow processing speed and a high intra-individual variability in cognitive performance. Cognitive impairment was associated with a valid test performance, highlighting that the deficits observed were not likely to be explained by a lack of effort in the patient group. Attention is considered to play a key role in mFND pathophysiology, and the results suggest that such impairments are objectively measurable., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Pathophysiology explanations for functional movement disorders often assume a role for emotional hyperarousal. Pupillometry is a validated method for evaluation of emotional arousal by detecting changes in pupil size in response to emotional stimuli. In a case-control study design, we aimed to study objective and subjective emotional arousal using pupillometry and affective ratings. To assess attentional engagement by affective stimuli, we used videooculographic tracking of eye movement patterns (scanpath)., Methods: Twenty-five female patients with functional movement disorders (mean age: 40.9 [SD 12.7] years) and 23 age matched healthy female controls participated in the study. Using infrared high-resolution eye-tracker, both pupil size and eye movement pattern in response to emotionally charged erotic, adventure, threat, victim, and neutral pictures were recorded along with subjective ratings of emotional valence and arousal of the presented pictures., Results: A between-group comparison showed significantly smaller pupil dilation to adventure stimuli compared to neutral stimuli in patients compared to controls (P < 0.004, bootstrap, uncorr., adj. η2 = 0.00). No significant difference in pupillary response to other stimuli and scanpath parameters was found between the groups. Patients rated significantly lower emotional arousal to erotic pictures than controls (P < 0.001, bootstrap, uncorr., adj. η2 = 0.09)., Conclusion: This study did not find evidence of autonomous or subjective emotional hyperarousal. The mismatch between objective autonomic measures and subjective arousal ratings in patients is of pathophysiological interest and in line with recent findings of impaired interoception in functional movement disorders., Competing Interests: Conflict of interest V. Fabián is a co-owner and J. Erlebach is an employee of Medicton Group Ltd. Other authors have no competing interests to report., (Copyright © 2022. Published by Elsevier Inc.)

Background: There are gaps in our neurobiological understanding of functional movement disorder (FMD)., Objectives: We investigated gray matter volumetric profiles in FMD, and related findings to resting-state functional connectivity (rsFC) profiles using Human Connectome Project data., Methods: Volumetric differences between 53 FMD patients and 50 controls were examined, as well as relationships between individual differences in FMD symptom severity and volumetric profiles. Atrophy network mapping was also used to probe whether FMD-related structural alterations preferentially impacted brain areas with dense rsFC., Results: Compared to controls without neurological comorbidities (albeit with mild depression and anxiety as a group), the FMD cohort did not show any volumetric differences. Across patients with FMD, individual differences in symptom severity negatively correlated with right supramarginal and bilateral superior temporal gyri volumes. These findings remained significant adjusting for FMD subtype or antidepressant use, but did not remain statistically significant adjusting for depression and anxiety scores. Symptom severity-related structural alterations mapped onto regions with dense rsFC-identifying several disease epicenters in default mode, ventral attention, and salience networks., Conclusions: This study supports that FMD is a multinetwork disorder with an important role for the temporoparietal junction and its related connectivity in the pathophysiology of this condition. More research is needed to explore the intersection of functional neurological symptoms and mood., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Functional movement disorders, a common cause of neurological disabilities, can occur with heterogeneous motor manifestations including functional weakness. However, the underlying mechanisms related to brain function and connectivity are unknown., Objective: To identify brain connectivity alterations related to functional weakness we assessed network centrality changes in a group of patients with heterogeneous motor manifestations using task-free functional MRI in combination with different network centrality approaches., Methods: Task-free functional MRI was performed in 48 patients with heterogeneous motor manifestations including 28 patients showing functional weakness and 65 age- and sex-matched healthy controls. Functional connectivity differences were assessed using different network centrality approaches, i.e. global correlation, eigenvector centrality, and intrinsic connectivity. Motor symptom severity was assessed using The Simplified Functional Movement Disorders Rating Scale and correlated with network centrality., Results: Comparing patients with and without functional weakness showed significant network centrality differences in the left temporoparietal junction and precuneus. Patients with functional weakness showed increased centrality in the same anatomical regions when comparing functional weakness with healthy controls. Moreover, in the same regions, patients with functional weakness showed a positive correlation between motor symptom severity and network centrality. This correlation was shown to be specific to functional weakness with an interaction analysis, confirming a significant difference between patients with and without functional weakness., Conclusions: We identified the temporoparietal junction and precuneus as key regions involved in brain connectivity alterations related to functional weakness. We propose that both regions may be promising targets for phenotype-specific non-invasive brain stimulation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a "rule-in" procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting., Methods: This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross-validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation)., Results: FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%)., Conclusions: The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with an increased risk of developing Parkinson's disease (PD). Low uric acid (UA) levels are associated with the risk of development and progression of PD. Allantoin is the major oxidation product of UA and is considered as a biomarker of oxidative stress. We aimed to compare serum levels of UA, allantoin, and allantoin/UA ratio in RBD patients with those in healthy controls, and to examine their associations with clinical severity., Methods: We evaluated serum levels of UA, allantoin, and allantoin/UA ratio in 38 RBD patients (one female, mean age 66.8 (SD 6.3) years) and in 47 controls (four females, 66.8 (7.6) years). All RBD patients were assessed according to an examination protocol, which included structured interview, Montreal Cognitive Assessment (MoCA), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and dopamine transporter single-photon emission computed tomography (DAT-SPECT). The lower putaminal binding ratio from both hemispheres was used for analysis., Results: Mean serum allantoin concentration and allantoin/UA ratio were significantly increased in the RBD group compared to controls (2.6 (1.8) vs. 1.4 (0.7) μmol/l, p = 0.0004, and 0.008 (0.004) vs. 0.004 (0.002), p < 0.0001, respectively). There were no significant differences in UA levels between the two groups. No significant associations between any biochemical parameter and RBD duration, putaminal binding ratio on DAT-SPECT, MDS-UPDRS, or MoCA score were found., Conclusion: Serum allantoin and allantoin/UA ratio are increased in RBD patients in comparison to controls, which may reflect increased systemic oxidative stress in prodromal synucleinopathy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications., Objectives: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity)., Methods: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses., Results: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81., Conclusions: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations.

Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia., Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource., Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone., Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A startling auditory stimulus (SAS) induces a reflex response involving, among other reactions, a strong contraction of the orbicularis oculi muscle (OOc) and subsequent eye closure. A SAS also induces the StartReact effect, a significant shortening of reaction time in subjects ready for task execution. We examined the obvious conflict appearing when a StartReact paradigm requires participants with eyes closed to open their eyes to look for a visual target. We recorded OOc EMG activity and eyelid movements in healthy volunteers who were instructed to open their eyes at perception of a somatosensory imperative stimulus (IS) and locate the position of a Libet's clock's hand shown on a computer screen at 80 cm distance. In 6 out of 20 trials, we delivered a SAS simultaneously with the IS. The main outcome measures were reaction time at onset of eyelid movement and the time gap (TG) separating subjective assessment of the clock's hand position from real IS issuing. Control experiments included reaction time to eye closing and target location with eyes open to the same IS. Reaction time was significantly faster in SAS than in noSAS trials and slower for eye opening than for eye closing in both conditions. In the eye-opening task, TG was significantly shorter in SAS with respect to noSAS trials, despite the presence of the SAS-related burst in the OOc before EMG cessation. Our results indicate that the StartReact effect speeds up eye opening and location of a target in the visual field despite the startle reaction opposing the task., (© 2020 Society for Psychophysiological Research.)

Functional gait disorders are common in clinical practice. They are also usually disabling for affected individuals. The diagnosis is challenging because no single walking pattern is pathognomonic for a functional gait disorder. Establishing a diagnosis is based not primarily on excluding organic gait disorders but instead predominantly on recognizing positive clinical features of functional gait disorders, such as an antalgic, a buckling, or a waddling gait. However, these features can resemble and overlap with organic gait disorders. It is therefore necessary to also look for inconsistency (variations in clinical presentation that cannot be reconciled with an organic lesion) and incongruity (combination of symptoms and signs that is not seen with organic lesions). Yet, these features also have potential pitfalls as inconsistency can occur in patients with dystonic gait or those with freezing of gait. Similarly, patients with dystonia or chorea can present with bizarre gait patterns that may falsely be interpreted as incongruity. A further complicating factor is that functional and organic gait disorders may coexist within the same patient. To improve the diagnostic process, we present a sign-based approach-supported by videos-that incorporates the diverse clinical spectrum of functional gait disorders. We identify 7 groups of supportive gait signs that can signal the presence of functional gait disorders. For each group of signs, we highlight how specific clinical tests can bring out the inconsistencies and incongruencies that further point to a functional gait disorder., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Clinical motor and non-motor effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) seem to depend on the stimulation site within the STN. We analysed the effects of the position of the stimulation electrode within the motor STN on subjective emotional experience, expressed as emotional valence and arousal ratings to pictures representing primary rewards and aversive fearful stimuli in 20 PD patients. Patients' ratings from both aversive and erotic stimuli matched the mean ratings from a group of 20 control subjects at similar position within the STN. Patients with electrodes located more posteriorly reported both valence and arousal ratings from both the rewarding and aversive pictures as more extreme. Moreover, posterior electrode positions were associated with a higher occurrence of depression at a long-term follow-up. This brain-behavior relationship suggests a complex emotion topography in the motor part of the STN. Both valence and arousal representations overlapped and were uniformly arranged anterior-posteriorly in a gradient-like manner, suggesting a specific spatial organization needed for the coding of the motivational salience of the stimuli. This finding is relevant for our understanding of neuropsychiatric side effects in STN DBS and potentially for optimal electrode placement.

The aim of this study was to evaluate associations of motor and non-motor symptoms with dopamine transporter binding in prodromal stage of synucleinopathies. We examined 74 patients with idiopathic REM sleep behavior disorder (RBD), which is a prodromal synucleinopathy, and 39 controls using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test (UPSIT), Farnsworth-Munsell 100 hue test, orthostatic test, Scales for Outcomes in PD-Autonomic, Beck depression inventory-II, State-Trait Anxiety Inventory, and video-polysomnography. Electromyographic muscle activity during REM sleep was quantified according to Sleep Innsbruck-Barcelona criteria. In 65 patients, dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging was performed, putaminal binding ratio was calculated and scans were classified as normal, borderline, or abnormal. Compared to controls, RBD patients had significantly more severe scores in all examined tests. Patients with abnormal DAT-SPECT had higher MDS-UPDRS motor score (p = 0.006) and higher prevalence of orthostatic hypotension (p = 0.008). Putaminal binding ratio was positively associated with UPSIT score (p = 0.03) and negatively associated with tonic (p = 0.003) and phasic (p = 0.01) muscle activity during REM sleep. These associations likely reflect simultaneous advancement of underlying pathology in substantia nigra and susceptible brainstem and olfactory nuclei in prodromal synucleinopathy.

Background: Patients with functional movement disorders also typically have functional somatic symptoms, including pain, fatigue, and sensory disturbance. A potentially unifying mechanism for such symptoms is a failure in processing of sensory inputs. Prepulse inhibition is a neurophysiological method that allows for the study of preconscious somatosensory processing., Objective: The objective of this study was to assess prepulse inhibition in patients with functional movement disorders and healthy control subjects., Methods: We analyzed the effect of a weak electrical stimulus to the index finger (prepulse) on the magnitude of the R2 response of the blink reflex induced by electrical stimuli delivered to the supraorbital nerve in 22 patients with clinically established functional movement disorders and 22 matched controls. Pain, depression, anxiety, and obsessive-compulsive symptoms were assessed using self-rated questionnaires. In addition, in patients we assessed motor symptom severity., Results: Prepulses suppressed the R2 response of the blink reflex in both groups, by 36.4% (standard deviation: 25.6) in patients and by 67.3% (standard deviation: 16.4) in controls. This difference was significant (P < 0.001). There was no significant correlation between motor and nonmotor symptom measures and prepulse inhibition size., Conclusions: Impaired prepulse inhibition of the blink reflex suggests an abnormal preconscious processing of somatosensory inputs, which can be interpreted within predictive coding accounts of both functional movement disorders and functional somatic syndromes. Our results, along with previous findings of a reduced prepulse inhibition in fibromyalgia syndrome, support a possible unified pathophysiology across functional neurological and somatic syndromes with noteworthy implications for diagnostic classification and development of novel biomarkers and treatments. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objectives: The prevalence of restless legs syndrome (RLS) in functional movement disorders (FMD) is not known. Patients with FMD often present with multiple motor and sensory symptoms. Some of these symptoms might be due to comorbid RLS. Therefore, our objective was to evaluate possible association between FMD and RLS., Design: Case-control study., Setting: Movement Disorders Center, 1st Faculty of Medicine and General University Hospital in Prague, Czech Republic., Participants: 96 consecutive patients with clinically established FMD (80 females, mean age (SD) 45.0 (13) years), and 76 matched controls., Primary and Secondary Outcome Measures: The primary outcome measure was prevalence of RLS based on updated International RLS Study Group criteria. Secondary outcome measures included prevalence of periodic limb movements (PLM) using actigraphy; pain, motor and sensory symptoms in lower limbs; organic comorbidities and medication affecting RLS., Results: RLS criteria were fulfilled in 43.8% of patients (95% CI 34 to 54) and in 7.9% of controls (95% CI 3 to 17, p<0.00001). Both RLS and PLM indices (PLMi) ≥22.5/hour were found in 21.2% of patients with FMD and 2.6% of controls. Patients with FMD with RLS had a higher mean PLMi (p<0.001) and a higher proportion of PLMi ≥22.5/hour (p<0.01) than RLS-negative patients. Patients with RLS had higher prevalence of pain and sensory symptoms in lower limbs, no difference was found in medication and prevalence of organic comorbidities in patients with FMD with and without RLS., Conclusions: We found an increased prevalence of RLS in patients with FMD. Clinical diagnosis of RLS was supported by actigraphic measurement of clinically relevant PLM in a significant proportion of patients with FMD. Although functional motor and sensory symptoms may mimic RLS, RLS may be unrecognised in patients with FMD. This finding may have clinical implications in management of FMD, and it raises the possibility of common pathophysiological mechanisms of FMD and RLS/PLM., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Pain, fatigue, cognitive complaints and psychiatric comorbidities are common in patients with functional movement disorder and may significantly affect their quality of life. The aim of the study was to assess the impact of motor and non-motor symptoms on health-related quality of life in patients with functional movement disorder., Methods: Sixty-one patients with clinically established functional movement disorder and 61 matched healthy controls completed standardized questionnaires for depression, anxiety, cognitive complaints, fatigue, pain, sleepiness, apathy and health-related quality of life. Motor disorder severity was assessed using The Simplified Functional Movement Disorders Rating Scale. Personality traits were assessed using the 44-Item Big Five Inventory., Results: Compared to controls, patients reported significantly lower health-related quality of life and higher levels of all assessed non-motor symptoms except for apathy. No difference was found in personality traits. In both groups, health-related quality of life scores negatively correlated with depression, anxiety, pain, cognitive complaints, apathy, and neuroticism. No correlation was found between health-related quality of life and motor symptom severity in patients with functional movement disorder. Multiple regression analysis of the predictors of health-related quality of life showed significant impact of trait anxiety and cognitive complaints scores., Conclusions: Multiple non-motor symptoms but not motor symptom severity correlated with impaired health-related quality of life in patients with functional movement disorder. Impaired health-related quality of life was predicted by anxiety and cognitive complaints. Our results highlight the importance of assessing and treating both motor and non-motor symptoms in patients with functional movement disorder., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Wilson's disease (WD) is a hereditary disorder caused by ATP7B mutations resulting in systemic copper accumulation. WD may manifest as early-adulthood parkinsonism; and atypical cases may be difficult to distinguish from early-onset Parkinson's disease (EO-PD), a neurodegenerative disorder with onset ≤40 years of age. The aim of our study was to compare transcranial sonography (TCS)-magnetic resonance fusion imaging in WD and EO-PD and examine whether TCS can provide clinically useful information., Methods: We examined 22 WD, 16 EO-PD, and 24 healthy control subjects. We measured echogenicity and determined presence of MRI signal changes in T2-weighted images in the substantia nigra (SN) and lentiform nucleus (NL). TCS with the capability of magnetic resonance fusion and Virtual Navigator was used. The echogenicity indices of SN and NL were processed using digital image analysis to eliminate subjective evaluation errors., Results: Mean SN echogenicity index in EO-PD (39.8 ± 5.9 [SD]) was higher compared to WD (28.0 ± 4.6, p < 0.0001) and control subjects (28.8 ± 4.9, p < 0.0001). Mean NL echogenicity index was higher in WD (117.5 ± 37.0) compared to EO-PD (61.6 ± 5.4, p < 0.0001) and control subjects (54.9 ± 11.2, p < 0.0001). The SN hyperechogenicity had sensitivity 93.8%, and specificity 90.9%, while the NL hyperechogenicity had sensitivity 95.5% and specificity 93.8% for differentiation of WD and EO-PD. NL hyperechogenicity was more pronounced in WD subjects with putaminal MRI T2 hyperintensity (p < 0.05) but was also present in subjects without MRI abnormality., Conclusions: There are distinct TCS findings in WD and EO-PD complementary to MRI that can be utilized as highly sensitive and specific biomarkers of these disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Both animal studies and studies using deep brain stimulation in humans have demonstrated the involvement of the subthalamic nucleus (STN) in motivational and emotional processes; however, participation of this nucleus in processing human emotion has not been investigated directly at the single-neuron level. We analyzed the relationship between the neuronal firing from intraoperative microrecordings from the STN during affective picture presentation in patients with Parkinson's disease (PD) and the affective ratings of emotional valence and arousal performed subsequently. We observed that 17% of neurons responded to emotional valence and arousal of visual stimuli according to individual ratings. The activity of some neurons was related to emotional valence, whereas different neurons responded to arousal. In addition, 14% of neurons responded to visual stimuli. Our results suggest the existence of neurons involved in processing or transmission of visual and emotional information in the human STN, and provide evidence of separate processing of the affective dimensions of valence and arousal at the level of single neurons as well.

Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.

The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control.

Objective: To assist other eye movement investigators in the design and analysis of their studies., Methods: We examined basic saccadic eye movements and smooth pursuit in the horizontal and vertical directions with video-oculography in a group of 145 healthy subjects between 19 and 82 years of age., Results: Gender and education level did not influence eye movement metrics. With age, the latency of leftward and vertical pro- and antisaccades increased (p<0.001), velocity of upward prosaccades decreased (p<0.001), gain of rightward and upward prosaccades diminished (p<0.001), and the error rate of antisaccades increased (p<0.001). Prosaccades and antisaccades were influenced by the direction of the target, resulting in a right/left and up/down asymmetry. The skewness of the saccade velocity profile was stable throughout the lifespan, and within the range of saccades analyzed in the present study, correlated with amplitude and duration only for antisaccades (p<0.001)., Conclusions: Some eye movement metrics must be separated by the direction of movement, others according to subject age, while others may be pooled., Significance: This study provides important information for new oculomotor laboratories concerning the constitution of subject groups and the analysis of eye movement metrics., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Changes in motivational processing may play a role in weight gain and other non-motor side effects in Parkinson's disease (PD) patients treated with deep brain stimulation of the subthalamic nucleus., Objective/hypothesis: We aimed to assess changes in aversive and appetitive motivational activation using modulation of the acoustic blink reflex (ABR) by rewarding and aversive stimuli., Methods: ABR elicited during the viewing of erotic, food, aversive and neutral pictures was recorded in 11 off-medicated patients with the subthalamic stimulation switched ON and OFF, and in 11 control subjects., Results: ABR to erotic stimuli was larger in patients in the ON compared to the OFF condition and controls (P < 0.01). Aversive stimuli caused a larger increase in the ABR in patients with the ON condition than in controls (P < 0.05). Additionally, we found a negative correlation of the ABR magnitude to food pictures in the ON condition with weight gain following subthalamic stimulation (P < 0.01, after adjustment to OFF condition)., Conclusions: Our results suggest that subthalamic stimulation affects motivational processing. Subthalamic stimulation may disturb appetitive engagement by erotic cues and increase aversive activation in PD patients. Additionally, postoperative weight gain may be related to changes in the processing of food cues due to subthalamic stimulation., (Copyright © 2013 Elsevier Inc. All rights reserved.)