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Background and purpose: Acute health events, including infections, can trigger the onset of functional neurological disorder (FND). It was hypothesized that a proportion of people with long COVID might be experiencing functional symptoms. Methods: A systematic review of studies containing original data on long COVID was performed. The frequency and characteristics of neurological symptoms were reviewed, looking for positive evidence suggesting an underlying functional disorder and the hypothesized causes of long COVID. Results: In all, 102 studies were included in our narrative synthesis. The most consistently reported neurological symptoms were cognitive difficulties, headaches, pain, dizziness, fatigue, sleep-related symptoms and ageusia/anosmia. Overall, no evidence was found that any authors had systematically looked for positive features of FND. An exception was three studies describing temporal inconsistency. In general, the neurological symptoms were insufficiently characterized to support or refute a diagnosis of FND. Moreover, only 13 studies specifically focused on long COVID after mild infection, where the impact of confounders from the general effects of severe illness would be mitigated. Only one study hypothesized that some people with long COVID might have a functional disorder, and another eight studies a chronic-fatigue-syndrome-like response. Discussion: Neurological symptoms are prevalent in long COVID, but poorly characterized. The similarities between some manifestations of long COVID and functional disorders triggered by acute illnesses are striking. Unfortunately, the current literature is plagued by confounders, including the mixing of patients with initial mild infection with those with severe acute medical complications. The hypothesis that long COVID might in part correspond to a functional disorder remains untested.

Background Subthalamic nucleus (STN) stimulation is an effective treatment for Parkinson's disease and induced local field potential (LFP) changes that have been linked with clinical improvement. STN stimulation has also been used in dystonia although the internal globus pallidus is the standard target where theta power has been suggested as a physiomarker for adaptive stimulation. Objective We aimed to explore if enhanced theta power was also present in STN and if stimulation-induced spectral changes that were previously reported for Parkinson's disease would occur in dystonia. Methods We recorded LFPs from 7 patients (12 hemispheres) with isolated craniocervical dystonia whose electrodes were placed such that inferior, middle, and superior contacts covered STN, zona incerta, and thalamus. Results We did not observe prominent theta power in STN at rest. STN stimulation induced similar spectral changes in dystonia as in Parkinson's disease, such as broadband power suppression, evoked resonant neural activity (ERNA), finely-tuned gamma oscillations, and an increase in aperiodic exponents in STN-LFPs. Both power suppression and ERNA localize to STN. Based on this, single-pulse STN stimulation elicits evoked neural activities with largest amplitudes in STN, which are relayed to the zona incerta and thalamus with changing characteristics as the distance from STN increases. Conclusions Our results show that STN stimulation–induced spectral changes are a nondisease-specific response to high-frequency stimulation, which can serve as placement markers for STN. This broadens the scope of STN stimulation and makes it an option for other disorders with excessive oscillatory peaks in STN. © 2022 The Authors. Movement Disorders 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.

What if the patients most health professionals actively seek to avoid, people with "medically unexplained" or functional symptoms, were those who hold the key to a more successful, more rewarding and more just system of medical practice for all? I think they do. They force us to answer the question, to paraphrase Wittgenstein: What is left over, if I subtract the fact that I have a disease, from the fact that I am ill? Within the answer to this question is the human, participatory aspect of illness, which, despite hundreds of mission statements to the contrary from healthcare organisations the world over, is not adequately addressed in our medical training, practice and principles. We can and should do better, and this is a proposal for how.

Recent observations suggest that autism spectrum disorder (ASD) co-occurs in people with a functional neurological disorder (FND), but little systematic data are available on the relationship between FND and autism. The study aimed to assess the self-reported autistic traits via a standardized questionnaire and the prevalence of previously diagnosed ASD among people with FND and their 1st-degree relatives. We performed a survey of members of the patient organization FNDHope, using a self-completed questionnaire for screening for autistic traits and ASD: the adult autism subthreshold spectrum (AdAS spectrum). There were 344 respondents diagnosed with FND with a mean age of 39.8 ± 11.6 years (female sex 90%). Eight per cent of respondents volunteered a previous diagnosis of ASD, and 24% reported a 1st-degree relative with a formal diagnosis of ASD, mostly their children. We found that 69% of respondents had scores in the AdAS spectrum indicating a clinically significant ASD and 21% indicating autistic traits. Further studies are needed to provide more evidence regarding the prevalence of ASD in people with FND and how this may influence the aetiology, treatment selection and prognosis.

Functional neurological disorder (FND) is characterized by neurological symptoms that cannot be explained by a structural neurological cause. Among the different aetiological models that have been proposed for FND, of note is the Bayesian predictive coding model, which posits that perception relies on top-down cortical predictions (priors) to infer the source of incoming sensory information. This model can also apply to non-pathological experiences, such as placebo and nocebo effects, wherein sensory information is shaped by prior expectations and learning. To date, most studies of the relationship between placebo and nocebo effects and FND have focused on the use of placebos for diagnosis and treatment of FND. Here, we propose that this relationship might go beyond diagnosis and therapy. We develop a framework in which shared cognitive, personality and neuroanatomical factors justify the consideration of a deeper link between FND and placebo and nocebo effects. This new perspective might offer guidance for clarification of the pathogenesis of FND and for the identification of potential biomarkers and therapeutic targets.

Pain is a frequent and poorly treated symptom of Parkinson’s disease, mainly due to scarce knowledge of its basic mechanisms. In Parkinson’s disease, deep brain stimulation of the subthalamic nucleus is a successful treatment of motor symptoms, but also might be effective in treating pain. However, it has been unclear which type of pain may benefit and how neurostimulation of the subthalamic nucleus might interfere with pain processing in Parkinson’s disease. We hypothesized that the subthalamic nucleus may be an effective access point for modulation of neural systems subserving pain perception and processing in Parkinson’s disease. To explore this, we discuss data from human neurophysiological and psychophysical investigations. We review studies demonstrating the clinical efficacy of deep brain stimulation of the subthalamic nucleus for pain relief in Parkinson’s disease. Finally, we present some of the key insights from investigations in animal models, healthy humans and Parkinson’s disease patients into the aberrant neurobiology of pain processing and consider their implications for the pain-relieving effects of subthalamic nucleus neuromodulation. The evidence from clinical and experimental studies supports the hypothesis that altered central processing is critical for pain generation in Parkinson’s disease and that the subthalamic nucleus is a key structure in pain perception and modulation. Future preclinical and clinical research should consider the subthalamic nucleus as an entry point to modulate different types of pain, not only in Parkinson’s disease but also in other neurological conditions associated with abnormal pain processing.

Background\ud Evidence supports that neurodevelopmental diseases, such as Tourette syndrome (TS), may involve dysfunctional neural‐immune crosstalk. This could lead to altered brain maturation and differences in immune and stress responses. Dendritic cells (DCs) play a major role in immunity as professional antigen‐presenting cells; changes in their frequency have been observed in several autoimmune conditions.\ud \ud Methods\ud In 18 TS patients (15 on stable pharmacological treatment, three unmedicated) and 18 age‐matched healthy volunteers (HVs), we explored circulating blood‐derived DCs and their relationship with clinical variables and brain metabolites, measured via proton magnetic resonance spectroscopy (1H‐MRS). DC subsets, including plasmacytoid and myeloid type 1 and 2 dendritic cells (MDC1, MDC2), were studied with flow cytometry. 1H‐MRS was used to measure total choline, glutamate plus glutamine, total creatine (tCr), and total N‐acetylaspartate and N‐acetylaspartyl‐glutamate levels in frontal white matter (FWM) and the putamen.\ud \ud Results\ud We did not observe differences in absolute concentrations of DC subsets or brain inflammatory metabolites between patients and HVs. However, TS patients manifesting anxiety showed a significant increase in MDC1s compared to TS patients without anxiety (p = 0.01). We also found a strong negative correlation between MDC1 frequency and tCr in the FWM of patients with TS (p = 0.0015), but not of HVs.\ud \ud Conclusion\ud Elevated frequencies of the MDC1 subset in TS patients manifesting anxiety may reflect a proinflammatory status, potentially facilitating altered neuro‐immune crosstalk. Furthermore, the strong inverse correlation between brain tCr levels and MDC1 subset frequency in TS patients suggests a potential association between proinflammatory status and metabolic changes in sensitive brain regions.

BackgroundPatients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation reflects disembodiment, which may be related to changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalogram (EEG) marker of interoceptive processing.AimTo assess whether alterations in interoceptive processing indexed by HEP occur prior to FS and compare this with epileptic seizures (ES).MethodsHEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and were compared between interictal and preictal states. HEP amplitude difference was calculated as preictal HEP amplitude minus interictal HEP amplitude. A receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of HEP amplitude difference in discriminating FS from ES.ResultsThe FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (effect size rB=0.612, false discovery rate (FDR)-corrected q=0.030) and C4 (rB=0.600, FDR-corrected q=0.035). No differences in HEP amplitude were found between states in the ES group. Between diagnostic groups, HEP amplitude difference differed between the FS and ES groups at F8 (rB=0.423, FDR-corrected q=0.085) and C4 (rB=0.457, FDR-corrected q=0.085). Using HEP amplitude difference at frontal and central electrodes plus sex, we found that the ROC curve demonstrated an area under the curve of 0.893, with sensitivity=0.840 and specificity=0.842.ConclusionOur data support the notion that aberrant interoception occurs prior to FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS and may have diagnostic utility in differentiating FS and ES.

Functional neurological disorder (FND) is a prevalent, disabling and costly condition at the neurology-psychiatry intersection. After being marginalized in the late 20(th) century, there has been renewed interest in this field. In this article, we review advances that have occurred over the past decade (2011-2020) across diagnosis, mechanisms, etiologies, treatments, and stigma in patients with motor functional neurological disorder (mFND, i.e., functional movement disorder and functional limb weakness). In each content area, we also discuss the implications of recent advances and suggest future directions that will help continue the momentum of the past decade. In diagnosis, a major advance has been the emphasis on rule-in physical signs that are specific for hyperkinetic and hypokinetic functional motor symptoms. Mechanistically, greater importance has been given to determining ‘how’ functional neurological symptoms develop, highlighting roles for mis-directed attention, expectation and self-agency, as well as abnormal influences of emotion/threat processing brain areas on motor control circuits. Etiologically, while roles for adverse life experiences remain of interest in mFND, there is recognition of other etiologic contributors, and efforts are needed to investigate links between etiological factors and mechanisms. This decade has seen the first randomized controlled trials for physiotherapy, multidisciplinary rehabilitation and psychotherapy performed in the field, with consensus recommendations for physiotherapy, occupational therapy and outcome measures also published. Across patients, clinicians, healthcare systems and society, stigma remains a major concern. While challenges persist, a patient-centered integrated clinical neuroscience approach is primed to carry forward the momentum of the past decade into the future.

We describe a patient who presented with gender identity dysphoria and stroke-like symptoms who we diagnosed with Munchausen's syndrome (factitious disorder). We discuss whether a brain lesion in the left frontal cortex is a possible risk factor, and support this hypothesis through neuropsychological investigation, EEG abnormalities, and a personality assessment. This case report supports previous suggestions that underlying brain disease/lesions might be risk factors for Munchausen's syndrome (factitious disorder).

BACKGROUND AND PURPOSE Functional neurological disorder (FND) is a common diagnosis within neurology. Effective communication of the diagnosis is known to be an important part of treatment and can result in reduction or cessation of symptoms, as well as decreased healthcare utilisation. A single group education session, facilitated by professionals commonly involved in the care of patients with FND, was developed to further enhance patients' and relatives' understanding and acceptance of diagnosis. METHODS Patients and relatives attending a single education session were asked to complete self-report ratings of understanding of diagnosis, acceptance of diagnosis, belief in treatability and hopefulness regarding recovery, at the beginning and end of the session. Satisfaction data were also collected. RESULTS Data were obtained from 193 patients and 153 relatives. Patients had experienced a median duration of symptoms of 4 years, and more than 80% of patients reported more than one functional neurological symptom. There were significant increases in terms of understanding, acceptance, belief in treatability and hopefulness for patients and relatives. Effect sizes ranged from large for improved understanding of FND to small-to-medium for increased agreement with FND diagnosis. High levels of satisfaction were also reported. CONCLUSIONS A multidisciplinary, single group education session is an effective and acceptable method of increasing understanding and acceptance of an FND diagnosis, even for patients with a long duration of symptoms and high symptom burden. It could help improve readiness for further treatment.

Objective\ud Dissociative traits represent a disturbance in selfhood that may predispose to, and trigger, functional seizures (FSs). The predictive representation and control of the internal physiological state of the body (interoception) are proposed to underpin the integrity of the sense of self (“minimal selfhood”). Therefore, discrepancies between objective and subjective aspects of interoception may relate to symptom expression in patients with FSs. Here, we tested whether individual differences in trait measures of interoception relate to dissociative symptoms, and whether state interoceptive deficits predict FS occurrence.\ud \ud Methods\ud Forty‐one participants with FSs and 30 controls completed questionnaire ratings of dissociation, and measures of (1) interoceptive accuracy (IA)—objective performance on heartbeat detection tasks; (2) trait interoceptive sensibility—subjective sensitivity to internal sensations (using the Porges Body Perception Questionnaire); and (3) state interoceptive sensibility—subjective trial‐by‐trial measures of confidence in heartbeat detection. Interoceptive trait prediction error (ITPE) was calculated from the discrepancy between IA and trait sensibility, and interoceptive state prediction error (ISPE) from the discrepancy between IA and state sensibility.\ud \ud Results\ud Patients with FSs had significantly lower IA and greater trait interoceptive sensibility than healthy controls. ITPE was the strongest predictor of dissociation after controlling for trait anxiety and depression in a regression model. ISPE correlated significantly with FS frequency after controlling for state anxiety.\ud \ud Significance\ud Patients with FSs have disturbances in interoceptive processing that predict both dissociative traits reflecting the disrupted integrity of self‐representation, and the expression of FSs. These findings provide insight into the pathophysiology of functional neurological disorder, and could lead to novel diagnostic and therapeutic approaches.

Functional neurological disorder (FND) is a common cause of persistent and disabling neurological symptoms. These symptoms are varied and include abnormal control of movement, episodes of altered awareness resembling epileptic seizures and abnormal sensation and are often comorbid with chronic pain, fatigue and cognitive symptoms. There is increasing evidence for the role of neurologists in both the assessment and management of FND. The aim of this review is to discuss strategies for the management of FND by focusing on the diagnostic discussion and general principles, as well as specific treatment strategies for various FND symptoms, highlighting the role of the neurologist and proposing a structure for an interdisciplinary FND service.

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).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.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).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.

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022., 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., The study was supported by the Ministry of Health of the Czech Republic, AZV No. 16-29651A.

Hypoglycaemic coma can present with acute neurological dysfunction mimicking stroke. It may be masked by normoglycaemia due to physiological compensatory mechanisms (Somogyi phenomenon). Specific MR brain scan changes should alert the clinician to consider this alternative to stroke in the acute setting in patients with a history of recurrent hypoglycaemia, even when the blood glucose is not low at presentation. Rapid identification and treatment of hypoglycaemia may confer a good prognosis with radiological resolution.

Persistent symptoms following a minor head injury can cause significant morbidity, yet the underlying mechanisms for this are poorly understood. The shortcomings of the current terminology that refer to non-specific symptom clusters is discussed. This update considers the need for a multi-dimensional approach for the heterogenous mechanisms driving persistent symptoms after mild traumatic brain injury. Relevant pathophysiology is discussed to make the case for mild traumatic brain injury to be conceptualized as an interface disorder spanning neurology, psychiatry and psychology. The relevance of pre-injury factors, psychological co-morbidities and their interaction with the injury to produce persistent symptoms are reviewed. The interplay with psychiatric diagnoses, functional and somatic symptom disorder presentations and the influence of the medicolegal process is considered. The judicious use and interpretation of investigations given the above complexity is discussed, with suggestions of how the explanation of the diagnostic formulation to the patient can be tailored, including insight into the above processes, to aid recovery. Moving beyond the one-dimensional concept of ‘postconcussional syndrome’ and reframing the cause of persistent symptoms following mild traumatic brain injury in a bio-psycho-socio-ecological model will hopefully improve understanding of the underlying contributory mechanistic interactions and facilitate treatment.

A characteristic and intriguing feature of functional neurological disorder is that symptoms typically manifest with attention and improve or disappear with distraction. Attentional phenomena are therefore likely to be important in functional neurological disorder, but exactly how this manifests is unknown. The aim of the study was to establish whether in functional tremor the attentional focus is misdirected, and whether this misdirection is detrimental to the movement, or rather reflects a beneficial compensatory strategy. Patients with a functional action tremor, between the ages of 21–75, were compared to two age and gender matched control groups: healthy control participants and patients with an organic action tremor. The groups included between 17 and 28 participants. First, we compared the natural attentional focus on different aspects of a reaching movement (target, ongoing visual feedback, proprioceptive-motor aspect). This revealed that the attentional focus in the functional tremor group, in contrast to both control groups, was directed to ongoing visual feedback from the movement. Next, we established that all groups were able to shift their attentional focus to different aspects of the reaching movement when instructed. Subsequently, the impact of attentional focus on the ongoing visual feedback on movement performance was evaluated under several conditions: the reaching movement was performed with direct, or indirect visual feedback, without any visual feedback, under three different instruction conditions (as accurately as possible/very slowly/very quickly) and finally as a preparatory movement that was supposedly of no importance. Low trajectory length and low movement duration were taken as measures of good motor performance. For all three groups, motor performance deteriorated with attention to indirect visual feedback, to accuracy and when instructed to move slowly. It improved without visual feedback and when instructed to move fast. Motor performance improved, in participants with functional tremor only, when the movement was performed as a preparatory movement without any apparent importance. In addition to providing experimental evidence for improvement with distraction, we found that the normal allocation of attention during aimed movement is altered in functional tremor. Attention is disproportionately directed towards the ongoing visual feedback from the moving hand. This altered attentional focus may be partly responsible for the tremor, since it also worsens motor performance in healthy control participants and patients with an organic action tremor. It may have its detrimental impact through interference with automatic movement processes, due to a maladaptive shift from lower- to higher-level motor control circuitry., Huys et al. report that attention in functional tremor is misdirected onto a movement’s ongoing visual feedback. This altered attentional focus impairs movement in patients with organic tremor and healthy control participants, thus implying a degree of causality. The mechanism may be a maladaptive shift from implicit to explicit movement control.

Musician’s dystonia presents with a persistent deterioration of motor control during musical performance. A predominant hypothesis has been that this is underpinned by maladaptive neural changes to the somatotopic organization of finger representations within primary somatosensory cortex. Here, we tested this hypothesis by investigating the finger-specific activity patterns in the primary somatosensory and motor cortex using functional MRI and multivariate pattern analysis in nine musicians with dystonia and nine healthy musicians. A purpose-built keyboard device allowed characterization of activity patterns elicited during passive extension and active finger presses of individual fingers. We analysed the data using both traditional spatial analysis and state-of-the art multivariate analyses. Our analysis reveals that digit representations in musicians were poorly captured by spatial analyses. An optimized spatial metric found clear somatotopy but no difference in the spatial geometry between fingers with dystonia. Representational similarity analysis was confirmed as a more reliable technique than all spatial metrics evaluated. Significantly, the dissimilarity architecture was equivalent for musicians with and without dystonia. No expansion or spatial shift of digit representation maps were found in the symptomatic group. Our results therefore indicate that the neural representation of generic finger maps in primary sensorimotor cortex is intact in musician’s dystonia. These results speak against the idea that task-specific dystonia is associated with a distorted hand somatotopy and lend weight to an alternative hypothesis that task-specific dystonia is due to a higher-order disruption of skill encoding. Such a formulation can better explain the task-specific deficit and offers alternative inroads for therapeutic interventions.

BACKGROUND: There is a long-standing research history on the presumed psychological origin of functional movement disorders. Most studies do not address the heterogeneity in functional movement disorders and do not distinguish between risk factors, causes and consequences. We studied the associations between negative affect and objective as well as subjective symptom levels in patients with functional and organic tremor.METHODS: Thirty-three patients with a functional (14) or organic tremor (19) completed a web-based diary on subjective symptom burden and negative affect, five times a day for 30 days (total number of observations = 4759). During the same period, the participants wore an accelerometer to objectively record tremor. Vector autoregressive modelling was used to determine the time-lagged and contemporaneous associations between negative affect and objective/subjective tremor symptoms, both on an individual and a group level.RESULTS: In contrast to previous literature, patients with a functional or organic tremor showed a weak contemporaneous association between negative affect and objective/subjective tremor symptoms (on average r = 0.038 and 0.174 respectively). Time-lagged associations between negative affect and objective/subjective tremor symptoms were mixed in effect and direction and only present in a subset of patients, with no differences between patients with functional or organic tremor.CONCLUSIONS: Negative affect is only weakly associated with objective/subjective tremor symptoms, both on the contemporaneous and time-lagged associations, and these associations were mainly similar between patients with functional or organic tremor. These results argue against a strong influence of daily stress on tremor symptoms in patients with a functional or organic tremor.

ObjectivesEvaluate patients’ and healthcare professionals’ attitudes towards deceptive and open-label placebo treatments, its perceived effectiveness and current use.MethodsA sixteen-item anonymous survey explored attitudes towards deceptive and open-label placebo treatments in clinical practice, its perceived effectiveness and current use. The following groups completed the survey: 288 people with a neurological condition, 138 people with a functional neurological disorder, 61 people with a medical condition, 59 healthy controls and 112 healthcare professionals, of which 45 neurologists and 20 psychiatrists/psychologists.ResultsThe overall attitude to deceptive placebo treatments was favourable amongst non-professionals (69% in favour). The healthcare professionals were more conservative, with only 48% being in favour. However, a considerable number strongly opposed deceptive placebo: 15% of medical patients, 11% of neurological patients and 22% of patients with a functional neurological disorder. Forty-one percent of functional neurological disorder patients, 46% of patients with presumed organic conditions and 70% of healthy controls believed that a deceptive placebo would improve their own symptoms. Healthcare professionals estimated that deceptive placebo treatments would be effective in 31% of purely organic symptoms and in 55% of purely functional symptoms. Major concerns surrounding deceptive placebo involved undermining trust in the medical profession. There was marked scepticism with regards to open-label placebo in all groups, with the general underlying belief that open-label placebo is fairly ineffective.Two-thirds of healthcare professionals had never used deceptive nor open-label placebo. Those who had used it, had done so rarely and mostly for non-specific or functional symptoms or for diagnostic purposes.ConclusionsDespite a generally perceived high effectiveness of deceptive placebo treatments, its prohibition in the UK seems to be in line with general concerns and some strong opposition. Future studies will show if the negative attitude to open-label placebo is justified or if this ethically viable option deserves more consideration.

Background Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration. Objectives The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. Methods We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. Results PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology. Conclusions Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUNDParkinson’s disease is the second most common neurodegenerative condition and associated with increasing cognitive dysfunction as the disease progresses. However, subtle cognitive deficits can be detected at diagnosis in 42% of individuals, suggesting that damage may already be present. Our aim was to determine clinical and structural differences in those recently diagnosed with PD who later develop cognitive impairment, and whether these changes predict future cognitive decline.METHODSClinical and imaging data was acquired from the Parkinson’s Progression Markers Initiative for 318 individuals with a diagnosis of Parkinson’s disease and baseline 3T T1-weighted MRI. The cohort was divided according to cognitive status over follow-up, with 9 individuals developing Parkinson’s disease dementia, 102 developing mild cognitive impairment and 207 remaining cognitively unaffected.FINDINGSAt baseline, those who went on to develop cognitive impairment (mild cognitive impairment or dementia) wereolder with more severe motor and non-motor symptoms (anosmia, rapid eye movement sleep behaviour disorder, depression). Grey matter loss was present in those destined for Parkinson’s disease dementia in theprecuneus, hippocampi, primary olfactory cortex, lingual gyrus, temporal cortex and cerebellum. Those who later developed mild cognitive impairment had an attenuated but similar pattern ofgrey matter loss in the temporal lobe, lingual gyrus and cerebellum. Using support vector machines with a feature selection step, future cognitive impairment could be predicted using 11 clinical variables (AUC = 0.81), structural imaging (AUC = 0.72) or a combination of these two modalities (AUC = 0.85). These models more accurately predicted those who developed dementia (subgroup sensitivity 100%).INTERPRETATIONSignificant abnormalities in cortical structure is present at least three years before dementia manifests in Parkinson’s disease, with associated differences in clinical profiles. Combining this data provides a technique to accurately identify future cognitive impairment, providing a non-invasive way to stratify individuals early on.

Structured AbstractBackgroundImpaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered.ObjectiveTo systematically examine the influence of dystonia, dystonia subtype and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex.MethodsOriginal neurophysiological data from all published studies were shared to an age and sex matched control group. Two raters blinded to participant identity scored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block was entered into a mixed repetitive measures model.ResultsMuch variability of eyeblink conditioning was seen in both groups. All dystonia versus controls showed no difference in conditioning (p=0.517). Analysis of dystonia subgroup, with age and sex as covariates did not reveal evidence that eyeblink conditioning is impaired in specific subtypes (cervical dystonia, DYT-TOR1A, DYT-THAP1 or focal hand dystonia). The presence of tremor did not significantly influence levels of eyeblink conditioning.ConclusionsCollaborative efforts such as this article allow larger number of patients to be evaluated and provide more balanced estimates of disease effects over experimental outcomes. Intact eyeblink conditioning is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question.

Functional neurological disorder is a common and phenomenologically diverse condition. Resultant disability is caused by both the dominant clinical presentation, e.g. paralysis or tremor and additional symptomatology such as cognitive symptoms. Recently the similarity of neuropsychiatric profiles across a range of functional syndromes has been highlighted. This is suggestive of a common underlying mechanism with a theoretical deficit of information processing proposed. Identification of an experimental biomarker for such deficits could offer novel assessment and therapeutic strategies. In this study, we took the temporal discrimination threshold as a paradigm that can be used to model sensory processing in functional movement disorders. Our hypothesis was that we would be able to delineate markers of slowed information processing in this paradigm removed from the phenomenological presentation with a movement disorder. We recorded both response accuracy and reaction time in a two-choice temporal resolution/discrimination task in 36 patients with functional movement disorders and 36 control subjects. A psychometric function was fitted to accuracy data for each individual revealing both abnormally high threshold values (P = 0.0053) and shallow psychometric slopes in patients (P = 0.0015). Patients with functional movement disorders also had significantly slower response times (P = 0.0065). We then used a well-established model for decision-making (the drift diffusion model) that uses both response accuracy and reaction time data to estimate mechanistic physiological dimensions of decision-making and sensory processing. This revealed pathologically reduced drift rate in the patient group, a parameter that quantifies the quality and rate of information accumulation within this sensory task (P = 0.002). We discuss how the deficits we observed in patients with functional movement disorders are likely to stem from abnormal allocation of attention that impairs the quality of sensory information available. Within a predictive coding framework sensory information could be down-weighted in favour of predictions encoded by the prior. Our results therefore offer a parsimonious account for a range of experimental and clinical findings. Reduced drift rate is a potential experimental marker for a generalized deficit in information processing across functional disorders that allows diverse symptomatology to be quantified under a common disease framework.

The prolonged reaction times seen in Parkinson's disease (PD) have been linked to a dopaminergic-dependent deficit in using prior information to prepare responses, but also have been explained by an altered temporal processing. However, an underlying cognitive mechanism linking dopamine, temporal processing and response preparation remains elusive. To address this, we studied PD patients, with or without medication, and age-matched healthy individuals using a variable foreperiod task requiring speeded responses to a visual stimulus occurring at variable onset-times, with block-wise changes in the temporal predictability of visual stimuli. Compared with controls, unmedicated patients showed impaired use of prior information to prepare their responses, as reflected by slower reaction times, regardless of the level of temporal predictability. Crucially, after dopamine administration normal performance was restored, with faster responses for high temporal predictability. Using Bayesian hierarchical drift-diffusion modelling, we estimated the parameters that determine temporal preparation. In this theoretical framework, impaired temporal preparation under dopaminergic depletion was driven by inflexibly high decision boundaries (i.e. participants were always extremely cautious). This indexes high levels of uncertainty about temporal predictions irrespectively of stimulus onset predictability. Our results suggest that dopaminergic depletion in PD affects the uncertainty of predictions about the timing of future events (temporal predictions), which are crucial for the anticipatory preparation of responses. Dopamine, which is affected in PD, controls the ability to predict the timing of future events., Highlights • Parkinson’s patients cannot use prior temporal information to prepare motor responses. • Temporal preparation is restored to normality by dopamine administration. • Temporal preparation declines with increasing uncertainty about temporal predictions. • Dopaminergic depletion linked to inflexibly high uncertainty in temporal predictions. • Dopamine regulates the uncertainty of predictions about the timing of future events.

Background:Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia.Methods:We performed a systematic review of studies of the treatment of tardive dyskinesia. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.Results:Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada.Conclusion:Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.

Background: Patients with functional motor disorder are perceived as difficult by health care professionals, but we know very little about the patients' perspective. Understanding the experiences and perceptions of patients could help to improve clinical services and patient outcomes.Purpose: To explore the experiences and perspectives of patients with functional motor disorder using qualitative research methods.Methods: This qualitative study was embedded within a feasibility study of specialist physiotherapy. Eleven patients with functional motor disorder participated in semi-structured qualitative interviews prior to receiving treatment. The interview transcripts were subjected to an inductive thematic analysis.Results: The data were arranged into six themes: (1) the burden of living with functional motor disorder; (2) nobody knew what was wrong; (3) dissatisfaction with psychological explanations; (4) patients feel abandoned; (5) iatrogenic harm; and (6) powerlessness.Discussion and Conclusion: The study participants experienced substantial physical and emotional burdens associated with functional motor disorder. They were generally dissatisfied with psychological explanations for their symptoms and commonly felt misunderstood and abandoned by health care professionals, which appeared to leave them vulnerable to iatrogenic harm. A lack of understanding of functional motor disorder left participants feeling unable to help themselves. This research highlights a number of inadequacies within current clinical services for patients with functional motor disorder.Implications for rehabilitationCareful communication is required to help patients understand and accept the diagnosis of functional motor disorder.It is important to listen to the patient's narrative in order to help them make sense of their illness experience.A nuanced biopsychosocial explanatory model is needed to help patients understand how psychological factors can be relevant to physical symptoms and symptoms that are often perceived to be precipitated by a physical event.A lack of understanding and acceptance of the diagnosis may leave patients vulnerable to iatrogenic harm and powerless to help themselves.

DystoniaNet; Xarxa europea; Distonia DytoniaNet; Red europea; Distonía DystoniaNet; European network; Dystonia Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the American Dystonia Coalition, the European Cooperation in Science and Technology (COST—which however only existed for a limited time), and the Dutch DystonieNet project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.