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A major concept in cognitive neuroscience is that brains are “prediction machines”. Yet, conceptual frameworks on how perception and action become integrated still lack the concept of predictability and it is unclear how neural processes may implement predictive coding during dynamic perception-action integration. We show that distinct neurophysiological mechanisms of nonlinearly directed connectivities in the theta and alpha band between cortical structures underlie these processes. During the integration of perception and motor codes, especially theta band activity in the insular cortex and temporo-hippocampal structures is modulated by the predictability of upcoming information. Here, the insular cortex seems to guide processes. Conversely, the retrieval of such integrated perception-action codes during actions heavily relies on alpha band activity. Here, directed top-down influence of alpha band activity from inferior frontal structures on insular and temporo-hippocampal structures is key. This suggests that these top-down effects reflect attentional shielding of retrieval processes operating in the same neuroanatomical structures previously involved in the integration of perceptual and motor codes. Through neurophysiology, the present study connects predictive coding mechanisms with frameworks specifying the dynamic integration of perception and action.

Abstract Background Motor and vocal tics are the main symptom of Gilles de la Tourette-syndrome (GTS). A particular complex vocal tic comprises the utterance of swear words, termed coprolalia. Since taboo words are socially inappropriate, they are normally suppressed by people, which implies cognitive control processes. Method To investigate the control of the unintentional pronunciation of taboo words and the associated processes of conflict monitoring, we used the “Spoonerisms of Laboratory Induced Predisposition” (SLIP) paradigm. Participants read multiple inductor word pairs with the same phonemes, followed by pronouncing a target pair with inverse phonemes. This led to a conflict between two competing speech plans: the correct word pair and the word pair with inverted phonemes. Latter speech error, a spoonerism, could result in a neutral or taboo word. We investigated 19 patients with GTS and 23 typically developed controls (TDC) and measured participants’ electroencephalography (EEG) during the SLIP task. Results At the behavioral level less taboo than neutral word spoonerisms occurred in both groups without significant differences. Event-related brain potentials (ERP) revealed a difference between taboo and neutral word conditions in the GTS group at the midline electrodes in a time range of 250–400 ms after the speech prompt, which was not found in the TDC group. The extent of this effect depended on the number of inductor word pairs, suggesting an increasing level of cognitive control in the GTS group. Conclusion The differences between taboo and neutral word conditions in patients with GTS compared to TDC suggest an altered recruitment of cognitive control processes in GTS, likely enlisted to suppress taboo words.

Executive functions are essential for adaptive behavior. One executive function is the so-called ‘interference control’ or conflict monitoring another one is inhibitory control (i.e., action restraint and action cancelation). Recent evidence suggests an interplay of these processes, which is conceptually relevant given that newer conceptual frameworks imply that nominally different action/response control processes are explainable by a small set of cognitive and neurophysiological processes. The existence of such overarching neural principles has as yet not directly been examined. In the current study, we therefore use EEG tensor decomposition methods, to look into possible common neurophysiological signatures underlying conflict-modulated action restraint and action cancelation as mechanism underlying response inhibition. We show how conflicts differentially modulate action restraint and action cancelation processes and delineate common and distinct neural processes underlying this interplay. Concerning the spatial information modulations are similar in terms of an importance of processes reflected by parieto-occipital electrodes, suggesting that attentional selection processes play a role. Especially theta and alpha activity seem to play important roles. The data also show that tensor decomposition is sensitive to the manner of task implementation, thereby suggesting that switch probability/transitional probabilities should be taken into consideration when choosing tensor decomposition as analysis method. The study provides a blueprint of how to use tensor decomposition methods to delineate common and distinct neural mechanisms underlying action control functions using EEG data.

Abstract Background Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington’s disease (HD). Objectives To identify stimulation-dependent effects on motor symptoms and to determine if these alterations are associated with the local impact of DBS on different pallidal parcellations. Methods We prospectively evaluated the effects of bilateral GPi-DBS within one year in 5 HD patients. We evaluated the effects of GPi-DBS on choreatic symptoms and UHDRS. Electrode placement in the pallidum was localized, and the local impact of DBS was estimated. Results The chorea subscore (p

Abstract Background In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. Methods An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. Results 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. Conclusions This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

In the literature on human action control, it is assumed that features of stimuli (S) and responses (R) are integrated into internal representations (so-called event files) that are involved in the execution of an action. Experimentally, the impact of this integration on action control is typically analyzed via S-R binding effects. Recent theorizing in the BRAC framework (Frings et al., 2020) suggests to disentangle the processes of S-R binding proper from S-R retrieval as two independent components contributing to S-R binding effects. Since the literature on age effects on S-R binding effects is scarce and does not provide information on whether the existing findings about the two processes can be generalized to older age groups, this is the first study addressing the effects of older age separately on S-R binding proper vs. S-R retrieval. In two established variants of S-R binding tasks (cumulative n = 262), we contrasted binding (by using a saliency manipulation at the time of binding proper) versus retrieval processes (by manipulating the onset of the distractor at the time of retrieval), replicating previous results in younger (18–30 years) and also in older healthy controls (50–70 years). We therefore found no evidence for age effects on S-R binding proper or S-R retrieval. We thus conclude that the processes contributing to S-R binding effects are – at least in the age groups analyzed in this study – robust and age-independent. Statement of significance: In human action control, binding proper and retrieval of features in stimulus-response episodes typically lead to so-called S-R binding effects. Against the background of recent theorizing, binding proper and retrieval should be studied independently. In this article, we ran a younger and an older age group and analyzed possible age-related differences in integration or retrieval. Both groups showed the expected pattern for binding and retrieval as expected from the literature.

In recent years, there has been many efforts to establish a comprehensive theoretical framework explaining the working mechanisms involved in perception-action integration. This framework stresses the importance of the immediate past on mechanisms supporting perception-action integration. The present study investigates the neurophysiological principles of dynamic perception-action bindings, particularly considering the influence of the immediate history on action control mechanisms. For this purpose, we conducted an established stimulus-response binding paradigm during EEG recording. The SR-task measures stimulus-response binding in terms of accuracy and reaction time differences depending on the degree of feature overlap between conditions. Alpha, beta and theta band activity in distinct time domains as well as associated brain regions were investigated applying time-frequency analyses, a beamforming approach as well as correlation analyses. We demonstrate, for the first time, interdependencies of neuronal processes relying on the immediate past. The reconfiguration of an action seems to overwrite immediately preceding processes. The analyses revealed modulations of theta (TBA), alpha (ABA) and beta band activity (BBA) in connection with fronto-temporal structures supporting the theoretical assumptions of the considered conceptual framework. The close interplay of attentional modulation by gating irrelevant information (ABA) and binding and retrieval processes (TBA) is reflected by the correlation of ABA in all pre-probe-intervals with post-probe TBA. Likewise, the role of BBA in maintaining the event file until retrieval is corroborated by BBA preceding the TBA-associated retrieval of perception-action codes. Following action execution, TBA shifted towards visual association cortices probably reflecting preparation for upcoming information, while ABA and BBA continue to reflect processes of attentional control and information selection for goal-directed behavior. The present work provides the first empirical support for concepts about the neurophysiological mechanisms of dynamic management of perception and action.

Myoclonus-Dystonia is a rare, neurological movement disorder, clinically characterized by myoclonic jerks and dystonic symptoms, such as cervical dystonia and writer’s cramp. Psychiatric symptoms, like anxiety, depression, and addiction, are frequently reported. Monogenic Myoclonus-Dystonia is mostly caused by pathogenic variants in the ε-sarcoglycan gene, which is among other regions highly expressed in the cerebellum. The current pharmacological treatment is not satisfactory. Neurophysiological and imaging studies in this patient population are scarce with partly heterogeneous results and sometimes important limitations. However, some studies point towards subcortical alterations, e.g., of the cerebellum and its connections. Further studies addressing previous limitations are important for a better understanding of the underlying pathology of Myoclonus-Dystonia and might build a bridge for the development of future treatment.

Abstract Goal-directed behavior requires integrated mental representations of perceptions and actions. The neurophysiological underpinnings of these processes, however, are not yet understood. It is particularly undetermined, which oscillatory activities in which brain regions are involved in the management of perception-action representations. We examine this question with a focus on response inhibition processes and show that the dynamics of perception-action representations reflected in theta band activity (TBA) are particularly evident in the supplementary motor area and the occipito-temporal cortex. Mental representations coded in alpha band activity (ABA) during perception-action integration are associated with the occipito-temporal cortex. Crucially, perception-action representations are exchanged between theta and alpha frequency bands. The results imply that ABA functions as dynamic top-down control over binding, retrieval and reconfiguration processes during response inhibition, which in turn are reflected by TBA. Our study thus highlights how the interplay of oscillatory activity enables the management of perception-action representations for goal-directed behavior.

Abstract It seems natural that motor responses unfold smoothly and that we are able to easily concatenate different components of movements to achieve goal-directed actions. Theoretical frameworks suggest that different motor features have to be bound to each other to achieve a coherent action. Yet, the nature of the “glue” (i.e., bindings) between elements constituting a motor sequence and enabling a smooth unfolding of motor acts is not well understood. We examined in how far motor feature bindings are affected by reward magnitude or the effects of an unsigned surprise signal. We show that the consistency of action file binding strength is modulated by unsigned surprise, but not by reward magnitude. On a conceptual and theoretical level, the results provide links between frameworks, which have until now not been brought into connection. In particular, theoretical accounts stating that only the unexpectedness (surprisingness) is essential for action control are connected to meta-control accounts of human action control.

Beste and colleagues propose a theoretical framework that reconsiders the functional relevance of oscillatory activity in the context of action control.

Abstract When facing particular combinations of stimuli and responses, people create temporary event-files integrating the corresponding stimulus and response features. Subsequent repetition of one or more of these features retrieves the entire event-file, which impairs performance if not all features are repeated (partial-repetition costs). In the literature, different decay functions have been reported presumably dependent on the type of feature that is repeated (e.g. target vs. distractor features). Here, we use a variant of the S1R1-S2R2 and distractor-response binding task and analyze for the first time target-based and distractor-based event-file decay functions within the same task and sample. While we found evidence for decay functions and also stronger retrieval due to target than distractor repetitions, slopes of the decay functions were comparable suggesting that the decay process itself is equal irrespective of the type of stimulus feature that is repeated. Our study thereby confirms overarching approaches that summarize paradigm specific findings with the same set of core processes.

An evaluation of predictions from the proposed BRAC framework of sensorimotor integration suggests that the catecholaminergic system might impact sensorimotor integration during response inhibition by modulating the stability of the representational content.

Abstract Premonitory urges preceding tics are a cardinal feature of Gilles de la Tourette syndrome (GTS), a developmental disorder usually starting during middle childhood. However, the temporal relation between urges and tics has only been investigated in adults. In 25 children and adolescents with GTS (8–18 years), we assess urge-tic associations, including inter-individual differences, correlation to clinical measures, and in comparison to a previously reported sample of adult GTS patients. Group-level analyses confirmed positive associations between urges and tics. However, at the individual level, less than half of participants showed positive associations, a similar proportion did not, and in two participants, the association was reversed. Tic expression and subjective urge levels correlated with corresponding clinical scores and participants with more severe tics during the urge monitor exhibited stronger urge-tic associations. Associations between reported urge levels and instantaneous tic intensity tended to be less pronounced in children and adolescents than in adult GTS patients. The observed heterogeneity of urge-tic associations cast doubt on the notion that tics are directly caused by urges. More severe tics may facilitate anticipation of tics and thereby lead to more pronounced urge-tic associations, consistent with a hypothesis of urges as a byproduct of tics.

Abstract Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia and parkinsonism. However, the effect of GCH1 mutations and levodopa treatment on motor control beyond simple movements, such as timing, action preparation and feedback processing, have not been investigated so far. In an active time estimation task with trial-by-trial feedback, participants indicated a target interval (1200 ms) by a motor response. We compared 12 patients tested (in fixed order) under their current levodopa medication ("ON") and after levodopa withdrawal ("OFF") to matched healthy controls (HC), measured twice to control for repetition effects. We assessed time estimation accuracy, trial-to-trial adjustment, as well as task- and feedback-related pupil-linked arousal responses. Patients showed comparable time estimation accuracy ON medication as HC but reduced performance OFF medication. Task-related pupil responses showed the reverse pattern. Trial-to-trial adjustments of response times were reduced in DRD, particularly OFF medication. Our results indicate differential alterations of time estimation accuracy and task-related arousal dynamics in DRD patients as a function of dopaminergic medication state. A medication-independent alteration of task repetition effects in DRD cannot be ruled out with certainty but is discussed as less likely.

Summary: TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.

Abstract The error-related negativity (ERN) is an event-related potential component indexing processes of performance monitoring during simple stimulus-response tasks: the ERN is typically enhanced for error processing and conflicting response representations. Investigations in healthy participants and different patient groups have linked the ERN to the dopamine system and to prefrontal information processing. As in patients with Tourette Syndrome (TS) both dopamine release and prefrontal information processing are impaired, we hypothesized that performance monitoring would be altered, which was investigated with magnetencephalography (MEG). We examined performance monitoring in TS patients by assessing the magnetic equivalent of the ERN (mERN). The mERN was investigated in tic-free trials of eight adult, unmedicated TS patients without clinically significant comorbidity and ten matched healthy controls while performing a Go/NoGo task in selected frontocentral channels. The analysis of the response-related amplitudes of the event-related magnetic field showed that TS patients, in contrast to controls, did not show earlier amplitude modulation (between 70 and 105 ms after response onset) depending on response type (errors or correct responses). In both groups significant mERN amplitudes in the time-window between 105 and 160 ms after response onset were detected thus pointing at only later error processing in TS patients. In TS patients, early error-related processing might be affected by an enhanced motor control triggered by a conflict between the targeted high task performance and tic suppression. TS patients seem to tend to initially process all responses as erroneous responses.

Transcranial current stimulation (tCS) techniques have been shown to induce cortical plasticity. As an important relay in the motor system, the cerebellum is an interesting target for plasticity induction using tCS, aiming to modulate its excitability and connectivity. However, until now it remains unclear, which is the most effective tCS method for inducing plasticity in the cerebellum. Thus, in this study, the effects of anodal transcranial direct current stimulation (tDCS), 50 Hz transcranial alternating current stimulation (50 Hz tACS), and high frequency transcranial random noise stimulation (tRNS) were compared with sham stimulation in 20 healthy subjects in a within-subject design. tCS was applied targeting the cerebellar lobe VIIIA using neuronavigation. We measured corticospinal excitability, short-interval intracortical inhibition (SICI), short-latency afferent inhibition (SAI), and cerebellar brain inhibition (CBI) and performed a sensor-based movement analysis at baseline and three times after the intervention (post1 = 15 min; post2 = 55 min; post3 = 95 min). Corticospinal excitability increased following cerebellar tACS and tRNS compared to sham stimulation. This effect was most pronounced directly after stimulation but lasted for at least 55 min after tACS. Cortico-cortical and cerebello-cortical conditioning protocols, as well as sensor-based movement analyses, did not change. Our findings suggest that cerebellar 50 Hz tACS is the most effective protocol to change corticospinal excitability.

Cerebellar transcranial alternating current stimulation (tACS) is an emerging non-invasive technique that induces electric fields to modulate cerebellar function. Although the effect of cortical tACS seems to be state-dependent, the impact of concurrent motor activation and the duration of stimulation on the effects of cerebellar tACS has not yet been examined. In our study, 20 healthy subjects received neuronavigated 50 Hz cerebellar tACS for 40 s or 20 min, each during performance using a motor sequence learning task (MSL) and at rest. We measured the motor evoked potential (MEP) before and at two time points after tACS application to assess corticospinal excitability. Additionally, we investigated the online effect of tACS on MSL. Individual electric field simulations were computed to evaluate the distribution of electric fields, showing a focal electric field in the right cerebellar hemisphere with the highest intensities in lobe VIIb, VIII and IX. Corticospinal excitability was only increased after tACS was applied for 40 s or 20 min at rest, and motor activation during tACS (MSL) cancelled this effect. In addition, performance was better (shorter reaction times) for the learned sequences after 20 min of tACS, indicating more pronounced learning under 20 min of tACS compared to tACS applied only in the first 40 s.

Background: Gilles de la Tourette Syndrome (GTS) is a neurodevelopmental disorder with a peak of symptom severity around late childhood and early adolescence. Previous findings in adult GTS suggest that changes in perception-action integration, as conceptualized in the theory of event coding framework, are central for the understanding of GTS. However, the neural mechanisms underlying these processes in adolescence are elusive. Methods: A total of 59 children/adolescents aged 9 to 18 years (n = 32 with GTS, n = 27 typically developing youths) were examined using a perception-action integration task (event file task) derived from the theory of event coding. Event-related electroencephalogram recordings (theta and beta band activity) were analyzed using electroencephalogram–beamforming methods. Results: Behavioral data showed robust event file binding effects in both groups without group differences. Neurophysiological data showed that theta and beta band activity were involved in event file integration in both groups. However, the functional neuroanatomical organization was markedly different for theta band activity between the groups. The typically developing group mainly relied on superior frontal regions, whereas the GTS group engaged parietal and inferior frontal regions. A more consistent functional neuroanatomical activation pattern was observed for the beta band, engaging inferior parietal and temporal regions in both groups. Conclusions: Perception-action integration processes lag behind in persisting GTS but not in the GTS population as a whole, underscoring differences in developmental trajectories and the importance of longitudinal investigations for the understanding of GTS. The findings corroborate known differences in the functional/structural brain organization in GTS and suggest an important role of theta band activity in these patients.

Abstract We present a female patient in her early twenties with global development delay, progressive ataxia, epilepsy, and myoclonus caused by a stop mutation in the SEMA6B gene. Truncating DNA variants located in the last exon of SEMA6B have recently been identified as a cause of autosomal dominant progressive myoclonus epilepsy. In many cases, myoclonus in the context of progressive myoclonic epilepsy is refractory to medical treatment. In the present case, treatment with zonisamide caused clinical improvement, particularly of positive and negative truncal myoclonus, considerably improving patient’s gait and thus mobility.

Abstract It is a common phenomenon that somatosensory sensations can trigger actions to alleviate experienced tension. Such “urges” are particularly relevant in patients with Gilles de la Tourette (GTS) syndrome since they often precede tics, the cardinal feature of this common neurodevelopmental disorder. Altered sensorimotor integration processes in GTS as well as evidence for increased binding of stimulus- and response-related features (“hyper-binding”) in the visual domain suggest enhanced perception–action binding also in the somatosensory modality. In the current study, the Theory of Event Coding (TEC) was used as an overarching cognitive framework to examine somatosensory-motor binding. For this purpose, a somatosensory-motor version of a task measuring stimulus–response binding (S-R task) was tested using electro-tactile stimuli. Contrary to the main hypothesis, there were no group differences in binding effects between GTS patients and healthy controls in the somatosensory-motor paradigm. Behavioral data did not indicate differences in binding between examined groups. These data can be interpreted such that a compensatory “downregulation” of increased somatosensory stimulus saliency, e.g., due to the occurrence of somatosensory urges and hypersensitivity to external stimuli, results in reduced binding with associated motor output, which brings binding to a “normal” level. Therefore, “hyper-binding” in GTS seems to be modality-specific.

Abstract Dystonia is conceptualized as a network disorder involving basal ganglia, thalamus, sensorimotor cortex and the cerebellum. The cerebellum has been implicated in dystonia pathophysiology, but studies testing cerebellar function in dystonia patients have provided equivocal results. This study aimed to further elucidate motor network deficits in cervical dystonia with special interest in the role of the cerebellum. To this end we investigated motor learning tasks, that differ in their dependence on cerebellar and basal ganglia functioning. In 18 cervical dystonia patients and 18 age matched healthy controls we measured implicit motor sequence learning using a 12-item serial reaction time task mostly targeting basal ganglia circuitry and motor adaptation and eyeblink conditioning as markers of cerebellar functioning. ANOVA showed that motor sequence learning was overall impaired in cervical dystonia (p = 0.01). Moreover, unlike healthy controls, patients did not show a learning effect in the first part of the experiment. Visuomotor adaptation and eyeblink conditioning were normal. In conclusion, these data lend support to the notion that motor learning deficits in cervical dystonia relate to basal ganglia-thalamo-cortical loops rather than being a result of defective cerebellar circuitry.

European clinical guidelines recommend the use of Exposure and Response Prevention (ERP) and Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatments for tic disorders. Although ongoing efforts in research are being made to understand the mechanisms underlying these behavioral approaches, as of yet, the neurophysiological mechanisms behind behavioral interventions are poorly understood. However, this is essential to tailor interventions to individual patients in order to increase compliance and efficacy. The Theory of Event Coding (TEC) and its derivative BRAC (Binding and Retrieval in Action Control) provide a theoretical framework to investigate cognitive and neural processes in the context of tic disorders. In this context, tics are conceptualized as a phenomenon of enhanced perception–action binding, with premonitory urges constituting the perceptual and the motor or vocal expression constituting the action part of an event file. Based on this, CBIT is assumed to strongly affect stimulus–response binding in the context of response selection, whereas the effects of ERP presumably unfold during stimulus–response binding in the response inhibition context. Further studies are needed to clarify the neurophysiological processes underlying behavioral interventions to enable the individualization and further development of therapeutic approaches for tic disorders.

Increased activity in the left inferior parietal cortex (BA40) plays a role in the generation of tics in the Gilles de la Tourette syndrome (GTS). Thus, inhibitory repetitive transcranial magnetic stimulation (rTMS) applied to BA40 was hypothesized to alleviate symptoms in GTS. We investigated the immediate effects of single-session 1 Hz rTMS and sham stimulation delivered to the left BA40 on tics assessed with the Rush video protocol in 29 adults with GTS. There were no significant effects on tic symptoms following rTMS or sham stimulation. Moreover, there was no difference when comparing the effects of both stimulation conditions. Bayesian statistics indicated substantial evidence against an intervention effect. The left BA40 appears not to be a useful target for 1 Hz rTMS to modulate tic symptoms in GTS patients.

Abstract Non-invasive brain stimulation techniques including repetitive transcranial magnetic stimulation (rTMS), continuous theta-burst stimulation (cTBS), paired associative stimulation (PAS), and transcranial direct current stimulation (tDCS) have been applied over the cerebellum to induce plasticity and gain insights into the interaction of the cerebellum with neo-cortical structures including the motor cortex. We compared the effects of 1 Hz rTMS, cTBS, PAS and tDCS given over the cerebellum on motor cortical excitability and interactions between the cerebellum and dorsal premotor cortex / primary motor cortex in two within subject designs in healthy controls. In experiment 1, rTMS, cTBS, PAS, and tDCS were applied over the cerebellum in 20 healthy subjects. In experiment 2, rTMS and PAS were compared to sham conditions in another group of 20 healthy subjects. In experiment 1, PAS reduced cortical excitability determined by motor evoked potentials (MEP) amplitudes, whereas rTMS increased motor thresholds and facilitated dorsal premotor-motor and cerebellum-motor cortex interactions. TDCS and cTBS had no significant effects. In experiment 2, MEP amplitudes increased after rTMS and motor thresholds following PAS. Analysis of all participants who received rTMS and PAS showed that MEP amplitudes were reduced after PAS and increased following rTMS. rTMS also caused facilitation of dorsal premotor-motor cortex and cerebellum-motor cortex interactions. In summary, cerebellar 1 Hz rTMS and PAS can effectively induce plasticity in cerebello-(premotor)-motor pathways provided larger samples are studied.

Abstract Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder. Because motor signs are the defining feature of GTS, addressing the neurophysiology of motor processes is central to understanding GTS. The integration of voluntary motor processes is subject to so-called “binding problems”, i.e., how different aspects of an action are integrated. This was conceptualized in the theory of event coding, in which ‘action files’ accomplish the integration of motor features. We examined the functional neuroanatomical architecture of EEG theta band activity related to action file processing in GTS patients and healthy controls. Whereas, in keeping with previous data, behavioral performance during action file processing did not differ between GTS and controls, underlying patterns of neural activity were profoundly different. Superior parietal regions (BA7) were predominantly engaged in healthy controls, but superior frontal regions (BA9, BA10) in GTS indicated that the processing of different motor feature codes was central for action file processing in healthy controls, whereas episodic processing was more relevant in GTS. The data suggests a cascade of cognitive branching in fronto-polar areas followed by episodic processing in superior frontal regions in GTS. Patients with GTS accomplish the integration of motor plans via qualitatively different neurophysiological processes.

VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.

Humans differ in their capacity for integrating perceived events and related actions. The “Theory of event coding” (TEC) conceptualizes how stimuli and actions are cognitively bound into a common functional representation (or “code”), known as the “event file”. To date, however, the neural processes underlying the development of event file coding mechanisms across age are largely unclear. We investigated age-related neural changes of event file coding from late childhood to early adulthood, using EEG signal decompositions methods. We included a group of healthy participants (n = 91) between 10 and 30 years, performing an event file paradigm. Results of this study revealed age-related effects on event file coding processes both at the behavioural and the neurophysiological level. Performance accuracy data showed that event file unbinding und rebinding processes become more efficient from late childhood to early adulthood. These behavioural effects are reflected by age-related effects in two neurophysiological subprocesses associated with the superior parietal cortex (BA7) as revealed in the analyses using EEG signal decomposition. The first process entails mapping and association processes between stimulus and response; whereas, the second comprises inhibitory control subprocesses subserving the selection of the relevant motor programme amongst competing response options.

Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenic de novo variants in KCNA1 (p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants in SLC2A1 (p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the ARCA Registry, a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.

Gilles de la Tourette syndrome (TS) is a neuropsychiatric neurodevelopmental disorder with the cardinal clinical features of motor and phonic tics. Clinical phenomenology can be complex since, besides tics, there are other features including premonitory urges preceding tics, pali-, echo-, and coprophenomena, hypersensitivity to external stimuli, and symptom dependency on stress, attention, and other less well-defined factors. Also, the rate of comorbidities, particularly attention deficit hyperactivity disorder and obsessive-compulsive disorder, is high. Mirroring the complexities of the clinical course and phenomenology, pathophysiological findings are very diverse, and etiology is disputed. It has become clear, though, that abnormalities in the basal ganglia and their connections with cortical areas are key for the understanding of the pathophysiology and as regards etiology, genetic factors are crucial. Against this background, both adequate clinical management of TS and TS-related research require multidisciplinary preferably international cooperation in larger groups or networks to address the multiple facets of this disorder and yield valid and useful data. In particular, large numbers of patients are needed for brain imaging and genetic studies. To meet these requirements, a number of networks and groups in the field of TS have developed over the years creating an efficient, lively, and supportive international research community. In this review, we will provide an overview of these groups and networks.

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

Because tics are the defining clinical feature of Tourette syndrome, it is conceptualized predominantly as a motor disorder. There is some evidence though suggesting that the neural basis of Tourette syndrome is related to perception–action processing and binding between perception and action. However, binding processes have not been examined in the motor domain in these patients. If it is particularly perception–action binding but not binding processes within the motor system, this would further corroborate that Tourette syndrome it is not predominantly, or solely, a motor disorder.Here, we studied N = 22 Tourette patients and N = 24 healthy controls using an established action coding paradigm derived from the Theory of Event Coding framework and concomitant EEG-recording addressing binding between a planned but postponed, and an interleaved immediate reaction with different levels of overlap of action elements. Behavioral performance during interleaved action coding was normal in Tourette syndrome. Response locked lateralized readiness potentials reflecting processes related to motor execution were larger in Tourette syndrome, but only in simple conditions. However, pre-motor processes including response preparation and configuration reflected by stimulus-locked lateralized readiness potentials were normal. This was supported by a Bayesian data analysis providing evidence for the null hypothesis. The finding that processes integrating different action-related elements prior to motor execution are normal in Tourette syndrome suggests that Tourette it is not solely a motor disorder. Considering other recent evidence, the data show that changes in “binding” in Tourette syndrome are specific for perception–action integration but not for action coding.

Tics, often preceded by premonitory urges, are the clinical hallmark of Tourette syndrome. They resemble spontaneous movements, but are exaggerated, repetitive and appear misplaced in a given communication context. Given that tics often go unnoticed, it has been suggested that they represent a surplus of action, or motor noise. In this conceptual position paper, we propose that tics and urges, but also patterns of the cognitive profile in Tourette syndrome might be explained by the principle of processing of neural noise and adaptation to it during information processing. We review evidence for this notion in the light of Tourette pathophysiology and outline why neurophysiological and imaging approaches are central to examine a possibly novel view on Tourette syndrome. We discuss how neurophysiological data at multiple levels of inspections, i.e., from local field potentials using intra-cranial recording to scalp-measured EEG data, in combination with imaging approaches, can be used to examine the neural noise account in Tourette syndrome. We outline what signal processing methods may be suitable for that. We argue that, as a starting point, the analysis of 1/f neural noise or scale-free activity may be suitable to investigate the role of neural noise and its adaptation during information processing in Tourette syndrome. We outline, how the neural noise perspective, if substantiated by further neurophysiological studies and re-analyses of existing data, may pave the way to novel interventions directly targeting neural noise levels and patterns in Tourette syndrome.

Tourette syndrome is a neurodevelopmental disorder associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased sensitivity to positive reinforcement and increases in choice impulsivity. In this study, we examine whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference for smaller-but-sooner over larger-but-later rewards. We assessed intertemporal choice in two studies including nineteen adolescents (age: mean[sd] = 14.21[±2.37], 13 male subjects) and twenty-five adult patients (age: mean[sd] = 29.88 [±9.03]; 19 male subjects) with Tourette syndrome and healthy age- and education matched controls. Computational modeling using exponential and hyperbolic discounting models via hierarchical Bayesian parameter estimation revealed reduced temporal discounting in adolescent patients, and no evidence for differences in adult patients. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting. Specifically, adolescents might show attenuated discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. Future studies would benefit from a longitudinal approach to further elucidate the developmental trajectory of these effects.

Gilles de la Tourette syndrome is a multifaceted and complex neuropsychiatric disorder. Given that tics as motor phenomena are the defining and cardinal feature of Tourette syndrome, it has long been conceptualized as a motor/movement disorder. However, considering premonitory urges preceding tics, hypersensitivity to external stimuli and abnormalities in sensorimotor integration perceptual processes also seem to be relevant in the pathophysiology of Tourette syndrome. In addition, tic expression depends on attention and tics can, at least partly and transiently, be controlled, so that cognitive processes need to be considered as well. Against this background, explanatory concepts should encompass not only the motor phenomenon tic but also perceptual and cognitive processes. Representing a comprehensive theory of the processing of perceptions and actions paying particular attention to their interdependency and the role of cognitive control, the Theory of Event Coding seems to be a suitable conceptual framework for the understanding of Tourette syndrome. In fact, recent data suggests that addressing the relation between actions (i.e., tics) and perceptions (i.e., sensory phenomena like premonitory urges) in the context of event coding allows to gaining relevant insights into perception-action coding in Tourette syndrome indicating that perception action binding is abnormally strong in this disorder.

Gilles de la Tourette Syndrome is a multifaceted neuropsychiatric disorder typically commencing in childhood and characterized by motor and phonic tics. Its pathophysiology is still incompletely understood. However, there is convincing evidence that structural and functional abnormalities in the basal ganglia, in cortico-striato-thalamo-cortical circuits, and some cortical areas including medial frontal regions and the prefrontal cortex as well as hyperactivity of the dopaminergic system are key findings. Conventional therapeutic approaches in addition to counseling comprise behavioral treatment, particularly habit reversal therapy, oral pharmacotherapy (antipsychotic medication, alpha-2-agonists) and botulinum toxin injections. In treatment-refractory Tourette syndrome, deep brain stimulation, particularly of the internal segment of the globus pallidus, is an option for a small minority of patients. Based on pathophysiological considerations, non-invasive brain stimulation might be a suitable alternative. Repetitive transcranial magnetic stimulation appears particularly attractive. It can lead to longer-lasting alterations of excitability and connectivity in cortical networks and inter-connected regions including the basal ganglia through the induction of neural plasticity. Stimulation of the primary motor and premotor cortex has so far not been shown to be clinically effective. Some studies, though, suggest that the supplementary motor area or the temporo-parietal junction might be more appropriate targets. In this manuscript, we will review the evidence for the usefulness of repetitive transcranial magnetic stimulation and transcranial electric stimulation as treatment options in Tourette syndrome. Based on pathophysiological considerations we will discuss the rational for other approaches of non-invasive brain stimulation including state informed repetitive transcranial magnetic stimulation.

The existing therapeutic strategies of Tourette syndrome (TS) do not lead to sufficient improvement in a significant number of patients. Recently published studies show that paying attention to tics increases whereas directing attention away decreases tic frequency. The aim of the present case series in three patients with TS was to investigate the effect of attention training technique (ATT) on TS symptoms. ATT is a technique derived from metacognitive therapy that aims on training patients to consciously (re-)focus their attention away from themselves. Friedman’s chi-square test indicated a trend regarding the reduction of tic frequency and tic severity and a significant reduction of positive metacognitions from pre-baseline to follow-up. Reliable Change Indices (RCIs) are given for each measure and patient. Given the small number of patients, further studies including randomized controlled trials appear warranted.

Background: Parkinson’s disease is associated with severe nigro-striatal dopamine depletion, leading to motor dysfunction and altered reward processing. We previously showed that drug-naïve patients with Parkinson’s disease had a consistent attenuation of reward signalling in the mesolimbic and mesocortical system. Here, we address the neurobiological effects of dopaminergic therapy on reward sensitivity in the mesolimbic circuitry, and how this may contribute to neuropsychiatric symptoms. Objectives: We tested the hypothesis that (1) dopaminergic treatment would restore the attenuated, mesolimbic and mesocortical responses to reward; and (2) restoration of reward responsivity by dopaminergic treatment would predict motor performance and the emergence of impulse control symptoms. Methods: In 11 drug-naïve Parkinson patients, we prospectively assessed treatment-induced changes in reward processing before, and eight weeks after initiation of monotherapy with dopamine agonists. They were compared to 10 non-medicated healthy controls who were also measured longitudinally. We used whole-brain functional magnetic resonance imaging at 3 Tesla to assess the reward responsivity of the brain to monetary gains and losses, while participants performed a simple consequential gambling task. Results: In patients, dopaminergic treatment improved clinical motor symptoms without significantly changing task performance. Dopamine agonist therapy induced a stronger reward responsivity in the right hippocampus with higher doses being less effective. None of the patients developed impulse control disorders in the follow-up period of four years. Conclusions: Short-term treatment with first-ever dopaminergic medication partially restores deficient reward-related processing in the hippocampus in de novo Parkinson’s disease.

Pathological synchronisation of beta frequency (12–35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25–35Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD.

Abstract Evidence suggests that Tourette syndrome is characterized by an increase in dopamine transmission and structural as well as functional changes in fronto-striatal circuits that might lead to enhanced multi-component behaviour integration. Behavioural and neurophysiological data regarding multi-component behaviour was collected from 15 patients with Tourette syndrome (mean age = 30.40 ± 11.10) and 15 healthy controls (27.07 ± 5.44), using the stop-change task. In this task, participants are asked to sometimes withhold responses to a Go stimulus (stop cue) and change hands to respond to an alternative Go stimulus (change cue). Different onset asynchronies between stop and change cues were implemented (0 and 300 ms) in order to vary task difficulty. Tourette patients responded more accurately than healthy controls when there was no delay between stop and change stimulus, while there was no difference in the 300 ms delay condition. This performance advantage was reflected in a smaller P3 event related potential. Enhanced multi-component behaviour in Tourette syndrome is likely based on an enhanced ability to integrate information from multiple sources and translate it into an appropriate response sequence. This may be a consequence of chronic tic control in these patients, or a known fronto-striatal networks hyperconnectivity in Tourette syndrome.