EEG tensor decomposition delineates neurophysiological principles underlying conflict-modulated action restraint and action cancellation.

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.

Neural representations of statistical and rule-based predictions in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a disorder characterised by motor and vocal tics, which may represent habitual actions as a result of enhanced learning of associations between stimuli and responses (S-R). In this study, we investigated how adults with GTS and healthy controls (HC) learn two types of regularities in a sequence: statistics (non-adjacent probabilities) and rules (predefined order). Participants completed a visuomotor sequence learning task while EEG was recorded. To understand the neurophysiological underpinnings of these regularities in GTS, multivariate pattern analyses on the temporally decomposed EEG signal as well as sLORETA source localisation method were conducted. We found that people with GTS showed superior statistical learning but comparable rule-based learning compared to HC participants. Adults with GTS had different neural representations for both statistics and rules than HC adults; specifically, adults with GTS maintained the regularity representations longer and had more overlap between them than HCs. Moreover, over different time scales, distinct fronto-parietal structures contribute to statistical learning in the GTS and HC groups. We propose that hyper-learning in GTS is a consequence of the altered sensitivity to encode complex statistics, which might lead to habitual actions.

Slips of the tongue in patients with Gilles de la Tourette syndrome.

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.

GPi/GPe borderland- a potential sweet spot for deep brain stimulation for chorea in Huntington's disease?

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 < 0.001) and UHDRS total motor score was significantly reduced postoperatively (p = 0.019). Pallidal DBS did not improve other motor symptoms. Activation of the lateral GPi/GPe was associated with improvement in choreatic symptoms (p = 0.048; r = 0.90). CONCLUSIONS: Our findings indicate that stimulation of the lateral GPi has a stable effect on choreatic symptoms. The modulation of the electrical field is relevant for motor outcome.

It's not distance but similarity of distance: changing stimulus relations affect the control of action sequences.

Interacting with our environment happens on different levels of complexity: While there are individual and simple actions like an isolated button press, most actions are more complex and involve sequences of simpler actions. The degree to which multiple simple actions are represented as one action sequence can be measured via so-called response-response binding effects. When two or more responses are executed consecutively, they are integrated into one representation so that repetition of one response can start retrieval of the other. Executing such an action sequence typically involves responding to multiple objects or stimuli. Here, we investigated whether the spatial relation of these stimuli affects action sequence execution. To that end, we varied the distance between stimuli in a response-response binding task. Stimulus distance might affect response-response binding effects in one of two ways: It might directly affect the representation of the response sequence, making integration and retrieval between responses more likely if the responses relate to close stimuli. Alternatively, the similarity of stimulus distribution during integration and retrieval might be decisive, leading to larger binding effects if stimulus distance is identical during integration and retrieval. We found stronger binding effects with constant than with changing stimulus distance, indicating that action integration and retrieval can easily affect performance also if responses refer to separated objects. However, this effect on performance is diminished by changing spatial distribution of stimuli at the times of integration and retrieval.

Resting network architecture of theta oscillations reflects hyper-learning of sensorimotor information in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by motor and vocal tics. It is associated with enhanced processing of stimulus-response associations, including a higher propensity to learn probabilistic stimulus-response contingencies (i.e. statistical learning), the nature of which is still elusive. In this study, we investigated the hypothesis that resting-state theta network organization is a key for the understanding of superior statistical learning in these patients. We investigated the graph-theoretical network architecture of theta oscillations in adult patients with Gilles de la Tourette syndrome and healthy controls during a statistical learning task and in resting states both before and after learning. We found that patients with Gilles de la Tourette syndrome showed a higher statistical learning score than healthy controls, as well as a more optimal (small-world-like) theta network before the task. Thus, patients with Gilles de la Tourette syndrome had a superior facility to integrate and evaluate novel information as a trait-like characteristic. Additionally, the theta network architecture in Gilles de la Tourette syndrome adapted more to the statistical information during the task than in HC. We suggest that hyper-learning in patients with Gilles de la Tourette syndrome is likely a consequence of increased sensitivity to perceive and integrate sensorimotor information leveraged through theta oscillation-based resting-state dynamics. The study delineates the neural basis of a higher propensity in patients with Gilles de la Tourette syndrome to pick up statistical contingencies in their environment. Moreover, the study emphasizes pathophysiologically endowed abilities in patients with Gilles de la Tourette syndrome, which are often not taken into account in the perception of this common disorder but could play an important role in destigmatization.

DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery.

Dystonia due to pathogenic variants in the THAP1 gene (DYT-THAP1) shows variable expressivity and reduced penetrance of ~ 50%. Since THAP1 encodes a transcription factor, modifiers influencing this variability likely operate at the gene expression level. This study aimed to assess the transferability of differentially expressed genes (DEGs) in neuronal cells related to pathogenic variants in the THAP1 gene, which were previously identified by transcriptome analyses. For this, we performed quantitative (qPCR) and Digital PCR (dPCR) in cultured fibroblasts. RNA was extracted from THAP1 manifesting (MMCs) and non-manifesting mutation carriers (NMCs) as well as from healthy controls. The expression profiles of ten of 14 known neuronal DEGs demonstrated differences in fibroblasts between these three groups. This included transcription factors and targets (ATF4, CLN3, EIF2A, RRM1, YY1), genes involved in G protein-coupled receptor signaling (BDKRB2, LPAR1), and a gene linked to apoptosis and DNA replication/repair (CRADD), which all showed higher expression levels in MMCs and NMCs than in controls. Moreover, the analysis of genes linked to neurological disorders (STXBP1, TOR1A) unveiled differences in expression patterns between MMCs and controls. Notably, the genes CUEDC2, DRD4, ECH1, and SIX2 were not statistically significantly differentially expressed in fibroblast cultures. With > 70% of the tested genes being DEGs also in fibroblasts, fibroblasts seem to be a suitable model for DYT-THAP1 research despite some restrictions. Furthermore, at least some of these DEGs may potentially also serve as biomarkers of DYT-THAP1 and influence its penetrance and expressivity.

Separating binding and retrieval of event files in older adults.

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.

Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases.

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.

[Conclusion instead of exclusion-The clinical diagnosis of functional movement disorders]. / Abschluss statt Ausschluss ­ die klinische Diagnosesicherung funktioneller Bewegungsstörungen.

Functional neurological movement disorders are common in neurological practice and lead to a high degree of impairment and chronification. Affected patients usually receive a diagnosis with considerable delay and often do not get disease-specific treatment. The reasons for this delay are related to extensive diagnostic measures to exclude other nonfunctional neurological diseases. As a consequence, functional movement disorders are typically communicated as diagnoses of exclusion, which makes it difficult for patients to understand and accept the diagnosis. This is particularly unfortunate, because in the majority of patients the diagnosis can be made with confidence based on clinical features, i.e., inconsistency and incongruence. The clarification of the symptoms and the resulting treatment options should be supplemented by patient-friendly explanations of the pathophysiological basis of the disease. In this way, patients are enabled to understand and accept the diagnosis. Moreover, it can put an end to the search for a diagnosis, which can sometimes take decades, and paves the way for treatment. Thus, the diagnosis by exclusion itself becomes the starting point for treatment and can itself have a therapeutic effect.

Neurophysiological processes reflecting the effects of the immediate past during the dynamic management of actions.

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.

Rethinking Movement Disorders.

At present, clinical practice and research in movement disorders (MDs) focus on the "normalization" of altered movements. In this review, rather than concentrating on problems and burdens people with MDs undoubtedly have, we highlight their hidden potentials. Starting with current definitions of Parkinson's disease (PD), dystonia, chorea, and tics, we outline that solely conceiving these phenomena as signs of dysfunction falls short of their complex nature comprising both problems and potentials. Such potentials can be traced and understood in light of well-established cognitive neuroscience frameworks, particularly ideomotor principles, and their influential modern derivatives. Using these frameworks, the wealth of data on altered perception-action integration in the different MDs can be explained and systematized using the mechanism-oriented concept of perception-action binding. According to this concept, MDs can be understood as phenomena requiring and fostering flexible modifications of perception-action associations. Consequently, although conceived as being caught in a (trough) state of deficits, given their high flexibility, people with MDs also have high potential to switch to (adaptive) peak activity that can be conceptualized as hidden potentials. Currently, clinical practice and research in MDs are concerned with deficits and thus the "deep and wide troughs," whereas "scattered narrow peaks" reflecting hidden potentials are neglected. To better delineate and utilize the latter to alleviate the burden of affected people, and destigmatize their conditions, we suggest some measures, including computational modeling combined with neurophysiological methods and tailored treatment. © 2024 International Parkinson and Movement Disorder Society.

The Ability to Voluntarily Regulate Theta Band Activity Affects How Pharmacological Manipulation of the Catecholaminergic System Impacts Cognitive Control.

BACKGROUND: The catecholaminergic system influences response inhibition, but the magnitude of the impact of catecholaminergic manipulation is heterogeneous. Theoretical considerations suggest that the voluntary modulability of theta band activity can explain this variance. The study aimed to investigate to what extent interindividual differences in catecholaminergic effects on response inhibition depend on voluntary theta band activity modulation. METHODS: A total of 67 healthy adults were tested in a randomized, double-blind, cross-over study design. At each appointment, they received a single dose of methylphenidate or placebo and performed a Go/Nogo task with stimuli of varying complexity. Before the first appointment, the individual's ability to modulate theta band activity was measured. Recorded EEG data were analyzed using temporal decomposition and multivariate pattern analysis. RESULTS: Methylphenidate effects and voluntary modulability of theta band activity showed an interactive effect on the false alarm rates of the different Nogo conditions. The multivariate pattern analysis revealed that methylphenidate effects interacted with voluntary modulability of theta band activity at a stimulus processing level, whereas during response selection methylphenidate effects interacted with the complexity of the Nogo condition. CONCLUSIONS: The findings reveal that the individual's theta band modulability affects the responsiveness of an individual's catecholaminergic system to pharmacological modulation. Thus, the impact of pharmacological manipulation of the catecholaminergic system on cognitive control most likely depends on the existing ability to self-modulate relevant brain oscillatory patterns underlying the cognitive processes being targeted by pharmacological modulations.

POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature.

Different pathogenic variants in the DNA polymerase-gamma2 (POLG2) gene cause a rare, clinically heterogeneous mitochondrial disease. We detected a novel POLG2 variant (c.1270 T > C, p.Ser424Pro) in a family with adult-onset cerebellar ataxia and progressive ophthalmoplegia. We demonstrated altered mitochondrial integrity in patients' fibroblast cultures but no changes of the mitochondrial DNA were found when compared to controls. We consider this novel, segregating POLG2 variant as disease-causing in this family. Moreover, we systematically screened the literature for POLG2-linked phenotypes and re-evaluated all mutations published to date for pathogenicity according to current knowledge. Thereby, we identified twelve published, likely disease-causing variants in 19 patients only. The core features included progressive ophthalmoplegia and cerebellar ataxia; parkinsonism, neuropathy, cognitive decline, and seizures were also repeatedly found in adult-onset heterozygous POLG2-related disease. A severe phenotype relates to biallelic pathogenic variants in POLG2, i.e., newborn-onset liver failure, referred to as mitochondrial depletion syndrome. Our work underlines the broad clinical spectrum of POLG2-related disease and highlights the importance of functional characterization of variants of uncertain significance to enable meaningful genetic counseling.

Turning the Light Switch on Binding: Prefrontal Activity for Binding and Retrieval in Action Control.

According to action control theories, responding to a stimulus leads to the binding of response and stimulus features into a common representation, that is, an event file. Repeating any component of an event file retrieves all previously bound information, leading to performance costs for partial repetitions measured in so-called binding effects. Although otherwise robust and stable, binding effects are typically completely absent in "localization tasks," in which participants localize targets with spatially compatible responses. Yet, it is possible to observe binding effects in such when location features have to be translated into response features. We hypothesized that this modulation of binding effects is reflected in task involvement of the dorsolateral pFC (DLPFC). Participants localized targets with either direct (i.e., spatially compatible key) or translated (i.e., diagonally opposite to the spatially compatible key) responses. We measured DLPFC activity with functional near-infrared spectroscopy. On the behavioral level, we observed binding effects in the translated response condition, but not in the direct response condition. Importantly, prefrontal activity was also higher in the translated mapping condition. In addition, we found some evidence for the strength of the difference in binding effects in behavioral data being correlated with the corresponding effects in prefrontal activity. This suggests that activity in the DLPFC reflects the amount of executive control needed for translating location features into responses. More generally, binding effects seem to emerge only when the task at hand involves DLPFC recruitment.

Neuronavigated Cerebellar 50 Hz tACS: Attenuation of Stimulation Effects by Motor Sequence Learning.

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.

Neural, physiological and behavioural correlates of empathy for pain in Tourette syndrome.

Persons with Tourette syndrome show altered social behaviours, such as echophenomena and increased personal distress in emotional situations. These symptoms may reflect an overactive mirror neuron system, causing both increased automatic imitation and a stronger tendency to share others' emotions. To test this, we measured the individual level of echophenomena with a video protocol and experimentally induced empathy for pain in 21 participants with Tourette syndrome and 25 matched controls. In the empathy for pain paradigm, pictures of hands and feet in painful or neutral situations were presented, while we measured participants' EEG and skin conductance response. Changes in somatosensory mu suppression during the observation of the pictures and pain ratings were compared between groups, and correlations were calculated with the occurrence of echophenomena, self-reported empathy and clinical measures. Our Tourette syndrome sample showed significantly more echophenomena than controls, but the groups showed no behavioural differences in empathic abilities. However, controls, but not patients with Tourette syndrome, showed the predicted increased mu suppression when watching painful compared to neutral actions. While echophenomena were present in all persons with Tourette syndrome, the hypothesis of an overactive mirror neuron system in Tourette syndrome could not be substantiated. On the contrary, the Tourette syndrome group showed a noticeable lack of mu attenuation in response to pain stimuli. In conclusion, we found a first hint of altered processing of others' emotional states in a brain region associated with the mirror neuron system.

Compulsive sexual behavior and paraphilic interests in adults with chronic tic disorders and Tourette syndrome: a survey-based study.

Early research suggested that compulsive sexual behavior (CSB) and paraphilic interests (PI) are more prevalent in adults with primary tic disorders compared to the general population. However, recent data on this topic remain scarce. We conducted an anonymous online survey capturing data on CSB and PI in adult patients with primary tic disorders. We also explored the role of antipsychotic tic medication and the impact of neuropsychiatric comorbidities like attention-deficit hyperactivity disorder and depression. In total, 62 participants (26 females/36 males) completed the survey. The prevalence of CSB and PI were 12.9% and 19.4%, respectively. There was no association with antipsychotic medication nor with symptoms of depression. However, the presence of attention-deficit hyperactivity disorder was associated with a higher prevalence of both CSB and PI. The current results contrast with earlier reports and show that in adults with primary tic disorders, the prevalence of CSB and PI is not overly prominent.