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.

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.

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.

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.

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.

Extra Movements in Healthy People: Challenging the Definition and Diagnostic Practice of Tic Disorders.

The occurrence of motor/vocal tics, that is, "extra movements" and/or "extra vocalizations," is the leading diagnostic criterion for tic disorders. We show that extra movements are common also in healthy controls, so that a surplus of movements per se is not indicative of the presence of a tic disorder. This questions the usefulness of Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for tic disorders in clinical practice. Apparently, it is not solely a surplus of movements that defines tic disorders. Instead, movement characteristics and patterns seem to play a crucial role. ANN NEUROL 2023;93:472-478.

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients.

OBJECTIVE: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. METHODS: Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2-8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes. RESULTS: Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), and fluctuating decreases/increases. All subitems except nose-finger showed moderate-to-strong correlations to activities of daily living, indicating that metric properties-not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG-ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20 to 25%. INTERPRETATION: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023;94:470-485.

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.

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.

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.

Neurophysiological principles of inhibitory control processes during cognitive flexibility.

Inhibitory control plays an indispensable role in cognitive flexibility. Nevertheless, the neurophysiological principles underlying this are incompletely understood. This owes to the fact that the representational dynamics, as coded in oscillatory neural activity of different frequency bands has not been considered until now-despite being of conceptual relevance. Moreover, it is unclear in how far distinct functional neuroanatomical regions are concomitantly involved in the processing of representational dynamics. We examine these questions using a combination of EEG methods. We show that theta-band activity plays an essential role for inhibitory control processes during cognitive flexibility across informational aspects coded in distinct fractions of the neurophysiological signal. It is shown that posterior parietal structures and the inferior parietal cortex seem to be the most important cortical region for inhibitory control processes during cognitive flexibility. Theta-band activity plays an essential role in processes of retrieving the previously inhibited representations related to the current task during cognitive flexibility. The representational content relevant for inhibitory processes during cognitive flexibility is coded in the theta frequency band. We outline how the observed neural mechanisms inform recent overarching cognitive frameworks on how flexible action control is accomplished.

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.

[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.

Distinguishing functional from primary tics: a study of expert video assessments.

BACKGROUND: Reliably applied criteria to differentiate functional from primary tics are lacking. In the absence of biological markers, the development of new diagnostic criteria to assist clinicians is predicated on expert judgement and consensus. This study examines the level of diagnostic agreement of experts in tic disorders using video footage and clinical descriptions. METHODS: Using a two-part survey, eight experts in the diagnosis and management of tics were first asked to study 24 case videos of adults with primary tics, functional tics or both and to select a corresponding diagnosis. In the second part of the survey, additional clinical information was provided, and the diagnosis was then reconsidered. Inter-rater agreement was measured using Fleiss' kappa. In both study parts, the factors which influenced diagnostic decision-making and overall diagnostic confidence were reviewed. RESULTS: Based on phenomenology alone, the diagnostic agreement among the expert raters was only fair for the pooled diagnoses (κ=0.21) as well as specifically for functional (κ=0.26) and primary tics (κ=0.24). Additional clinical information increased overall diagnostic agreement to moderate (κ=0.51) for both functional (κ=0.6) and primary tics (κ=0.57). The main factors informing diagnosis were tic semiology, age at tic onset, presence of premonitory urges, tic suppressibility, the temporal latency between tic onset and peak severity, precipitants and tic triggers and changes in the overall phenotypic presentation. CONCLUSIONS: This study confirmed that in the absence of clinical information, the diagnostic distinction between primary and functional tics is often difficult, even for expert clinicians.

Impaired Metacognition of Voluntary Movement in Functional Movement Disorder.

BACKGROUND: Motor symptoms in functional movement disorders (FMDs) are experienced as involuntary but share characteristics of voluntary action. Clinical and experimental evidence indicate alterations in monitoring, control, and subjective experience of self-performed movements. OBJECTIVE: The objective of this study was to test the prediction that FMDs are associated with a reduced ability to make accurate (metacognitive) judgments about self-performed movements. METHODS: We compared 24 patients with FMD (including functional gait disturbance, functional tremor, and functional tics) with 24 age- and sex-matched healthy control subjects in a novel visuomotor-metacognitive paradigm. Participants performed target-directed movements on a graphics tablet with restricted visual feedback, decided which of two visually presented trajectories was closer to their preceding movement, and reported their confidence in the visuomotor decision. We quantified individual metacognitive performance as participants' ability to assign high confidence preferentially to correct visuomotor decisions. RESULTS: Patients and control subjects showed comparable motor performance, response accuracy, and use of the confidence scale. However, visuomotor sensitivity in the trajectory judgment was reduced in patients with FMD compared with healthy control subjects. Moreover, metacognitive performance was impaired in patients, that is, their confidence ratings were less predictive of the correctness of visuomotor decisions. Exploratory subgroup analyses suggest metacognitive deficits to be most pronounced in patients with a functional gait disturbance or functional tremor. CONCLUSIONS: Patients with FMD exhibited deficits both when making visuomotor decisions about their own movements and in the metacognitive evaluation of these decisions. Reduced metacognitive insight into voluntary motor control may play a role in FMD pathophysiology and could lay the groundwork for new treatment strategies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Perception-Action Integration Is Altered in Functional Movement Disorders.

BACKGROUND: Although functional neurological movement disorders (FMD) are characterized by motor symptoms, sensory processing has also been shown to be disturbed. However, how the integration of perception and motor processes, essential for the control of goal-directed behavior, is altered in patients with FMD is less clear. A detailed investigation of these processes is crucial to foster a better understanding of the pathophysiology of FMD and can systematically be achieved in the framework of the theory of event coding (TEC). OBJECTIVE: The aim was to investigate perception-action integration processes on a behavioral and neurophysiological level in patients with FMD. METHODS: A total of 21 patients and 21 controls were investigated with a TEC-related task, including concomitant electroencephalogram (EEG) recording. We focused on EEG correlates established to reflect perception-action integration processes. Temporal decomposition allowed to distinguish between EEG codes reflecting sensory (S-cluster), motor (R-cluster), and integrated sensory-motor processing (C-cluster). We also applied source localization analyses. RESULTS: Behaviorally, patients revealed stronger binding between perception and action, as evidenced by difficulties in reconfiguring previously established stimulus-response associations. Such hyperbinding was paralleled by a modulation of neuronal activity clusters, including reduced C-cluster modulations of the inferior parietal cortex and altered R-cluster modulations in the inferior frontal gyrus. Correlations of these modulations with symptom severity were also evident. CONCLUSIONS: Our study shows that FMD is characterized by altered integration of sensory information with motor processes. Relations between clinical severity and both behavioral performance and neurophysiological abnormalities indicate that perception-action integration processes are central and a promising concept for the understanding of FMD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automated Motor Tic Detection: A Machine Learning Approach.

BACKGROUND: Video-based tic detection and scoring is useful to independently and objectively assess tic frequency and severity in patients with Tourette syndrome. In trained raters, interrater reliability is good. However, video ratings are time-consuming and cumbersome, particularly in large-scale studies. Therefore, we developed two machine learning (ML) algorithms for automatic tic detection. OBJECTIVE: The aim of this study was to evaluate the performances of state-of-the-art ML approaches for automatic video-based tic detection in patients with Tourette syndrome. METHODS: We used 64 videos of n = 35 patients with Tourette syndrome. The data of six subjects (15 videos with ratings) were used as a validation set for hyperparameter optimization. For the binary classification task to distinguish between tic and no-tic segments, we established two different supervised learning approaches. First, we manually extracted features based on landmarks, which served as input for a Random Forest classifier (Random Forest). Second, a fully automated deep learning approach was used, where regions of interest in video snippets were input to a convolutional neural network (deep neural network). RESULTS: Tic detection F1 scores (and accuracy) were 82.0% (88.4%) in the Random Forest and 79.5% (88.5%) in the deep neural network approach. CONCLUSIONS: ML algorithms for automatic tic detection based on video recordings are feasible and reliable and could thus become a valuable assessment tool, for example, for objective tic measurements in clinical trials. ML algorithms might also be useful for the differential diagnosis of tics. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

European Society for the Study of Tourette Syndrome 2022 criteria for clinical diagnosis of functional tic-like behaviours: International consensus from experts in tic disorders.

BACKGROUND AND PURPOSE: In 2020, health professionals witnessed a dramatic increase in referrals of young people with rapid onset of severe tic-like behaviours. We assembled a working group to develop criteria for the clinical diagnosis of functional tic-like behaviours (FTLBs) to help neurologists, pediatricians, psychiatrists, and psychologists recognize and diagnose this condition. METHODS: We used a formal consensus development process, using a multiround, web-based Delphi survey. The survey was based on an in-person discussion at the European Society for the Study of Tourette Syndrome (ESSTS) meeting in Lausanne in June 2022. Members of an invited group with extensive clinical experience working with patients with Tourette syndrome and FTLBs discussed potential clinical criteria for diagnosis of FTLBs. An initial set of criteria were developed based on common clinical experiences and review of the literature on FTLBs and revised through iterative discussions, resulting in the survey items for voting. RESULTS: In total, 24 members of the working group were invited to participate in the Delphi process. We propose that there are three major criteria and two minor criteria to support the clinical diagnosis of FTLBs. A clinically definite diagnosis of FTLBs can be confirmed by the presence of all three major criteria. A clinically probable diagnosis of FTLBs can be confirmed by the presence of two major criteria and one minor criterion. CONCLUSIONS: Distinguishing FTLBs from primary tics is important due to the distinct treatment paths required for these two conditions. A limitation of the ESSTS 2022 criteria is that they lack prospective testing of their sensitivity and specificity.

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder.

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.

On the Role of Memory Representations in Action Control: Neurophysiological Decoding Reveals the Reactivation of Integrated Stimulus-Response Feature Representations.

Efficient response selection is essential to flexible, goal-directed behavior. Prominent theoretical frameworks such as the Theory of Event Coding and Binding and Retrieval in Action Control have provided insights regarding the dynamics of perception-action integration processes. According to Theory of Event Coding and Binding and Retrieval in Action Control, encoded representations of stimulus-response bindings influence later retrieval processes of these bindings. However, this concept still lacks conclusive empirical evidence. In the current study, we applied representational decoding to EEG data. On the behavioral level, the findings replicated binding effects that have been established in previous studies: The task performance was impaired when an event file had to be reconfigured. The EEG-decoding results showed that retrieval processes of stimulus-response bindings could be decoded using the representational content developed after the initial establishment of these stimulus-response bindings. We showed that stimulus-related properties became immediately reactivated when re-encountering the respective stimulus-response association. These reactivations were temporally stable. In contrast, representations of stimulus-response mappings revealed a transient pattern of activity and could not successfully be decoded directly after stimulus-response binding. Information detailing the bindings between stimuli and responses were also retrieved, but only after having been loaded into a memory system. The current study supports the notion that stimulus-response integration and memory processes are intertwined at multiple levels.