Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia.

Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.

Tourette syndrome research highlights from 2022.

This is the ninth yearly article in the Tourette Syndrome Research Highlights series, summarizing selected research reports from 2022 relevant to Tourette syndrome. The authors briefly summarize reports they consider most important or interesting.

Structural hyperconnectivity of the subthalamic area with limbic cortices underpins anxiety and impulsivity in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, which is often associated with psychiatric comorbidities. Dysfunction of basal ganglia pathways might account for the wide spectrum of symptoms in TS patients. Although psychiatric symptoms may be related to limbic networks, the specific contribution of different limbic structures remains unclear. We used tractography to investigate cortical connectivity with the striatal area (caudate, putamen, core and shell of the nucleus accumbens), the subthalamic nucleus (STN), and the adjacent medial subthalamic region (MSR) in 58 TS patients and 35 healthy volunteers. 82% of TS patients showed psychiatric comorbidities, with significantly higher levels of anxiety and impulsivity compared to controls. Tractography analysis revealed significantly increased limbic cortical connectivity of the left MSR with the entorhinal (BA34), insular (BA48), and temporal (BA38) cortices in TS patients compared to controls. Furthermore, we found that left insular-STN connectivity was positively correlated with impulsivity scores for all subjects and with anxiety scores for all subjects, particularly for TS. Our study highlights a heterogenous modification of limbic structure connectivity in TS, with specific abnormalities found for the subthalamic area. Abnormal connectivity with the insular cortex might underpin the higher level of impulsivity and anxiety observed in TS.

How does Tourette syndrome impact adolescents' daily living? A text mining study.

Tourette syndrome is a neurodevelopmental disease in which clinical manifestations are essentially present during childhood and adolescence, corresponding to one of the critical development phases. However, its consequences on the daily lives of young patients have been insufficiently investigated. Here, we aimed to investigate this using a statistical text mining approach, allowing for the analysis of a large volume of free textual data. Sixty-two adolescents with Tourette syndrome participated in an interview in which they discussed their daily life (i) in school, (ii) at home, and (iii) with strangers, (iv) the aspect of Tourette syndrome which caused the most difficulty, and (v) their thoughts regarding their future as adults. Following data pre-processing, these corpora were analyzed separately using the IRAMUTEQ software through factorial correspondence analysis to identify the most commonly recurring topics of each corpus, and their relations with clinical features. The main difficulty corpus was directly related to comorbidities of Tourette syndrome. Daily life at home was correlated with executive functioning. Difficulties at school were related to a higher severity of tics. Thoughts regarding future daily life were worst for the youngest patients and were correlated with executive functioning and a higher depression score. Taken altogether, our results highlighted that social stigma was a pervasive topic among our corpora. From a clinical standpoint, tic severity was especially related to difficulties at school, while comorbidities had a high impact on social daily living and cost for managing both tics and symptoms of comorbidities. TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04179435.

Decision-making under risk and ambiguity in adults with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) as well as its most common comorbidities are associated with a higher propensity for risky behaviour in everyday life. However, it is unclear whether this increased risk propensity in real-life contexts translates into a generally increased attitude towards risk. We aimed to assess decision-making under risk and ambiguity based on prospect theory by considering the effects of comorbidities and medication. METHODS: Fifty-four individuals with TS and 32 healthy controls performed risk and ambiguity decision-making tasks under both gains and losses conditions. Behavioural and computational parameters were evaluated using (i) univariate analysis to determine parameters difference taking independently; (ii) supervised multivariate analysis to evaluate whether our parameters could jointly account for between-group differences (iii) unsupervised multivariate analysis to explore the potential presence of sub-groups. RESULTS: Except for general 'noisier' (less consistent) decisions in TS, we showed no specific risk-taking behaviour in TS or any relation with tics severity or antipsychotic medication. However, the presence of comorbidities was associated with distortion of decision-making. Specifically, TS with obsessive-compulsive disorder comorbidity was associated with a higher risk-taking profile to increase gain and a higher risk-averse profile to decrease loss. TS with attention-deficit hyperactivity disorder comorbidity was associated with risk-seeking in the ambiguity context to reduce a potential loss. CONCLUSIONS: Impaired valuation of risk and ambiguity was not related to TS per se. Our findings are important for clinical practice: the involvement of individuals with TS in real-life risky situations may actually rather result from other factors such as psychiatric comorbidities.

Tourette syndrome research highlights from 2021.

We summarize selected research reports from 2021 relevant to Tourette syndrome that the authors consider most important or interesting. The authors welcome article suggestions and thoughtful feedback from readers.

Tourette syndrome research highlights from 2020.

We present here research from 2020 relevant to Tourette syndrome (TS). The authors briefly summarize a few reports they consider most important or interesting.

The Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease on Associative Learning of Verbal and Non-Verbal Information by Trial and Error or with Corrective Feedback.

BACKGROUND: Parkinson's disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS) are both known to induce cognitive changes. OBJECTIVE: The aim of our study was to investigate the impact of STN-DBS on two forms of conditional associative learning (CAL), trial and error or corrective feedback learning, which differed in difficulty to test the load-dependency hypothesis of the cognitive effects of STN-DBS in PD. METHODS: We recruited two groups of PD patients, those who had STN-DBS surgery bilaterally (n = 24) and a second unoperated group (n = 9) who were assessed on two versions of a task of visual CAL involving either a more difficult trial and error learning or a relatively easier corrective feedback learning. Each task was completed twice by both groups, On and Off STN-DBS for the operated group and a first and second time by the unoperated group. RESULTS: With STN-DBS Off, corrective feedback learning was superior to trial and error CAL, but not with STN-DBS On. The unoperated PD group had improved performance during the second assessment. To control for the improvement observed with repeated assessment in the PD control group, we split the STN-DBS group into two subgroups based on the condition of the first assessment (Off first vs. On first). While we found no STN-DBS effects for the Off first subgroup (N = 14), we observed improved performance during the second STN-DBS Off session for the On first subgroup (N = 10). CONCLUSION: The findings suggest that in PD, STN-DBS interferes with use of corrective feedback and its integration in the conditional associative learning process. Also STN stimulation affected the ability of operated patients to resolve proactive interference during learning of the arbitrary visual associations by trial and error or with corrective feedback.

Compromised reactive but intact proactive inhibitory motor control in Tourette disorder.

Tourette disorder (TD) is characterized by tics, which are sudden repetitive involuntary movements or vocalizations. Deficits in inhibitory control in TD patients remain inconclusive from the traditional method of estimating the ability to stop an impending action, which requires careful interpretation of a metric derived from race model. One possible explanation for these inconsistencies is that race model's assumptions of independent and stochastic rise of GO and STOP process to a fixed threshold are often violated, making the classical metric to assess inhibitory control less robust. Here, we used a pair of metrics derived from a recent alternative model to address why stopping performance in TD is unaffected despite atypical neural circuitry. These new metrics distinguish between proactive and reactive inhibitory control and estimate them separately. When these metrics in adult TD group were contrasted with healthy controls (HC), we identified robust deficits in reactive control, but not in proactive control in TD. The TD group exhibited difficulty in slowing down the speed of movement preparation, which they rectified by their intact ability to postpone the movement.

Subthalamic stimulation breaks the balance between distal and axial signs in Parkinson's disease.

In Parkinson's disease (PD), the effects of both Ldopa and subthalamic deep brain stimulation (STN-DBS) are known to change cost-valuation. However, this was mostly studied through reward-effort task involving distal movements, while axial effort, less responsive to treatments, have been barely studied. Thus, our objective was to compare the influence of both Ldopa and STN-DBS on cost-valuation between two efforts modalities: vowel production (as an example of axial movement) and hand squeezing (as an example of distal movement). Twelve PD patients were recruited to participate in this study. The task consisted in deciding whether to accept or reject trials based on a reward-effort trade-off. Participants performed two blocks with hand squeezing, and two with vowel production, in the four treatment conditions (Ldopa On/Off; STN-DBS On/Off). We found that STN-DBS changed the ratio difference between hand and phonation efforts. Vowel production effort was estimated easier to perform with STN-DBS alone, and harder when associated with Ldopa. The difference between hand and phonation efforts was correlated with quality of life in Off/Off and On Ldopa alone conditions, and with impulsive assessment On STN-DBS alone. We highlighted that STN-DBS could introduce an imbalance between the actual motor impairments and their subjective costs. With this finding, we also suggest paying particular attention to the different treatment effects that should be expected for axial and distal movement dysfunctions.

The sooner the better: clinical and neural correlates of impulsive choice in Tourette disorder.

Reward sensitivity has been suggested as one of the central pathophysiological mechanisms in Tourette disorder. However, the subjective valuation of a reward by introduction of delay has received little attention in Tourette disorder, even though it has been suggested as a trans-diagnostic feature of numerous neuropsychiatric disorders. We aimed to assess delay discounting in Tourette disorder and to identify its brain functional correlates. We evaluated delayed discounting and its brain functional correlates in a large group of 54 Tourette disorder patients and 31 healthy controls using a data-driven approach. We identified a subgroup of 29 patients with steeper reward discounting, characterised by a higher burden of impulse-control disorders and a higher level of general impulsivity compared to patients with normal behavioural performance or to controls. Reward discounting was underpinned by resting-state activity of a network comprising the orbito-frontal, cingulate, pre-supplementary motor area, temporal and insular cortices, as well as ventral striatum and hippocampus. Within this network, (i) lower connectivity of pre-supplementary motor area with ventral striatum predicted a higher impulsivity and a steeper reward discounting and (ii) a greater connectivity of pre-supplementary motor area with anterior insular cortex predicted steeper reward discounting and more severe tics. Overall, our results highlight the heterogeneity of the delayed reward processing in Tourette disorder, with steeper reward discounting being a marker of burden in impulsivity and impulse control disorders, and the pre-supplementary motor area being a hub region for the delay discounting, impulsivity and tic severity.

Acoustic, perceptual and clinical correlates of speech and voice in isolated dystonia: Preliminary findings.

BACKGROUND: Hyperkinetic dysarthria is often present in isolated dystonia (ID) and is still understudied. Four main clusters of deviant speech dimensions in dystonia hyperkinetic dysarthria were initially provided: articulatory inaccuracy, phonatory stenosis, prosodic excess and prosodic insufficiency. AIM: The aim of our exploratory study was to provide preliminary data on both perceptual and acoustic analyses in relation to three out of these four main clusters. METHODS & PROCEDURES: Eleven patients with ID and 11 healthy controls (HC) participated in this study. Clinical/perceptual assessments and acoustic analyses of speech recordings were performed, the latter allowing for the analysis of parameters referring to aerophonatory control, voice quality, prosodic features and speech intelligibility estimated by nine listeners. Between-group statistical comparisons were performed (Wilcoxon tests, p < 0.05). Single-case differences between each patient and the control group were also carried out (effect size index and t < 0.05). OUTCOMES & RESULTS: Between-group comparisons confirmed the presence of a 'phonatory stenosis'; in addition, deficit in aerophonatory control and hypophonia was also displayed. 'Prosodic insufficiency' was confirmed, but not at the individual level. 'Prosodic excess' manifested only in patients with marked and severe dysarthria. Correlations between altered maximum phonation time, loudness variation, speech and articulatory rates on the one hand, and several clinical speech assessments on the other hand, were also found. CONCLUSIONS & IMPLICATIONS: From these findings, altogether, perceptual characteristics of hyperkinetic dysarthria, as suggested by Darley et al., were quantified by the acoustic parameters we measured. As regards to our data obtained in a small participant sample, we would suggest that Darley et al.'s clusters of excess and insufficiency prosody should be questioned in future studies involving larger numbers of dystonic patients. Our study provides novel and preliminary results that demonstrate the relevance of using quantitative measures to further characterise speech/voice deficits in patients with ID.

Impulsive prepotent actions and tics in Tourette disorder underpinned by a common neural network.

Tourette disorder (TD), which is characterized by motor and vocal tics, is not in general considered as a product of impulsivity, despite a frequent association with attention deficit hyperactivity disorder and impulse control disorders. It is unclear which type of impulsivity, if any, is intrinsically related to TD and specifically to the severity of tics. The waiting type of motor impulsivity, defined as the difficulty to withhold a specific action, shares some common features with tics. In a large group of adult TD patients compared to healthy controls, we assessed waiting motor impulsivity using a behavioral task, as well as structural and functional underpinnings of waiting impulsivity and tics using multi-modal neuroimaging protocol. We found that unmedicated TD patients showed increased waiting impulsivity compared to controls, which was independent of comorbid conditions, but correlated with the severity of tics. Tic severity did not account directly for waiting impulsivity, but this effect was mediated by connectivity between the right orbito-frontal cortex with caudate nucleus bilaterally. Waiting impulsivity in unmedicated patients with TD also correlated with a higher gray matter signal in deep limbic structures, as well as connectivity with cortical and with cerebellar regions on a functional level. Neither behavioral performance nor structural or functional correlates were related to a psychometric measure of impulsivity or impulsive behaviors in general. Overall, the results suggest that waiting impulsivity in TD was related to tic severity, to functional connectivity of orbito-frontal cortex with caudate nucleus and to structural changes within limbic areas.

Dissociation in reactive and proactive inhibitory control in Myoclonus dystonia.

Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive-compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.

Dissociable effects of subthalamic nucleus deep brain stimulation surgery and acute stimulation on verbal fluency in Parkinson's disease.

OBJECT: Verbal fluency (VF) is the cognitive test which shows the most consistent and persistent post-operative decline after subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD). However, the reasons are not completely understood, and the debate has focused on two hypotheses: a surgical effect or an acute STN-DBS effect. METHODS: We recruited 3 PD samples: (1) a group assessed before and after STN-DBS surgery (2) a group assessed On vs. Off STN-DBS and (3) an unoperated PD control group. All groups performed letter, category and switching category VF tasks. The total number of correct words generated were noted and measures of clustering and switching were also obtained. RESULTS: We found a significant effect of STN-DBS surgery on all VF tasks which was associated with a post-operative decline in the total number of words generated, and a reduction of phonemic switching during the letter and category VF tasks, and a reduction of semantic clustering for category VF. By contrast to the effects of surgery, acute On vs. Off stimulation did not influence the number of words generated on any of the VF tasks. Acute stimulation only produced two effects on the category VF task: increased semantic cluster size and decreased number of semantic switches when STN-DBS was switched On. CONCLUSIONS: This study differentiates between the effects of STN-DBS surgery and acute stimulation on VF performance. Our findings indicate that the STN-DBS effect on VF are a surgical and not an acute STN stimulation effect.

Structural and functional abnormalities within sensori-motor and limbic networks underpin intermittent explosive symptoms in Tourette disorder.

BACKGROUND: Intermittent explosive outbursts (IEO), manifesting as sudden episodes of verbal or physical aggression, are frequently present in patients with Tourette disorder (TD) and considered as one of the most disabling symptoms by patients and families. The neuronal correlates of these behaviours are poorly understood, and this was the primary objective of the present study. METHODS: We assessed the presence of IEO in 55 patients with TD and then compared the subgroup of the patients with IEO to those without these manifestations using a multimodal neuroimaging approach. RESULTS: 47% of TD patients presented IEO, which was frequently associated with attention deficit hyperactivity disorder (ADHD). TD patients (without ADHD) with IEO compared to TD without IEO, showed structural changes in the right supplementary motor area as well as in the right hippocampus (increased fractional anisotropy), and in the left orbitofrontal cortex (decreased mean diffusivity). Using these three nodes as seeds for resting state functional connectivity, we showed a lower connectivity within the sensori-motor cortico-basal ganglia network, and an altered connectivity pattern among the orbito-frontal cortex, amygdala and hippocampus. CONCLUSIONS: Overall, our results indicate that TD with IEO is associated with brain dysfunction related to a less efficient top-down control on action selection, and impairments related to emotional regulation, impulse control and aggressive behaviours.

Neural correlates and role of medication in reactive motor impulsivity in Tourette disorder.

Abnormality of inhibitory control is considered to be a potential cognitive marker of tics in Tourette disorder (TD), attention deficit hyperactivity disorder (ADHD), and impulse control disorders. The results of the studies on inhibitory control in TD showed discrepant results. The aim of the present study was to assess reactive inhibitory control in adult TD patients with and without antipsychotic medication, and under emotional stimulation (visual images with positive, neutral and negative content). We assessed 31 unmedicated and 19 medicated TD patients and 26 matched healthy controls using the stop signal task as an index of reactive motor impulsivity and emotional stimulation with the aim to increase impulsivity. We performed a multimodal neuroimaging analysis using a regions of interest approach on grey matter signal, resting-state spontaneous brain activity and functional connectivity analyses. We found a higher reactive motor impulsivity in TD patients medicated with antipsychotics compared to unmedicated TD patients and controls. This propensity for reactive motor impulsivity in medicated TD patients was not influenced by ADHD or emotional stimulation. Neuroimaging results in medicated TD patients suggested that reactive motor impulsivity was underpinned by an increased grey matter signal from the right supplementary motor area and inferior frontal gyrus; decreased resting-state spontaneous activity of the left putamen; higher functional connectivity between the inferior frontal gyrus and the superior temporal gyri (bilaterally); lower functional connectivity between the cerebellum and the right subthalamic nucleus. Taken together, our data suggested (i) a deficit in reactive motor impulsivity in TD patients medicated with atypical antipsychotics that was unrelated to ADHD and (ii) that motor impulsivity was underpinned by structures and by functional connectivity of the fronto-temporo-basal ganglia-cerebellar pathway.

Subthalamic Nucleus Stimulation Does Not Have Any Acute Effects on Verbal Fluency or on Speed of Word Generation in Parkinson's Disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been shown to be generally safe from a cognitive perspective, with consistent evidence that the major impact of STN-DBS in Parkinson's disease (PD) is on verbal fluency. OBJECTIVE: The aim of this study was first to identify the influence of acute manipulation of STN-DBS in PD on the number and time pattern of word generation on different verbal fluency (VF) tasks, phonemic, switching, and cued switching, and second to determine whether cueing improved VF and if cueing effects interacted with STN-DBS effects. METHODS: Parallel versions of these three verbal fluency tasks were completed by 31 patients with Parkinson's disease who had had bilateral DBS of the STN, twice, with DBS On and Off, with the order counterbalanced across patients. RESULTS: There was no effect of acute STN-DBS on the total number of words generated during verbal fluency. As expected, the number of words generated significantly declined over the six 10-second intervals of the verbal fluency tasks, but this time pattern of word generation was not altered by STN-DBS. External cueing significantly increased the number of words generated relative to an uncued switching verbal fluency task, but the cueing effect on VF was not altered by STN-DBS. CONCLUSION: In conclusion, (i) acute STN-DBS manipulation did not alter either verbal fluency performance or the time pattern of word generation and (ii) external cueing significantly improved verbal fluency performance both with STN-DBS On and Off.

Psychosocial Impact of Dysarthria: The Patient-Reported Outcome as Part of the Clinical Management.

BACKGROUND: Dysarthria in neurological disorders can have psychosocial consequences. The dysarthric speaker's perspective towards the disorder's psychosocial impact is essential in its global assessment and management. For such purposes, assessment tools such as the Dysarthria Impact Profile (DIP) are indispensable. OBJECTIVE: We aimed to confirm the relevance of using the DIP to quantify the psychosocial consequences of dysarthria in neurological diseases. METHODS: We studied 120 participants, 15 healthy controls and 105 patients with different kinds of dysarthria induced by several neurological disorders (Parkinson's disease [PD], Huntington's disease, dystonia, cerebellar ataxia, progressive supranuclear palsy [PSP], multiple system atrophy, lateral amyotrophic sclerosis). All participants underwent a cognitive evaluation and a speech intelligibility assessment and completed three self-reported questionnaires: the 36-Item Short Form Health Survey, the Voice Handicap Index (VHI), and the DIP. RESULTS: The psychometric properties of the DIP were confirmed, including internal consistency (α = 0.93), concurrent validity (correlation with the VHI: r = -0.77), and discriminant validity (accuracy = 0.93). Psychosocial impact of dysarthria was revealed by the DIP for all patients. Intelligibility loss was found strongly correlated with the psychosocial impact of dysarthria: for a similar level of intelligibility impairment, the DIP total score was similar regardless of the pathological group. However, our findings suggest that the psychosocial impact measured by the DIP could be partially independent from the severity of dysarthria (indirectly addressed here via speech intelligibility): the DIP was able to detect patients without any intelligibility impairment, but with a psychosocial impact. CONCLUSIONS: All patients reported a communication complaint, attested by the DIP scores, despite the fact that not all patients, notably PD, ataxic, and PSP patients, had an intelligibility deficit. The DIP should be used in clinical practice to contribute to a holistic evaluation and management of functional communication in patients with dysarthria.