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.

European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I: assessment.

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills.

Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review.

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society.

Personality and Neuropsychological Profiles in Friedreich Ataxia.

Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits.

Disentangling Tourette syndrome heterogeneity through hierarchical ascendant clustering.

AIM: To explore the heterogeneity of Tourette syndrome as part of a neurodevelopmental spectrum. METHOD: Using hierarchical ascendant clustering based on tic symptoms, developmental milestones, and neurodevelopmental comorbidities, we analyzed the heterogeneity of Tourette syndrome phenotypes in a sample of 174 children and adolescents with Tourette syndrome referred to a tertiary university clinic. RESULTS: The model yielded three distinct clusters characterized as follows. In cluster 1, we found many neurodevelopmental comorbidities (including intellectual disabilities, autism spectrum disorder, attention-deficit-hyperactivity disorder [ADHD], and learning disabilities) and academic impairments. In cluster 2, patients had no other neurodevelopmental comorbidities. In cluster 3, patients had higher intelligence, a high frequency of attentional impairment, school problems related to both ADHD and unspecific attention difficulties, and handwriting problems related to the tics themselves. Interestingly, clusters did not differ in terms of family history or anxious-depressive comorbidities. The only other differences that emerged were related to prenatal or perinatal risk factors (more represented in cluster 1) and treatment profiles (higher rates of stimulants in cluster 1). INTERPRETATION: We conclude that from a phenotypical perspective, Tourette syndrome is a heterogeneous syndrome with at least three main clusters that may help in addressing the etiological basis of Tourette syndrome and specific rehabilitative and therapeutic approaches. WHAT THIS PAPER ADDS: The clustering of Tourette syndrome based on comorbidity with other neurodevelopmental conditions reveals three clusters. A group of patients with Tourette syndrome show school difficulties related to non-specific attention and writing problems. Analysing only children and adolescents helps to distinguish between developmental comorbid conditions and coexistent disorders.

Executive functioning and risk-taking behavior in Parkinson's disease patients with impulse control disorders.

Impulse control disorders (ICD) are common in Parkinson's disease (PD) and are associated with dopaminergic medication. The purpose of this study was to investigate executive function and risk-taking behavior in PD patients with ICD. 17 PD patients with ICD (ICD-PD) were compared to 20 PD patients without ICD (CTRL-PD) using neuropsychological and experimental tasks. Executive functions were assessed using standard executive testing (Conner's Performance Test, Modified Wisconsin Card Sorting Test, Trail Making Test and phonological verbal fluency). Subjects were also submitted to an experimental gambling task consisted of three decks of money cards: neutral deck (equal opportunity for gains as losses), winning deck (small amount of money with a positive balance) and loser deck (high amount of money with a negative balance), evaluating risk-taking behavior (number of cards picked in each deck) and valuation of the reward (subjective appreciation of the value of each deck). There was no significant difference in executive functioning between groups. Both groups selected more cards in the losing deck (high amount of money) as compared to the neutral deck (Mann-Whitney test, ICD-PD, p = 0.02; CTRL-PD, p = 0.003) and to the winning deck (Mann-Whitney test, ICD-PD p = 0.0001; CTRL-PD p = 0.003), suggesting an increased risk-taking behavior. Interestingly, we found that ICD-PD patients estimated the value of decks differently from CTRL-PD patients, taking into account mainly the positive reinforced value of the decks (Mann-Whitney test, p = 0.04). This study showed that executive pattern and risk-taking behavior are similar between ICD-PD and CTRL-PD patients. However, ICD-PD patients showed a specific deficit of the subjective estimation of the reward. Links between this deficit and metacognitive skills are discussed.

Impact of Perceived Stress, Anxiety-Depression and Social Support on Coping Strategies of Parents Having A Child With Gilles de la Tourette Syndrome.

PURPOSE: Previous reports have indicated that raising a child with Gilles de la Tourette syndrome (GTS) could be considered a stressful experience. Thus our study aimed to assess the impact of perceived stress (i.e. parental cognitive perception of their child's disorder) and social support (number of people surrounding the subject providing support) on coping strategies-defined as processes of restoring balance between excessive demands and inadequate resources-of parents having a child with GTS. METHODS: Twenty-eight parents of 21 patients with GTS (aged 6 to 16years) completed questionnaires on perceived stress (ALE Scale), social support (SSQ6), coping strategies (WCC-R) and anxiety-depression (HAD). RESULTS: Principal component analysis showed a negative correlation between social support on one side and perceived stress and anxiety/depression on the other. Problem- and emotion-focused coping both correlated with social support, all of them being independent from perceived stress and anxiety/depression. Hierarchical ascendant classification showed three clusters of individuals in our parents' groups: i) those having high scores in perceived stress and anxiety-depression; ii) those having high scores in social support associated with low scores in perceived stress; iii) parents having lower than average scores on both problem- and emotion- focused coping and social support. CONCLUSION: Our results reinforce the need for developing training programs for parents with GTS children to better understand and tolerate the disorder to decrease their stress.

Comparison of the Movement Disorder Society Parkinson's disease dementia criteria with neuropsychological testing.

The objective of our study was to compare Movement Disorder Society Task Force criteria for diagnosis of Parkinson's disease dementia (PDD) with the gold standard of traditional neuropsychological testing. A short checklist (Level I) and a protocol of neuropsychological tests (Level II) have been proposed by a Movement Disorder Society Task Force but not fully validated in clinical practice. Ninety-one Parkinson's disease (PD) subjects were categorized as having dementia or no dementia based on a battery of neuropsychological test results and clinical judgment. The isolated components needed for Level I and Level II diagnoses were then culled from the neuropsychological evaluations and independently used to designate PDD. Compared with traditional neuropsychological testing, the sensitivity and specificity of Level I criteria for PDD was 66.7% and 98.8%, and for Level II criteria 100% and 92.7%, respectively. Using Level II criteria, 6 additional subjects were diagnosed with PDD that were classified as having no dementia when full neuropsychological data were used for the diagnosis. These 6 subjects had more education years and were less impaired on cognitive tests. The Movement Disorder Society's Level II criteria more frequently classify subjects with PDD than does traditional neuropsychological testing. Whereas Level II criteria may overclassify subjects as having PDD, they are very accurate in ruling out dementia. Movement Disorder Society's criteria are practical and timesaving, although full neuropsychological testing may still be needed.

Can we still dream when the mind is blank? Sleep and dream mentations in auto-activation deficit.

Bilateral damage to the basal ganglia causes auto-activation deficit, a neuropsychological syndrome characterized by striking apathy, with a loss of self-driven behaviour that is partially reversible with external stimulation. Some patients with auto-activation deficit also experience a mental emptiness, which is defined as an absence of any self-reported thoughts. We asked whether this deficit in spontaneous activation of mental processing may be reversed during REM sleep, when dreaming activity is potentially elicited by bottom-up brainstem stimulation on the cortex. Sleep and video monitoring over two nights and cognitive tests were performed on 13 patients with auto-activation deficit secondary to bilateral striato-pallidal lesions and 13 healthy subjects. Dream mentations were collected from home diaries and after forced awakenings in non-REM and REM sleep. The home diaries were blindly analysed for length, complexity and bizarreness. A mental blank during wakefulness was complete in six patients and partial in one patient. Four (31%) patients with auto-activation deficit (versus 92% of control subjects) reported mentations when awakened from REM sleep, even when they demonstrated a mental blank during the daytime (n = 2). However, the patients' dream reports were infrequent, short, devoid of any bizarre or emotional elements and tended to be less complex than the dream mentations of control subjects. The sleep duration, continuity and stages were similar between the groups, except for a striking absence of sleep spindles in 6 of 13 patients with auto-activation deficit, despite an intact thalamus. The presence of spontaneous dreams in REM sleep in the absence of thoughts during wakefulness in patients with auto-activation deficit supports the idea that simple dream imagery is generated by brainstem stimulation and is sent to the sensory cortex. However, the lack of complexity in these dream mentations suggests that the full dreaming process (scenario, emotions, etc.) require these sensations to be interpreted by higher-order cortical areas. The absence of sleep spindles in localized lesions in the basal ganglia highlights the role of the pallidum and striatum in spindling activity during non-REM sleep.

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.

Clinical validation of Movement Disorder Society-recommended diagnostic criteria for Parkinson's disease with dementia.

The objective of this work was to evaluate the Movement Disorders Society (MDS) Task Force-proposed screening checklist for detecting Parkinson's disease dementia (PD-D) in relation to full neuropsychological testing. An MDS Task Force has proposed diagnostic procedures for PD-D, which have not been fully validated against more extensive neuropsychological testing. PD subjects were recruited from 2 specialty centers. A neuropsychologist evaluated them for dementia as part of routine clinical care. Independent clinical neurologists administered the MDS PD-D screening checklist. Diagnosis of PD-D by the 2 methods was compared. Ninety-one PD subjects had a mean age of 66.3 (SD = 9.7) years and a mean PD duration of 8.8 (SD = 6.1) years. Seven subjects (7.7%) met all 8 screening checklist criteria from the MDS PD-D screening tool and were classified as probable PD-D. Fifteen (16.5%) subjects were classified as PD-D by full neuropsychological assessment. The screening checklist showed 100% specificity, but only 46.7% sensitivity, for diagnosing PD-D compared to the full neuropsychological assessment. PD-D cases missed by the PD-D screening tool were largely due to 2 checklist items that were not endorsed (absence of depression and Mini-Mental State Examination [MMSE] scores <26). There was moderate agreement between these 2 methods for determination of PD-D (kappa = 0.59, P < .001). The MDS-PD-D screening checklist is highly accurate for detecting PD-D if all items are endorsed. However, for cases that do not meet these criteria, full neuropsychological testing is needed to differentiate PD-D from milder cognitive impairment. Revision of the checklist by altering or eliminating the 2 problematic checklist items may improve sensitivity.

Stimulation of the pedunculopontine and cuneiform nuclei for freezing of gait and falls in Parkinson disease: Cross-over single-blinded study and long-term follow-up.

INTRODUCTION: Deep brain stimulation (DBS) of the mesencephalic locomotor region, composed of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, has been proposed to treat dopa-resistant gait and balance disorders in Parkinson's disease (PD). Here, we report the long-term effects of PPN- or CuN-DBS on these axial disorders. METHODS: In 6 PD patients operated for mesencephalic locomotor region DBS and prospectively followed for more than 2 years, we assessed the effects of both PPN- and CuN-DBS (On-dopa) in a cross-over single-blind study by using clinical scales and recording gait parameters. Patients were also examined Off-DBS. RESULTS: More than 2 years after surgery, axial and Tinetti scores were significantly aggravated with both PPN- or CuN-DBS relative to before and one year after surgery. Gait recordings revealed an increased double-stance duration with both PPN- or CuN-DBS, higher swing phase duration with CuN-DBS and step width with PPN-DBS. With PPN- versus CuN-DBS, the step length, velocity and cadence were significantly higher; and the double-stance and turn durations significantly lower. Irrespective the target, we found no significant change in clinical scores Off-DBS compared to On-DBS. The duration of anticipatory postural adjustments as well as step length were lower with versus without PPN-DBS. We found no other significant changes in motor, cognitive or psychiatric scores, except an increased anxiety severity. CONCLUSION: In this long-term follow-up study with controlled assessments, PPN- or CuN-DBS did not improve dopa-resistant gait and balance disorders with a worsening of these axial motor signs with time, thus indicating no significant clinical effect.

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.

Pedunculopontine and Cuneiform Nuclei Deep Brain Stimulation for Severe Gait and Balance Disorders in Parkinson's Disease: Interim Results from a Randomized Double-Blind Clinical Trial.

BACKGROUND: Dopa-resistant freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced Parkinson's disease (PD). OBJECTIVE: We investigate the effects of deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), comprised of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, for treating gait and balance disorders, in a randomized double-blind cross-over trial. METHODS: Six PD patients with dopa-resistant FOG and/or falls were operated for MLR-DBS. Patients received three DBS conditions, PPN, CuN, or Sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory-postural-adjustments (APAs) during gait initiation on a force platformResults:The anteroposterior APAs were not significantly different between the DBS conditions (median displacement [1st-3rd quartile] of 3.07 [3.12-4.62] cm with sham-DBS, 1.95 [2.29-3.85] cm with PPN-DBS and 2.78 [1.66-4.04] cm with CuN-DBS; p = 0.25). Step length and velocity were significantly higher with CuN-DBS vs. both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs. sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs. inclusion. We did not find any significant change in clinical scales between DBS conditions or one year after surgery. CONCLUSION: Two months of PPN-DBS or CuN-DBS does not effectively improve clinically dopa-resistant gait and balance disorders in PD patients.

Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.

BACKGROUND: Severe, refractory obsessive-compulsive disorder (OCD) is a disabling condition. Stimulation of the subthalamic nucleus, a procedure that is already validated for the treatment of movement disorders, has been proposed as a therapeutic option. METHODS: In this 10-month, crossover, double-blind, multicenter study assessing the efficacy and safety of stimulation of the subthalamic nucleus, we randomly assigned eight patients with highly refractory OCD to undergo active stimulation of the subthalamic nucleus followed by sham stimulation and eight to undergo sham stimulation followed by active stimulation. The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods. General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests. RESULTS: After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/-SD], 19+/-8 vs. 28+/-7; P=0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56+/-14 vs. 43+/-8, P=0.005). The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation. There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events. CONCLUSIONS: These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events. (ClinicalTrials.gov number, NCT00169377.)

Neuropsychological, neuropsychiatric, and quality of life issues in DBS for dystonia.

We review the impact of dystonia and its surgical treatment with deep brain stimulation (DBS) on cognitive function, psychiatric morbidity, and health-related quality of life. The current evidence suggests that globus pallidus internus (GPi) DBS does not cause cognitive decline in primary dystonia. However, we recommend general preoperative screening of cognition in patients with dystonia to evaluate baseline cognitive status and monitor for possible postoperative changes. Patients with mild to moderate depression appear to do well postoperatively; however, there are scant data about those with severe depression. This is particularly problematic given reports of postoperative suicide. Patients with tardive dystonia seem to do well post-GPi DBS despite often having a history of depression or even having active severe depression. We make recommendations for screening and basic management strategies of patients identified as having a major psychiatric illness pre- or postoperatively. Quality of life in dystonia patients quantified by generic measures such as the SF36 showed improvement in both mental and physical categories following DBS surgery.

European clinical guidelines for Tourette syndrome and other tic disorders. Part I: assessment.

A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of Tourette Syndrome (TS). The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members. Detailed clinical assessment guidelines of tic disorders and their comorbidities in both children and adults are presented. Screening methods that might be helpful and necessary for specialists' differential diagnosis process are suggested in order to further analyse cognitive abilities, emotional functions and motor skills. Besides clinical interviews and physical examination, additional specific tools (questionnaires, checklists and neuropsychological tests) are recommended.

Social cognitive impairment in early Parkinson's disease: A novel "mild impairment"?

INTRODUCTION: Social cognition (SC) deficit has recently been described in the early stages of Parkinson's disease (PD), but findings remain unclear. Our objective was to determine the frequency of SC impairment in newly-diagnosed PD patients and whether it is independent of Mild Cognitive Impairment (MCI). METHODS: We enrolled 109 patients with idiopathic PD diagnosed within the previous four years (ICEBERG cohort) and 39 healthy participants. SC was evaluated using the Mini-Social Cognition and Emotional Assessment (Mini-SEA) that allows a multi-domain assessment of SC. Relationships between SC and clinical characteristics, global cognitive efficiency, mood, anxiety, apathy and impulse control disorders, were also evaluated. RESULTS: 30% of patients had significant socio-emotional impairment. Moreover, SC deficit in isolation was 3.5 times more frequent than MCI in isolation (20.2% vs 5.5% respectively). Both emotion identification and Theory of Mind were impaired compared to healthy participants. No effect of age, level of education, disease severity, dopamine replacement therapy, or global cognitive efficiency were found. Only scores on the Frontal Assessment Battery were correlated with SC abilities. CONCLUSION: SC impairment is frequent in early PD and should be given more consideration. It often occurs in the absence of any other cognitive disorder and may represent the most common neuropsychological deficit in early-stage PD. In line with the definition of PD-MCI criteria, we consider the addition of a sixth MCI sub-type termed "Mild Social Cognition Impairment (MSCI)". Further studies are required to validate the addition of this new MCI domain.