Testing the specificity of phenomenological criteria for functional tic-like behaviours in youth with Tourette syndrome.

BACKGROUND AND PURPOSE: The aim was to test the specificity of phenomenological criteria for functional tic-like behaviours (FTLBs). The European Society for the Study of Tourette Syndrome (ESSTS) criteria for the diagnosis of FTLBs include three major criteria: age at symptom onset ≥12 years, rapid evolution of symptoms and specific phenomenology. METHODS: Children and adolescents with primary tic disorders have been included in a Registry in Calgary, Canada, since 2017. Using the Yale Global Tic Severity Scale, the proportion of youth with primary tic disorders who met specific phenomenological criteria for FTLBs at first visit was assessed: (1) having ≥1 specific complex motor tic commonly seen in FTLBs, including complex arm/hand movements, self-injurious behaviour, blocking, copropraxia; (2) having ≥1 specific complex phonic tic commonly seen in FTLBs, including saying words, phrases, disinhibited speech, coprolalia; (3) having a greater number of complex tics than simple tics. Children seen for the first time between 2017 and 2019 and between 2021 and 2023 were analysed separately. RESULTS: Of 156 participants included between 2017 and 2019, high specificity (94.2%) of the age at onset criterion (≥12 years) and of having at least two complex motor behaviours and one complex phonic behaviour at first visit (96.2%) was observed. Some of the complex motor tics had lower specificity. The specificity of the FTLB diagnostic criterion of having more complex tics than simple tics was 89.7%. There was no significant difference in specificity of the criteria for children seen for the first time between 2017 and 2019 and between 2021 and 2023 (n = 149). CONCLUSION: This information supports the use of the ESSTS criteria for FTLBs in clinical practice.

Prospective follow-up study of youth and adults with onset of functional tic-like behaviours during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: Very little is known about the long-term prognosis of patients with functional tic-like behaviours (FTLBs). We sought to characterize the trajectory of symptom severity over a 12-month period. METHODS: Patients with FTLBs were included in our prospective longitudinal child and adult clinical tic disorder registries at the University of Calgary. Patients were prospectively evaluated 6 and 12 months after their first clinical visit. Tic inventories and severity were measured with the Yale Global Tic Severity Scale (YGTSS). RESULTS: Eighty-three youths and adults with FTLBs were evaluated prospectively until April 2023. Mean YGTSS total tic severity scores were high at baseline, with a mean score of 29.8 points (95% confidence interval [CI] = 27.6-32.1). Fifty-eight participants were reevaluated at 6 months, and 32 participants were reevaluated at 12 months. The YGTSS total tic severity score decreased significantly from the first clinical visit to 6 months (raw mean difference = 8.9 points, 95% CI = 5.1-12.7, p < 0.0001), and from 6 to 12 months (raw mean difference = 6.4 points, 95% CI = 0.8-12.0, p = 0.01). Multivariable linear regression demonstrated that tic severity at initial presentation and the presence of other functional neurological symptoms were associated with higher YGTSS total tic scores at 6 months, whereas younger age at baseline, receiving cognitive behavioural therapy for anxiety and/or depression, and prescription of selective serotonin reuptake inhibitors were associated with lower YGTSS total tic scores at 6 months. CONCLUSIONS: We observed a meaningful improvement in tic severity scores in youth and adults with FTLBs over a period of 6-12 months.

Vibro-tactile stimulation of the neck reduces pain in people with cervical dystonia: a proof-of-concept study.

BACKGROUND: Pain is a common non-motor symptom in patients with cervical dystonia (CD), severely impacting their quality of life. The pathophysiology of CD is incompletely understood but it involves altered processing of proprioceptive and pain signals. OBJECTIVES: The purpose of this proof-of-concept study was to determine if vibro-tactile stimulation (VTS)-a non-invasive form of neuromodulation targeting the somatosensory system-can modulate neck pain in people with CD. METHODS: In a multi-center study, 44 CD patients received VTS to sternocleidomastoid and/or trapezius muscles for up to 45 min under 9 different stimulation conditions that either targeted a single or a pair of muscles. The primary outcome measure was a perceived pain score (PPS) rated by participants on a 100-point analogue scale. RESULTS: During VTS, 29/44 (66%) of participants experienced a reduction in PPS of at least 10% with 17/44 (39%) reporting a reduction in pain of 50% or higher. After VTS cessation, 57% of participants still reported a 10% or higher reduction in PPS. Effects were significant at the group level and persisted for up to 20 min post-treatment. No distinct optimal stimulation profiles were identified for specific CD phenotypes. Clinical markers of disease severity or duration did not predict the degree of VTS-induced pain reduction. CONCLUSION: This proof-of-concept study demonstrates the potential of VTS as a new non-invasive therapeutic option for treating neck pain associated with CD. Further research needs to delineate optimal dosage and long-term effects.

Premonitory Urge in Patients with Tics and Functional Tic-like Behaviors.

BACKGROUND: Premonitory urges (PU) are well described in primary tics, but their frequency and intensity in functional tic-like behaviors (FTLB) are unclear. OBJECTIVE: To study the experience of PU in patients with FTLB. METHODS: We compared the results of the premonitory urge for tics scale (PUTS) in adults with tics and FTLB in the University of Calgary Adult Tic Registry. RESULTS: We included 83 patients with tics and 40 with FTLB. When comparing patients with tics, FTLB with tics and FTLB only, we did not detect significant differences either in the total PUTS score (P = 0.39), or in any of the individual PUTS item sub-scores (P values ranging between 0.11 and 0.99). CONCLUSIONS: Patients with FTLB report PU at similar frequency and intensity to patients with tics. This finding confirms that PU are not a useful feature to discriminate FTLB from tics.

Psychological Factors Associated with Functional Tic-like Behaviours during the COVID-19 Pandemic.

Functional tic-like behaviours (FTLB) are a female predominant functional neurological disorder that escalated in incidence during the SARS CoV2 pandemic. This study compared social and adaptive functioning, social media use, pandemic experiences, and psychiatric comorbidities between FTLB (n = 35), Tourette Syndrome (TS) (n = 22), and neurotypical (NT) (n = 25) participants ages 11 to 25 years. The psychiatric comorbidity burden for participants with FTLB was formidable, with frequencies ranging from 1.5 to 10 times higher for major depressive disorder and panic disorder compared to TS and NT participants. Borderline personality disorder (BPD), agoraphobia, social anxiety disorder, and generalized anxiety disorder were also significantly more common in FTLB compared to NT participants. Vulnerable attachment scores, social phobia and social interaction anxiety symptoms were higher in participants with FTLB than NT but not TS. Overall distress tolerance, resilient coping, suggestibility, hours on social media, and exposure to tic and TS content were not significantly different between groups. FTLB participants rated their mental health declined more severely during the pandemic than both TS and NT participants and were more likely to experience trouble sleeping, loneliness, and difficulty affording housing and food than NT participants. Participants with FTLB were significantly more likely to identify as gender minority people than TS and NT, though there were no significant differences based on gender identity in the study variables within the FTLB group. The association and potential pathways explaining how psychiatric disorders may be contributing to FTLB, and why certain groups appear at particular risk are discussed.

What are the Key Phenomenological Clues to Diagnose Functional Tic-Like Behaviors in the Pandemic Era?

BACKGROUND: Functional tic-like behaviors (FTLBs) can be difficult to distinguish from tics. OBJECTIVES: To describe the phenomenology of FTLBs in youth and assess the movements and vocalizations most suggestive of the diagnosis. METHODS: We compared the phenomenology of tics between youth (<20 yr) with FTLBs and with primary tics from our Registry in Calgary, Canada. RESULTS: Two hundred and thirty-six youths were included: 195 with primary tics (75% males; mean age: 10.8 yr) and 41 with FTLBs (98% females; 16.1 yr). In the bivariate models, FTLBs were most associated with copropraxia (OR = 15.5), saying words (OR = 14.5), coprolalia (OR = 13.1), popping (OR = 11.0), whistling (OR = 9.8), simple head movements (OR = 8.6), and self-injurious behaviors (OR = 6.9). In the multivariable model, FTLBs were still associated with saying words (OR = 13.5) and simple head movements (OR = 6.3). Only 12.2% of youth with FTLBs had throat clearing tics (OR = 0.2). CONCLUSIONS: This study shall help physicians diagnose youth with FTLBs according to the presence/association of specific movements and vocalizations.

Symptom Severity and Health Impacts of Functional Tic-Like Behaviors in Youth.

BACKGROUND: We performed this study to improve understanding of the relationship between functional tic-like behaviors (FTLBs) and quality of life, loneliness, family functioning, anxiety, depression, and suicidality. METHOD: This cross-sectional study assessed self-reported quality of life, disability, loneliness, depression, anxiety, family functioning, tic severity, and suicide risk in age- and birth-sex matched youth with FTLBs, Tourette syndrome (TS), and neurotypical controls. We performed specific subanalyses comparing individuals with FTLBs who identified as transgender/gender diverse (TGD) with cisgender individuals. RESULTS: Eighty-two youth participated (age range 11 to 25, 90% female at birth), including 35 with FTLBs, 22 with TS, and 25 neurotypical controls. A significantly higher proportion of participants with FTLB identified as TGD (15 of 35) than TS (two of 22) and neurotypical control (three of 25) participants. Compared with neurotypical controls, individuals with FTLBs had significantly lower quality of life, greater disability, loneliness, social phobia, anxiety symptoms, depressive symptoms, and suicidality. Compared with individuals with TS, individuals with FTLBs had more school/work absences due to tics, had more depressive symptoms, were more likely to be at high risk for suicidality, and had disability in self-care and life activity domains. There were no significant differences between cisgender and TGD participants with FTLB in any of the domains assessed. CONCLUSIONS: Youth with FTLB have unique health care needs and associations with anxiety, depression, sex, and gender.

Are Cognitive Symptoms Part of the Phenotypic Spectrum of Idiopathic Adult-Onset Dystonia? Summary of Evidence from Controlled Studies.

BACKGROUND: Cognitive dysfunction has been reported in idiopathic adult-onset dystonia (IAOD), but whether this is a primary or secondary component of the disorder remains uncertain. OBJECTIVE: Here, we aimed to analyze the key domains of abnormal cognitive performance in IAOD and whether this is associated with motor or mood changes. METHODS: Article selection for our critical review was guided by PRISMA guidelines (mesh terms "dystonia" and "cognitive," publication period: 2000-2022). Only peer-reviewed, English-language original case-control studies involving patients with IAOD who were not exposed to dopamine- or acetylcholine-modulating agents and validated cognitive assessments were included. RESULTS: Abstract screening ultimately yielded 22 articles for full-text review and data extraction. A greater proportion of studies (17 of 22, 82%) reported abnormal cognitive performance in IAOD. Most of these studies focused on blepharospasm (BSP) and cervical dystonia (10 and 14, respectively). Most studies reporting cognitive impairment (11 of 17) identified multidomain impairment in cognition. Executive functions were the domain most frequently explored (14 of 22 studies), 79% of which detected worse performance in people with dystonia. Results related to other domains were inconclusive. Cognitive abnormalities were independent of motor symptoms in most studies (7 of 12) that explored this relationship and independent of mood status in all 8 that investigated this. CONCLUSIONS: Within IAOD, cognitive dysfunction (in particular, executive dysfunction) has been documented mainly in BSP and cervical dystonia. More comprehensive testing is warranted to assess abnormalities in other domains and in other forms of IAOD, as well as to evaluate longitudinal progression of cognitive disturbances in this condition.

The effect of transcranial ultrasound pulse repetition frequency on sustained inhibition in the human primary motor cortex: A double-blind, sham-controlled study.

BACKGROUND: Non-invasive brain stimulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation hold promise for inducing brain plasticity. However, their limited precision may hamper certain applications. In contrast, Transcranial Ultrasound Stimulation (TUS), known for its precision and deep brain targeting capabilities, requires further investigation to establish its efficacy in producing enduring effects for treating neurological and psychiatric disorders. OBJECTIVE: To investigate the enduring effects of different pulse repetition frequencies (PRF) of TUS on motor corticospinal excitability. METHODS: T1-, T2-weighted, and zero echo time magnetic resonance imaging scans were acquired from 21 neurologically healthy participants for neuronavigation, skull reconstruction, and the performance of transcranial ultrasound and thermal modelling. The effects of three different TUS PRFs (10, 100, and 1000 Hz) with a constant duty cycle of 10 % on corticospinal excitability in the primary motor cortex were assessed using TMS-induced motor evoked potentials (MEPs). Each PRF and sham condition was evaluated on separate days, with measurements taken 5-, 30-, and 60-min post-TUS. RESULTS: A significant decrease in MEP amplitude was observed with a PRF of 10 Hz (p = 0.007), which persisted for at least 30 min, and with a PRF of 100 Hz (p = 0.001), lasting over 60 min. However, no significant changes were found for the PRF of 1000 Hz and the sham conditions. CONCLUSION: This study highlights the significance of PRF selection in TUS and underscores its potential as a non-invasive approach to reduce corticospinal excitability, offering valuable insights for future clinical applications.

Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss.

Background: Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Method: Several MFN2-mediated functions were characterized in fibroblast cells from a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy, who harbours a novel homozygous MFN2 variant, D414V, which is found in a region of the HR1 domain of MFN2 where few pathogenic variants occur. Results: We found evidence for impairment of several MFN2-mediated functions. Consistent with reduced mitochondrial fusion, patient fibroblasts exhibited more fragmented mitochondrial networks and had reduced mtDNA copy number. Additionally, patient fibroblasts had reduced oxygen consumption, fewer mitochondrial-ER contacts, and altered lipid droplets that displayed an unusual perinuclear distribution. Conclusion: Overall, this work characterizes D414V as a novel variant in MFN2 and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.