Mitochondrial DNA variant spectrum and the association with chronic tic disorders.

BACKGROUND AND PURPOSE: Tic disorders (TDs) are childhood onset neuropsychiatric disorders characterized by single or multiple sudden, rapid, recurrent, and motor tics and/or vocal tics. Several nuclear genes that are involved in mitochondrial functions suggest a potential role of mitochondria in TDs. METHODS: To evaluate the association of mitochondrial DNA (mtDNA) variants with TDs, we screened the whole mitochondrial genomes in 493 TD patients and 109 age- and sex-matched healthy controls using next generation sequencing technology. RESULTS: A total of 1918 mtDNA variants including 1220 variants in patients only, 154 variants in controls only, and 544 variants shared by both cases and controls were identified. We found a higher number of overall mtDNA variants in TD patients (p = 0.00028). The variant density in MT-ATP6/8 and MT-CYB coding regions showed a significant difference between TD patients and controls (p = 0.0025 and p = 0.003, respectively). Furthermore, we observed a significant association of 15 common variants with TD based on an additive model, including m.14766C > T, m.14783 T > C, m.14905G > A, and m.15301G > A in MT-CYB; m.4769A > G, m.10398A > G, m.12705C > T, and m.12850A > G in MT-ND genes; m.7028C > T in MT-CO1; m.8701A > G in MT-ATP6; two variants with m.16223C > T, m.5580 T > C in noncoding regions; and three rRNA variants with m.1438A > G and m.750A > G in RNR1, and m.2352 T > C in RNR2. CONCLUSIONS: Our data provide evidence of mtDNA variants associated with TDs. The accumulation of the heteroplasmic levels may increase the risk of TDs. Replication studies with larger samples are necessary to understand the pathogenesis of TDs.

Controversies Surrounding the Pathophysiology of Tics.

Tics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations (phonic productions) that are commonly present in children and are required symptoms for the diagnosis of Tourette syndrome. Despite their frequency, the underlying pathophysiology of tics/Tourette syndrome remains unknown. In this review, we discuss a variety of controversies surrounding the pathophysiology of tics, including the following: Are tics voluntary or involuntary? What is the role of the premonitory urge? Are tics due to excess excitatory or deficient inhibition? Is it time to adopt the contemporary version of the cortico-basal ganglia-thalamocortical (CBGTC) circuit? and Do we know the primary abnormal neurotransmitter in Tourette syndrome? Data from convergent clinical and animal model studies support complex interactions among the various CBGTC sites and neurotransmitters. Advances are being made; however, numerous pathophysiologic questions persist.

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents.

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.

Pathophysiology of tic disorders.

Tics are the defining symptom of Tourette syndrome and other tic disorders (TDs); however, they form only a part of their overall symptoms. The recent surge of studies addressing the underlying pathophysiology of tics has revealed an intricate picture involving multiple brain areas and complex pathways. The myriad of pathophysiological findings stem, at least partially, from the multifaceted properties of tics and the disorders that express them. Distinct brain pathways mediate the expression of tics, whereas others are involved in the generation of the premonitory urge, associated comorbidities, and other changes in brain state. Expression of these symptoms is controlled by additional networks underlying voluntary suppression by the patient or those reflecting overall behavioral state. This review aims to simplify the complex picture of tic pathophysiology by dividing it into these key components based on converging data from human and animal model studies. Thus, involvement of the corticobasal ganglia pathway and its interaction with motor, sensory, limbic, and executive networks in each of the components as well as their control by different neuromodulators is described. This division enables a focused definition of the neuronal systems involved in each of these processes and allows a better understanding of the pathophysiology of TDs as a whole.

Cognitive-behavioral therapy induces sensorimotor and specific electrocortical changes in chronic tic and Tourette's disorder.

BACKGROUND: Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. METHODS: To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. RESULTS: Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy. CONCLUSIONS: Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given that LRPs are partially generated within the sensorimotor and supplementary motor area, the reported reduction in tic frequency and improvements of LRPs components suggest that CBT induced a physiological change in patients' motor area.

Genetic neuropathology of obsessive psychiatric syndromes.

Anorexia nervosa (AN), bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. In addition, few, if any, studies have interrogated postmortem brain tissue for evidence of expression quantitative trait loci (eQTLs) associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single-nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a nonpsychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, for example, ED (N=15) and OCD/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and nonpsychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared with controls and OCD cases compared with controls, respectively (false discovery rate (FDR) <5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

Prefrontal cortex volume reductions and tic inhibition are unrelated in uncomplicated GTS adults.

BACKGROUND: Tics in Gilles de la Tourette syndrome (GTS) are repetitive patterned movements, resembling spontaneous motor behaviour, but escaping voluntary control. Previous studies hypothesised relations between structural alterations in prefrontal cortex of GTS adults and tic severity using voxel-based morphometry (VBM), but could not demonstrate a significant association. The relation between prefrontal cortex structure and tic inhibition has not been investigated. METHODS: Here, we used VBM to examine 14 GTS adults without associated comorbidities, and 15 healthy controls. We related structural alterations in GTS to clinical measures of tic severity and tic control. RESULTS: Grey matter volumes in the right inferior frontal gyrus and the left frontal pole were reduced in patients relative to healthy controls. These changes were not related to tic severity and tic inhibition. CONCLUSION: Prefrontal grey matter volume reductions in GTS adults are not related to state measures of tic phenomenology.

[Relationship between tic symptom severity and amplitude of low frequency fluctuation of resting-state functional magnetic resonance imaging of Tourette syndrome].

OBJECTIVE: To examine the relationship between tic symptom severity and amplitude of low frequency fluctuation (ALFF) brain functioning of the first-episode Tourette syndrome through resting-state functional magnetic resonance imaging (fMRI). METHOD: Sixteen subjects were all recruited from the outpatient department of pediatrics, Beijing Anding Hospital, Capital Medical University and were all first-episode Tourette syndrome patients [male: 13, female: 3; age: 6-16 years; mean age: (11.00 ± 2.92) years]; mean education time: (5.06 ± 2.86) years; course: 14-104 months; mean (48.44 ± 25.00) months; scores of YGTSS at baseline: tic severity score: 37.88 ± 5.39; global damage score: 25.63 ± 12.63. All the subjects experienced resting-state fMRI scans and ALFF were calculated in three frequency ranges: 0.01-0.1 Hz, 0.01-0.027 Hz and 0.027-0.073 Hz. First-episode Tourette syndrome patients and 16 gender, age, and education-matched normal controls experienced resting-state fMRI scans. Correlation analysis was performed in between the amplitude of low frequency fluctuation (ALFF) and the severity of tic symptom. P < 0.05 and k value ≥ 10 were considered to be of significance. RESULT: In tic symptom patients, tic severity (total tic scores of YGTSS) was positively correlated with the ALFF values in the orbital part of left superior frontal gyrus (0.01-0.1 Hz:r = 0.83,0.027-0.073 Hz:r = 0.91, P < 0.05, respectively), right middle frontal gyrus (0.01-0.027 Hz:r = 0.85,0.027-0.073 Hz:r = 0.57, P < 0.05, respectively ) and orbital part of left middle frontal gyrus (0.01-0.027 Hz:r = 0.64, P < 0.05). Tic severity was negatively correlated with the ALFF values in the right calcarine fissure and surrounding cortex (0.01-0.1 Hz:r = -0.65,0.01-0.027 Hz:r = -0.69, P < 0.05, respectively ) and the left calcarine fissure and surrounding cortex (0.027-0.073 Hz:r = -0.81, P < 0.05). CONCLUSION: Tic symptom severity of the first-episode Tourette syndrome is associated with abnormal brain activity patterns of specific brain areas.

Tic disorders: what happens in the basal ganglia?

Motor tics are brief, repetitive, involuntary movements that interfere with behavior and appear in multiple neural disorders, most notably, Tourette syndrome. Converging evidence from different lines of research point to the involvement of the corticobasal ganglia system in tics, but the neural mechanism underlying motor tics is largely unknown. An animal model directly linking basal ganglia dysfunction and motor tics indicated that local disinhibition within the basal ganglia input structure, the striatum, induces the appearance of motor tics in both rats and monkeys. Recordings of neuronal activity from multiple brain regions performed in this model during the expression of motor tics showed that tics are associated with phasic changes of neuronal activity throughout the corticobasal ganglia pathway, culminating in the disinhibition of the cortex and the release of a tic. This line of research provides a mechanistic description of the underlying neurophysiology of motor tics and may supply the much needed infrastructure for methodical hypothesis-driven studies of novel clinical treatments.

Arachnoid cyst associated with painful tic convulsif.

Combined clinical presentation of hemifacial spasm and ipsilateral trigeminal neuralgia is known as painful tic convulsif (PTC). It is a rare condition and the most common cause is vascular compression. We report an arachnoid cyst of the posterior fossa that caused PTC in a 50-year-old woman. Her radiological evaluation revealed a median, well-circumscribed, cystic lesion of the posterior fossa suggestive of arachnoid cyst, pushing the cerebellum and brainstem anteriorly. Midline suboccipital craniotomy and marsupialization of cyst was performed with complete recovery of symptoms. To our knowledge, this is the first report of a retrocerebellar arachnoid cyst causing PTC.

Spatial and temporal properties of tic-related neuronal activity in the cortico-basal ganglia loop.

Motor tics are involuntary brief muscle contractions that interfere with ongoing behavior and appear as a symptom in several human disorders. While the pathophysiology of tics is still largely unknown, multiple lines of evidence suggest the involvement of the corticobasal ganglia loop in tic disorders. We administered local microinjections of bicuculline into the putamen of Macaca fascicularis monkeys to induce motor tics, while simultaneously recording neuronal activity from the primary motor cortex, putamen, and globus pallidus. These data were used to explore the spatial and temporal properties of tic-related neuronal activity within the cortico-basal ganglia system. In the putamen, tics were associated with brief bursts of activity of phasically active neurons (presumably the projection neurons) and complex excitation-inhibition patterns of tonically active neurons. Tic-related activity within the putamen was spatially focused and somatotopically organized. In the globus pallidus, tic-related activity was diffusely distributed throughout the motor territory. Tic-related activity in the putamen usually preceded the tic-related activations in the cortex, but in the globus pallidus, tic-related activity was mostly later than the cortex. These findings shed new light on the role of the different basal ganglia nuclei in the generation of motor tics. Despite the early and somatotopically focused nature of tic-related activity in the input stage of the basal ganglia, tic-related activity in the output nucleus is temporally late and diffusely distributed, making it incompatible with a role in tic initiation. Instead, abnormal basal ganglia activity may serve to modulate motor patterns or activate learning mechanisms, thus augmenting further tic expression.

The neurophysiological correlates of motor tics following focal striatal disinhibition.

The cortico-basal ganglia pathway is involved in normal motor control and implicated in multiple movement disorders. Brief repetitive muscle contractions known as motor tics are a common symptom in several basal ganglia related motor disorders. We used focal micro-injections of the GABA-A antagonist bicuculline to the sensorimotor putamen of behaving primates to induce stereotyped tics similar to those observed in human disorders. This focal disruption of GABA transmission in the putamen led to motor tics confined to a single or a few muscles. The temporal and structural properties of the tics were identified using electromyogram and frame-by-frame analysis of multi-camera video recordings. During experimental sessions the tics would wax and wane, but their size and shape remained highly stereotyped within the session. Neuronal spiking activity and local field potentials were recorded simultaneously from multiple locations along the cortico-basal ganglia pathway: motor cortex, putamen and globus pallidus external and internal segments. The local field potentials displayed stereotyped tic-related voltage transients lasting several hundred milliseconds. These 'local field potential spikes', which appeared throughout the cortico-basal ganglia pathway, were consistently observed in close temporal association to the motor tics. During tic expression, neuronal activity was altered in most of the recorded neurons in a temporally focal manner, displaying phasic firing rate modulations time locked to the tics. Consistent with theoretical models of tic generation, transient inhibition of the basal ganglia output nucleus prior to and during tic expression was observed. The phasic reduction of basal ganglia output was correlated with a disinhibition of cortical activity, manifesting as short bursts of activity in motor cortex. The results demonstrate that the basal ganglia provide a finely timed disinhibition in the output nuclei of the basal ganglia. However, a large fraction of the neurons were simultaneously inhibited during tics, although tics were only manifested in a small confined muscle group. This suggests that rather than representing a specific action within the basal ganglia itself, these nuclei provide a temporally exact but spatially distributed release signal. The tics induced by striatal disinhibition bear a striking resemblance to motor tics recognized in human pathologies associated with basal ganglia dysfunction. The neuronal changes observed during tic formation may provide valuable insights into the underlying mechanism of tic disorders, as well as into basic information processing in the cortico-basal ganglia loop.

Efficacy of botulinum toxin in severe Tourette syndrome with dystonic tics involving the neck.

Severe dystonic tics involving the neck may lead to the development of serious spine disease. The pharmacological treatment of tics offers symptomatic relief, but clinically relevant improvement of severe tics is not frequently achieved and serious adverse events may result. Botulinum toxin (BnT) appears to be a safe and effective treatment for tics, but some concern exists about which group of patients may benefit from treatment. We report a patient affected by Tourette syndrome with tetraparesis and cervical myelopathy secondary to violent dystonic tics involving the neck, in which a more aggressive course of treatment with BnT in addition to neuroleptic medication resulted in complete resolution of cervical tics after 12 months of follow-up.

A case of adult onset tic disorder following carbon monoxide intoxication.

BACKGROUND: Adult onset tic disorders are usually secondary in origin. We report a case of adult onset tic disorder following carbon monoxide (CO) intoxication with typical magnetic resonance imaging features. CASE REPORT: A 36-year-old woman developed temporarily suppressible patterned movements on her face, neck, and shoulder associated with sensory discomfort after CO poisoning. Magnetic resonance images showed bilateral symmetric cavitary changes in the globus pallidus. Clonazepam relieved much of her symptoms. CONCLUSION: Our patient developed a monosymptomatic tic disorder following CO intoxication. This further supports that altered outflow signals from the basal ganglia, especially the globus pallidus, may contribute to the development of tic disorders.