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Objectives Study the differences in the oscillatory activity of the internal globus pallidus (GPi) in Parkisnon’s disease, dystonia, chorea and Tourette’s síndrome Methods 13 patients with Deep Brain Stimulation (DBS) of the GPi were studied by means of local field potential (LFP) recordings through the stimulation electrode. Seven patients had dystonia, and two patients had Parkinson’s disease, chorea and Tourette’s syndrome, respectively. Long segments (>5 min) of GPi-LFP recordings at rest were selected from each patient (in PD patients, “on” and “off” medication). Results The two PD patients had low-beta, high-beta and HFO peaks in the “off” power spectrum. In the “on” state, the low-beta peak attenuated and the HFO peaks changed in frequency and power, as expected. The patients with dystonia showed theta and high-beta peaks. However, either no HFO peak or a much smaller one (in only two patients) was observed. The two patients with chorea had high-beta and HFO peaks only. The patients with Tourette’s síndrome had no evident beta peaks, but HFO activity was very evident. Conclusions The activity observed in PD patients in the GPi is similar to that observed in the STN, including the presence of HFOs. HFOs are also observed in patients with chorea or Tourette’s syndrome, but might be absent or smaller in patients with dystonia. Beta peaks were absent in the two patients with Tourette’s syndrome. Significance The GPi and STN show similar oscillatory activity in PD, including HFOs. Different neurologic diseases are associtated with different oscillatory activities in the GPi. [ABSTRACT FROM AUTHOR]

The Internal Globus Pallidus (GPi) is an output nucleus of the basal ganglia that has been used as a target for deep brain stimulation (DBS) in Dystonia and Tourette's syndrome. The goal of this study was to provide a detailed analysis of neurons' electrophysiological activity recorded in sub-territories of GPi used as a DBS targets for these clinical conditions. We used intraoperative microelectrode recording during stereotactic neurosurgery to guide implantation of DBS leads. We recorded 101 units in the medial anterior part of GPi (GPia) of 7 Tourette's patients under general anaesthesia. The mean and median activity were 32.1 and 21 Hz respectively, with 45% of spikes fired during bursts and 21.3 bursts per minute. We recorded 27 units in the latero-posterior part of GPi (GPip) of 7 dystonic patients under local anaesthesia. The mean and median activity were 46.1 and 30.6 Hz respectively, and a mean of 21.7 bursts per minute was observed, with 30% of all spikes occurring during these bursts. We grouped units from each region based on their activity pattern - slow-irregular, fast-irregular or fast-regular - and compared their respective proportions between the two targets. An analysis of local field potential power revealed that peak power in different frequency bands was not correlated with recording depth. We found significant differences in activity between the two regions with neurons in GPia (Tourette's patients) showing narrower action potentials, more bursting and stronger oscillation. Furthermore, LFP power in the alpha band was lower in Tourette's patients (GPia) as compared to dystonic patients (GPip). Although similar firing patterns were present in the two groups of patients, the distribution of cells grouped by firing modes (fast regular, fast irregular and slow regular) was different. The electrophysiological characteristics of GPia and GPip can potentially be used to assist DBS electrode targeting in patients with the surgical conditions considered. This electrophysiological characterisation will also support the refinement of pathophysiological models of Tourette's syndrome and Dystonia. [ABSTRACT FROM AUTHOR]

Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression.

Tics and compulsions in comorbid Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) are associated with chronic hyperactivity of parallel cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Comorbid TS- & OCD-like behaviors have likewise been observed in D1CT-7 mice, in which an artificial neuropotentiating transgene encoding the cAMP-elevating intracellular subunit of cholera toxin (CT) is chronically expressed selectively in somatosensory cortical & amygdalar dopamine (DA) D1 receptor-expressing neurons that activate cortico/amygdalo-striatal glutamate (GLU) output. We've now examined in D1CT-7 mice whether the chronic GLU output from their potentiated cortical/limbic CSTC subcircuit afferents associated with TS- & OCD-like behaviors elicits desensitizing neurochemical changes in the striatum (STR). Microdialysis-capillary electrophoresis and in situ hybridization reveal that the mice's chronic GLU-excited STR exhibits pharmacodynamic changes in three independently GLU-regulated measures of output neuron activation, co-excitation, and desensitization, signifying hyperactive striatal CSTC output and compensatory striatal glial and neuronal desensitization: 1) Striatal GABA, an output neurotransmitter induced by afferent GLU, is increased. 2) Striatal d-serine, a glial excitatory co-transmitter inhibited by afferent GLU, is decreased. 3) Striatal Period1 (Per1), which plays a non-circadian role in the STR as a GLU + DA D1- (cAMP-) dependent repressor thought to feedback-inhibit GLU + DA- triggered ultradian urges and motions, is transcriptionally abolished. These data imply that chronic cortical/limbic GLU excitation of the STR desensitizes its co-excitatory d-serine & DA inputs while freezing its GABA output in an active state to mediate chronic tics and compulsions - possibly in part by abolishing striatal Per1-dependent ultradian extinction of urges and motions., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

This paper examined neurocognitive functioning and its relationship to behavior treatment response among youth with Tourette's Disorder (TD) in a large randomized controlled trial. Participants diagnosed with TD completed a brief neurocognitive battery assessing inhibitory functions, working memory, and habit learning pre- and post-treatment with behavior therapy (CBIT, Comprehensive Behavioral Intervention for Tics) or psychoeducation plus supportive therapy (PST). At baseline, youth with tics and Attention Deficit Hyperactivity Disorder (ADHD) exhibited some evidence of impaired working memory and simple motor inhibition relative to youth with tics without ADHD. Additionally, a small negative association was found between antipsychotic medications and youth's performance speed. Across treatment groups, greater baseline working memory and aspects of inhibitory functioning were associated with a positive treatment response; no between-group differences in neurocognitive functioning at post-treatment were identified. Within the behavior therapy group, pre-treatment neurocognitive status did not predict outcome, nor was behavior therapy associated significant change in neurocognitive functioning post-treatment. Findings suggest that co-occurring ADHD is associated with some impairments in neurocognitive functioning in youth with Tourette's Disorder. While neurocognitive predictors of behavior therapy were not found, participants who received behavior therapy exhibited significantly reduced tic severity without diminished cognitive functioning., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tourette syndrome is a neuropsychiatric syndrome characterized by motor and vocal tics with further co-morbidities, e.g. obsessive-compulsive disorder and attention deficit hyperactivity disorder. There is only a single prior case report in pregnancy in addition to a postal questionnaire study including 10 pregnancies. In a series of 11 pregnancies in patients assessed by the authors, there were no adverse effects on the pregnancy, although some obstetricians were unduly concerned. There was no consistent effect on the severity of the tics, although in some women there seemed to be a significant improvement during pregnancy. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette syndrome (TS) is a complex developmental neuropsychiatric condition in which motor manifestations are often accompanied by comorbid conditions that impact the patient's quality of life. In the DSM-5, TS belongs to the "neurodevelopmental disorders" group, together with other neurodevelopmental conditions, frequently co-occurring. In this study, we searched the PubMed database using a combination of keywords associating TS and all neurodevelopmental diagnoses. From 1009 original reports, we identified 36 studies addressing TS and neurodevelopmental comorbidities. The available evidence suggests the following: (1) neurodevelopmental comorbidities in TS are the rule, rather than the exception; (2) attention deficit/hyperactivity disorder (ADHD) is the most frequent; (3) there is a continuum from a simple (TS + ADHD or/and learning disorder) to a more complex phenotype (TS + autism spectrum disorder). We conclude that a prompt diagnosis and a detailed description of TS comorbidities are necessary not only to understand the aetiological basis of neurodevelopmental disorders but also to address specific rehabilitative and therapeutic approaches.

A decade before the rise of optogenetics, the first behavioral "circuit-test" - transgenically modulating the output of a genetically-specified brain circuit element to examine its effect on behavior - was performed. The behaviors emulated in those mice were comorbid tics and compulsions, elicited by a gene borrowed from cholera bacteria and tailored to intracellularly neuropotentiate glutamatergic somatosensory cortical and limbic output neurons of cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Two decades later, cutting-edge chemogenetic and optogenetic methods are again being devoted to further characterize the circuits thought to trigger, mediate, aggravate, or ameliorate TS & OCD symptoms. These tour de force studies support essential roles in tics and compulsions for topographically-parallel corticostriatal and amygdalar glutamatergic output neurons; their target dorsal striatal & ventral striatal (nucleus accumbens) medium spiny neurons (MSNs) of the direct striatothalamic (urge & motor activating) vs. indirect striatopallidal (urge & motor suppressing) output pathways; and their converging modulatory dopaminergic and histaminergic afferents. Going "back to the future" to circuit-map tics and compulsions will give us precision targets for future psychological, drug, medtech, and gene therapies; look for "dopamine bypasses" on your next trip in the DeLorean., (Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.)

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology., (© 2017 Wiley Periodicals, Inc.)

TicHelper.com ("TicHelper") is an interactive online treatment program for youth with chronic tic disorders (CTDs) or Tourette Syndrome (TS) and their parents. It is based on Comprehensive Behavioral Intervention for Tics (CBIT), an individual, outpatient therapy protocol shown to effectively reduce tics in randomized controlled trials. The TicHelper website offers a user-friendly dashboard that is effective in making it easy to navigate through different treatment modules. Modules parallel core CBIT procedures and consist of interactive exercises, informational videos, and self-report ratings. TicHelper has some weaknesses (e.g., no outcomes research specific to the program has been published to date); however, its strengths (easily navigable, clear instructions, appropriate content) outweigh its weaknesses, making it a potentially useful dissemination tool to make CBIT more accessible to families and youth with tics.

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1 , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in ( i ) locomotor activity, ( ii ) stereotypy, and ( iii ) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1 -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D 1 receptor binding in the dorsal striatum of Slc1a1 -STOP mice. Slc1a1 -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1 /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1 -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors., Competing Interests: Conflict of interest statement: C.K. has received research funding from Forest. C.K.J. has received research funding from AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, and Seaside Therapeutics. J.V. has consulted or served on advisory boards for Roche, Novartis, and SynapDx and has received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, and Forest.

Background: Autism spectrum disorder (ASD), tic disorder (TD), and hyperkinetic syndrome of childhood (attention deficit disorder [ADD]/attention deficit hyperactivity disorder [ADHD]) are disorders recently defined as abnormal connectivity spectrum disorders (ACSDs) because they show a similar pattern of abnormal brain connectivity. This study examines whether these disorders are associated with exposure to thimerosal, a mercury (Hg)-based preservative., Methods: A hypothesis testing case-control study evaluated the Vaccine Safety Datalink for the potential dose-dependent odds ratios (ORs) for diagnoses of ASD, TD, and ADD/ADHD compared to controls, following exposure to Hg from thimerosal-containing Haemophilus influenzae type b vaccines administrated within the first 15 months of life. Febrile seizures, cerebral degeneration, and unspecified disorders of metabolism, which are not biologically plausibly linked to thimerosal, were examined as control outcomes., Results: On a per 25 μg Hg basis, cases diagnosed with ASD (OR = 1.493), TD (OR = 1.428), or ADD/ADHD (OR = 1.503) were significantly ( P < .001) more likely than controls to have received increased Hg exposure. Similar relationships were observed when separated by gender. Cases diagnosed with control outcomes were no more likely than controls to have received increased Hg exposure., Conclusion: The results suggest that Hg exposure from thimerosal is significantly associated with the ACSDs of ASD, TD, and ADD/ADHD., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: There are no competing financial interests. Three of the four authors have been involved in vaccine/biologic litigation. Dr. Mark Geier, Mr. David Geier, and Dr. Janet Kern have been involved as consultants and expert witnesses for petitioners in the No-Fault National Vaccine Injury Compensation Program (NVICP) and have also been consultants and expert witness for plaintiffs in civil litigation. The cases that Dr. Janet Kern, Mr. David Geier, and Dr. Mark Geier participated in involved the outcome of autism, and none of the other neurodevelopmental outcomes examined in this study. Dr. Mark Geier and Mr. David Geier are currently involved in no cases, have not been involved in any cases for several years, and have no plans to be involved in any future cases. Dr. Janet Kern is not involved in any current cases and has no plans to be involved in any future cases.

Tourette's syndrome (TS) is a neurologic condition characterized by both motor and phonic tics and is typically associated with psychiatric comorbidities, including obsessive-compulsive disorder/behavior and attention-deficit hyperactivity disorder, and can be psychologically and socially debilitating. It is considered a disorder of the cortico-striato-thalamo-cortical circuitry, as suggested by pathophysiology studies and therapeutic options. Among these, deep brain stimulation (DBS) of the centromedian-parafascicular nucleus (CM-Pf) of the thalamus is emerging as a valuable treatment modality for patients affected by severe, treatment-resistant TS. Here, we review the most recent experimental evidence for the pivotal role of CM-Pf in the pathophysiology of TS, discuss potential mechanisms of action that may mediate the effects of CM-Pf DBS in TS, and summarize its clinical efficacy.

In patients with severe, treatment-refractory Gilles de la Tourette syndrome (GTS), deep brain stimulation (DBS) of various targets has been increasingly explored over the past 15 years. The multiplicity of surgical targets is intriguing and may be partly due to the complexity of GTS, specifically the various and frequent associated psychiatric comorbidities in this disorder. Thus, the target choice may not only be aimed at reducing tics but also comorbidities. While this approach is laudable, it also carries the risk to increase confounding factors in DBS trials and patient evaluation. Moreover, I question whether DBS should really be expected to alleviate multiple symptoms at a time. Rather, I argue that tic reduction should remain our primary objective in severe GTS patients and that this intervention may subsequently allow an improved psychotherapeutic and/or pharmacological treatment of comorbidities. Thus, I consider DBS in GTS not as a single solution for all our patients' ailments but as a stepping stone to improved holistic care made possible by tic reduction., Competing Interests: No competing interests were disclosed.

The first World Congress on Tourette Syndrome and Tic Disorders was held in London, June 2016 by the Tourette Association of America, Tourettes Action (UK), and the European Society for the Study of Tourette Syndrome. Presentations arising from large-scale collaborative projects were an important component of the scientific programme. This article focuses on areas raised in the hot topics session and two moderated debates, which covered emerging research in etiology and treatment. The hot topics ranged across genetics, arguably including the first confirmed Tourette Syndrome (TS) susceptibility gene NRXN1, neurocognition, and neurophysiology, including the possibility of a neurocognitive endophenotype for TS and the use of depth and cortical surface electrodes to investigate the neurophysiology of tics on the background of the evolving field of deep brain stimulation (DBS), to novel treatment approaches such as dental orthotics and an online behavioral intervention. The debates aired controversies in treatment; pharmacotherapy vs. behavioral treatment and the place of medical cannabinoids. These sessions demonstrate the vibrancy of a field that has considerably expanded in the last decade, the significant progress that has been made, and the direction that some of the most fruitful next phases of research will take.

Problem: Tourette's syndrome (TS) is a neuropsychiatric disorder associated with adverse outcomes. High rates of comorbidity (80-90%) complicate presentation, yet the relationship among TS, common comorbid diagnoses, and adversity is not well understood. This research investigated the impact of comorbidity, and the discrete effects of common comorbid diagnoses, on quality of life (QoL) and functioning of youth with TS., Methods: A community sample of parents of youth with TS (n = 86) participated in this survey-based study. Differences in QoL (Pediatric Quality of Life Inventory) and rates of psychological, behavioral, and social difficulties (Strength and Difficulties Questionnaire) reported for youth with or without comorbid disorder were determined, in addition to outcomes associated with individual disorders., Findings: Parametric and nonparametric analyses revealed strong associations between comorbidity and decreased global QoL, impaired emotional and school functioning, and increased emotional symptomatology (p < .001). The impact of individual comorbid disorders was restricted and disorder specific, and TS was uniquely associated with impaired social functioning and peer relationship problems., Conclusions: Understanding the risks associated with TS, particularly to psychosocial well-being, and the specific risks accompanying individual comorbid disorders, may improve assessment, prioritization of treatment goals, and interventions targeting the individual, multidimensional needs of youth with TS., (© 2016 Wiley Periodicals, Inc.)

Background: Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS., Methods: In this prospective open-label trial, eight patients (three female, five male) 19-56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset., Results: Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome., Conclusions: Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: A significant proportion of patients with Tourette syndrome (TS) continue to experience symptoms across adulthood that in severe cases fail to respond to standard therapies. For these cases, deep brain stimulation (DBS) is emerging as a promising treatment option., Objective: We conducted a systematic literature review to evaluate the efficacy of DBS for GTS., Methods: Individual data of case reports and series were pooled; the Yale Global Tic Severity Scale (YGTSS) was chosen as primary outcome parameter., Results: In total, 57 studies were eligible, including 156 cases. Overall, DBS resulted in a significant improvement of 52.68% (IQR = 40.74, p < 0.001) in the YGTSS. Analysis of controlled studies significantly favored stimulation versus off stimulation with a standardized mean difference of 0.96 (95% CI: 0.36-1.56). Disentangling different target points revealed significant YGTSS reductions after stimulation of the thalamus, the posteroventrolateral part and the anteromedial part of the globus pallidus internus, the anterior limb of the internal capsule and nucleus accumbens with no significant difference between these targets. A significant negative correlation of preoperative tic scores with the outcome of thalamic stimulation was found., Conclusions: Despite small patient numbers, we conclude that DBS for GTS is a valid option for medically intractable patients. Different brain targets resulted in comparable improvement rates, indicating a modulation of a common network. Future studies might focus on a better characterization of the clinical effects of distinct regions, rather than searching for a unique target., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Five patients with palatal tics and Gilles de la Tourette syndrome have been previously reported. Little is known about the characteristics of palatal tics given that there are so few reports. On one hand, palatal tics may be rare. Alternatively, they may be less well recognized than repetitive eye blinking or sniffing, which are both obvious and, therefore, more often reported. We describe 3 patients with palatal tics and Gilles de la Tourette syndrome. We also review the 5 patients reported in the literature and explore whether there are characteristic features among this group of 8 cases. The 8 patients had the following features: (1) Personal history of other multiple motor/vocal tics, (2) the presence of typical Gilles de la Tourette syndrome comorbidities, (3) positive family history of tics and/or Gilles de la Tourette syndrome comorbidities, (4) the presence of audible "ear clicks," (5) younger age at onset (2 years). We suggest that palatal tics are underreported., (© The Author(s) 2014.)

A hypothesis testing, case-control study evaluated automated medical records for exposure to organic-Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) administered at specific intervals in the first six-months-of-life among cases diagnosed with a tic disorder (TD) or cerebral degeneration (CD) (an outcome not biologically plausibly linked to TM exposure) in comparison to controls; both cases and controls were continuously enrolled from birth (born from 1991-2000) within the Vaccine Safety Datalink (VSD) database. TD cases were significantly more likely than controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (odds ratio (OR)=1.59, p<0.00001), first two-months-of-life (OR=1.59, p<0.00001), and first six-months-of-life (OR=2.97, p<0.00001). Male TD cases were significantly more likely than male controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (OR =1.65, p<0.0001), first two-months-of-life (OR=1.64, p<0.0001), and first six months-of-life (OR=2.47, p<0.05), where as female TD were significantly more likely than female controls to have received increased organic-Hg from TM-HepB administered within the first six-months-of-life (OR=4.97, p<0.05). By contrast, CD cases were no more likely than controls to have received increased organic-Hg exposure from TM-HepB administered at any period studied within the first six-months-of-life. Although routine childhood vaccination is considered an important public health tool to combat infectious diseases, the present study associates increasing organic-Hg exposure from TM-HepB and the subsequent risk of a TD diagnosis.

Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and often one or more comorbid psychiatric disorders. Premonitory sensory urges before tic execution and desire for "just-right" perception are central features. The pathophysiology involves cortico-striato-thalamo-cortical circuits and possibly dopaminergic system. TS is considered a genetic disorder but the genetics is complex and likely involves rare mutations, common variants, and environmental and epigenetic factors. Treatment is multimodal and includes education and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ (11)C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS)., Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS., Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain., Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa's effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects., Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.

The membrane protein SLITRK1 functions as a developmentally regulated stimulator of neurite outgrowth and variants in this gene have been implicated in Tourette syndrome. In the current study we have cloned and characterized the porcine SLITRK1 gene. The genomic organization of SLITRK1 lacks introns, as does its human and mouse counterparts. RT-PCR cloning revealed two SLITRK1 transcripts: a full-length mRNA and a transcript variant that results in a truncated protein. The encoded SLITRK1 protein, consisting of 695 amino acids, displays a very high homology to human SLITRK1 (99%). The porcine SLITRK1 gene is expressed exclusively in brain tissues.

Tourette syndrome has been examined using many different neuroimaging techniques. There has been a recent surge of neuroimaging research papers related to Tourette syndrome that are exploring many different aspects of the disorder and its comorbidities. This brief review focuses on recent MRI-based imaging studies of pediatric Tourette syndrome, including anatomical, functional, resting state, and diffusion tensor MRI techniques. Consistencies across studies are explored, and particularly important issues involved in acquiring data from this special population are discussed.

Background: Tourette syndrome (TS) is a disorder characterized by childhood onset of motor and phonic tics, often with improvement of tic symptoms by young adult years. The temporal course of tics and commonly comorbid behavioral symptoms is still not well characterized., Methods: In order to clarify the time course of tics and comorbid attention deficit hyperactivity disorder (ADHD) or obsessive compulsive disorder (OCD) in TS, we administered a brief survey regarding the course of symptoms at a single point in time to 53 TS patients aged 13-31 years., Results: Mean age (±SD) at symptom onset was 7.9 (±3.6) years for tics, 7.9 (±3.5) for ADHD, and 9.2 (±5.0) for OCD. Age at peak symptom severity was 12.3 (±4.6) years for tics, 10.8 (±3.8) for ADHD, and 12.6 (±5.5) for OCD. Tics, ADHD, and OCD were reported to be no longer present in 32.0%, 22.8%, and 21.0% of subjects, respectively. Decline in symptom severity began at age 14.7 (±3.7) years for tics, 13.9 (±2.9) for ADHD, and 15.1 (±5.0) for OCD. Remission of symptoms occurred at age 17.4 (±3.8) years for tics, 17.4 (±1.3) for ADHD, and 15.6 (±2.3) for OCD., Discussion: Our data confirm and expand previously reported TS spectrum symptom milestones and may guide design of future research aimed at improving the course of TS.

We present the case of a nine-year-old boy with Tourette syndrome and reading disorder with a history of a severe infectious process in the late neonatal period. Brain MRI showed a left parietal malacotic cavity and diffusion tensor imaging and tractography showed a striking disruption of the white matter bundle that joins the left parietal region with the ipsilateral frontal region with involvement of the left superior longitudinal fasciculus and of the left arcuate fasciculus. Although Tourette syndrome and reading disorder are fundamentally hereditary neuropsychiatric disorders, they can also occur secondary to cerebral alterations like those existing in this boy. The introduction of modern neuroimaging techniques in patients with neuropsychiatric disorders (or the risk of developing them) can be very useful in the diagnosis and prognosis in the future., (Copyright © 2011 SERAM. Published by Elsevier Espana. All rights reserved.)

This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role--Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function., (© 2014 Elsevier Inc. All rights reserved.)

Background: Genetic, environmental, immunological, and hormonal factors contribute to the etiology of Tourette syndrome (TS). From the genetic standpoint, TS is a heterogeneous disorder. In our previous study, we found that a single nucleotide polymorphism (SNP) of x-ray repair cross-complementing group 1 (XRCC1), a DNA repair gene, was associated with TS. Previous studies also showed that tyrosyl-DNA phosphodiesterase 1 (TDP1) interacts with XRCC1 to repair damaged DNA. However, the relationship between TS and SNPs of TDP1 gene is unknown. Therefore, the aim of this study was to test the hypothesis that if the TDP1 SNP, rs28365054 (c.400G>A, Ala134Thr), was associated with TS or not., Methods: A case-control study was designed to test the hypothesis. A total of 122 TS children and 106 normal children participated in the study. We used polymerase chain reaction to identify the SNP, rs28365054, of the TDP1 gene in the TS patients and the normal children., Results: A polymorphism at position rs28365054 in the TDP1 gene had a significant difference (P < 0.05) in the genotype distributions between the TS patients and the control group. The AG genotype was a risk factor for TS with an odds ratio of 2.26 for the AG versus AA genotype (95% CI 1.08-4.72)., Conclusion: The findings of this study suggested that variants in the TDP1 gene might play a role in TS susceptibility., (© 2013 Wiley Periodicals, Inc.)

The therapeutic success of haloperidol in the treatment of Tourette syndrome (TS) put an end to the discussion about a "hysteric" or "neurotic" origin of TS. The cortico-striato-thalamo-cortical circuit has been identified as an underlying neurobiological correlate of TS. In this review we explore the main findings of structural alterations in TS including cortical areas, basal ganglia, hippocampus, amygdala, midbrain, and cerebellum. Based on the structural changes we examine the functional pattern described by the findings of fMRI and (15)O-PET/(18)FDG PET investigations. From the neuroimaging findings a cortical origin of the generation of tics is indicated. Future research on the neuronal footprint of TS should be directed towards addressing the question of which patterns of connectivity distinguish individuals in whom tics disappear during early adulthood from those in whom the tics persist. The understanding of this pathomechanism could provide a key on how to influence dysconnectivity in TS, for example, by more specific pharmaceutical intervention or by individually adopted EEG and/or fMRI neurofeedback., (© 2013 Elsevier Inc. All rights reserved.)

Introduction: Tics disorders and Tourette syndrome are commonly encountered in clinical practice. Currently, a vast number of behavioural, pharmacological and surgical treatments are available., Methods: Relevant and recent articles about clinical features, neurobiology and treatment of tic disorders and Tourette syndrome were reviewed and summarized., Results: Tic disorders and Tourette syndrome are frequently associated with comorbid conditions such as obsessive compulsive symptoms, attention deficit and hyperactivity disorder, anxiety and depression, behavioural disorders and sleep difficulties. Fronto-striatal circuits and the dopaminergic system are believed to be involved in the pathophysiology of TS and tics. Pharmacological options that have been studied for treatment of tic disorders are reviewed. Behavioural therapy such as habit reversal training, and surgical treatment are other options. It is essential to identify and address comorbid conditions such as attention deficit disorder, obsessive-compulsive symptoms, depression, behavioural disorders and sleep disturbances, as they often cause more distress and disability than the tics themselves., Conclusion: Tic disorders frequently do not require pharmacological treatment, but if required, first line treatment options include dopamine modulators, tetrabenazine, clonidine and behavioural therapy.