The microstructural change of the brain and its clinical severity association in pediatric Tourette syndrome patients.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a prevalent pediatric neurological disorder. Most studies point to abnormalities in the cortico-striato-thalamocortical (CSTC) circuits. Neuroimaging studies have shown GTS's extensive impact on the entire brain. However, due to participant variability and potential drug and comorbidity impact, the results are inconsistent. To mitigate the potential impact of participant heterogeneity, we excluded individuals with comorbidities or those currently undergoing medication treatments. Based on the hypothesis of abnormality within the CSTC circuit, we investigated microstructural changes in white matter using diffusion spectrum imaging (DSI). This study offers the first examination of microstructural changes in treatment-naïve pediatric patients with pure GTS using diffusion spectrum imaging. METHODS: This single-center prospective study involved 30 patients and 30 age- and gender-matched healthy volunteers who underwent sagittal T1-weighted MRI and DSI. We analyzed generalized fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. RESULTS: No significant differences were observed in mean diffusivity and axial diffusivity values between the two groups. However, the patient group exhibited significantly higher generalized fractional anisotropy values in the right frontostriatal tract of the dorsolateral prefrontal cortex, the right frontostriatal tract of the precentral gyrus, and bilateral thalamic radiation of the dorsolateral prefrontal cortex. Additionally, the generalized fractional anisotropy value of the right frontostriatal tract of the precentral gyrus is inversely correlated with the total tic severity scores at the most severe condition. CONCLUSION: Treatment-naïve pediatric GTS patients demonstrated increased connectivity within the CSTC circuit as per diffusion spectrum imaging, indicating possible CSTC circuit dysregulation. This finding could also suggest a compensatory change. It thus underscores the necessity of further investigation into the fundamental pathological changes in GTS. Nevertheless, the observed altered connectivity in GTS patients might serve as a potential target for therapeutic intervention.

Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus has been reportedly used to treat severe Tourette syndrome, yielding promising outcomes. However, it remains unclear how DBS electrode position and stimulation parameters modulate the specific area and related networks. The authors aimed to evaluate the relationships between the anatomical location of stimulation fields and clinical responses, including therapeutic and side effects. METHODS: The authors collected data from 8 patients with Tourette syndrome who were treated with DBS. The authors selected the active contact following threshold tests of acute side effects and gradually increased the stimulation intensity within the therapeutic window such that acute and chronic side effects could be avoided at each programming session. The patients were carefully interviewed, and stimulation-induced side effects were recorded. Clinical outcomes were evaluated using the Yale Global Tic Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, and the Hamilton Depression Rating Scale. The DBS lead location was evaluated in the normalized brain space by using a 3D atlas. The volume of tissue activated was determined, and the associated normative connective analyses were performed to link the stimulation field with the therapeutic and side effects. RESULTS: The mean follow-up period was 10.9 ± 3.9 months. All clinical scales showed significant improvement. Whereas the volume of tissue activated associated with therapeutic effects covers the centromedian and ventrolateral nuclei and showed an association with motor networks, those associated with paresthesia and dizziness were associated with stimulation of the ventralis caudalis and red nucleus, respectively. Depressed mood was associated with the spread of stimulation current to the mediodorsal nucleus and showed an association with limbic networks. CONCLUSIONS: This study addresses the importance of accurate implantation of DBS electrodes for obtaining standardized clinical outcomes and suggests that meticulous programming with careful monitoring of clinical symptoms may improve outcomes.

Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization.

OBJECTIVE: It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. METHODS: Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. RESULTS: Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. CONCLUSIONS: These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

LRRTM4 Terminal Exon Duplicated in Family with Tourette Syndrome, Autism and ADHD.

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by motor and vocal tics and strong association with autistic deficits, obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). The genetic overlap between TS and autism spectrum disorder (ASD) includes those genes that encode the neurexin trans-synaptic connexus (NTSC) inclusive of the presynaptic neurexins (NRXNs) and postsynaptic neuroligins (NLGNs), cerebellin precursors (CBLNs in complex with the glutamate ionotropic receptor deltas (GRIDs)) and the leucine-rich repeat transmembrane proteins (LRRTMs). In this study, we report the first evidence of a TS and ASD association with yet another NTSC gene family member, namely LRRTM4. Duplication of the terminal exon of LRRTM4 was found in two females with TS from the same family (mother and daughter) in association with autistic traits and ASD.

Regulatory effects of Ningdong granule on microglia-mediated neuroinflammation in a rat model of Tourette's syndrome.

Tourette's syndrome (TS) is an inherited neurologic disorder characterized by involuntary stereotyped motor and vocal tics. Its pathogenesis is still unclear and its treatment remains limited. Recent research has suggested the involvement of immune mechanisms in the pathophysiology of TS. Microglia are the brain's resident innate immune cells. They can mediate neuroinflammation and regulate brain development and homeostasis. A traditional Chinese medicine (TCM), Ningdong granule (NDG), has been found to be efficacious in the treatment of TS while causing few adverse reactions. In the current study, a rat model of 3,3'-iminodipropionitrile (IDPN)-induced TS was used to explore the regulating effects and mechanisms of NDG on microglia-mediated neuroinflammation. IDNP led to robust pathological changes and neurobehavioral complications, with activation of microglia in the striatum of rats with TS. After activation by IDNP, microglia strongly responded to this specific injury, and TNF-α, IL-6, and MCP-1 were released in the striatum and/or serum of rats with TS. Interestingly, NDG inhibited the activation of microglia and decreased the abnormal expression of TNF-α, IL-6, and MCP-1 in the striatum and/or serum of rats with TS, thus controlling tics. However, there were no significant changes in the striatum and/or serum of rats with TS after treatment with haloperidol. The anti-TS action of haloperidol might occur not through microglial activation and neuroinflammation but through the DAT system, thus controlling tics. In conclusion, microglia might play key roles in mediating neuroinflammatory responses in TS, triggering the release of TNF-α, IL-6, and MCP-1.NDG inhibited tics in rats with TS, and this mechanism may be associated with a reduction in the increased number of activated microglia and a decrease in the expression of pro-inflammatory cytokines and chemokines in the striatum and/or serum.

Altered structural cerebral cortex in children with Tourette syndrome.

PURPOSE: In this study, we used magnetic resonance imaging (MRI) to investigate the anatomical alterations of cerebral cortex in children with Tourette syndrome (TS) and explore whether such deficits were related with their clinical symptoms. METHODS: All subjects were scanned in a 3.0T MRI scanner with three-dimensional T1-weighted images (3DT1WI). Then, some surface-based features were extracted by using the FreeSurfer software. After that, the between-group differences of those features were assessed. RESULTS: Sixty TS patients and 52 age- and gender-matched healthy control were included in this study. Surface-based analyses revealed altered cortical thickness, cortical sulcus, cortical curvature and local gyrification index (LGI) in TS group compared with healthy controls. The brain regions with significant-group differences in cortical thickness included postcentral gyrus, superiorparietal gyrus, rostral anterior cingulate cortex in the left hemisphere and frontal pole, lateral occipital gyrus, inferior temporal gyrus in the right hemisphere. In addition, the superior temporal gyrus, medial orbitofrontal gyrus, supramarginal gyrus, medial orbitofrontal gyrus, superiorparietal gyrus and lateral occipital gyrus showed significant between-group differences for cortical sulcus. Moreover, the brain regions with significant between-group differences in cortical curvature were located in caudal anterior cingulate cortex, supramarginal gyrus, inferior parietal gyrus and lateral occipital gyrus. The alteration of LGI were most prominent in the inferior temporal gyrus and insula. Additionally, there was no statistical difference in brain surface area for TS children compared with controls. CONCLUSION: The results of this study revealed that cortical thickness, sulcus, cortical curvature and LGI were changed in multiple brain regions for children with TS.

Cingulate role in Tourette syndrome.

This chapter comprehensively reviews the published record for neurosurgical, neurostimulatory, and neuroimaging evidence of the involvement of the cingulate gyrus in Gilles de la Tourette syndrome (TS). The most noteworthy evidence comes from neuroimaging. Neuroimaging findings were rarely exclusive to the cingulate cortex and tended to implicate multiple other cortices as well. Some results are reflective of obsessive-compulsive (OC) symptoms of TS. Copious findings, however, drawn from structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (rsfMRI), task fMRI, and positron emission tomography (PET) implicate six of the eight cingulate subregions in TS. Gauged by MRI, cortical thinning and/or below-normal volume are seen in subgenual anterior cingulate cortex (sACC), pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and posterior middle cingulate cortex (pMCC), correlating with tic severity in sACC, pACC, and aMCC. Moreover, in pMCC, dorsal posterior cingulate cortex (dPCC), and ventral posterior cingulate cortex (vPCC), cortical thickness is a candidate biomarker shared across siblings with TS. Loss of cortex may reflect excitotoxicity secondary to insufficient local GABAergic inhibition, a notion supported by the few relevant MRS and PET studies conducted to date, recommending continued development of GABAergic and glutamatergic pharmacologic agents to treat TS. Measurements of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) obtained with DTI indicate that the white matter proximal to sACC, pACC, pMCC, and dPCC may also represent a seat of pathology in TS. rsfMRI reveals abnormal functional connectivity of pACC and dPCC with the globus pallidus internus, a favored target of therapeutic deep brain stimulation (DBS) for TS. In whole-brain network (graph theory) analysis, dPCC functional connectivity is related to the severity and complexity of tics. In task fMRI, in contrast, the pMCC seems to play a preeminent role in premonitory urges and preparation for tics as well as normal urges to urinate, swallow, and yawn. Strong monkey PET and EEG evidence ties vocal tics to spike discharges, α-activity, and regional blood flow in the pACC unleashed by failure of GABAergic inhibition in the ventral striatum. Tic suppression in fMRI scans is associated with increased blood oxygenation level-dependent activity in sACC, pACC, and aMCC, but decreased activity in pMCC and dPCC. Activity in the former three subregions may represent volitional effort, physical discomfort, and emotional distress that accompanies mounting tic urges; pMCC and dPCC may be more instrumental in amplifying than suppressing urges. Needs for future neuroimaging work in TS include longitudinal studies-particularly those striving to predict which individual pediatric patients will continue to suffer from TS as adults and studies of treatment response-particularly of behavioral therapies, which are as efficacious as pharmacology. Transcranial magnetic stimulation and related therapies such as cranial electrotherapy stimulation, which showed good efficacy in a recent trial, merit continued exploration. TS research using DTI, MRS, and PET will no doubt continue to benefit in coming years from technological advances such as ultrahigh-field scanners, multichannel head coils, and novel (including GABAergic and glutamatergic) ligands.

Regulatory effects of Ningdong granule on dopaminergic and serotonergic neurotransmission in a rat model of Tourette syndrome assessed by PET.

Dysfunctions in dopamine (DA) and serotonin (5­HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5­HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'­iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micro­positron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5­HT2A receptors (5­HT2ARs) and 5­HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5­HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.

Gastrodin attenuates neuroinflammation in DOI-induce Tourette syndrome in rats.

OBJECTIVE: Tourette syndrome (TS) is a chronic neuropsychiatric disorder. Its clinical manifestations are involuntary and recurrent muscle twitch, resulting in motor twitch and occurrence twitch. Traditional Chinese medicine has obvious advantages in treating TS. The aim of this study was to investigate the effects and mechanism of gastrodin on 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced TS in rats. METHODS: TS model was induced by DOI. Behaviors in TS rats were detected. The striatum, serum inflammatory factors interleukin-6, interleukin-1ß, and tumor necrosis factor-a were detected by enzyme-linked immunosorbent assay. Western blot technique was used to detect the expressions of TLR/NF-κB and TLR/MAPK signaling pathways in the striatum. RESULTS: Gastrodin can significantly improve behavioral changes of TS rats induced by DOI, reduce inflammatory factors in serum and striatum in TS rats, and inhibit activation of TLR/NF-κB and TLR/MAPK signaling in striatum in TS rats. CONCLUSION: Gastrodin can significantly relieve the TS induced by DOI in rats. Its mechanism is related to the inhibition of striatal TLR/NF-κB and TLR/MAPK signaling activation.

Neuroimaging Applications in Tourette's Syndrome.

Tics are neurodevelopmental hyperkinetic symptoms typically associated with unpleasant sensory experiences called premonitory urges. Tourette syndrome (TS) is the primary chronic tic disorder for which medical surveillance is most frequently required, and is associated with a complex phenotypical spectrum encompassing different types of abnormal behaviors. Animal models of tics support their link to phasic activity changes throughout the sensorimotor loop of the cortico-basal ganglia-thalamo-cortical network. Event-related functional magnetic resonance imaging (fMRI) studies on patients with TS showed that the supplementary motor area relays preparatory signals related to tics to the primary motor area and other cortical regions relevant to action monitoring, following which cortico-basal ganglia-thalamo-cortical activation leads to the manifestation of tics. Despite their methodological heterogeneity, structural MRI studies highlighted the existence of anatomical markers of distinct sub-phenotypes of the TS spectrum. Initial evidence suggests that combining MRI structural methods and functional intrinsic connectivity assessed during resting state could even discriminate between TS patients and control groups. MR-spectroscopy and positron emission tomography studies suggest that TS may be related to a complex interplay between different neurotransmitters (particularly dopamine, GABA and glutamate), but discrepancy across studies prevents firm conclusions. Recent volumetric, cortical thickness and fMRI studies results showed an association between premonitory urges and somatosensory and insular cortical regions, involved in the processing of interoceptive and enteroceptive stimuli and motor output modulation. Finally, both structural and functional MRI studies have provided important support to the subtyping of the TS spectrum with respect to behavioral co-morbidities, in line with a "dimensional approach" to the classification of neuropsychiatric disorders, which is based on the identification of neurocognitive endophenotypes and of their anatomical substrate.

Face perception enhances insula and motor network reactivity in Tourette syndrome.

Tourette syndrome is a neurodevelopmental disorder, characterized by motor and phonic tics. Tics are typically experienced as avolitional, compulsive, and associated with premonitory urges. They are exacerbated by stress and can be triggered by external stimuli, including social cues like the actions and facial expressions of others. Importantly, emotional social stimuli, with angry facial stimuli potentially the most potent social threat cue, also trigger behavioural reactions in healthy individuals, suggesting that such mechanisms may be particularly sensitive in people with Tourette syndrome. Twenty-one participants with Tourette syndrome and 21 healthy controls underwent functional MRI while viewing faces wearing either neutral or angry expressions to quantify group differences in neural activity associated with processing social information. Simultaneous video recordings of participants during neuroimaging enabled us to model confounding effects of tics on task-related responses to the processing of faces. In both Tourette syndrome and control participants, face stimuli evoked enhanced activation within canonical face perception regions, including the occipital face area and fusiform face area. However, the Tourette syndrome group showed additional responses within the anterior insula to both neutral and angry faces. Functional connectivity during face viewing was then examined in a series of psychophysiological interactions. In participants with Tourette syndrome, the insula showed functional connectivity with a set of cortical regions previously implicated in tic generation: the presupplementary motor area, premotor cortex, primary motor cortex, and the putamen. Furthermore, insula functional connectivity with the globus pallidus and thalamus varied in proportion to tic severity, while supplementary motor area connectivity varied in proportion to premonitory sensations, with insula connectivity to these regions increasing to a greater extent in patients with worse symptom severity. In addition, the occipital face area showed increased functional connectivity in Tourette syndrome participants with posterior cortical regions, including primary somatosensory cortex, and occipital face area connectivity with primary somatosensory and primary motor cortices varied in proportion to tic severity. There were no significant psychophysiological interactions in controls. These findings highlight a potential mechanism in Tourette syndrome through which heightened representation within insular cortex of embodied affective social information may impact the reactivity of subcortical motor pathways, supporting programmed motor actions that are causally implicated in tic generation. Medicinal and psychological therapies that focus on reducing insular hyper-reactivity to social stimuli may have potential benefit for tic reduction in people with Tourette syndrome.

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

Tourette syndrome research highlights from 2017.

This is the fourth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2017 relevant to Tourette syndrome and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The  highlights from 2018 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the Tics collection on F1000Research.

Tourette syndrome: a disorder of the social decision-making network.

Tourette syndrome is a common neurodevelopmental disorder defined by characteristic involuntary movements, tics, with both motor and phonic components. Tourette syndrome is usually conceptualized as a basal ganglia disorder, with an emphasis on striatal dysfunction. While considerable evidence is consistent with these concepts, imaging data suggest diffuse functional and structural abnormalities in Tourette syndrome brain. Tourette syndrome exhibits features that are difficult to explain solely based on basal ganglia circuit dysfunctions. These features include the natural history of tic expression, with typical onset of tics around ages 5 to 7 years and exacerbation during the peri-pubertal years, marked sex disparity with higher male prevalence, and the characteristic distribution of tics. The latter are usually repetitive, somewhat stereotyped involuntary eye, facial and head movements, and phonations. A major functional role of eye, face, and head movements is social signalling. Prior work in social neuroscience identified a phylogenetically conserved network of sexually dimorphic subcortical nuclei, the Social Behaviour Network, mediating many social behaviours. Social behaviour network function is modulated developmentally by gonadal steroids and social behaviour network outputs are stereotyped sex and species specific behaviours. In 2011 O'Connell and Hofmann proposed that the social behaviour network interdigitates with the basal ganglia to form a greater network, the social decision-making network. The social decision-making network may have two functionally complementary limbs: the basal ganglia component responsible for evaluation of socially relevant stimuli and actions with the social behaviour network component responsible for the performance of social acts. Social decision-making network dysfunction can explain major features of the neurobiology of Tourette syndrome. Tourette syndrome may be a disorder of social communication resulting from developmental abnormalities at several levels of the social decision-making network. The social decision-making network dysfunction hypothesis suggests new avenues for research in Tourette syndrome and new potential therapeutic targets.

Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome.

Trichotillomania/hair pulling disorder (HPD) and excoriation/skin picking disorder (SPD) are childhood-onset, body-focused repetitive behaviors that are thought to share genetic susceptibility and underlying pathophysiology with obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We sought to determine the prevalence of DSM-5 HPD and SPD in TS patients, and to identify clinical factors most associated with their co-morbidity with TS. Participants included 811 TS patients recruited from TS specialty clinics for a multi-center genetic study. Patients were assessed using standardized, validated semi-structured interviews. HPD and SPD diagnoses were determined using a validated self-report questionnaire. HPD/SPD prevalence rates were calculated, and clinical predictors were evaluated using regression modeling. 3.8 and 13.0% of TS patients met DSM-5 criteria for HPD and SPD, respectively. In univariable analyses, female sex, OCD, and both tic and obsessive-compulsive symptom severity were among those associated with HPD and/or SPD. In multivariable analyses, only lifetime worst-ever motor tic severity remained significantly associated with HPD. Female sex, co-occurring OCD, ADHD, and motor tic severity remained independently associated with SPD. This is the first study to examine HPD and SPD prevalence in a TS sample using semi-structured diagnostic instruments. The prevalence of HPD and SPD in TS patients, and their association with increased tic severity and co-occurring OCD, suggests that clinicians should screen children with TS and related disorders for HPD/SPD, particularly in females and in those with co-occurring OCD. This study also helps set a foundation for subsequent research regarding HPD/SPD risk factors, pathophysiology, and treatment models.

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits.

Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, which thereby determines the precise responses of synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders.

Altered topology of structural brain networks in patients with Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by tics. Abnormal neuronal circuits in a wide-spread structural and functional network involved in planning, execution and control of motor functions are thought to represent the underlying pathology. We therefore studied changes of structural brain networks in 13 adult GTS patients reconstructed by diffusion tensor imaging and probabilistic tractography. Structural connectivity and network topology were characterized by graph theoretical measures and compared to 13 age-matched controls. In GTS patients, significantly reduced connectivity was detected in right hemispheric networks. These were furthermore characterized by significantly reduced local graph parameters (local clustering, efficiency and strength) indicating decreased structural segregation of local subnetworks. Contrasting these results, whole brain and right hemispheric networks of GTS patients showed significantly increased normalized global efficiency indicating an overall increase of structural integration among distributed areas. Higher global efficiency was associated with tic severity (R = 0.63, p = 0.022) suggesting the clinical relevance of altered network topology. Our findings reflect an imbalance between structural integration and segregation in right hemispheric structural connectome of patients with GTS. These changes might be related to an underlying pathology of impaired neuronal development, but could also indicate potential adaptive plasticity.

Speechlessness in Gilles de la Tourette Syndrome: Cannabis-Based Medicines Improve Severe Vocal Blocking Tics in Two Patients.

We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4-33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics.

Behavioral and stereological characterization of Hdc KO mice: Relation to Tourette syndrome.

A premature termination codon in the human histidine decarboxylase (Hdc) gene has been identified in a family suffering from Guilles de la Tourette syndrome (GTS). In the current study we investigated if mice lacking the histamine producing enzyme HDC share the morphological and cytological phenotype with GTS patients by using magnetic resonance (MRI) and diffusion tensor imaging (DTI), unbiased stereology and immunohistochemistry. Behavior of Hdc knock-out (Hdc KO) mice was assessed in an open field test. The results of stereological, volumetric and DTI analysis measurements showed no significant differences between control and Hdc KO mice. The numbers and distribution of GABAergic parvalbumin or nitric oxide-expressing and cholinergic interneurons were normal in Hdc KO mice. Cortical morphology and layering in adult Hdc KO mice were also preserved. In open field test Hdc KO mice showed impaired exploratory activity and habituation when introduced to novel environment. Our results indicate that Hdc deficiency in mice does not disturb the development of striatal and cortical interneurons and does not lead to the morphological and cytological phenotypes characterized by humans with GTS. Nevertheless, histamine deficiency leads to behavioral alterations probably due to neurotransmitter dysbalance on the level of the striatum.

Altered Spontaneous Brain Activity in Children with Early Tourette Syndrome: a Resting-state fMRI Study.

Tourette syndrome (TS) is a childhood-onset chronic disorder characterized by the presence of multiple motor and vocal tics. This study investigated the alterations of spontaneous brain activities in children with TS by resting-state functional magnetic resonance imaging (rs-fMRI). We obtained rs-fMRI scans from 21 drug-naïve and pure TS children and 29 demographically matched healthy children. The amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF) and regional homogeneity (ReHo) of rs-fMRI data were calculated to measure spontaneous brain activity. We found significant alterations of ALFF or fALFF in vision-related structures including the calcarine sulcus, the cuneus, the fusiform gyrus, and the left insula in TS children. Decreased ReHo was found in the right cerebellum. Further analysis showed that the ReHo value of the right cerebellum was positively correlated with TS duration. Our study provides empirical evidence for abnormal spontaneous neuronal activity in TS patients, which may implicate the neurophysiological mechanism in TS children. Moreover, the right cerebellum can be potentially used as a biomarker for the pathophysiology of early TS in children.