Childhood-onset Neuropsychiatric Disorder Research Articles

MicroRNAs as potential biomarkers for diagnosis of attention deficit hyperactivity disorder.

Inappropriate levels of hyperactivity, impulsivity, and inattention characterize attention deficit hyperactivity disorder, a common childhood-onset neuropsychiatric disorder. The cognitive function and learning ability of children with attention deficit hyperactivity disorder are affected, and these symptoms may persist to adulthood if they are not treated. The diagnosis of attention deficit hyperactivity disorder is only based on symptoms and objective tests for attention deficit hyperactivity disorder are missing. Treatments for attention deficit hyperactivity disorder in children include medications, behavior therapy, counseling, and education services which can relieve many of the symptoms of attention deficit hyperactivity disorder but cannot cure it. There is a need for a molecular biomarker to distinguish attention deficit hyperactivity disorder from healthy subjects and other neurological conditions, which would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated. Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of attention deficit hyperactivity disorder. The recent studies reviewed had performed microRNA profiling in whole blood, white blood cells, blood plasma, and blood serum of children with attention deficit hyperactivity disorder. A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies. From the studies that had included a validation set of patients and controls, potential candidate biomarkers for attention deficit hyperactivity disorder in children could be miR-140-3p, let-7g-5p, -30e-5p, -223-3p, -142-5p, -486-5p, -151a-3p, -151a-5p, and -126-5p in total white blood cells, and miR-4516, -6090, -4763-3p, -4281, -4466, -101-3p, -130a-3p, -138-5p, -195-5p, and -106b-5p in blood serum. Further studies are warranted with children and adults with attention deficit hyperactivity disorder, and consideration should be given to utilizing rat models of attention deficit hyperactivity disorder. Animal studies could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.

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

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. 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. 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. 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.

A Pilot Study on Plasma and Urine Neurotransmitter Levels in Children with Tic Disorders.

Background: Tic disorders (TDs), including Tourette syndrome, are childhood-onset neuropsychiatric disorders characterized by motor and/or vocal tics that commonly affect children’s physical and mental health. The pathogenesis of TDs may be related to abnormal neurotransmitters in the cortico-striatal-thalamo-cortical circuitry, especially dopaminergic, glutamatergic, and serotonergic neurotransmitters. The purpose of this study was to preliminarily investigate the differences in the three types of neurotransmitters in plasma and urine between children with TD and healthy children. Methods: We collected 94 samples of plasma and 69 samples of urine from 3–12-year-old Chinese Han children with TD before treatment. The plasma and urine of the same number of healthy Chinese Han children, matched for age and sex, participating in a physical examination, were collected. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the three types of neurotransmitters in the above samples. Results: The plasma levels of norepinephrine, glutamic acid, and γ-aminobutyric acid, and the urine levels of normetanephrine and 5-hydroxyindoleacetic acid were higher in the TD children than in healthy children. The area under the curve (AUC) values of the above neurotransmitters in plasma and urine analyzed by receiver operating characteristic curve analysis were all higher than 0.6, with significant differences. Among them, the combined AUC of dopamine, norepinephrine, normetanephrine, glutamic acid, and γ-aminobutyric acid in the 8–12-year-old subgroup was 0.930, and the sensitivity and specificity for TD were 0.821 and 0.974, respectively (p = 0.000). Conclusions: There are differences in plasma and urine neurotransmitters between TD children and healthy children, which lays a foundation for further research on the pathogenesis of TD.

Comprehensive behavioural intervention for tics: a neurophysiological intervention.

Gilles de la Tourette Syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterised by motor and vocal tics. While Comprehensive Behavioural Intervention for Tics (CBIT) is an effective, non-pharmacological treatment for patients with GTS, the underlying neurophysiological basis of this intervention has not been investigated. To investigate the clinical effectiveness of CBIT in reducing tic severity in young people with GTS and explore neurophysiological mechanisms associated with clinical change. There was a significant overall improvement in tic severity of large effect size. The Cortical Silent Period (CSP) to motor evoked potential (MEP) ratio (CSP/MEP ratio) increased after the intervention with a small effect size. Other neurophysiological measures of inhibition were not significantly related to the change in tic severity. Alongside significant clinical improvements, these results suggest a role for motor cortical Gamma-aminobutyric acid (GABA)-ergic inhibitory circuitry in the neurophysiological changes underlying CBIT treatment. These findings need to be replicated in larger studies using control samples.

The Behavioral and Emotional Profile of Pediatric Tourette Syndrome Based on CBCL in a Chinese Sample.

BackgroundTourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that has a unique status of a quintessentially neuropsychiatric condition at the interface of neurology (movement disorder) and psychiatry (behavioral/emotional condition). However, the behavioral and emotional profile has seemed to be neglected in the literature thus far. This study aimed to investigate the behavioral and emotional profile of TS.MethodsA total of 124 patients aged 6–16 years with TS were included in this study, including age- and sex-matched health control, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and major depressive disorder (MDD) groups. The Child Behavior Checklist (CBCL) was used to screen the behavioral and emotional profile of the TS and other compared groups. The Yale Global Tic Severity Scale (YGTSS) was used to assess TS tic severity. Analysis of variance (ANOVA) was used to investigate the difference between the TS and other compared groups.ResultsThe results showed that the eight factors of the CBCL had no association with motor tics, vocal tics, or tic severity (p > 0.05). However, positive correlations were identified between functional impairments (subscales of YGTSS) and thought problems (TP) and rule-breaking behavior (RBB). Based on the eight-factor profile of the CBCL, TS showed a similar profile to MDD but different from ADHD and OCD, which showed similar profiles.ConclusionsBased on the assessment of the CBCL of TS, it was found that “pure” TS might show fewer behavioral and emotional problems than OCD, ADHD, and MDD. Similar behavioral and emotional profiles were identified between TS and MDD, but not OCD and ADHD. More attention needs to be paid to the thought problems and rule break problems in the CBCL in the screening stage, which might have a potential influence on the functional impairments of TS.

Multivariate Classification of Brain Blood-Oxygen Signal Complexity for the Diagnosis of Children with Tourette Syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by the presence of multiple motor and vocal tics. Because of its varied clinical expressions and lack of reliable diagnostic biomarker, present TS diagnosis still depends on qualitative descriptions of symptoms. Our study aimed to investigate whether the complexity of resting state brain activity can serve as a potential biomarker for TS diagnosis, since it has been used successfully in various neuropsychiatric disorders, including two common TS comorbidities: attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). In the current study, we used both univariate analysis and multivariate searchlight analysis with both linear and non-linear classification methods to explore the group differences in the complexity of resting state brainblood oxygen level-dependent (BOLD) signals between 25 TS boys without comorbidity and 25 sex, age and educational years matched healthy controls (HCs). We also investigated the relation between symptom severity in TS patients (YGTSS scores) and complexity indices derived from different analysis methods. We found: i) univariate analysis revealed reduced complexity in TS patients in the left cerebellum, left superior frontal gyrus, and left medial frontal gyrus; ii) multivariate analysis with non-linear classification method achieved thehighest performance (accuracy: 0.94, sensitivity: 0.96, specificity: 0.92, AUC: 0.95) in bilateral supplementary motor areas; iii) significant correlationswere found between complexity index derived from multivariate analysis with non-linear classification method and Tic severity (YGTSS scores) in the left cerebellum (r = 0.523, with YGTSS phonic) and in theright supplementary motor area (r = 0.767, with YGTSS motor). Taken together, theseresults suggested that complexity of resting stateBOLD activity is a highly effective index for differentiating TS patients from normal controls. Ithas agood potential to be a quantitative biomarker for TS diagnosis.

Gray matter networks associated with attention and working memory deficit in ADHD across adolescence and adulthood

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disorder and may persist into adulthood. Working memory and attention deficits have been reported to persist from childhood to adulthood. How neuronal underpinnings of deficits differ across adolescence and adulthood is not clear. In this study, we investigated gray matter of two cohorts, 486 adults and 508 adolescents, each including participants from ADHD and healthy controls families. Two cohorts both presented significant attention and working memory deficits in individuals with ADHD. Independent component analysis was applied to the gray matter of each cohort, separately, to extract cohort-inherent networks. Then, we identified gray matter networks associated with inattention or working memory in each cohort, and projected them onto the other cohort for comparison. Two components in the inferior, middle/superior frontal regions identified in adults and one component in the insula and inferior frontal region identified in adolescents were significantly associated with working memory in both cohorts. One component in bilateral cerebellar tonsil and culmen identified in adults and one component in left cerebellar region identified in adolescents were significantly associated with inattention in both cohorts. All these components presented a significant or nominal level of gray matter reduction for ADHD participants in adolescents, but only one showed nominal reduction in adults. Our findings suggest although the gray matter reduction of these regions may not be indicative of persistency of ADHD, their persistent associations with inattention or working memory indicate an important role of these regions in the mechanism of persistence or remission of the disorder.

Automatic imitation in youngsters with Gilles de la Tourette syndrome: A behavioral study

ABSTRACT It is widely known that humans have a tendency to imitate each other and that appropriate modulation of automatic imitative behaviors has a crucial function in social interactions. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterized by motor and phonic tics. Apart from tics, patients with GTS are often reported to show an abnormal tendency to automatically imitate others’ behaviors (i.e., echophenomena), which may be related to a failure in top-down inhibition of imitative response tendencies. The aim of the current study is to explore the top-down inhibitory mechanisms on automatic imitative behaviors in youngsters with GTS. Error rates and reaction times from 32 participants with GTS and 32 controls were collected in response to an automatic imitation task assessing the influence of observed movements displayed in the first-person perspective on congruent and incongruent motor responses. Results showed that participants with GTS had higher error rates than controls, and their responses were faster than those of controls in incompatible stimuli. Our findings provide novel evidence of a key difference between youngsters with GTS and typically developing participants in the ability to effectively control the production of own motor responses to sensory inputs deriving from observed actions.

Generation of human induced pluripotent stem cell line FDCHDPi001-A from a Chinese Han Tourette's syndrome patient.

Tourette's syndrome (TS) is a childhood onset neuropsychiatric disorder. The underlying pathogenesis of TS remains unclear. A human induced pluripotent stem cell (hiPSC) line, derived from the peripheral blood mononuclear cells (PBMCs) from a TS patient, was generated by the reprogramming with episomal vectors expressing OCT4, SOX2, KLF4 and c-MYC. The generated hiPSC line is free of episomal vectors, with normal karyotype, expressing pluripotency markers and can differentiate into three germ layers in vivo. This hiPSC line from TS patient can offer a useful resource for studying the pathological mechanism of TS and screening effective drugs for therapeutic purpose.

Clinical features and neuropsychiatric comorbidities in pediatric patients with tic disorders: a retrospective chart review study from South Korea

BackgroundTic disorders are childhood-onset neuropsychiatric disorders characterized by multiple motor or vocal tics with frequent comorbidities and a broad spectrum of phenotypic presentations. In this study, we aimed to investigate the clinical characteristics and comorbid neuropsychiatric conditions in pediatric patients with tic disorders.MethodsWe retrospectively reviewed the medical records of 119 pediatric patients (89 males, 30 females) who were diagnosed with tic disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) at Uijeongbu St. Mary’s Hospital, Republic of Korea, between January 2012 and July 2019.ResultsThe mean age of tic onset was 6.9 years (range, 1–14) and the mean age at diagnosis was 8 years (range, 1–17). The mean lag between tic onset and diagnosis was 13.3 months (range, 0.25–132). The most common, first-presenting tics were eye blinking (50.4%), followed by jaw or lip movement (29.4%) and throat clearing (29.4%). Thirty-seven (31.1%) patients had at least one co-occurring neuropsychiatric disorder at the time of tic diagnosis. Subtypes of tic disorders, types of initial tics, and presence of neuropsychiatric comorbidities were not associated with tic severity. Tic severity was associated with greater functional impairment and tic noticeability (p < 0.05). A relatively shorter time to diagnosis was associated with tic severity (Spearman’s ρ = − 0.14, p = 0.11).ConclusionsThe evolving nature of tic expression and severity, high prevalence of neuropsychiatric comorbidities, and associated functional impairments emphasize the importance of comprehensive assessment during the disease course for determining and prioritizing goals of treatment.

Refractory Gilles de la Tourette Syndrome-Many Pieces That Define the Puzzle.

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive–compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.

Tourette’s disorder and obsessive compulsive disorder: a case report

Tourette’s disorder is a childhood onset neuropsychiatric disorder characterized by multiple motor and vocal tics for at least one year in duration. Occasionally this disorder may be associated with obsessive compulsive disorder. This case was presented here to demonstrate the co-occurrence of these two disorders as well as the effectiveness of pharmacological treatment for the improvement of the condition. The case report described the history of a 21 years old male patient with 7 years history of Tourette’s disorder and obsessive compulsive disorder. He was seriously disabled by his symptoms that necessitated thorough evaluation to exclude causes, differential diagnoses and or any other co morbidities. Treatment with fluoxetine 60 mg daily and quitiapine 100 mg daily in divided dose improved his symptoms and he was able to return his functional life, that he had been mislaid because of his illness.&#x0D; Bang J Psychiatry June 2017; 31(1): 24-26

Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

44.4 MANAGING TOURETTE'S DISORDER AND CO-OCCURRING ADHD

Tourette’s disorder is a childhood-onset neuropsychiatric disorder characterized by at least 2 motor and at least one vocal tic with the age of onset before age 18 years. In Tourette’s disorder, comorbidity is the rule rather than the exception, with up to 90 percent of affected individuals having at least one co-occurring condition. The most common co-occurring conditions include OCD and ADHD, although there are also increased rates of anxiety and mood disorders and other disruptive behavior disorders.

Effect of diet, exercise and sleep on tic severity: a scoping review protocol

IntroductionTourette syndrome is a common childhood-onset neuropsychiatric disorder, with tics that wax and wane in frequency and severity over time. The purpose of the proposed scoping review is to map...

PANDAS and PANS: Clinical, Neuropsychological, and Biological Characterization of a Monocentric Series of Patients and Proposal for a Diagnostic Protocol

Objectives: Whether PANS (pediatric acute-onset neuropsychiatric syndrome) and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) represent true clinical entities is debated and data for a characteristic phenotype are still controversial. In this study, we aim to characterize clinical, neuropsychological, and biochemical aspects in a sample of PANS and PANDAS patients. Methods: Patients fulfilling a clinical diagnosis of PANS or PANDAS from 2014 to 2017 were enrolled. Neurological and psychiatric examination and biochemical and instrumental assessment results were collected. A neuropsychological battery was administered. For comparison purposes, a control group of patients with Sydenham's chorea (SC) was evaluated. Descriptive and comparative statistical analyses were performed. Results: Seven subjects received a diagnosis of PANS, 12 of PANDAS, and 11 of SC. Clinical presentation of PANS children showed statistically significant differences compared with both PANDAS and SC, in particular, with the presence of obsessive symptoms, behavioral regression, and somatic symptoms in the first group. Moreover, all PANS patients showed some neuropsychological deficits in visual-motor abilities, short- and long-term memory, and processing speed. Conclusions: Our experience confirms that patients with PANS had a complex clinical presentation and a compromised neuropsychological profile with respect to patients with PANDAS or SC. However, the absence of biological markers or instrumental alterations made the diagnosis of the two entities, PANS and PANDAS, a matter of exclusion. For these reasons, we propose a pilot diagnostic protocol that (when applied in a prospective manner) will allow comparison with similar childhood-onset neuropsychiatric disorders, such as obsessive-compulsive or tic disorders, and efficacy evaluation of different therapeutic approaches.

SU4 - GENOME-WIDE EXAMINATION OF PARENT-OF-ORIGIN EFFECTS IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

Background Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common and most heritable childhood-onset neuropsychiatric disorders, characterized by multifaceted genetics. To date, genetic studies of ADHD focused on additive effects only, explaining just a fraction of its heritability. Thus, we aimed at examining parent of origin effects (POE) together with maternal and additive effects, providing novel insight into the complex genetic architecture of ADHD. Methods We compiled parent-offspring data collected through the Psychiatric Genomics Consortium and the Norwegian Mother and Child Cohort, consisting of 2060 trios and 328 duos. Additional parent-offspring data is being added. ADHD was diagnosed based on DSM-IV, ICD-10 and child behavior checklist. POE, maternal and additive genetic effects are being evaluated using multinomial modelling implemented in EMIM software. We explored our signals in the light of known imprinted genes (POE) and the largest ADHD Genome-Wide Association Study (GWAS) in children (N=17666). Gene based analyses are being performed using MAGMA software. Heritability estimates and genetic correlations of the examined effects are being calculated using LD score regression. Results Our preliminary results indicate the presence of non-additive genetic effects in the development of ADHD. Our preliminary strongest imprinting signal is located in CALD1 locus (rs11980823, effect=0.77, SE=0.14, P=1.21E-07). This gene also revealed strong association signal in the previously reported large-scale childhood ADHD GWAS (rs79846815, P=2.03E-06). CALD1 plays essential an role in nerve regeneration, a function previously implicated in a number of neuropsychiatric disorders. Our preliminary gene-based analyses of the known imprinted genes revealed strong association with TP73 locus (P=0.0034), encoding a transcription factor implicated in disorders of nervous system (e.g. neuroblastoma). Additional hits were noted in the non-coding RNA genes, adding to the recent observations in neuropsychiatric genetics of gene regulation playing a pivotal role in the development of disorders of mental health. Discussion In conclusion, this is the first and the largest genome-wide parent-offspring study in ADHD, exploring its non-additive genetic effects by detecting and distinguishing between POE (imprinting), maternal and child effects. As we increase our sample size, we will provide estimates of such effects as well as those of their heritability and genetic correlations.

Activation in Children and Adolescents Treated With Selective Serotonin Reuptake Inhibitors: A Weighty Reason?

Activation is a behavioral adverse event related to the use of psychotropic medication. Its high incidence in pediatrics and in childhood-onset neuropsychiatric disorders suggests it may be linked to neurodevelopment. However, previous studies have scarcely examined the role that factors relevant to developmental pharmacokinetics, such as body weight, may play in the onset of activation in children and adolescents. We conducted a retrospective analysis of hospitalized patients to identify the risk factors for activation in children and adolescents treated with selective serotonin reuptake inhibitors. Our focus was on factors related to development, including body weight, to explore the relationship between activation and neurodevelopmental processes. Among the 139 participants (mean age, 14 ± 2.3 years), activation appeared in 29 (20.9%). Age 12 years or younger and comorbid diagnosis of autism spectrum disorder were associated with statistically significant increases in the risk of activation, but no association was found regarding body weight. Our findings support the hypothesis that activation is closely linked to brain development processes. Longitudinal studies are needed to explore this line of research further.

Transcranial Magnetic Stimulation in Tourette Syndrome: A Historical Perspective, Its Current Use and the Influence of Comorbidities in Treatment Response.

Background. Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder consisting of impairing motor and vocal tics which often persists adolescent and adult years. In this older refractory group, standard treatments such as pharmacotherapy and psychotherapeutic interventions may only have limited effects. Based on electrical cortical dysregulation in individuals with TS, a novel approach has employed brain stimulation strategies to modulate the putative aberrant neural electrical activity in pathways that may underlie tics, such as insula-supplementary motor area (SMA) connectivity. Methods. This review will examine all published clinical trials employing transcranial magnetic stimulation (TMS) to ameliorate tics, and discuss a framework for the pathophysiology of TS in relation to electrical brain activity. A framework for future research in tic disorders using TMS and imaging targeting neuroplasticity will be discussed. Results. Therapeutic electrical brain activity modulation with TMS has been carried out in stroke neuro-rehabilitation and neuropsychiatry, including trials in TS. Eleven trials document the use of TMS in TS targeting several brain areas, a positive effect is seen for those trials targeting the SMA. In particular, it appears that younger individuals with concurrent attention-deficit hyperactivity disorder (ADHD) benefit the most. Conclusions. TMS can be used as an effective tool to explore the psychophysiology of TS and potentially provide a therapeutic option. Ultimately, translational research using TMS in TS needs to explore connectivity differences pre- and post-treatment in individuals with TS that are linked to improvement in tic symptoms, with an emphasis on approaches using functional neuroimaging as well as other probes of neuroplasticity.