GABA and Glutamate in Children with Primary Complex Motor Stereotypies: An 1H-MRS Study at 7T.

BACKGROUND AND PURPOSE: Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements that stop with distraction. They can occur in otherwise normal healthy children (primary stereotypies) as well in those with autism spectrum disorders (secondary stereotypies). The underlying neurobiologic basis for these movements is unknown but is thought to involve cortical-striatal-thalamo-cortical pathways. To further clarify potential neurochemical alterations, gamma-aminobutyric acid (GABA), glutamate, glutamine, N-acetylaspartate, and choline levels were measured in 4 frontostriatal regions by using (1)H MRS at 7T. MATERIALS AND METHODS: A total of 18 children with primary complex motor stereotypies and 24 typically developing controls, ages 5-10 years, completed MR spectroscopy at 7T. Single voxel STEAM acquisitions from the anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex, and striatum were obtained, and metabolites were quantified with respect to Cr by using LCModel. RESULTS: The 7T scan was well tolerated by all the participants. Compared with the controls, children with complex motor stereotypies had lower levels of GABA in the anterior cingulate cortex (GABA/Cr, P = .049; GABA/Glu, P = .051) and striatum (GABA/Cr, P = .028; GABA/Glu, P = .0037) but not the dorsolateral prefrontal cortex or the premotor cortex. Glutamate, glutamine, NAA, and Cho levels did not differ between groups in any of the aforementioned regions. Within the complex motor stereotypies group, reduced GABA to Cr in the anterior cingulate cortex was significantly associated with greater severity of motor stereotypies (r = -0.59, P = .021). CONCLUSIONS: These results indicate possible GABAergic dysfunction within corticostriatal pathways in children with primary complex motor stereotypies.

Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: single-point and longitudinal assessments.

Single-point-in-time ELISA optical densities for three putative antibodies identified in Sydenham's chorea, the streptococcal group A carbohydrate antigen, N-acetyl-beta-d-glucosamine, tubulin, and the dopamine 2 receptor, showed no differences in children with PANDAS (n=44) or Tourette syndrome (n=40) as compared to controls (n=24). Anti-tubulin and D2 receptor antibodies assessed in serial samples from 12 PANDAS subjects obtained prior to a documented exacerbation, during the exacerbation (with or without a temporally associated streptococcal infection), and following the exacerbation, showed no evidence of antibody levels correlating with a clinical exacerbation. These data do not support hypotheses suggesting an autoimmune hypothesis in either TS or PANDAS.

Disproportionate increases of white matter in right frontal lobe in Tourette syndrome.

OBJECTIVE: Based on previous findings implicating abnormalities of cortico-striatal-thalamo-cortical circuitry in Tourette syndrome (TS), the authors performed a volumetric analysis of frontal and nonfrontal tissue (gray + white matter) in boys with TS, with and without attention deficit hyperactivity disorder (ADHD). METHODS: Frontal and nonfrontal gray and white matter compartment volumes, obtained by a MRI protocol, were analyzed with a 2 x 2 factorial multivariate analysis of variance approach for associations with a TS or ADHD factor in 11 boys with TS only, 14 with TS + ADHD, 12 with ADHD only, and 26 healthy boys. RESULTS: In subjects with TS, the right frontal lobe showed a larger proportion of white matter. In addition, results were consistent with previous reports of reduced frontal lobe volumes associated with ADHD. Our analyses suggested these reductions to be mainly the consequence of smaller gray matter volumes, particularly on the left. CONCLUSIONS: These findings, suggesting the volumetric composition of frontal lobe tissue to be different in TS, support the hypothesis proposing frontostriatal pathway involvement in the pathophysiology of the disorder. Differences in composition of right frontal lobe attributable to white matter do not definitively implicate the hypothesized fiber pathways; however, considered in the context of the unilateral directionality of frontal-striatal circuitry, these results suggest the white matter connections as one explanation for basal ganglia anomalies (loss of normal left > right asymmetry) in TS.

Striatal antibodies in children with Tourette's syndrome: multivariate discriminant analysis of IgG repertoires.

Antineuronal antibodies have been postulated to be the underlying pathophysiology in TS and other neuropsychiatric disorders. Serum antibodies from 20 children with TS, and 21 control subjects against human striatum, globus pallidus, muscle, and HTB-10 cells were assayed by Western blot techniques. A MANOVA differentiated between TS and control blots, and a discriminant analysis demonstrated which variables contributed most to differences between groups. Prominent differences between TS and control blots were identified using striatal epitopes in contrast to similar patterns shown between groups for globus pallidus, muscle and HTB-10 tissue, supporting striatal autoimmune involvement in TS pathophysiology.

Tourette syndrome: clinical characteristics and current management strategies.

Tourette Syndrome (TS) is a disorder comprised of involuntary motor and phonic tics often associated with psychiatric conditions. The etiology for TS is unclear, with both genetic and immunological theories being studied to date. When pharmacotherapy is considered by the patient and physician to be required, owing to either functional impairment from tics or comorbid psychiatric illness, dopamine receptor antagonists are commonly used. Our first-line agents for tic suppression include clonidine, guanfacine, clonazepam and baclofen. Should these agents be ineffective, we would recommend pimozide, fluphenazine, risperidone or haloperidol. The potential benefit of other agents, such as olanzapine, ziprasidone, pergolide and botulinum toxin, is encouraging. Despite many years of concern, we have found little exacerbation of tics with stimulant medications for attention deficit hyperactivity disorder, but clearly clonidine and guanfacine can ameliorate both comorbid conditions. Obsessive compulsive disorder, when associated with TS, may be treated with either a selective serotonin reuptake inhibitor in association with a dopamine receptor antagonist or risperidone alone. New therapies for all aspects of TS and its comorbid conditions are in active clinical trials.

Executive function in fluency and recall measures among children with Tourette syndrome or ADHD.

This study assessed two relevant aspects of executive dysfunction in children with either Tourette syndrome (TS) or ADHD. Process variables derived from existing neuropsychological measures were used to clarify the executive function construct. Clustering of responses on measures of verbal fluency, figural fluency, and verbal learning was examined to assess strategic response organization. Rule breaks, intrusions, and repetition errors were recorded to assess inhibition errors. No significant differences were found among the three groups (TS, ADHD, and controls) on tasks of response organization (clustering). In our sample, both the ADHD and the TS groups were largely free from executive function impairment, and their performance on the fluency and list learning tasks was in the average range. There was a significant group difference on one of the disinhibition variables, with both TS and ADHD groups showing significantly more intrusions on verbal list learning trials than controls. When more traditional total score variables were analyzed among the three groups, there were no significant differences; however, analysis of effect size revealed medium-to-large effect sizes for Letter Word Fluency total score differences (ADHD vs. controls), and for Semantic Word Fluency total score differences (ADHD vs. TS), with the ADHD group having weaker performance in both comparisons. Results provide some support for the use and analysis of process variables-particularly those related to inhibition and intrusion errors, in addition to the total score variables when assessing executive function deficits in children with ADHD and TS. While group differences may be found, children with uncomplicated TS should not routinely be considered to have significant executive function impairments, and when deficits are found, they may be attributable to other comorbid disorders.

Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial.

OBJECTIVE: To investigate the effectiveness of baclofen for the treatment of tics in children with Tourette syndrome (TS). BACKGROUND: Baclofen, which contains both gamma-aminobutyric acid (GABA) and phenylethylamine moieties, was suggested in an open-label protocol to be an effective treatment for TS. This is a double-blind, placebo-controlled study to investigate this medication in children with TS. METHODS: Subjects received, in a randomized sequence, 4-week medication cycles of baclofen (20 mg three times daily) and placebo with a 2-week intervening washout period between the cycles. Outcome measures included the Clinical Global Impression (CGI) scale, and the Yale Global Tic Severity Scale (YGTSS), the latter including subscales for total tics and overall impairment. Measures were assessed at baseline and on days 28, 42, and 70 of the study. RESULTS: Ten children (seven boys and three girls, aged 8 to 14) with TS participated. Nine subjects completed the protocol; one dropped out for psychosocial reasons. No major side effects were reported. The mean change in CGI score (-0.9) after 4 weeks of baclofen treatment as compared with placebo treatment showed a significant improvement (95% CI, -1.7 to -0.1; p = 0.04). All subjects showed some amelioration in total YGTSS score during baclofen treatment. The mean change in total YGTSS score (-14.7) approached significance (95% CI, -30.3 to 0.9; p = 0.06). Examination of differences between baclofen and placebo treatment groups expressed as a percent change from baseline showed that baclofen had a statistically significant effect on both outcome measures. Subscales of the YGTSS showed that the reduction in total tic scores was primarily due to a reduction in the impairment score rather than a decrease in tics. CONCLUSIONS: Children with TS may benefit from treatment with baclofen, although improvements may be related to factors other than tics. Larger studies directly comparing baclofen against other tic-suppressing agents are recommended.

Oculomotor abnormalities in boys with tourette syndrome with and without ADHD.

OBJECTIVE: To assess saccadic eye movements in boys with Tourette syndrome (TS) with and without attention-deficit hyperactivity disorder (ADHD), comparing performance with that of an age-matched group of male controls. METHOD: Three different saccade tasks (prosaccades, antisaccades, and memory-guided saccades) were used to examine functions necessary for the planning and execution of eye movements, including motor response preparation, response inhibition, and working memory. The study included 14 boys with TS without ADHD (TS-only), 11 boys with TS and ADHD (TS+ADHD), and 10 male controls. RESULTS: Latency of prosaccades was prolonged in boys with TS (both with and without ADHD) compared with controls. Variability in prosaccade latency was greater in the groups of boys with TS+ADHD compared with both the TS-only and control groups. Response inhibition errors on both the antisaccade task (directional errors) and memory-guided saccade task (anticipatory errors) were increased in boys with TS+ADHD compared with those with TS-only. There were no significant differences among the three groups in accuracy of memory-guided saccades. CONCLUSIONS: Oculomotor findings suggest that TS is associated with delay in initiation of motor response as evidenced by excessive latency on prosaccades. Signs of impaired response inhibition and variability in motor response appear to be associated with the presence of ADHD.

The treatment of tics.

Tics are the essential component of a variety of disorders, notably Tourette syndrome. Because the mere presence of tics does not require therapeutic intervention, criteria are essential for determining a functional disability. Suggested tic-suppressing treatments have been extremely diverse, including hydrotherapy, behavioral treatments, pharmacotherapy, botulinum toxin, immunomodulatory therapy, and surgery. This manuscript reviews each of these approaches with emphasis on more recent pharmacologic trials.

Language-based cognitive functioning in parents of offspring with ADHD comorbid for Tourette syndrome or learning disabilities.

The parents of children diagnosed with attention deficit hyperactivity disorder (ADHD) were examined for characteristics symptomatic of 2 comorbidities (Co) within their offspring with ADHD: Tourette syndrome (TS) and language-based learning disabilities (LD). A 2 x 2 multivariate analysis of variance design was used; the parents were divided according to whether the offspring with ADHD had TS (Co-TS) or not (No Co-TS) and whether offspring had LD (Co-LD) or not (No Co-LD). Parents (86 mothers and 70 fathers) were administered the short form of the Wechsler Adult Intelligence Scale--Revised (WAIS-R; Wechsler, 1981), subtests of the Woodcock-Johnson Cognitive and Achievement Batteries (Woodcock & Johnson, 1989), and word fluency (semantic and letter; Benton & Hamsher, 1989; Wiig & Semel, 1987). The fathers of offspring with Co-TS were more likely to be diagnosed with LD and had lower WAIS-R Vocabulary, Arithmetic, and Picture Arrangement scores. In addition, when the WAIS-R full scale IQ was used as a covariate, these fathers had lower Woodcock-Johnson Oral Vocabulary, Spelling, and Reading scores (as measured by Letter-Word Identification). The mothers of children with Co-TS had lower WAIS-R Vocabulary scores. Parents of the children with No Co-TS showed a higher proportion of error patterns on the word fluency tasks involving repetitions and rule breaks. The findings show that it was the parents of the children with Co-TS, not the parents of the children with Co-LD, who showed language-based learning problems. In separate discriminant analyses for the fathers and mothers, when the aforementioned significant parental measures were used as predictors, 81% of offspring with Co-TS were correctly classified as having a diagnosis of TS, solely on the basis of characteristics in their parents.

Infection: a stimulus for tic disorders.

The object of this study was to investigate the potential association of infections, especially group A hemolytic streptococcal infection, with the abrupt onset/exacerbation of tics or obsessive-compulsive behaviors. A structured clinical interview was used to evaluate 80 consecutive children, 5-17 years of age, with a diagnosis of tic disorder. Forty-two patients (53%) described a sudden, explosive onset or worsening of tic symptoms; 15 of these 42 had their exacerbation historically associated with an infection, nine of the 15 specifically with a streptococcal infection. Comparisons between those nine individuals and the remainder of the study population are presented. The results of this study reveal that descriptions of an abrupt tic onset or exacerbation are not uncommon in children with tic disorders; approximately 11% of children with tic disorders described abrupt changes of tic behavior within a 6-week period after a streptococcal infection.

Subcortical volumes in girls with tourette syndrome: support for a gender effect.

OBJECTIVE: To test whether girls with Tourette syndrome (TS) show subcortical morphology that differentiates them from control subjects. METHODS: MRI-based subcortical assessment was completed on 19 girls with TS age 7 to 15 years, 11 with TS only, and 8 with TS plus attention deficit hyperactivity disorder (TS + ADHD), and on 21 age- and sex-matched controls. The structures measured were the caudate, putamen, globus pallidus, and lateral ventricle volumes. Whole-brain-corrected volumes and asymmetry indices were compared using two- and three-group designs (i.e., TS versus control; TS-only versus TS + ADHD versus control). RESULTS: Two-group comparisons demonstrated no robust significant differences between girls with TS and gender-matched controls. Three-group comparisons demonstrated that TS-only subjects had significantly small lateral ventricles compared with TS + ADHD and control subjects. Because the two-group comparisons of the current study differed from previous reports of putamen asymmetry index as a marker for TS, retrospective comparisons with data from boys were performed. These additional comparisons showed that girls with TS had putamen asymmetry indices similar to those of boys with TS; however, control girls also showed those same patterns. CONCLUSIONS: Basal ganglia volume and asymmetry differences do not distinguish the girls with TS from matched controls. Gender differences confound the association between putamen asymmetry and TS. Although the numbers are small and the clinical significance is unclear, this study further indicates that girls with TS-only have smaller lateral ventricular volumes than control subjects and those with TS + ADHD.

Corpus callosum measurements in girls with Tourette syndrome.

The objective of this study was to examine whether abnormalities in corpus callosum morphology, previously reported in boys with Tourette syndrome (TS), were also present in girls with this disorder. Among the three groups of girls-TS, TS and attention deficit hyperactivity disorder, and controls-there were no significant differences in the size of the corpus callosum or any of five individual subregions. The findings suggest that abnormalities in corpus callosum morphology in TS are a gender-related phenomenon.