Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Associative plasticity in supplementary motor area - motor cortex pathways in Tourette syndrome.

The important role of the supplementary motor area (SMA) in the generation of tics and urges in Gilles de la Tourette syndrome (GTS) is underscored by an increased SMA-motor cortex (M1) connectivity. However, whether plasticity is also altered in SMA-M1 pathways is unclear. We explored whether SMA-M1 plasticity is altered in patients with Tourette syndrome. 15 patients with GTS (mean age of 33.4 years, SD = 9.9) and 19 age and sex matched healthy controls were investigated with a paired association stimulation (PAS) protocol using three transcranial magnetic stimulation (TMS) coils stimulating both M1 and the SMA. Standard clinical measures for GTS symptoms were collected. There was a significant PAS effect showing that MEP amplitudes measured in blocks during and after PAS were significantly higher compared to those in the first block. However, the degree of PAS was not differentially modulated between patients and controls as shown by a Bayesian data analysis. PAS effects in GTS correlated positively with the YGTSS motor tic severity. Plasticity previously reported to be altered in sensorimotor pathways in GTS is normal in SMA-M1 projections suggesting that the dysfunction of the SMA in GTS is not primarily related to altered plasticity in SMA-M1 connections.

Altered perceptual binding in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a common multifaceted neuropsychiatric disorder. Research in GTS has traditionally focussed on mechanisms underlying changes in motor processes in these patients. There is, however, growing interest in GTS related sensory phenomena. According to the Theory of Event-coding (TEC), sensory stimuli do not only serve representational functions but also action-related functions. In the current study, we use the TEC framework to examine whether the way perceptual features are processed is altered in GTS. The results show that basic perceptual processes differ between GTS patients and healthy controls which might be central for the understanding of this disorder. Details or features of perceptual objects were less bound in GTS suggesting that perceptual features integration is attenuated in them. Behavioural findings were unrelated to patient characteristics implying that they might represent trait abnormalities. It is possible that altered perceptual processing in GTS is due to a long-range under-connectivity of parietal areas with other brain regions repeatedly been described in these patients.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.

The relation between attention and tic generation in Tourette syndrome.

OBJECTIVE: Many neuropsychiatric disorders involve abnormal attentional processing. Systematic investigations of how attention may affect tic frequency in Tourette syndrome are lacking. METHOD: Patients performed rhythmic finger movements, approximately once every 2 s. Each movement triggered a unique visual color stimulus. Patients were asked to monitor and remember their finger actions, the external colors caused by their actions, or their tics. Sixteen adult Tourette syndrome patients performed each task twice: once while inhibiting tics, and once without inhibiting tics. RESULTS: During the "freely tic" condition, patients had significantly fewer tics when attending to finger movements, or to the ensuing colors, compared with when attending to their tics. Attention to fingers produced the fewest tics overall. During tic suppression, tic frequency was reduced to an equal level in all conditions. CONCLUSIONS: Focusing attention away from tics significantly reduces tic frequency. This attentional process may operate by regulating motor noise.