Chronic alcohol exposure during critical developmental periods differentially impacts persistence of deficits in cognitive flexibility and related circuitry.

Cognitive flexibility in decision making depends on prefrontal cortical function and is used by individuals to adapt to environmental changes in circumstances. Cognitive flexibility can be measured in the laboratory using a variety of discrete, translational tasks, including those that involve reversal learning and/or set-shifting ability. Distinct components of flexible behavior rely upon overlapping brain circuits, including different prefrontal substructures that have separable impacts on decision making. Cognitive flexibility is impaired after chronic alcohol exposure, particularly during development when the brain undergoes rapid maturation. This review examines how cognitive flexibility, as indexed by reversal and set-shifting tasks, is impacted by chronic alcohol exposure in adulthood, adolescent, and prenatal periods in humans and animal models. We also discuss areas for future study, including mechanisms that may contribute to the persistence of cognitive deficits after developmental alcohol exposure and the compacting consequences from exposure across multiple critical periods.

Gilles de la Tourette syndrome in a cohort of deaf people.

We present six patients with Gilles de la Tourette syndrome (TS) who are also deaf. TS has been observed previously, but rarely reported in deaf people, and to date, so called "unusual" phenomenology has been highlighted. TS occurs almost worldwide and in all cultures, and the clinical phenomenology is virtually identical. In our cohort of deaf patients (we suggest another culture) with TS, the phenomenology is the same as in hearing people, and as in all other cultures, with classic motor and vocal/phonic tics, as well as associated phenomena including echo-phenomena, pali-phenomena and rarer copro-phenomena. When "words" related to these phenomenon (e.g. echolalia, palilalia, coprolalia or mental coprolalia) are elicited in deaf people, they occur usually in British Sign Language (BSL): the more "basic" vocal/phonic tics such as throat clearing are the same phenomenologically as in hearing TS people. In our case series, there was a genetic predisposition to TS in all cases. We would argue that TS in deaf people is the same as TS in hearing people and in other cultures, highlighting the biological nature of the disorder.

Deep brain stimulation for treatment of refractory Tourette syndrome: long-term follow-up.

BACKGROUND: Eighteen patients with severe and refractory Tourette Syndrome underwent bilateral thalamic deep brain stimulation. The surgical procedures and stimulation processes of the cohort were reported in 2008; the 2 year follow-up was reported in 2009. The aim of the research is the assessment of long-term outcome (5-6 years) on tics, obsessional behaviours, anxiety, mood, and on the overall general health of the patients and their general satisfaction. METHOD: In this study, all 18 of the original patients will be discussed, pre- and post-DBS, according to our protocol using standardized objective schedules, as well as the clinical impressions of both clinicians and patients. As there were no substantial nor statistical differences on measures of cognitive functioning between pre-DBS and 2 year follow-up, we decided not to continue this aspect of the formal assessment, particularly as there were also no clinical indications. RESULTS: At 5-6 year follow-up, there was a significant reduction in tic severity (p < 0.001), and significant improvements in obsessive compulsive behaviours (p = 0.003), anxiety (p < 0.001) and depressive (p < 0.001) symptoms. Patients, in general, required less medication for tics, co-morbid conditions and/or co-existent psychopathologies. The long-term outcome/satisfaction were not unanimous between patients and the medical team. CONCLUSIONS: At long-term follow-up, DBS was very successful in terms of a significant improvement in tics and also a significant reduction in the potentially disabling symptoms of obsessionality, anxiety and depression. However, compared with our more positive overall results at 2 years, these later results demonstrate long-term difficulties as follows: non-compliance, long-term complications , and the differences in the opinions between the (a) medical, (b) the surgical teams and (c) the post-DBS patients as to their outcome/satisfaction with the procedures. Our experience highlights the need for controlled studies, for long-term follow up, and the need to improve the selection of patients for DBS.

Quality of life in young people with Tourette syndrome: a controlled study.

Quality of life (QoL) may be adversely affected by Tourette syndrome (TS). Although the core symptoms of this complex neurodevelopmental disorder are tics, patients often present with an array of behavioural difficulties, such as co-morbid obsessive compulsive disorder (OCD) or attention deficit hyperactivity disorder (ADHD). In this study we investigated whether young people with TS exhibited poorer QoL in comparison to healthy individuals and an epilepsy control group. We also analysed whether greater tic severity or co-morbid OCD and\or ADHD led to greater differences in perceived QoL. The Youth Quality of Life Instrument-Research Version (Edwards et al. in J Adolesc 25:275-286, 2002) was used to assess QoL and a range of clinical scales were administered to assess anxiety, depression and other behavioural symptoms. TS was associated with significant differences in aspects of QoL related to home and social activities, involving peer and family interactions. Patients with more severe tics reported a greater negative impact on QoL. Patients with TS and no associated diagnoses (pure TS) presented with lower QoL scores in the environment domain, poorer perceived QoL in general, and depressive features. Co-morbid OCD appeared to exert a greater impact on self and relationship QoL domains. The presence of both OCD and ADHD as co-morbidities led to more widespread problems. In conclusion, TS can be associated with poorer perceived QoL. Although social aspects of QoL may be more vulnerable to TS in general, co-morbid conditions make an important contribution in determining which aspects of QoL are most affected in the individual.

Quality of life in young people with treatment-responsive epilepsy: A controlled study.

OBJECTIVE: Quality of life (QoL) has been shown to be lower in individuals with epilepsy than the general public. However, few studies have investigated the QoL of individuals with well-controlled epilepsy. This study investigated the effects of epilepsy on QoL in persons with treatment-responsive seizures, beyond factors directly related to the presence of seizures. METHODS: Fifty young patients with controlled epilepsy and 102 healthy controls completed a generic, multidimensional, self-report QoL instrument, along with standardized scales assessing anxiety, depression, and other emotional or behavioral difficulties. RESULTS: Young people with epilepsy reported increased anxiety (P=0.037) and more emotional and behavioral difficulties (P<0.001). Though there were was no difference between the groups in Total QoL score, treatment-responsive epilepsy was associated with lower QoL within the Self domain (P=0.016). CONCLUSIONS: Epilepsy may exert a negative influence on QoL in relation to thoughts and feelings about the self in the context of complete seizure remission. Future research should investigate the therapeutic value of interventions targeting detrimental changes to self-perception in young people living with controlled epilepsy.

Streptococcal infection, Tourette syndrome, and OCD: is there a connection?

BACKGROUND: A causal relationship of common streptococcal infections and childhood neuropsychiatric disorders has been postulated. OBJECTIVE: To test the hypothesis of an increased rate of streptococcal infections preceding the onset of neuropsychiatric disorders. METHODS: Case-control study of a large primary care database comparing the rate of possible streptococcal infections in patients aged 2-25 years with obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and tics with that in controls matched for age, gender, and practice (20 per case). We also examined the influence of sociodemographic factors. RESULTS: There was no overall increased risk of prior possible streptococcal infection in patients with a diagnosis of OCD, TS, or tics. Subgroup analysis showed that patients with OCD had a slightly higher risk than controls of having had possible streptococcal infections without prescription of antibiotics in the 2 years prior to the onset of OCD (odds ratio 2.59, 95% confidence interval 1.18, 5.69; p = 0.02). Cases with TS or tics were not more likely to come from more affluent or urban areas, but more cases lived in areas with a greater proportion of white population (p value for trend = 0.05). CONCLUSIONS: The present study does not support a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder and Tourette syndrome. However, it is possible that a weak association (or a stronger association in a small susceptible subpopulation) was not detected due to nondifferential misclassification of exposure and limited statistical power. The data are consistent with previous reports of greater rates of diagnosis of Tourette syndrome or tics in white populations.

Thalamic deep brain stimulation for treatment-refractory Tourette syndrome: two-year outcome.

BACKGROUND: Eighteen patients with severe and refractory Tourette syndrome (TS) underwent bilateral thalamic deep brain stimulation (DBS). OBJECTIVE: To assess the long-term outcome on tics, behavioral symptoms, and cognitive functions in the largest case series of thalamic DBS for TS to date. METHODS: In this prospective cohort study, 15 of the original 18 patients were evaluated before and after surgery according to a standardized protocol that included both neuropsychiatric and neuropsychological assessments. RESULTS: In addition to marked reduction in tic severity (p = 0.001), 24-month follow-up ratings showed improvement in obsessive-compulsive symptoms (p = 0.009), anxiety symptoms (p = 0.001), depressive symptoms (p = 0.001), and subjective perception of social functioning/quality of life (p = 0.002) in 15 of 18 patients. There were no substantial differences on measures of cognitive functions before and after DBS. CONCLUSIONS: At 24-month follow-up, tic severity was improved in patients with intractable Tourette syndrome (TS) who underwent bilateral thalamic deep brain stimulation. Available data from 15 of 18 patients also showed that neuropsychiatric symptoms were improved and cognitive performances were not disadvantaged. Controlled studies on larger cohorts with blinded protocols are needed to verify that this procedure is effective and safe for selected patients with TS. LEVEL OF EVIDENCE: This study provides class IV evidence that bilateral thalamic deep brain stimulation reduces global tic severity measured 24 months after implantation in patients with severe intractable Tourette syndrome.

Adults with Tourette's syndrome with and without attention deficit hyperactivity disorder.

OBJECTIVE: Comorbidity between Tourette's syndrome (TS) and attention deficit hyperactivity disorder (ADHD) is high. In children, those with both TS+ADHD fare less well than those with TS-only on measures of both psychopathology and behaviour. The objective of this study was to document such measures in adult patients. METHOD: Eighty adults with TS-only were compared to 64 with TS+ADHD using a clinical interview and standardised measures of depression, anxiety and obsessionality. RESULTS: The two groups were no different on measures of TS severity. TS+ADHD patients had significantly more depression, anxiety, obsessive-compulsive behaviour and maladaptive behaviours than patients with TS-only. There were also significant differences in the incidence of copro- and echo-phenomena and family history of ADHD. CONCLUSION: The finding of increased overall behavioural difficulties and psychopathology in adult patients with TS+ADHD when compared with TS-only is in agreement with previous findings in children with TS. Appropriate treatment of ADHD in TS patients during childhood may prevent many behavioural problems in adulthood.

Gilles de la Tourette syndrome in pregnancy: a retrospective series.

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

The Gilles de la Tourette syndrome-quality of life scale (GTS-QOL): development and validation.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a chronic neuropsychiatric disorder which has a significant detrimental impact on the health-related quality of life (HR-QOL) of patients. However, no patient-reported HR-QOL measures have been developed for this population. OBJECTIVE: The development and validation of a new scale for the quantitative assessment of HR-QOL in patients with GTS. METHODS: In stage 1 (item generation), a pool of 40 potential scale items was generated based on interviews with 133 GTS outpatients, literature review, and consultation with experts. In stage 2 (scale development), these items were administered to a sample of 192 GTS outpatients. Standard statistical methods were used to develop a rating scale satisfying criteria for acceptability, reliability, and validity. In stage 3 (scale evaluation), the psychometric properties of the resulting scale were tested in a second sample of 136 subjects recruited through the UK-Tourette Syndrome Association. RESULTS: Response data analysis and item reduction methods led to a final 27-item GTS-specific HR-QOL scale (GTS-QOL) with four subscales (psychological, physical, obsessional, and cognitive). The GTS-QOL demonstrated satisfactory scaling assumptions and acceptability; both internal consistency reliability and test-retest reliability were high (Cronbach alpha > or =0.8 and intraclass correlation coefficient > or =0.8); validity was supported by interscale correlations (range 0.5-0.7), confirmatory factor analysis, and correlation patterns with other rating scales and clinical variables. CONCLUSIONS: The Gilles de la Tourette syndrome (GTS)-specific health-related quality of life (HR-QOL) scale (GTS-QOL) is proposed as a new disease-specific patient-reported scale for the measurement of HR-QOL in patients with GTS, taking into account the complexity of the clinical picture of GTS.

Anti-basal ganglia antibodies and Tourette's syndrome: a voxel-based morphometry and diffusion tensor imaging study in an adult population.

Anti-basal ganglia antibodies (ABGAs) have been suggested to be a hallmark of autoimmunity in Gilles de la Tourette's syndrome (GTS), possibly related to prior exposure to streptococcal infection. In order to detect whether the presence of ABGAs was associated with subtle structural changes in GTS, whole-brain analysis using independent sets of T(1) and diffusion tensor imaging MRI-based methods were performed on 22 adults with GTS with (n = 9) and without (n = 13) detectable ABGAs in the serum. Voxel-based morphometry analysis failed to detect any significant difference in grey matter density between ABGA-positive and ABGA-negative groups in caudate nuclei, putamina, thalami and frontal lobes. These results suggest that ABGA synthesis is not related to structural changes in grey and white matter (detectable with these methods) within frontostriatal circuits.

Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: the surgery and stimulation.

BACKGROUND: There have been several reports of successful deep brain stimulation (DBS) for the treatment of severe Gilles de la Tourette syndrome (GTS). METHOD: 18 cases of GTS who were resistant to at least 6 months of standard and innovative treatments, as well as to psychobehavioural techniques, underwent DBS. DBS was placed bilaterally in the centromedian-parafascicular (CM-Pfc) and ventralis oralis complex of the thalamus. Patients were evaluated after surgery, with immediate and formal assessments at least every 3 months, including "on-off" and "sham off" in the first nine patients. RESULTS: All patients responded well to DBS, although to differing degrees. The duration of follow-up assessments ranged from 3 to 18 months. The comorbid symptoms of obsessive-compulsive behaviour, obsessive-compulsive disorder, self-injurious behaviours, anxiety and premonitory sensations decreased after treatment with DBS. There were no serious permanent adverse effects. CONCLUSIONS: DBS is a useful and safe treatment for severe GTS. The results of ours and previous DBS reports suggest that the CM-Pfc and ventralis oralis complex of the thalamus may be a good DBS target for GTS.

Schizotypal personality traits in Gilles de la Tourette syndrome.

OBJECTIVES: Gilles de la Tourette syndrome (GTS) is a chronic tic disorder associated with comorbid psychopathology, including obsessionality, affective instability and attention-deficit hyperactivity disorder. Evidence linking GTS with schizophrenia-like symptoms is limited and equivocal, despite a common putative substrate involving dopaminergic dysfunction within frontostriatal circuits. The aim of this study was to quantify the prevalence of schizotypal traits in GTS and to detail the relationship between schizotypy and comorbid psychopathology. MATERIALS AND METHODS: A total of 102 subjects with GTS were evaluated using the Schizotypal Personality Questionnaire and standardized neurological and psychiatric rating scales. The predictive interrelation between schizotypy, tic-related symptoms and psychiatric comorbidities was investigated using correlation and multiple regression analyses. RESULTS: In our clinical population, 15% of the subjects were diagnosed with the schizotypal personality disorder according to the DSM-IV criteria. The strongest predictors of schizotypy were obsessionality and anxiety ratings. The presence of multiple psychiatric comorbidities correlated positively with schizotypy scores. CONCLUSIONS: Schizotypal traits are relatively common in patients with GTS, and reflect the presence of comorbid psychopathology, related to the anxiety spectrum. In particular, our preliminary results are consistent with a shared neurochemical substrate for the mechanisms underpinning tic expression, obsessionality and specific schizotypal traits.

An individual with Gilles de la Tourette syndrome and Smith-Magenis microdeletion syndrome: is chromosome 17p11.2 a candidate region for Tourette syndrome putative susceptibility genes?

This is the first published case description in the current literature of the association of definite Gilles de la Tourette syndrome (GTS) and the Smith-Magenis syndrome (SMS), both confirmed by DSM-IV-TR criteria and molecular cytogenetic analysis, respectively. The co-occurrence of GTS, SMS and their common behavioural/neuropsychiatric abnormalities should warrant further genetic investigation of chromosome 17p11.2 deletion site as it may be a promising region for containing a gene(s) of aetiological importance in the development of the GTS phenotype. Alternatively, the co-occurrence may be due to the common endophenotypic mechanisms shared by these disorders, rather than being specific for GTS that could be explored using strategies of quantitative trait loci - endophenotype-based approach. Research into this genomic region may also benefit psychiatric genetic research in enhancing understanding of the biological and molecular underpinnings of common behavioural problems that are seen in both GTS and SMS. This would lead to advancement in neurobehavioural/neuropsychiatric genetics which will help in further explaining the broader perspective of gene-brain-behaviour interrelationships.

Beck Depression Inventory is a useful screening tool for major depressive disorder in Gilles de la Tourette syndrome.

This study determined the prevalence of and factors associated with comorbid major depressive disorder (MDD) in patients with Gilles de la Tourette syndrome (GTS). How a simple self-report instrument, the Beck Depression Inventory (BDI), correlates with clinical assessment of comorbid MDD in this population was assessed. In a continuous sample of 114 adult patients with GTS, assessed clinically using the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, 26 (23%) patients met criteria for MDD; more severe tics as measured with the Yale Global Tic Severity Scale, conduct disorder in childhood or higher age at the time of assessment were associated with MDD. The BDI score had a high negative predictive value for diagnosis of MDD, but a low positive predictive value. Using the BDI as a screening tool for comorbid MDD in patients with GTS is suggested.

Soluble adhesion molecules in Gilles de la Tourette's syndrome.

To investigate the immune-mediated response in TS, and its relationship with streptococcal infection, we measured serum levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with TS, compared to healthy and diseased controls. Soluble VCAM-1 and sE-selectin were significantly elevated in children and adults with TS, and sVCAM-1 was higher among anti-basal ganglia antibodies (ABGA)-positive adults with TS. No correlation of adhesion molecule levels to clinical severity or anti-streptococcal antibodies was observed. Children with Sydenham's chorea and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) showed an increased level of sICAM-1, but not sVCAM-1 and sE-selectin. These results provide initial evidence for a role of adhesion molecules and systemic inflammation in TS, and support the hypothesis of an ongoing immune-mediated process in this condition.