A key aspect of higher cognitive function is the ability to switch rapidly and efficiently between alternative modes of response where this is appropriate behaviourally. Such suppression appears to be highly dependent upon the integrity of the prefrontal cortex, yet other cortical areas are likely to be necessary to implement response switching. Language switching in bilingual speakers is a clear example of a task in which response switching is required. Functional brain imaging studies have demonstrated parietal cortex activation during repeated language switching within a translation task. Here we used event-related dense-sensor EEG recording techniques to examine the time course of language switching during a visually cued naming task in which bilingual participants named digits in either their first or second language. Switch-related modulation of ERP components was evident over parietal and frontal cortices, and in the latter case showed an asymmetry across first and second languages. Correspondence with a frontal ERP component found when suppressing manual responding in a Go/No-Go reaction time task may imply that similar inhibitory mechanisms are involved in both response suppression and language switching.

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SummaryChildren with neurological disorders may follow unique developmental trajectories whereby they undergo compensatory neuroplastic changes in brain structure and function that help them gain control over their symptoms [1–6]. We used behavioral and brain imaging techniques to investigate this conjecture in children with Tourette syndrome (TS). Using a behavioral task that induces high levels of intermanual conflict, we show that individuals with TS exhibit enhanced control of motor output. Then, using structural (diffusion-weighted imaging) brain imaging techniques, we demonstrate widespread differences in the white matter (WM) microstructure of the TS brain that include alterations in the corpus callosum and forceps minor (FM) WM that significantly predict tic severity in TS. Most importantly, we show that task performance for the TS group (but not for controls) is strongly predicted by the WM microstructure of the FM pathways that lead to the prefrontal cortex and by the functional magnetic resonance imaging blood oxygen level-dependent response in prefrontal areas connected by these tracts. These results provide evidence for compensatory brain reorganization that may underlie the increased self-regulation mechanisms that have been hypothesized to bring about the control of tics during adolescence.

SummaryTourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4–7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8–11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.

We investigated the extent to which a common neural mechanism is involved in task set-switching and response withholding, factors that are frequently confounded in task-switching and go/no-go paradigms. Subjects' brain activity was measured using event-related electrical potentials (ERPs) and event-related functional MRI (fMRI) neuroimaging in separate studies using the same cognitive paradigm. Subjects made compatible left/right keypress responses to left/right arrow stimuli of 1000 msec duration; they switched every two trials between responding at stimulus onset (GO task-green arrows) and stimulus offset (WAIT task-red arrows). With-holding an immediate response (WAIT vs. GO) elicited an enhancement of the frontal N2 ERP and lateral PFC activation of the right hemisphere, both previously associated with the "no-go" response, but only on switch trials. Task-switching (switch vs. nonswitch) was associated with frontal N2 amplification and right hemisphere ventrolateral PFC activation, but only for the WAIT task. The anterior cingulate cortex (ACC) was the only brain region to be activated for both types of task switch, but this activation was located more rostrally for the WAIT than for the GO switch trials. We conclude that the frontal N2 ERP and lateral PFC activation are not markers for withholding an immediate response or switching tasks per se, but are associated with switching into a response-suppression mode. Different regions within the ACC may be involved in two processes integral to task-switching: processing response conflict (rostral ACC) and overcoming prior response suppression (caudal ACC).

BackgroundTourette syndrome (TS) is a neurodevelopmental condition characterised by chronic motor and vocal tics affecting up to 1% of school-age children and young people and is associated with significant distress and psychosocial impairment.ObjectiveTo conduct a systematic review of the benefits and risks of pharmacological, behavioural and physical interventions for tics in children and young people with TS (part 1) and to explore the experience of treatment and services from the perspective of young people with TS and their parents (part 2).Data SourcesFor the systematic reviews (parts 1 and 2), mainstream bibliographic databases, The Cochrane Library, education, social care and grey literature databases were searched using subject headings and text words for tic* and Tourette* from database inception to January 2013.Review/research methodsFor part 1, randomised controlled trials and controlled before-and-after studies of pharmacological, behavioural or physical interventions in children or young people (aged < 18 years) with TS or chronic tic disorder were included. Mixed studies and studies in adults were considered as supporting evidence. Risk of bias associated with each study was evaluated using the Cochrane tool. When there was sufficient data, random-effects meta-analysis was used to synthesize the evidence and the quality of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. For part 2, qualitative studies and survey literature conducted in populations of children/young people with TS or their carers or in health professionals with experience of treating TS were included in the qualitative review. Results were synthesized narratively. In addition, a national parent/carer survey was conducted via the Tourettes Action website. Participants included parents of children and young people with TS aged under 18 years. Participants (young people with TS aged 10–17 years) for the in-depth interviews were recruited via a national survey and specialist Tourettes clinics in the UK.ResultsFor part 1, 70 studies were included in the quantitative systematic review. The evidence suggested that for treating tics in children and young people with TS, antipsychotic drugs [standardised mean difference (SMD) –0.74, 95% confidence interval (CI) –1.08 to –0.41;n = 75] and noradrenergic agents [clonidine (Dixarit®, Boehringer Ingelheim) and guanfacine: SMD –0.72, 95% CI –1.03 to –0.40;n = 164] are effective in the short term. There was little difference among antipsychotics in terms of benefits, but adverse effect profiles do differ. Habit reversal training (HRT)/comprehensive behavioural intervention for tics (CBIT) was also shown to be effective (SMD –0.64, 95% CI –0.99 to –0.29;n = 133). For part 2, 295 parents/carers of children and young people with TS contributed useable survey data. Forty young people with TS participated in in-depth interviews. Four studies were in the qualitative review. Key themes were difficulties in accessing specialist care and behavioural interventions, delay in diagnosis, importance of anxiety and emotional symptoms, lack of provision of information to schools and inadequate information regarding medication and adverse effects.LimitationsThe number and quality of clinical trials is low and this downgrades the strength of the evidence and conclusions.ConclusionsAntipsychotics, noradrenergic agents and HRT/CBIT are effective in reducing tics in children and young people with TS. The balance of benefits and harms favours the most commonly used medications: risperidone (Risperdal®, Janssen), clonidine and aripiprazole (Abilify®, Otsuka). Larger and better-conducted trials addressing important clinical uncertainties are required. Further research is needed into widening access to behavioural interventions through use of technology including mobile applications (‘apps’) and video consultation.Study registrationThis study is registered as PROSPERO CRD42012002059.FundingThe National Institute for Health Research Health Technology Assessment programme.

Tourette syndrome (TS) is a neurological disorder characterized by vocal and motor tics. TS is associated with impairments in behavioral inhibition, dysfunctional signaling of the inhibitory neurotransmitter GABA, and alterations in the balance of excitatory and inhibitory influences within brain networks implicated in motor learning and the selection of actions. We review evidence that increased control over motor outputs, including the suppression of tics, may develop during adolescence in TS and be accompanied by compensatory, neuromodulatory, alterations in brain structure and function. In particular, we argue that increased control over motor outputs in TS is brought about by local increases in 'tonic' inhibition that lead to a reduction in the 'gain' of motor excitability.