Tourette Syndrome Research Highlights from 2017 [version 1; referees: 3 approved]

This is the fourth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2017 relevant to Tourette syndrome and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The highlights from 2018 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the Tics collection on F1000Research

Tourette syndrome research highlights from 2019

This is the sixth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2019 relevant to Tourette syndrome and other tic disorders. The highlights from 2020 is being drafted on the Authorea online authoring platform; readers are encouraged to add references or give feedback on our selections comments feature on this page. After the calendar year ends, this article is submitted as the annual update for the Tics collection F1000Research

Distinct risk factors for obsessive and compulsive symptoms in chronic schizophrenia

BACKGROUND: Obsessive-compulsive disorder (OCD) is common in clozapine-treated patients although the actual prevalence, phenomenology and risk factors remain unclear. The aim of the present study was to address the three aforementioned questions. METHODS: The electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined. RESULTS: OCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p = 0.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean = 5.1; SD = 3.6) correlated with length of clozapine treatment (r = 0.21; p = 0.026), and obsessing factor (mean = 4.8; SD = 3.6) correlated with psychosis severity (r = 0.59; p = 0.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plasma levels, after correcting for psychosis severity. CONCLUSIONS: Screening for OCD in clozapine patients, and probably in those treated with structurally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients

Motor Timing in Tourette Syndrome: The Effect of Movement Lateralization and Bimanual Coordination

The study of motor timing informs on how temporal information integrates with motor acts. Cortico-basal ganglia and cortico-cerebellar circuits control this integration, whereas transcallosal interhemispheric connectivity modulates finely timed lateralized or bimanual actions. Motor timing abilities are under-explored in Tourette syndrome (TS). We adopted a synchronization-continuation task to investigate motor timing in sequential movements in TS patients. We studied 14 adult TS patients and 19 age-matched healthy volunteers. They were asked to tap in synchrony with a metronome cue (SYNC) and then, when the tone stopped, to keep tapping, maintaining the same rhythm (CONT). We tested both a sub-second and a supra-second inter-stimulus interval between the cues. Subjects randomly performed a single-hand task with the right hand and a bimanual task using both hands simultaneously wearing sensor-engineered gloves. We measured the temporal error and the interval reproduction accuracy index. We also performed MRI-based diffusion tensor imaging and probabilistic tractography of inter-hemispheric corpus callosum (CC) connections between supplementary motor areas (SMA) and the left SMA-putamen fiber tract. TS patients were less accurate than healthy individuals only on the single-hand version of the CONT task when asked to reproduce supra-second time interval. Supra-second time processing improved in TS patients in the bimanual task, with the performance of the right hand on the bimanual version of the CONT task being more accurate than that of the right hand on the single-hand version of the task. We detected a significantly higher fractional anisotropy (FA) in both SMA-SMA callosal and left-sided SMA-putamen fiber tracts in TS patients. In TS patients only, the structural organization of transcallosal connections between the SMAs and of the left SMA-putamen tract was higher when the motor timing accuracy of the right hand on the bimanual version of the task was lower. Abnormal timing performance for supra-second time processing is suggestive of a defective network inter-connecting the striatum, the dorsolateral prefrontal cortex and the SMA. An increase in accuracy on the bimanual version of the CONT task may be the result of compensatory processes linked to self-regulation of motor control, as witnessed by plastic rearrangement of inter-hemispheric and cortical-subcortical fiber tracts

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

BACKGROUND: Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. METHODS: We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. RESULTS: Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control. CONCLUSIONS: The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.This work was supported by a Wellcome Trust programme grant to T.W.R. (089589/z/09/z). The Behavioral and Clinical Neuroscience Institute is jointly funded by the MRC and the Wellcome Trust (G00001354).This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/ijnp/pyv01

A cross sectional study of impact and clinical risk factors of antipsychotic-induced OCD.

A large proportion of schizophrenia patients treated with second generation antipsychotics will develop Obsessive Compulsive Disorder (OCD). However, there are few studies about the impact of this comorbidity and who is at higher risk. In this study of clozapine-treated patients, we aimed to determine the impact on outcome of clozapine-induced OCD, as well as the clinical and sociodemographic risk factors related to OCD-onset in clozapine patients. We had strict and novel inclusion criteria to minimise mis-identification of cases. The Obsessive-Compulsive Inventory-Revised (OCI-R) was used to divide 231 clozapine-treated patients into extreme cases of OCD (OCI  ≥ 24 or checking subscale ≥6) versus non-OCD (OCI <15 and checking subscale <4). The Global Assessment of Functioning (GAF), short version of Warwick-Edinburgh Wellbeing scale and Clinical Global Impression for schizophrenia (CGI) scales were used to determine outcome. Socio-demographic information was used to identify the risk factors for OCD development. We found that schizophrenia patients with OCD symptoms had a significantly lower patient rated wellbeing scores (p < 0.001) only (no difference in clinician rated wellbeing scores), higher CGI positive (p < 0.01) and higher CGI depressive scores (p < 0.05). The only risk factors that reached significance level were higher treatment dose (p < 0.01) and younger paternal age at birth (p < 0.05). There is scope for future studies based on e.g. imaging and genetic studies to further investigate causality, and in improving clinician screening for OCD.MB was supported by her studentship from the Mental Health Research UK. YW is supported by the Association Française du syndrome de Gilles de la Tourette, Foundation de recherche Medicale and Dystonia Foundation for Medical Research (USA). NF has held research or networking grants from the ECNP, UK NIHR, EU H2020, has accepted paid speaking engagements including travel and hospitality in industry supported symposia for Abbott, SunPharma, has accepted travel and hospitality expenses from the BAP, ECNP, RCPsych, CINP, receives payment from Taylor and Francis for editorial duties. TWR was supported by Wellcome Trust Senior Investigator Award 104631/X/14/Z. EF received intramural funding from CPFT/NIHR-CRN supported setting the database

Distinct risk factors for obsessive and compulsive symptoms in chronic schizophrenia

Objective: Obsessive-compulsive disorder (OCD) is common in clozapine-treated patients alt-hough the actual prevalence, phenomenology and risk factors remain unclear. The aim of the pre-sent study was to address the three aforementioned questions. Method: The electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined. Results: OCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p=.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean=5.1; SD=3.6) correlated with length of clozapine treatment (r=.21; p=.026), and obsessing factor (mean=4.8; SD=3.6) correlated with psychosis severity (r=.59; p=.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plas-ma levels, after correcting for psychosis severity. Conclusion: Screening for OCD in clozapine patients, and probably in those treated with structur-ally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients.Dr. Fernandez-Egea was supported by 2009 Young investigator award and intramural funding from CPFT/NIHR-CRN supported setting the database. Prof. Bernardo is funded by the Spanish Ministry of Science and Education, the Spanish Ministry of Economy and Competiveness, Centro de Inves-tigación Biomédica en Red de Salud Mental (CIBERSAM), from the Government of Catalonia, Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014SGR441), from the Foundation European Group for Research In Schizophrenia (EGRIS) , and from the 7th Framework Program of the European Union. Dr. Y Worbe is supported by Association Française du syndrome de Gilles de la Tourette, Founda-tion de recherche Medicale and Dystonia Foundation for Medical Research (USA). Prof. TW Robbins' research is funded by a Wellcome Senior Investigator Award (104631/Z/14/Z). Work was completed at the Behavioural and Clinical Neuroscience Institute, which was supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354)

Specific effect of a dopamine partial agonist on counterfactual learning: evidence from Gilles de la Tourette syndrome.

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication