"Manual Dexterity and Oculomotor Control in Schizophrenia" (MADOCS)

University of Paris 5 - Rene Descartes, Institut National de la Santé Et de la Recherche Médicale, France

The investigators recently showed that visuomotor integration was significantly altered in schizophrenic patients during: (i) a grip force task (Teremetz et al., 2014), and (ii) a saccadic paradigm (oculomotor task)(Amado et al., 2008). Given this findings, the investigators propose a combined study of oculomotor and grip force control to better characterize the sensorimotor integration deficit. This approach may allow for identification of behavioural biomarkers of vulnerability to develop schizophrenia.

1 - Scientific background and rational Use of sensory cues is essential for execution and correction of voluntary movements. The motor areas and their regulation is of special interest in patients with schizophrenia as there is clear evidence of motor abnormalities independent of the effects of antipsychotic medication, even before the onset of the disorder. Sensorimotor abnormalities have been proposed as a valid endophenotype in schizophrenia. Our global objective is to study and provide vulnerability markers for schizophrenia. Control of manual dexterity will be assessed by a force sensor (Power Grip Manipulandum, PGM) Oculomotor movements during behavioral task will be recorded using a video-oculography device The involvement of cortical inhibition in this volitional inhibition task will be studied by neuronavigation guided TMS coupled to EMG recording 2 - Description of the project methodology There is strong evidence for schizophrenia being a neuro-developmental disorder (Rapoport et al., 2005). It has been shown, for many years, that patients with schizophrenia exhibit abnormal patterns of sensorimotor integration (Manschreck et al., 1982), which is the capacity to integrate different sensory stimuli into appropriate motor actions. It is clinically relevant, in terms of early diagnosis and prevention, whether deficient sensorimotor integration is present in the prodromal phase of schizophrenia, and whether this constitutes a vulnerability marker for the disease. Our global objective is to study the interactions and related substratum of oculomotor movements during force control task. The secondary objectives: (i) To show that increased motor noise is indeed present in schizophrenia. (ii) To show by TMS that cortical excitability in the primary motor cortex (M1) is task-modulated and decreased in schizophrenia. (iii) Assess the role of deficient cortical inhibition in these behavioral deficits To this end, three different groups of subjects will be studied: schizophrenic patients, non-affected siblings, ultra high risk patients, non-treated schizophrenic patients and healthy control subjects.

The involvement of cortical inhibition in this volitional inhibition task will be studied by neuronavigation guided TMS coupled to EMG recording

Inclusion Criteria: All groups: 18>yrs<50 Medical visit completed Visual acuity (9/10 for each eye or corrected) Provided written informed consent Group of patient suffering from schizophrenia: 4. DSM-IV-TR diagnostic criteria for schizophrenia 5. Treatment: stable atypical anti-psychotic medication for >3 months prior to the study Group of UHR patient: 6. 18>yrs<30 7. Fulfill at risk criteria of CAARMS diagnostic tool Exclusion Criteria: • All groups: IQ<70, Contraindications for TMS protocol: no previous history of neurosurgery or seizures or 1st degree relative with history of seizures, heart disease, drug abuse or addiction in the last 12 months, medications that lower seizure threshold including clozapine, bupropion, méthadone or theophylline. Metallic implant in head (except dental fillings) Pacemaker, or other electronic implanted devices Central neurological disease: parkinsonism, x Severe heart attack Instable clinical state (e.g. stroke) Previous history of drug abuse lasting more than 5 years or during the last year Life event with a moderate to severe impact Caffeine intake in the last two hours preceding visuomotor assessment • Groups of Siblings and Healthy controls: No previous history of psychiatric disease, psychotic spectrum disorder (according to DIGS 3.0) No previous history of antipsychotic medication (entire life) • Groups of UHR patient: Chlorpromazine dose >100mg over more than 12 weeks No previous history of autism spectrum disorder, bipolar disorder or diagnozed schizophrenia (according to DSM-IV-TR criteria), isolated anxiety disorders (e.g. social phobia, agoraphobia)

Teremetz M, Amado I, Bendjemaa N, Krebs MO, Lindberg PG, Maier MA. Deficient grip force control in schizophrenia: behavioral and modeling evidence for altered motor inhibition and motor noise. PLoS One. 2014 Nov 4;9(11):e111853. doi: 10.1371/journal.pone.0111853. eCollection 2014.

Amado I, Landgraf S, Bourdel MC, Leonardi S, Krebs MO. Predictive saccades are impaired in biological nonpsychotic siblings of schizophrenia patients. J Psychiatry Neurosci. 2008 Jan;33(1):17-22.