Role of the Noradrenergic System in the Regulation of Learning Dynamics: Evaluation of the Effect of a Low-dose Selective Noradrenaline Reuptake Inhibitor (NOISYXETINE)

Centre Hospitalier St Anne160 enrolled

Overview

Administration of low-dose selective noradrenaline reuptake inhibitor (sNRI) (e.g. atomoxetine) to healthy subjects is a validated model of increasing cortical noradrenaline levels which, combined with computational modelling of behaviour, allows fine-grained analysis of the impact on learning processes of noradrenaline's fluctuations in the human cortex. The study goal is to characterize the modifications of certain cognitive processes and associated brain circuits under low-dose sNRI using validated computational learning models. The study will be interested in how subjects will modify their learning under the effect of the drug across two separate investigations; one utilizing in a stable evidence accumulation task and one utilising a changing evidence accumulation task. This approach will help to better understand the link between noradrenaline and accumulation of evidence in healthy subjects, and indirectly in some neuropsychiatric pathologies. The study is a single centre, double-blinded, randomized, placebo-controlled, cross-over study involving evaluable healthy adults separated in 2 cohorts: A for participants having the stable task and B for those having the changing one. Participants will then be randomized in a 1:1 ratio to one of the following treatment sequences: * Atomoxetine 40 mg - Placebo (Subgroups A1 or B1); * Placebo - Atomoxetine 40 mg (Subgroups A2 or B2).

Hundred and sixty healthy volunteers will be enrolled (80 / task) in 24 months. The maximum duration of participation for each subject is 51 days.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Enrollment

160

Conditions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 39 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Right-handed, assessed by the Edinburgh scale; * Written signed informed consent; * Subject covered by a social security regimen. Exclusion Criteria: * Pregnant, parturient or breastfeeding woman; * First-degree family history of axis I disorder (DSM-IV-TR), excepted unipolar mood and anxiety disorders with OCD; * Personal history of axis I disorder (DSM-IV-TR) in the 6 months preceding the study entry; * Dependence on a psychoactive substance in the 12 months preceding the study entry, excluding nicotine, any behavioural disorder incompatible with a 2-hour electroencephalographic recording; * Neuro/psychotropic treatment ongoing or stopped less than 1 month ago; * Personal history of neurological pathology (e.g.: congenital malformation, benign or malignant tumour, degenerative disease of the central nervous system (CNS), epilepsy, inflammatory or infectious disease of the CNS, etc.); * Personal history of chronic disease of infectious, neoplastic, vascular, dysimmune or inflammatory, metabolic or endocrine, degenerative or genetic aetiology. In particular, angle-closure glaucoma, pheochromocytoma, known high blood pressure or measured blood pressure greater than 140/90 mm Hg at baseline, congenital heart disease, known ischemic heart disease, known heart failure, supraventricular or ventricular heart rhythm disorder, nephropathy, known liver disease and any pathology likely to be aggravated by an increase in blood pressure; * Any medical treatment in the month preceding the study entry, apart from effective contraceptive treatment; * Subject deprived of liberty by a judicial or administrative decision; * Person subject to a legal protection measure or unable to express consent; * Known intolerance to atomoxetine; * Need to wear glasses and/or lenses to obtain normal vision; * Subject in an exclusion period or enrolled in an interventional study.

Outcomes

Primary Outcomes

Apparent Learning rate

Paired difference in the apparent learning rates (in both environmental contexts: stable task and changing task), between the sNRI (atomoxetine) and control (placebo) conditions. Apparent learning rate will be calculate with the following formula: αt=(vt- vt-(1) )/(xt- vt-1) according to Foucault and Meyniel (Foucault C, Meyniel F (2024) Two Determinants of Dynamic Adaptive Learning for Magnitudes and Probabilities. Open Mind : Discov Cogn Sci 8:615-638) The learning rate measures the amount of update of the learned value (from vt-(1 to vt) induced by the observation xt in proportion to its deviation from the previously learned value.