Enhancement of Learning Associated Neural Plasticity by Selective Serotonin Reuptake Inhibitors

Study Overview
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Brief Summary
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Background: Conclusive evidence states that the serotonergic system mediates neuroplasticity from early embryonic development until brain maturation in adulthood. This study aims to demonstrate that selective serotonin reuptake inhibitors (SSRIs) enhance learning-dependent neuroplasticity in vivo, hereby contributing to the investigators understanding of the mechanism of action of therapy with SSRIs. Objectives: To prove a positive influence of SSRIs on structural remodeling during learning, reflected by enhancements of gray and white matter microstructure, connectivity and functionality in brain regions involved in learning processes. To show that this effect is topologically specific, i.e. that enhancements of plasticity markers are found in different regions depending on their involvement during the performance of specific learning tasks. Study design: Randomized, double-blind, placebo-controlled, longitudinal mono-center study. 80 healthy subjects will undergo three MRI scanning sessions: 1. baseline, at study entry, 2. after 3 weeks of facial/emotional (n=40) or Chinese character-meaning learning (n=40) and 3. after 3 weeks learning of new associations under administration of an SSRI or placebo. Methods: MRI measurements will be performed on a 3 Tesla PRISMA MAGNETOM MR scanner. Changes in gray matter microstructure will be assessed using high-resolution structural MRI and analyzed with voxel-based morphometry (VBM). Diffusion tensor imaging (DTI) enables non-invasive investigation of neuroplasticity in the human brain based on the reduction in mean diffusivity associated with swelling of astrocytes after increased synaptic activity. Resting-state functional MRI (fMRI) will allow for the measurement of changes in functional coupling between brain regions, and fMRI during tasks will assess differential activity in brain regions during learning. Relevance and implications: This study aims to provide evidence that SSRIs facilitate cytoarchitectonical restructuring. In addition to expanding the investigators current knowledge on the trophic effects of SSRIs, the results of this study will also elucidate interactions between the serotonergic system and changes to neuronal networks during learning as well as their behavioral consequences. By probing the neurobiological correlates of the antidepressant and anti-anxiety effects of SSRIs, this study will provide a rationale for targeted interventions that harness the neuroplasticity enhancing properties of SSRIs to facilitate therapeutic processes.

Official Title
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Enhancement of Learning Associated Neural Plasticity by Selective Serotonin Reuptake Inhibitors

Conditions
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Ssri, Neuronal Plasticity

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Placebo
* Other: 3xMR scan (fMRI, DTI, strucutral MRI)
* Behavioral: Association learning paradigm
* Behavioral: Association re-learning paradigm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General health based on medical history, physical examination and structured clinical interview for DSM-IV (SCID) Willingness and competence to sign the informed consent form Right-handedness Non-smoker, and non-alcohol drinker Exclusion Criteria: Any medical, psychiatric or neurological illness Current or former substance abuse Any implant or stainless steel graft or any other contraindications for MRI First degree relatives with a history of psychiatric illness or substance abuse Color blindness, any Chinese language skills Failure to comply with the study protocol or to follow the instructions of the investigating team Lifetime use of SSRIs or related psychotropic agents Non-Caucasian

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SSRI treatment<br>Subjects will receive 21 days of 10mg escitalopram treatment while performing learning paradigms. | Drug: Escitalopram<br>* Tablet 10mg, 21 days<br>Other: 3xMR scan (fMRI, DTI, strucutral MRI)<br>* 3 Tesla PRISMA MAGNETOM MR scanner; performed at baseline, after 21 days of performing learning paradigms and after 21 days of drug/placebo treatment and re-learning paradigms<br>Behavioral: Association learning paradigm<br>* 21 daily internet-based sessions (20min) of learning associations (pairs) of stimuli<br>Behavioral: Association re-learning paradigm<br>* 21 daily internet-based sessions (20min) of learning new associations (pairs) of stimuli performed during escitalopram/placebo treatment<br>|
| Placebo Comparator: Placebo treatment<br>Subjects will receive 21 days of placebo treatment while performing learning paradigms. | Drug: Placebo<br>* Tablet, 21 days<br>Other: 3xMR scan (fMRI, DTI, strucutral MRI)<br>* 3 Tesla PRISMA MAGNETOM MR scanner; performed at baseline, after 21 days of performing learning paradigms and after 21 days of drug/placebo treatment and re-learning paradigms<br>Behavioral: Association learning paradigm<br>* 21 daily internet-based sessions (20min) of learning associations (pairs) of stimuli<br>Behavioral: Association re-learning paradigm<br>* 21 daily internet-based sessions (20min) of learning new associations (pairs) of stimuli performed during escitalopram/placebo treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gray matter volume | voxel based morphometry (T1 weighted MPRAGE sequence) | 21 days | 
| Mean diffusivity | diffusion tensor imaging | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BOLD signal | functional MRI (learning paradigms) | 21 days |