Enhancement of learning associated neural plasticity by SSRIs

Background: Conclusive evidence states that the serotonergic system, a neurotransmitter system in the brain, mediates neuroplasticity, the ability of the brain to adapt to new circumstances, from early embryonic development until brain maturation in adulthood. This study aims to demonstrate that selective serotonin reuptake inhibitors (SSRIs), a class of drugs used for the treatment of depression and anxiety disorders, enhance neuroplasticity in the human brain. This will contribute our understanding of the mechanism of action of therapy with SSRIs. Objectives: (1) To prove a positive influence of SSRIs on brain structural remodeling during learning, reflected by enhancements of gray and white matter microstructure, connectivity and functionality in brain regions involved in learning processes. (2) To show that this effect is topologically specific, that is 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 Magnet resonance imaging (MRI) scanning sessions: 1. baseline, at study entry, 2. after 3 weeks of facial/emotional (n=40) or Chinese charactermeaning 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 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 increased synaptic activity, which reflects the swelling of astrocytes, cells involved in the maintenance of neuronal functioning. 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 our 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.

Several studies during the last decades have revealed the brain's remarkable capability to adapt functionally, structurally, and adaptively. These changes depending on their use are called neuroplasticity. This study investigates functional and microstructural changes in the brain during learning when administered Selective Serotonin Reuptake Inhibitors (SSRIs). Learning has been shown to alter the structure of neurons in brain regions associated with memory. Here, the brain messenger serotonin controls the maturation and formation of nerve cells and their connections both during brain development and in adulthood. It is known that patients with depression and anxiety disorders show altered maturation and shaping of their nerve cells in brain regions that control emotions. These disorders are very often treated with SSRIs. These increase the serotonin content in synapses, the interfaces between two nerve cells, which is the therapeutic effect of these drugs. The best treatment for these patients is the administration of SSRIs in combination with psychotherapy. It is believed that the effect of psychotherapy is to unlearn maladaptive behaviors and feelings. This study mimics this therapeutic process with specific daily learning tasks and the administration of SSRIs and examines the changes in the shape of neurons in the brain that occur. Analyses revealed that SSRIs modulate insula activation, which in turn demonstrates the translation of relearning as a mechanism of SSRIs in humans. A detailed examination of the neurochemical basis further showed that SSRIs indirectly modulate the glutamatergic and GABAergic systems, which in turn promotes neuroplastic processes. A higher baseline GABA level in the hippocampus was also found to be associated with better recall performance in an associative learning paradigm. Functional network analysis using 3 Tesla fMRI revealed that SSRIs influence connectivity changes induced by semantic learning. More specifically, escitalopram intake facilitates content-dependent network adaptations during relearning. Enhanced neuroplasticity may therefore be the main underlying mechanism in psychiatric therapies. The results of this study could add to the knowledge of how best to treat depression. Through the investigations carried out in the framework of the study, it is possible to create a model of depression treatment and to visualize changes in the brain that take place in the process.