Project

Discipline

Cortical ischemic stroke; Serotoninergic neuromodulation; Neuroplasticity; Motor efficiency; Neurorehabilitation

Lead
Studien haben gezeigt, dass Medikamente welche die selektive Serotonin-Wiederaufnahme hemmen, einen positiven Einfluss auf die motorische Rehabilitation nach Schlaganfall haben. Die zugrunde liegenden Mechanismen der Erholung nach Störungen der Handfunktion sind nicht hinreichend geklärt. Diese Studie soll diese Fragen klären.
Lay summary
Titel des Forschungsprojekts Untersuchung medikamentös unterstützter Reorganisation des Gehirns bei Schlaganfallpatienten mit Störungen der Handfunktion: eine Placebo-kontrollierte Studie Effects of serotonergic neuromodulation on behavioural recovery and motor network plasticity after cortical ischemic stroke: a longitudinal, placebo-controlled study Inhalt und Ziele des Forschungsprojekts Es wird untersucht ob und wie das in der Schweiz bereits zugelassene Medikament Escitalopram (Cipralex ®) ein selektiver Serotonin-Wiederaufnahmehemmer, Einfluss auf die Erholung nach einem Schlaganfall hat. Ziel der Studie ist es herauszufinden, wie sich gewisse Regionen im Gehirn nach einem Schlaganfall verändern bzw. neu organisieren und ob die Veränderungen schneller sind, wenn sie medikamentös unterstützt werden. Mittels Magnetresonanztomographie (MRT) wird über verschiedene Zeitpunkte nach dem Schlaganfall die Veränderung im Gehirn sichtbar gemacht. Die Studiendauer beträgt neun Monate wobei insgesamt drei MRT- Untersuchungen stattfinden werden und monatlich die Handfunktion überprüft wird. Die Studie wird dazu beitragen, den neuromodulatorischen Effekt von Cipralex® bei Schlaganfallpatienten mit Störungen der Handfunktion besser zu verstehen. Wissenschaftlicher Kontext des Forschungsprojekts Die Studie ist so aufgebaut, das die Hälfte der Patienten Cipralex® erhält, die andere Hälfte erhält ein Placebo. Damit die Resultate nicht beeinflusst werden können, weiss weder der Patient noch der Arzt ob Cipralex® oder ein Placebo verabreicht wird.

Direct link to Lay Summary

Last update: 04.02.2016

Active participation

Active participation

Number	Title	Start	Funding scheme

Neuroplasticity, i.e. the human brain’s innate capacity to structurally remodel and functionally reorganize its neural networks, is essential for recovery of impaired sensorimotor function after focal ischemic injury. However, the potential for spontaneous recovery in the adult brain is limited and needs to be augmented through rehabilitative programs, e.g. intensive exercise, brain stimulation or pharmacologic neuromodulation.Clinical studies have shown that post-stroke recovery can be augmented by long-term administration of selective serotonin reuptake inhibitors (SSRI). Serotonin modulates excitatory glutamatergic neurotransmission and induces long-term potentiation (LTP), an important mediator of neuroplasticity that supports sensorimotor learning in the healthy brain and reorganization in the post-stroke perilesional cortex. Preliminary data indicate that a single dose of the SSRI escitalopram is sufficient to induce LTP-like effects in the motor cortex of healthy volunteers (measured by repetitive transcranial magnetic stimulation (rTMS)), and to increase the efficiency of large-scale functional connectivity networks engaged in tactile object manipulation ( measured with functional magnetic resonance imaging (fMRI)).We thus hypothesize that serotonergic neuromodulation might enhance post-stroke recovery through enlarged plasticity and processing efficiency along integrated neuronal networks, leading to reinforced connectivity and behavioral performance. To test this hypothesis, we aim to conduct a longitudinal, double-blind, placebo-controlled trial in two neurological centers. We aim to test the effect of a daily administered single dose of escitalopram over a three months period after cortical ischemic stroke to plasticity changes in the primary sensorimotor cortices (S1 and M1). We will apply behavioural measures of hand function, rTMS and advanced MRI techniques as outcome variables. At its core, our experimental protocol will investigate the relationship between (i) movement precision and effort, (ii) electrophysiological measures of LTP, (iii) task-based functional connectivity of the sensorimotor network, and (iv) perilesional grey matter morphology. We will measure hand function kinematics with video-based motion tracking, and movement-related elector-dermal responses to better understand the contribution of effort to hand function recovery and brain activation. Moreover, we intend to apply MR-Spectroscopy of the perilesional premotor cortex, guided by real-time fMRI analysis, as a tool to assess local glutamatergic transmission. Finally, measurements of plasma drug levels and determination of genetic polymorphisms of the escitalopram-metabolizing gene CYP2P19 and the blood-brain barrier transporter ABCB1 will help us to assess and control for interindividual variance in escitalopram bioavailability.We expect that SSRI-augmented neuroplasticity will lead to increased efficiency in the allocation of neuronal resources in the post-stroke brain, resulting in more precise and less effortful movements, facilitation of LTP-like phenomena, reduced extent of functional connectivity networks, increased grey matter volume of spared perilesional premotor cortex and possibly higher glutamate peaks in the same areas, as compared to placebo treatment.By combining standard and innovative methods, our study will provide mechanistic insight into the processes that drive cortical neuroplasticity in the post-stroke human brain. From a clinical perspective, results from our study are expected to provide a scientific rationale to select patients that might benefit from SSRI-augmented neurorehabilitation.