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Effects of serotonergic neuromodulation on behavioural recovery and motor network plasticity after cortical ischemic stroke: a longitudinal, placebo-controlled study

Applicant Wiest Roland
Number 160107
Funding scheme Project funding (Div. I-III)
Research institution Universitätsinstitut für Diagnostische, Interventionelle & Pädiatrische Radiologie Inselspital
Institution of higher education University of Berne - BE
Main discipline Neurology, Psychiatry
Start/End 01.01.2016 - 31.12.2019
Approved amount 429'000.00
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All Disciplines (2)

Discipline
Neurology, Psychiatry
Neurophysiology and Brain Research

Keywords (5)

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

Lay Summary (German)

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

Responsible applicant and co-applicants

Employees

Publications

Publication
Early prediction of long-term tactile object recognition performance after sensorimotor stroke
Abela Eugenio, Missimer John H., Pastore-Wapp Manuela, Krammer Werner, Wiest Roland, Weder Bruno J. (2019), Early prediction of long-term tactile object recognition performance after sensorimotor stroke, in Cortex, 115, 264-279.
Relating Acute Lesion Loads to Chronic Outcome in Ischemic Stroke–An Exploratory Comparison of Mismatch Patterns and Predictive Modeling
Habegger Simon, Wiest Roland, Weder Bruno J., Mordasini Pasquale, Gralla Jan, Häni Levin, Jung Simon, Reyes Mauricio, McKinley Richard (2018), Relating Acute Lesion Loads to Chronic Outcome in Ischemic Stroke–An Exploratory Comparison of Mismatch Patterns and Predictive Modeling, in Frontiers in Neurology, 9, 1-11.

Collaboration

Group / person Country
Types of collaboration
Radiology Department, Kantonsspital St. Gallen, 9007 St. Gallen Switzerland (Europe)
- Research Infrastructure
- Exchange of personnel
Department of Neurology, University Hospital Inselspital, 3010 Bern Switzerland (Europe)
- Research Infrastructure
Support Center for Advanced Neuroimaging, Institute for Diagnostic and Interventional Neuroradiology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
OHBM Alpine Chapter Meeting Individual talk A multimodal approach to characterize finger movement patterns in an active exploration task using a data glove and fMRI: results of healthy subjects serving as a control group for the CISS (Cortical Ischemic Stroke and Serotonin) study. OHBM Alpine Chapt 09.11.2018 Innsbruck, Austria Wiest Roland; Krammer Werner;
3rd Alpine Chapter Symposium Poster Investigating learning, fatigue and dexterity aspects of repeated left and right hand object manipulation task through glove data in healthy controls 03.11.2017 Bern, Switzerland Wiest Roland; Krammer Werner; Habegger Simon;
EAN 2017 Individual talk Changes in effective connectivity in the sensorimotor network after a single dose of Escitalopram evaluated by Dynamic Causal Modelling for fMRI 24.06.2017 Amsterdam, Netherlands Krammer Werner; Wiest Roland;
OHBM conference, Geneva, June 2016 Poster Long-term tactile object recognition after cortical sensorimotor stroke. OHBM conference 26.06.2016 Geneva, Switzerland Krammer Werner; Wiest Roland; Kaegi Georg;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Brain Week 2019 Talk 11.03.2019 Bern, Switzerland Wiest Roland;


Associated projects

Number Title Start Funding scheme
118018 The significance of sensory function for the recovery of hand paresis after ischemic stroke 01.01.2008 Project funding (Div. I-III)
170060 Stroke treatment goes personalized: Gaining added diagnostic yield by computer-assisted treatment selection (the STRAY-CATS project) 01.10.2017 Project funding (Div. I-III)
118018 The significance of sensory function for the recovery of hand paresis after ischemic stroke 01.01.2008 Project funding (Div. I-III)

Abstract

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.
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