In this study the investigators want to test the hypotheses that, serotonergic neuromodulation increases perilesional neuroplasticity, leading to improved behavioural outcomes through a more efficient allocation of functional resources, greater structural reorganization and less remapping via alternative circuits.
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)).
The investigators 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 behavioural performance.
To test this hypothesis, the investigators aim to conduct a longitudinal, double blind, placebo-controlled trial in two neurological centers. The investigators aim to test the effect of a daily-administered single dose of Escitalopram over a three months period after cortical ischemic stroke to promote plasticity changes in the perilesional zone of primary sensorimotor cortices (S1 and M1). The investigators will apply behavioural measures of hand function, rTMS and advanced magnetic resonance (MR) imaging techniques as outcome variables.
The investigators will measure hand function kinematics with a data glove to better understand the contribution of effort to hand function recovery and brain activation. Moreover, the investigators intend to apply MR-Spectroscopy of the perilesional premotor cortex, guided by real-time fMRI analysis, as a tool to assess local glutamatergic transmission. Measurements of plasma drug levels and determination of genetic polymorphisms of the Escitalopram-metabolizing genes will help them to assess and control for interindividual variance in Escitalopram bioavailability.
The investigators 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, 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, this study will provide mechanistic insight into the processes that drive cortical neuroplasticity in the post-stroke human brain. From a clinical perspective, results from the study are expected to provide a scientific rationale to select patients that might benefit from SSRI-augmented neurorehabilitation.
- Placebo Drug
ARM 1: Kind: Experimental Label: Placebo Description: Treatment 2: Starting with Placebo 5mg/day at the baseline-visit (day 14 (+-7) post stroke) for 7 days followed by a weekly dosage of 5mg/day till target dose of Placebo 20mg/day. Subjects will remain on Placebo 20mg/day until visit 3 (day 90 (+-14) post stroke) followed by Placebo 10mg/day for one week.
- Serotonin Uptake Inhibitors Drug
Other Names: Escitalopram, Cipralex ARM 1: Kind: Experimental Label: Serotonin Uptake Inhibitors Description: Treatment 1: Starting with Escitalopram 5mg/day at the baseline-visit (day 14 (+-7) post stroke) for 7 days followed by a weekly dosage increase of 5mg/day till target dose of Escitalopram 20mg/day. Subjects will remain on Escitalopram 20mg/day until visit 3 (day 90 (+-14) post stroke) followed by dosage reduction of Escitalopram 10mg/day for one week.
- Allocation: Randomized
- Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
- Purpose: Supportive Care
- Endpoint: Efficacy Study
- Intervention: Parallel Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Effect of escitalopram on sensorimotor network||fMRI at month 9||No|
|Secondary||Imaging patterns of rs-fMRI||rs-fMRI (baseline, month 3, month 9)||No|
|Secondary||Imaging patterns of act-fMRI||act-fMRI, performance of tactile manipulation of objects (baseline, month 3, month 9)||Yes|
|Secondary||Jebsen-Taylor Test (JTT)||JTT, monthly from baseline to month 9||No|
|Secondary||Mean cortical volume changes||T1 from baseline, month 3, month 9||No|
|Secondary||Serum concentration of escitalopram||Serum concentration at month 3||No|
|Secondary||Genetic polymorphisms in genes||Genetic polymorphisms in genes at month 3||No|