This is an exploratory study of neural mechanisms of fluoxetine mediated motor, cognitive, and language recovery after stroke. We aiming to do a Trial Within a Study (TWIST), using the EFFECTS as the mother study.

In MAP EFFECTS, stroke patients included in the Stroke Dept at Danderyd Hospital will be asked to participate. The aim is to recruit 50 stroke patients who will be randomized to treatment with Fluoxetine or placebo (according to EFFECTS protocol). Patients will be evaluated with additional tests of motor, cognitive and language functions during the early and late phases (2 weeks and 6 months after stroke).

Functional connectivity of brain motor, cognitive and language networks will be measured at both time points using resting-state functional MRI (rs-fMRI).

Specific aims of the MAP EFFECTS study

The specific aims of this study are:

(i) Neural mechanism of motor recovery: to study the effects of Fluoxetine (treatment compared to placebo) on the structural and functional integrity of the motor cortex and its projections and on different aspects of recovery of hand motor control after stroke.
Specifically, to test whether motor cortex connectivity in terms of

(a) functional interhemispheric M1-M1 connectivity (between motor cortices on lesioned and non-lesioned sides) and

(b) structural CST connectivity (degree of corticospinal tract injury) improve over time in intervention group compared to placebo group.

(ii) Prediction of motor recovery: to study whether the long-term effects on motor recovery can be predicted by initial measurements of motor cortex connectivity (both functional interhemispheric connectivity and structural CST integrity) and/or motor function measurements.

(iii) Generalizability of recovery across motor, cognitive and language domains: to study relation of recovery across motor, cognitive and language domains and to explore relation of recovery across domains with M1 connectivity. Here each patient’s degree of recovery will be expressed in % of possible recovery in each domain. Motor recovery (% of recovery on Fugl-Meyer scale) will be related to attention recovery (% of recovery according to computerized testing with CANTAB methodology and visuomotor tracking task with distractors) and aphasia recovery (% of recovery according to A-ning aphasia test).


This study will be undertaken at Danderyd Hospital, Karolinska Institute during 2017-2018. Measurements will be performed by medical doctor/physiotherapist/nurse/neuropsychologist/ speech and language therapist.

50 patients will be recruited from EFFECTS study. Patients with contraindications to MRI will be excluded (metal implants, pacemaker).

Evaluations of motor, cognitive and language functions will be performed blinded to treatment (Fluoxetine/placebo). Motor assessments (30 mins) include arm and hand function (Fugl-Mayer assessment), gross dexterity (Box and Blocks test), spasticity (NeuroFlexor), fine motor control and attention using visuomotor tracking test with visual distractors will be carried out.

Cantab software for cognitive testing (30 mins) will allow evaluation of attention and memory. Langauage testing will be done according to A-ning test (30 mins). Structural anatomical MRI along with fMRI will be collected. All measures will be collected at 2 weeks and 6 months after stroke.

MRI protocol

All patients will undergo two MRIs lasting about 30 mins (non-invasive, without contrast injection) including:
(i) Anatomical T1-weighted images for description of stroke lesion size and localisation
(ii) Resting state functional MRI for measurement of functional connectivity
(iii) Diffusion tensor imaging (DTI) sequence for quantification of white matter structure

Responsible researchers
* Rehabilitation medicine, Danderyd Hospital, Karolinska Institute: Påvel Lindberg, Jörgen Borg, Jeanette Plantin, Alison Godbolt, Helena Hybinnette, Marika Möller
* Stroke Dept, Danderyd Hospital, Karolinska Institute: Per Wester, Ann-Charlotte Laska, Eva Isaksson
* Radiology Dept, Danderyd Hospital, Karolinska Institute: Evaldas Laurencikas
* Neurology Dept, Karolinska Hospital Solna, Karolinska Institute: Erik Lundström

Register of the study: The Northern Irland Hub for Trials Methodology Reseach (pending)