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Running Head: fMRI assessment of motor learning and ... · PDF file 2020-05-19  · 26 in the excitatory and inhibitory balance of cortical networks, have been observed in healthy

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  • Running Head: fMRI assessment of motor learning and escitalopram

    Modulation of premotor cortex response to sequence motor learning during escitalopram- intake Eóin N. Molloy1,2,3,4, Karsten Mueller2,5, Nathalie Beinho�lzl1,3, Maria Blöchl2,3,8, Fabian A. Piecha1,3, André Pampel

    5, Christopher J. Steele3,12, Ulrike Scharrer1,3, Gergana Zheleva1,3, Ralf Regenthal9, Bernhard Sehm3,7,13, Vadim V. Nikulin3,6, Harald E. Mo�ller2,5, Arno Villringer2,3,4,10,11 & Julia Sacher1,2,3,10

    Emotion & Neuroimaging Lab, Max Planck Institute for Human Cognitive and Brain Sciences1 International Max Planck Research School NeuroCom2 Dept. of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences3

    Faculty of Medicine, Leipzig University4 Nuclear Magnetic Resonance Unit, Max Planck Institute for Human Cognitive and Brain Sciences5

    Centre for Cognition and Decision Making, Institute for Cognitive Neuroscience, National Research University Higher School of Economics6

    Neuroplasticity & Motor Recovery Group, Max Planck Institute for Human Cognitive and Brain Sciences7 Dept. of Psychology, University of Münster8

    Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig University9

    Clinic for Cognitive Neurology10

    Berlin School of Mind and Brain11

    Dept. of Psychology, Concordia University12

    Dept. of Neurology, Martin Luther University Halle-Wittenberg13

    Correspondence:

    Eoin N. Molloy, MSc - Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr. 1A, 04103, Leipzig, Germany, [email protected], tel: +49 341 9940-2215

    Julia Sacher, MD, PhD - Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr. 1A, 04103, Leipzig, Germany, [email protected], tel: +49 341 9940-2409

    Running Title: fMRI assessment of motor learning and escitalopram Figures: 4, Tables: 3 Supplementary Figures: 1, Supplementary Tables: 4

    Word Count (including headings):

    Abstract: 149 Introduction: 643 Materials and Methods: 1492 Results: 590 Discussion: 1382 Total (Including Abstract): 4256

    All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

    The copyright holder for this preprintthis version posted May 29, 2020. ; https://doi.org/10.1101/2020.05.19.20105346doi: medRxiv preprint

    NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

    https://doi.org/10.1101/2020.05.19.20105346

  • Running Head: fMRI assessment of motor learning and escitalopram

    Abstract:

    The contribution of selective serotonin reuptake inhibitors (SSRIs) to motor learning by inducing

    motor cortical plasticity remains controversial given diverse findings from positive preclinical

    data to negative findings in recent clinical trials. To empirically address this translational

    disparity, we use functional magnetic resonance imaging (fMRI) in a double-blind, randomized

    controlled study to assess whether 20 mg escitalopram improves sequence-specific motor

    performance and modulates cortical motor response in 64 healthy female participants. We found

    decreased left premotor cortex responses during sequence-specific learning performance

    comparing single dose and steady escitalopram state. Escitalopram plasma-levels negatively

    correlated with the premotor cortex response. We did not find evidence in support of improved

    motor performance after a week of escitalopram-intake. These findings do not support the

    conclusion that 1-week escitalopram intake increases motor performance but could reflect early

    adaptive plasticity with improved neural processing underlying similar task performance when

    steady peripheral escitalopram levels are reached.

    Key words: selective serotonin reuptake inhibitors, sequential motor learning, neural plasticity,

    functional MRI.

    All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

    The copyright holder for this preprintthis version posted May 29, 2020. ; https://doi.org/10.1101/2020.05.19.20105346doi: medRxiv preprint

    https://doi.org/10.1101/2020.05.19.20105346

  • Running Head: fMRI assessment of motor learning and escitalopram

    1

    Introduction: 1

    Motor learning is the improved performance of a motor task following practice1 and is modulated 2

    by monoaminergic transmission in cortical and subcortical motor networks2,3,4. Research on this 3

    monoaminergic basis of motor learning typically focuses on dopamine signaling in both health5,6 4

    and disease7. Evidence from rodents8 and stroke patients9, however, suggests that serotonin also 5

    critically modulates motor behavior. Selective serotonin reuptake inhibitors (SSRIs), commonly 6

    prescribed medications for depression and anxiety disorders10, increase extracellular serotonin 7

    and successfully treat post-stroke depression11. In the absence of depressive symptoms, several 8

    studies have also demonstrated an effect of SSRIs on the recovery of post-stroke motor 9

    dysfunction12. Notably, the FLAME trial (Fluoxetine for Motor Recovery After Acute Ischemic 10

    Stroke9) showed approximately 50% motor recovery in 57 patients following combined 11

    fluoxetine treatment and physiotherapy, in a multi-center Randomized Controlled Trial (RCT). 12

    These findings were further supported by a meta-analysis of 52 RCTs in 4,060 patients, which, 13

    however, also acknowledged heterogeneity and methodological shortcomings in a substantial 14

    proportion of trials13. 15

    16

    Possible mechanisms underlying SSRI modulation of motor performance and learning include 17

    anti-inflammatory14,15 and neurotrophic effects16 such as increased neurogenesis17, proliferation18, 18

    protein expression enhancement19, upregulation of beta1-adrenergic receptors20, downregulation 19

    of GABA-transmission21,22, and hippocampal long-term potentiation23. These findings suggest 20

    that SSRIs may increase responsivity to environmental stimuli, possibly via changes in inhibitory 21

    and excitatory balance24 and reorganization of cortical networks25-27. Studies in humans have 22

    provided support for this by demonstrating changes in resting state functional connectivity 23

    induced by a single dose of escitalopram28. Additionally, decreases in resting state alpha-24

    frequency band induced by tryptophan depletion29, which are hypothesized to reflect alterations 25

    All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

    The copyright holder for this preprintthis version posted May 29, 2020. ; https://doi.org/10.1101/2020.05.19.20105346doi: medRxiv preprint

    https://doi.org/10.1101/2020.05.19.20105346

  • Running Head: fMRI assessment of motor learning and escitalopram

    2

    in the excitatory and inhibitory balance of cortical networks, have been observed in healthy 26

    volunteers. Moreover, preliminary functional magnetic resonance imaging (fMRI) evidence has 27

    linked decreased functional responses in the motor network with improved motor performance 28

    following fluoxetine administration30-33. 29

    30

    Recent large-scale RCTs in stroke patients such as the TALOS34 and FOCUS trials35, involving 31

    over 642 and 3,000 patients, respectively, however, do not suggest beneficial effects of SSRIs on 32

    functional recovery. Critically, however36, these RCTs were conducted against the backdrop of 33

    routinely available rehabilitation and did not combine SSRI administration with a clearly defined 34

    motor learning paradigm, nor did they assess functional brain responses to SSRI intake. As a 35

    result, no previous study, either in healthy participants or in patients, has successfully leveraged 36

    prolonged training on an established motor learning paradigm in combination with SSRI-37

    administration and fMRI in an adequately powered sample. Therefore, the hypothesis of whether 38

    SSRI administration, specifically in combination with an established motor learning paradigm, 39

    induces a beneficial effect on motor learning performance and changes the cortical motor 40

    response underlying the learning performance, remains to be tested empirically. 41

    42

    The current study utilizes fMRI to address whether one week of SSRI administration in 43

    combination with a sequential motor learning task improves sequence specific motor 44

    performance and elicits changes in concurrent cortical motor response during task performance. 45

    In a double-blind, randomized controlled pharmaco-fMRI study, we administered 20 mg (to 46

    reach 80% serotonin transporter (5-HTT) occupancy)37 of escitalopram, the most 5-HTT selective 47

    and rapid onset SSRI38,39 or placebo, to healthy females undergoing parallel fMRI assessment and 48

    training on a variant of the sequential pinch force task (SPFT)40. We chose a hea

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