Original Research Primary Motor Cortex Excitability During Recovery After Stroke: Implications for Neuromodulation Cathy M. Stinear a, b , Matthew A. Petoe a, b , Winston D. Byblow b, c, * a Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand b Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand c Department of Sport & Exercise Science, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand article info Article history: Received 14 March 2015 Received in revised form 27 May 2015 Accepted 22 June 2015 Available online xxx Keywords: Stroke Sub-acute Upper limb Transcranial magnetic stimulation Motor cortex abstract Background: Non-invasive brain stimulation techniques may be useful adjuvants to promote recovery after stroke. They are typically used to facilitate ipsilesional cortical excitability directly, or indirectly by suppressing contralesional cortical excitability and reducing interhemispheric inhibition from the con- tralesional to ipsilesional hemisphere. However, most of the evidence for this approach comes from studies of patients at the chronic stage of recovery. Hypothesis: We hypothesized that corticomotor excitability and interhemispheric inhibition would initially be asymmetric, with greater interhemispheric inhibition from contralesional to ipsilesional M1. We also hypothesized that balancing of corticomotor excitability and interhemispheric inhibition would be associated with greater improvements in paretic upper-limb impairment and function. Methods: We conducted a retrospective analysis of longitudinal data collected from 46 patients during the first six months after stroke. Transcranial magnetic stimulation was used to measure rest motor threshold, stimulus-response curves, and ipsilateral silent periods from the extensor carpi radialis muscles of both upper limbs. Analyses of variance and linear regression modeling were used to evaluate the effect of time on corticomotor excitability and interhemispheric inhibition in both hemispheres, and associations between these effects and improvements in paretic upper-limb impairment and function. Results: All participants had subcortical damage and only two had motor cortex involvement. As ex- pected, ipsilesional corticomotor excitability was initially suppressed and increased over time, and this increase was associated with improved upper-limb impairment and function. However, interhemispheric inhibition was symmetrical and stable over time, and there was no evidence for a decrease in con- tralesional corticomotor excitability. Conclusions: Neuromodulation interventions applied during spontaneous recovery may be more bene- ficial if they facilitate ipsilesional corticomotor excitability directly. Ó 2015 Elsevier Inc. All rights reserved. Introduction Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stim- ulation (TDCS), may be useful adjuvants to promote recovery after stroke [1]. Meta-analyses have found that both can benefit upper- limb impairment and function after stroke [2,3], though recent Cochrane reviews are less optimistic [4,5]. They are typically applied to facilitate ipsilesional M1 excitability or suppress con- tralesional M1 excitability, in line with the interhemispheric imbalance model [6]. This model posits that ipsilesional excitability is reduced relative to contralesional, and that this asymmetry is reinforced by the contralesional M1 exerting more interhemi- spheric inhibition on the ipsilesional M1, than vice versa [1,7]. Ev- idence for this model, and the benefits of neuromodulation techniques, has come mostly from studies at the chronic stage of stroke [8]. At the sub-acute stage, contralesional suppressive TDCS can produce improvements in impairment [9] and independence [10], though a larger study found no effects [11]. Contralesional Abbreviations: ARAT, Action Research Arm Test; CME, corticomotor excitability; FM, Fugl-Meyer score; NIHSS, National Institutes of Health Stroke Scale; SAFE score, shoulder abduction, finger extension score. Sources of funding: The Health Research Council of New Zealand (09/164), Stroke Foundation Northern Region, and Julius Brendel Trust. Disclosures: The authors declare no competing financial interests. * Corresponding author. Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Tel.: þ649 3739999. E-mail address: w.byblow@auckland.ac.nz (W.D. Byblow). Contents lists available at ScienceDirect Brain Stimulation journal homepage: www.brainstimjrnl.com http://dx.doi.org/10.1016/j.brs.2015.06.015 1935-861X/Ó 2015 Elsevier Inc. All rights reserved. Brain Stimulation xxx (2015) 1e8