Supplemental Figure 1

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Supplemental Figure 1Axial and coronal T1-weighted anatomical MRI scans at the approximatelevel of maximum infarct volume (indicated by red region) for eachpatient. For two cases, images are flipped so that all lesions appear onthe right side.

Supplemental Figure 2

cs

(a) (b)

(c)

AH

y= ‐14y= ‐16y= ‐18

y= ‐2y= ‐4y= ‐8

Supplemental Figure 2Cortical stimulation site(a) Example of the position of the fiducial markers attached to the MR(a) Example of the position of the fiducial markers attached to the MR-compatible TMS coil for one participant, with the centre of the coilindicated in blue. (b, c) Individual stimulation locations. Each white crossindicates the MNI coordinate of the derived stimulation site for a singlepatient, with a summary shown on a sagittal view of the mean structuralimage at right, and example coronal slices at left. The group meanstimulation point was (mean ± std) x= 29 ± 4 y= 9 ± 5 z= 65 ± 4stimulation point was (mean ± std) x= -29 ± 4, y= -9 ± 5, z= 65 ± 4.Coronal and sagittal sections of the mean T1-weighted structural scans(averaged across all patients) are shown. AH: affected hemisphere(shown on right in each coronal example); cs: central sulcus.

TMSl TMShi h

Supplemental Figure 3

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Supplemental Figure 2Supplemental Figure 2Average grip peak-force, duration and onset time for each patient, shownseparately for TMSlow (blue bars) or TMShigh (pink bars) trials, withadjacent bars for each patient. Data are presented as means ± SD. Forpeak force, the dotted line indicates the required force level. For griponset, the dotted line represents the period of TMS pulse application.Note that TMS did not significantly affect any of these grip parametersNote that TMS did not significantly affect any of these grip parametersduring scanning in any patient. MVC: maximum voluntary contraction

Supplemental Discussion

An alternative (though not necessarily incompatible) interpretation of the present findingsAn alternative (though not necessarily incompatible) interpretation of the present findings

might involve a change in the effective timing of cPMd-iM1 interhemispheric interplay after

stroke. In this case, a fixed interval between the application of paired TMS pulses might in

effect probe different phases of the interhemispheric influence for different patients: at

different temporal latencies between paired TMS pulses, inhibition might then have been

observed in the facilitatory cases of our patient group. But even if this were the case, the

present results would still indicate that physiological changes in interhemispheric interactions

have a systematic relationship to residual motor function (and also to the remote BOLD

activity changes demonstrated in the fMRI experiment).

Local spread of the conditioning stimulus from cPMd to iM1 seems very unlikely to have

occurred here as the stimulation intensity was determined in relation to motor thresholds

within the contralesional hemisphere, which are not raised after unilateral subcortical stroke

(Byrnes et al., 2001;Shimizu et al., 2002). Moreover, altered intracortical excitability has

been reported in both the ipsilesional (Manganotti et al., 2008;Cicinelli et al., 2003) and

contralesional (Butefisch et al., 2003;Swayne et al., 2008) hemispheres. Stimulation

thresholds for activating the neuronal populations mediating the interhemispheric PMd-M1

influence could thus be altered in stroke patients. We adjusted the test stimulus intensity

individually according to the amplitude of the unconditioned MEP, to circumvent the

expected reduction of corticospinal excitability in the ipsilesional hemisphereexpected reduction of corticospinal excitability in the ipsilesional hemisphere.

Indeed, the paired-coil cPMd-iM1 TMS measure did not correlate with resting motor

thresholds and the correlation with combined clinical scores remained significant even whenthresholds, and the correlation with combined clinical scores remained significant even when

motor thresholds were taken into account. This suggests that the observed relationship

reflects genuine change in the strength of the cPMd-iM1 influence rather than merely

differences in the degree of corticospinal hypoexcitability. Moreover, the relationship

between cPMD-iM1 changes and the combined clinical score remain significant even when

accounting for rMTs and MEP size. Thus, systematic floor / ceiling effects of raised motor

thresholds or reduced MEP amplitudes are unlikely to explain the observed relationship

between greater motor impairment and a more facilitatory PMd-M1 interaction, which weg p y ,

interpret as reflecting abnormal effective connectivity in these pathways.

The relationship of the BOLD interaction (between task (grip or rest) and TMS intensity) to

residual motor function and to the interhemispheric cPMd-iM1 influence measured with

paired-coil TMS cannot be trivially explained by a systematic effect of high versus low

intensity TMS on behavior during scanning, as no such influence was found. Comparison of

the TMShigh and TMSlow conditions did not reveal any differential effect of TMS intensity on

mean peak force, grip onset, or grip duration. We suggest that the relationships to TMS

intensity in the fMRI data instead reflect genuine state-dependent influences of cPMd on

ipsilesional posterior sensorimotor cortex during impaired hand movement in our more

impaired patients, consistent with the involvement of these regions for hand grip and manual

bj t i l ti i h lth bj t (Bi k f ki t l 1999 Eh t l 2001 J lobject manipulation in healthy subjects (Binkofski et al., 1999; Ehrsson et al., 2001; Jenmalm

et al., 2006).

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