We recently demonstrated that a long-lasting transmission defect in cortical synapses caused motor dysfunction after brief middle cerebral artery (MCA) occlusion in the rat despite rapid recovery of axons. In this experimental study, we have examined the impact of differential recovery of synapses and axons on generation of motor-evoked potentials (MEP) recorded from contralateral paralyzed and ipsilateral unaffected muscles, to gain insight into mechanisms of MEPs recorded from stroke patients by transcranial magnetic stimulation (TMS). MEPs generated by focal electrical stimulation of the forelimb area of motor cortex were simultaneously recorded from the brain stem, contra- and ipsilateral forelimb and contralateral hindlimb muscles in rats subjected to transient MCA occlusion. The effect of ischemia on cortical activity and axonal conduction was differentially studied by proximal or distal occlusion of the MCA. Regional cerebral blood flow changes in the forelimb area were monitored by laser-Doppler flowmetry during ischemia and reperfusion. Lo addition, synaptic transmission within the forelimb area of motor cortex was examined by intracellular and extracellular recording of potentials generated by stimulation of the premotor area. No MEP response was recorded during ischemia. Upon reperfusion: (i) motor axons readily regained their excitability and cortical stimulation caused successive pyramidal volleys (recorded as D waves from the brain stem) and a MEP from contralateral paralytic muscles although synaptic activation of motor pathways was not feasible; (ii) the amplitude of pyramidal volley was increased; (iii) MEPs with a longer latency were recorded from the ipsilateral forelimb. In conclusion, differential recovery of synapses and axons after ischemia may account for some previously unexplained findings (such as preserved MEPs in paralysed muscles) observed in cortical stimulation studies of stroke patients. (C) 2000 Elsevier Science B.V. All rights reserved.