Bains AS, Schweighofer N. Time-sensitive reorganization of the somatosensory cortex poststroke depends on interaction between Hebbian and homeoplasticity: a simulation study. J Neurophysiol 112: 3240-3250, 2014. First published October 1, 2014 doi:10.1152/jn.00433.2013.-Together with Hebbian plasticity, homeoplasticity presumably plays a significant, yet unclear, role in recovery postlesion. Here, we undertake a simulation study addressing the role of homeoplasticity and rehabilitation timing poststroke. We first hypothesize that homeoplasticity is essential for recovery and second that rehabilitation training delivered too early, before homeoplasticity has compensated for activity disturbances postlesion, is less effective for recovery than training delivered after a delay. We developed a neural network model of the sensory cortex driven by muscle spindle inputs arising from a six-muscle arm. All synapses underwent Hebbian plasticity, while homeoplasticity adjusted cell excitability to maintain a desired firing distribution. After initial training, the network was lesioned, leading to areas of hyperand hypoactivity due to the loss of lateral synaptic connections. The network was then retrained through rehabilitative arm movements. We found that network recovery was unsuccessful in the absence of homeoplasticity, as measured by reestablishment of lesion-affected inputs. We also found that a delay preceding rehabilitation led to faster network recovery during the rehabilitation training than no delay. Our simulation results thus suggest that homeoplastic restoration of prelesion activity patterns is essential to functional network recovery via Hebbian plasticity.