Disclosed are methods and systems and methods for neuromodulation of the Motor Cortex and other areas of the brain impacted by stroke. The neuromodulation can produce acute effects or result in Long-Term Potentiation (LTP) or Long-Term Depression (LTD). Included is control of direction of the energy emission, intensity, pulse duration, frequency, firing pattern, and phase/intensity relationships to targeting and accomplishing up-regulation and/or down-regulation. The invention can be applied for mitigating the effects of stroke and/or in stroke rehabilitation.