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Assessing neurobiology of brain systems can provide information not available from anatomic or behavioral assessment. Such information may be of value in understanding, defining, and prescribing potential therapeutic interventions that target restorative brain events after stroke. A number of methods have been used to study stroke recovery, each with its relative merits and limitations. Several studies suggest that greater injury is associated with reduced laterality of brain activity. This might be in relation to changes in interhemispheric inhibition and is a phenomenon that is likely useful for functional gains in some patients. Many other features of brain activity change in the months after a stroke, including the site and size of activation in relevant brain network nodes. While there is incomplete agreement regarding which features of altered brain activity predict and parallel better behavioral outcome, studies converge on the conclusion that best outcome is achieved by activating the brain in a pattern that most resembles the normal state.