There is strong evidence to suggest that high levels of complex mental activity can improve clinical outcome from brain injury. What are the neurobiological mechanisms underlying this observation? This paper proposes that complex mental activity induces a spectrum of biological changes on brain structure and function which can be best understood in a multiscalar spatiotemporal framework. Short-term molecular changes may include induction of BDNF, NGF and endopeptidase genes and elevation of the high-energy phosphocreatine-creatine resting state equilibrium. Animal models have implicated these processes in the reduction and even reversal of neurodegenerative changes secondary to mental work. These mechanisms can therefore be described as neuroprotective. Medium-term cellular changes are diverse and include neurogenesis, synaptogenesis, angiogenesis and formation of more complex dendritic branching patterns. Importantly, these effects parallel behavioral improvement, and thus a neurogenerative class of mechanisms is implicated. Finally, in the post-lesion context, computation principles such as efficiency, small world connectivity and functional adaptation are identified as important, with supportive clinical evidence from neuroimaging studies. Thus, dynamic compensatory cortical network mechanisms may also be relevant, yet take some time to evolve. This paper will explore the neurobiological and clinical implications of this framework, in particular in the context of age-related brain disease.