Aging is associated with contrasting changes in local and distant cortical connectivity in the human motor system.

Pathophysiological changes in neurological and neuropsychiatric diseases are increasingly described in terms of abnormal network connectivity. However, the anatomical integrity and efficacy of connections among multiple brain regions change with aging, even in healthy adults. We combined low-frequency transcranial magnetic stimulation and positron emission tomography to study the age-related changes in regional activation and effective connectivity, associated with voluntary action by healthy adults between 22 and 68 years old. Contrasting effects of aging on the motor network were seen using analyses of regional activation, effective connectivity mediating task-related neuronal activation and effective connectivity in response to transcranial magnetic stimulation. Low-frequency rTMS reduced cerebral blood flow during both movement and resting conditions, at the site of stimulation and neighboring frontal cortex. Aging was associated with increased movement-related activation in premotor cortex, bilaterally. Increasing age also increased the susceptibility of the cortex to the inhibitory effects of rTMS, at the site of stimulation and its contralateral homologue. Moreover, older subjects showed enhanced local effective connectivity, centered on the left premotor cortex, but reduced effective connectivity between distant motor-related cortical areas. We discuss these results in relation to the HAROLD model of aging and propose that there are differential effects of aging on local and distributed neuronal subpopulations in the motor network. This differential effect of aging has important implications for the study of neurodegenerative and cerebrovascular diseases that primarily affect older people, as well as our understanding of the normal aging process.