Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei differs across the lifespan

Attentional states reflect the changing behavioral relevance of stimuli in one's environment, having important consequences for learning and memory. Supporting well-established cortical contributions, attentional states are hypothesized to originate from subcortical neuromodulatory nuclei, such as the basal forebrain (BF) and locus coeruleus (LC), which are among the first to change with aging. Here, we characterized the interplay between BF and LC neuromodulatory nuclei and their relation to two common afferent cortical targets important for attention and memory, the posterior cingulate cortex and hippocampus, across the adult lifespan. Using an auditory target discrimination task during functional MRI, we examined the influence of attentional and behavioral salience on task-dependent functional connectivity in younger (19-45 years) and older adults (66-86 years). In younger adults, BF functional connectivity was largely driven by target processing, while LC connectivity was associated with distractor processing. These patterns are reversed in older adults. This age-dependent connectivity pattern generalized to the nucleus basalis of Meynert and medial septal subnuclei. Preliminary data from middle-aged adults indicates a transitional stage in BF and LC functional connectivity. Overall, these results reveal distinct roles of subcortical neuromodulatory systems in attentional salience related to behavioral relevance and their potential reversed roles with aging, consistent with managing increased salience of behaviorally irrelevant distraction in older adults. Such prominent differences in functional coupling across the lifespan from these subcortical neuromodulatory nuclei suggests they may be drivers of widespread cortical changes in neurocognitive aging, and middle age as an opportune time for intervention.