Vagus nerve stimulation alters task-evoked pupillary responses in older but not younger adults: A single-blind active sham-controlled crossover trial.

Older adults showed smaller baseline pupil diameter but larger normalized task-evoked pupillary responses than younger adults.

• Study used a single-blind, sham-controlled, crossover design in 41 participants (21 younger adults, 20 older adults)
• Baseline pupil diameter differences between age groups were observed a priori
• Normalized task-evoked pupillary responses were larger in older adults compared to younger adults
• Participants completed a visual oddball task with pupillometry during transcutaneous auricular VNS

VNS produced age-specific effects on tonic pupil size, with older adults demonstrating increased tonic pupil size throughout stimulation.

• Older adults showed increased tonic pupil size throughout the stimulation period under verum VNS conditions
• Verum stimulation was delivered to the cymba concha; sham stimulation was delivered to the earlobe
• Approximately 30 minutes of washout separated the two conditions in the crossover design
• Younger adults showed no consistent VNS effects on tonic pupil size

Older adults demonstrated reduced oddball-evoked pupillary responses under verum VNS compared to sham.

• Oddball-evoked pupillary responses were reduced in older adults during verum VNS (cymba concha stimulation)
• Younger adults showed no consistent VNS effects on oddball-evoked responses
• The visual oddball task was used to elicit task-evoked pupillary responses indexing LC activity
• These opposing effects (increased tonic, decreased phasic) in older adults suggest modulation of LC arousal state

VNS effects on pupillary responses in older adults were stronger with more current.

• A dose-dependent relationship was observed in older adults, with stronger effects associated with higher current levels
• This current-dependent effect was specific to older adults
• Younger adults did not show consistent current-dependent VNS effects
• The finding suggests older adults' LC-noradrenergic systems are more responsive or sensitive to VNS modulation

The locus coeruleus undergoes age-related changes and is involved in Alzheimer's disease pathogenesis, motivating the investigation of VNS as a potential therapeutic modulator.

• LC is implicated in age-related neurodegeneration and Alzheimer's disease pathogenesis
• VNS may modulate LC activity and could be used therapeutically
• Age-related differences in VNS responses had remained unexplored prior to this study
• Transcutaneous auricular VNS (taVNS) was used as a non-invasive method of stimulation

Age-specific VNS effects may reflect different baseline LC activity states between younger and older adults.

• Older adults showed more robust VNS responses than younger adults overall
• The authors propose that differing baseline LC activity states may underlie the differential responses to VNS across age groups
• The pattern of increased tonic and decreased phasic pupil responses in older adults is consistent with a shift in LC firing mode
• These findings have implications for therapeutic use of VNS in aging populations