Intravenous midazolam alters short-interval paired-pulse TMS responses differently in younger and older adults

OBJECTIVE: Aging is associated with changes in cortical excitability and altered responsiveness to benzodiazepines, but the effects of benzodiazepine challenge on motor cortical paired-pulse physiology in older adults remain incompletely understood. We examined whether intravenous midazolam differentially modulates corticospinal excitability and short-interval paired-pulse transcranial magnetic stimulation (TMS) responses in younger and older adults. METHODS: Sixteen younger adults (18-35 years) and sixteen older adults (50-69 years) underwent single-pulse and paired-pulse (conditioning stimulus: 110% motor threshold; test stimulus: 143% motor threshold) TMS of the left primary motor cortex at baseline and during intravenous midazolam administration. Single-pulse motor evoked potential (MEP) amplitude was used to assess corticospinal excitability. Short-interval paired-pulse responses were quantified as the ratio of conditioned to unconditioned MEP amplitude. RESULTS: At baseline, younger adults showed greater corticospinal excitability than older adults, reflected by larger single-pulse MEP amplitudes (adjusted p = 0.04). Younger adults demonstrated paired-pulse inhibition at baseline, reflected by a conditioned/unconditioned MEP ratio below 1.0 (ratio = 0.73; adjusted p < 0.01), whereas older adults did not show inhibition and instead had a mean ratio above 1.0 (ratio = 1.25). Midazolam reduced single-pulse MEP amplitudes in both groups. During midazolam administration, paired-pulse inhibition was no longer observed in younger adults, and older adults continued to show no evidence of inhibition. CONCLUSIONS: Younger and older adults differed in baseline corticospinal excitability and in short-interval paired-pulse TMS responses. Intravenous midazolam reduced corticospinal excitability and altered paired-pulse response patterns, eliminating baseline paired-pulse inhibition in younger adults while producing little measurable change in older adults. These findings suggest that aging may modify the net motor cortical response to benzodiazepine challenge. The results should be interpreted in relation to the paired-pulse stimulation parameters used and support further studies using complementary approaches to characterize age-related differences in inhibitory and facilitatory motor cortical circuits.