Aging affects all levels of neural processing, including changes of intracortical inhibition and cortical excitability. Paired-pulse stimulation, the application of two stimuli in close succession, is a useful tool to investigate cortical excitability in humans. The paired-pulse behavior is characterized by the second response being significantly suppressed at short stimulus onset asynchronies. While in rat somatosensory cortex, intracortical inhibition has been demonstrated to decline with increasing age, data from human motor cortex of elderly subjects are controversial and there are no data for the human somatosensory cortex (SI). Moreover, behavioral implications of age-related changes of cortical excitability remain elusive. We therefore assessed SI excitability by combining paired-pulse median nerve stimulation with recording somatosensory evoked potentials in 138 healthy subjects aged 17-86 years. We found that paired-pulse suppression was characterized by substantial interindividual variability, but declined significantly with age, confirming reduced intracortical inhibition in elderly subjects. To link the age-related increase of cortical excitability to perceptual changes, we measured tactile two-point discrimination in a subsample of 26 aged participants who showed either low or high paired-pulse suppression. We found that tactile performance was particularly impaired in subjects showing markedly enhanced cortical excitability. Our data demonstrate that paired-pulse suppression of human SI is significantly reduced in older adults, and that age-related enhancement of cortical excitability correlates with degradation of tactile perception. These findings indicate that cortical excitability constitutes an important mechanism that links age-related neurophysiological changes to behavioral alterations in humans.

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Repetitive transcranial magnetic stimulation (rTMS) is an effective tool for inducing functional plastic changes in the brain. rTMS can also potentiate the effects of other interventions such as tactile coactivation, a form of repetitive stimulation, when both are applied simultaneously. In this study, we investigated the interaction of these techniques in affecting tactile acuity and cortical excitability, measured with somatosensory evoked potentials after paired median nerve stimulation. We first applied a session of 5-Hz rTMS, followed by a session of tactile repetitive stimulation, consisting of intermittent high-frequency tactile stimulation (iHFS) to a group of 15 healthy volunteers ("rTMS + iHFS" group). In a second group ("rTMS w/o iHFS"), rTMS was applied without iHFS, with a third assessment performed after a similar wait period. In the rTMS w/o iHFS group, the 5-Hz rTMS induced an increase in cortical excitability that continued to build for at least 25 min after stimulation, with the effect on excitability after the wait period being inversely correlated to the baseline state. In the rTMS + iHFS group, the second intervention prevented the continued increase in excitability after rTMS. In contrast to the effect on cortical excitability, rTMS produced an improvement in tactile acuity that remained stable until the last assessment, independent of the presence or absence of iHFS. Our results show that these methods can interact homeostatically when used consecutively, and suggest that different measures of cortical plasticity are differentially susceptible to homeostatic interactions.

Paired-pulse stimulation, the application of two stimuli in close succession, is a useful tool to investigate cortical excitability. Suppression of the second response after short interstimulus intervals characterizes paired-pulse behavior. Although paired-pulse suppression is often studied as a marker of cortical excitability in humans, little is known about the influence of stimulation intensity on paired-pulse suppression. To systematically explore the effect of stimulus intensity on paired-pulse suppression of median nerve somatosensory evoked potentials (MNSEPs), we recorded single-pulse or paired-pulse MNSEPs in healthy volunteers using stimulation intensities ranging from the sensory threshold to 1.2 times the motor threshold using interstimulus intervals of 10, 30, and 100 ms. Of the various somatosensory evoked potential components, only the N20-P25 component showed an effect of intensity, where higher intensities resulted in stronger paired-pulse suppression. However, when only intermediate intensities were considered, paired-pulse suppression was not or only weakly influenced. Our data suggest that stimulation intensity in contrast to single pulse-evoked MNSEPs has only a weak influence on the paired-pulse suppression of early MNSEPs. Paired-pulse suppression is believed to arise from inhibition generated by intracortical networks. The lack of intensity dependence within the range tested can be considered as a step toward creating invariance against fluctuations of stimulus intensity. Thus, intracortical computations as apparent in paired-pulse behavior might be characterized by different properties compared with feed-forward processing.