In the present study, we investigated age and hemispheric differences in mutual inhibition between motor cortices during voluntary activation using the iSP to probe TCI. Two main findings emerge from our observations. First, TCI indices derived from iSP characteristics (i.e., LTI, iSP area and TCT) were strongly influenced by age differences, whereas differences between hemispheres were only marginal. Second, correlation analyses revealed significant relationships between indices of TCI derived from each hemisphere and performance of the contralateral hand in dexterity and grip strength tests, so that left-to-right TCI correlated with right hand performance and vice-versa for right-to-left TCI and left hand performance. In the following discussion, we address the significance of these findings for the study of aging and its impact on motor systems.
Age and hemispheric differences in TCI
Contrary to evidence suggesting an asymmetry in the balance of mutual inhibition in favor of the dominant MI in right-handed individuals [17, 19, 20], only minor differences in TCI were found between the two hemispheres in our two groups of participants. In this respect, our results appear consistent with those of De Gennaro et al. , who found no difference in interhemispheric inhibition between the two hemispheres in resting state using bifocal TMS in young adults. Our observations for the senior group are also in line with those of Lewis & Perrault  who also failed to detect differences in paired-pulse SIHI between the dominant and non dominant hemisphere in their group of healthy senior adults, who served as controls for stroke patients. Interestingly, the absence of hemispheric asymmetry reported in Lewis & Perrault’s study was evident only when the target hand (contralateral to the test hemisphere) was active, irrespective of whether the ipsilateral hand was active or not. In the present study, the fact that iSP was tested during concurrent contraction of both hands might have been critical in attenuating possible asymmetries in the level of mutual inhibition in relation to manual dominance. It remains that the issue of hemispheric asymmetries in relation to manual dominance remains a controversial topic in the TMS literature [e.g., see  and more research is needed with larger groups of right- and left-handers to address the question.
Contrasting with the relatively minor difference found between hemispheres, a major difference was found between age groups, senior participants showing delayed LTI, prolonged TCT and reduced iSP area when compared to young participants. Given that our group of seniors exhibited signs of decreased corticomotor excitability, it is possible that the observed age difference in TCI might have reflected impaired motor activation or peripheral nerve dysfunction. This possibility seems unlikely, however, for several reasons. First, with regard to motor activation, the work of Giovannelli et al.  has clearly demonstrated that TMS-induced ispsilateral inhibition is little affected by the intensity of contraction in the test hand, the most important factor being rather the presence of light activity in the opposite hand. During testing, all our participants, and especially seniors, were encouraged to produce their maximum effort in the ispsilateral hand, while lightly contracting the other hand. Thus, by basing our assessment on Giovannelli’s method, we made sure that conditions would be optimal to elicit ipsilateral inhibition in each age group, in spite of individual variations in muscle activation. Second, as demonstrated by our secondary analysis (ANCOVAs), age-related variations in various indices of corticomotor excitability had little influence on measures of ispsilateral inhibition. In fact, the only significant interaction found was between LTI and contralateral MEP latency, which was expected. However, the computation of TCT, which largely removes the influence of MEP latency, showed that age differences were still highly significant. To summarize, while our seniors exhibited typical signs of corticomotor aging [e.g., , these changes could hardly account for the large age effect observed on iSP measures; pointing to central alterations in TCI as the primary cause.
In fact, our observations appear to be congruent with the proposal of Seidler’s group  that there is a shift with age in the balance of mutual inhibition between motor cortices towards excitatory processes. However, as noted earlier, these investigators  found only a trend when comparing the strength of ispsilateral inhibition in young and old adults. Their observation that young adults tended to show deeper levels of ipsilateral inhibition than older adults seems consistent with the age difference reported here. In more direct line with our results, Boudrias et al.  observed a strong age effect when comparing measures of interhemispheric inhibition derived from bi-focal TMS in young and older adults. In their study, a clear distinction was seen between young and older adults in that most seniors showed evidence of transcallosal facilitation rather than the typical inhibition. In the same vein, McGregor et al.  found that measures of ispsilateral inhibition were significantly reduced in older subjects when compared to young. Interestingly, the largest reductions were seen in the group of sedentary seniors, where iSP durations were on average 50% shorter than in young adults; a range comparable to the averaged reduction in iSP area reported here (57%). In physically active seniors, the reduced ipsilateral inhibition was less pronounced (~25%), which led McGregor et al. to conclude that engaging in regular physical activity could help to maintain levels of interhemispheric inhibition. Although we did not specifically control for activity level in our study, it is worth noting that the outlier senior who showed exceptionally long iSP duration (see Results) was also highly active as judged by self-report. It would be interesting for future studies to investigate how interactions between advancing age and levels of physical activity influence hemispheric interactions, but the small sample size used in the present study precludes any conclusion in this regard. Nevertheless, both the present findings and the results of recent TMS studies concur with the notion that transcallosally mediated inhibition becomes less efficient with age in line with reports describing structural alterations in the integrity of callosal fibres between motor cortices with advancing age [15, 24, 26].
Regarding the physiological mechanisms underlying the observed changes in iSP measures with age, the reduced iSP area points to a decrease in the excitability of ispsilateral transcallosal inhibitory neurons. Such a decrease would be consistent with reports of age-related reductions in the excitability of local inhibitory circuits mediating short-interval intra-cortical inhibition (SICI)  and short-latency afferent inhibition  reported in the motor cortex of seniors. As shown by Avenzino et al. , local interneurons involved in transcallosally mediated inhibition share common properties with those controlling excitability of pyramidal tract neurons; and thus, any alterations in intra-cortical excitability with age could also affect inhibitory connections between motor cortices. In parallel, the delayed LTI and prolonged TCT found in seniors are consistent with reports of structural alterations in callosal connectivity between motor cortices with age, as stated earlier. In fact, a growing body of evidence [12, 30] is now emerging linking preserved task-related functional connectivity between hemispheres in seniors with integrity of transcallosal connections. Indeed, as suggested by our correlational analysis, integrity of transcallosal connections seems to be important in allowing older adults to maintain certain levels of performance, as discussed below.
Relationship between ipsilateral inhibition and manual performance
The result of our correlation analysis revealed significant relationships between our different measures of TCI in each hemisphere and performance of the contralateral hand, so that left to right TCI (left hemisphere stimulated) correlated with right hand performance and vice versa for the left hand. Interestingly, these associations were particularly strong for the dexterity task, which is consistent with the purported role of TCI in preventing motor overflow when task demands require fine unilateral control of one hand . While correlations with grip strength were not as strong, good quality relationships were still found, for example, between iSP area and left hand; suggesting a role of TCI in unimanual force production. In line with this, Fling and Seidler  recently reported an inverse relationship between measures of ispsilateral inhibition and the ability of young individuals to suppress motor activity in the resting hand (i.e., motor overflow) during a unimanual force production task. Although we did not monitor motor activity in the resting hand during our tests of manual performance, our observations on the association between measures of TCI and manual performance are consistent with those of Fling and Seidler with regard to the role of TCI in allowing fine independent control of unimanual performance. In a related study from the same group of investigators , the association between functional motor activation and performance of a precision task with the dominant hand was examined in young and old adults. Much like in the present study, the authors found that increased ispsilateral motor recruitment (and presumably less efficient TCI) was associated with poorer task performance. The fact that this association was found only for the older group and not in younger subjects does not invalidate the comparison with the present findings since both their results and ours converge to show that proper levels of TCI is an important factor in leading to fine motor performance in the context of precision tasks, especially as people advance in age. In fact, there is ample evidence from TMS studies that levels of intra- and interhemispheric inhibition are critical for the performance of fine motor tasks [14, 32–34]. With regard to aging specifically, the observation that our group of seniors exhibited various levels of impaired ispsilateral inhibition and that these impairments were in part reflected in their dexterity performance would be consistent with other studies in which deterioration in motor performance and in inter-limb coordination with age was associated with a decreased ability to modulate inhibition at the central level [14, 34–36].