The relationship between interhemispheric transfer time and physical activity as well as cardiorespiratory fitness in healthy older adults

The structural and functional degradation of the corpus callosum (CC) has been shown to play an important role in the context of cognitive aging (Reuter-Lorenz and Stanczak, 2000). This is also reflected by findings of elongated interhemispheric transfer time (IHTT) in older adults (Riedel et al., 2022). At the same time, a pro- tective effect of physical activity (PA) and cardiorespiratory fitness (CRF) on brain health including the CC is widely accepted (Hillman et al., 2008; Loprinzi et al., 2020). Based on this idea, the present study investigated the relationship between IHTT and PA/CRF in 107 healthy older adults (m: 64, f: 43) aged 67.69 ± 5.18. IHTT was calculated detecting event-related potentials (ERPs) using an established Dimond-Task. PA was evaluated using accelerometry resulting in estimates of overall bodily motion and time spent at higher intensity PA. CRF was estimated using graded exercise testing, approximating running speed at 4 mmol/l blood lactate concen- tration. The results showed a negative correlation between IHTT right → left and PA overall as well as in the male subgroup and between IHTT left → right and CRF in women. This indicates a potential relationship between IHTT and PA/CRF. While the present investigation is only the first to hint at such a relationship taking into account the differential effects with regards to sex, mode of PA/CRF and IHTT direction, it is in line with previous findings and theoretical suggestions linking brain health to PA/CRF in the context of aging. Further research is needed in order to increase our understanding of the underlying mechanisms and of the influence of sex, PA intensity, degree of CRF and significance of IHTT direction.


Introduction
Age-related cognitive decline is a widely accepted phenomenon and has been demonstrated for a number of domains, such as memory, speed of information processing or executive function (Hedden and Gabrieli, 2004;Reuter-Lorenz and Stanczak, 2000). As these normal changes as well as age-related pathological decline may impact the quality of life throughout the aging process, it is important to understand their nature along with underlying mechanisms and modulators (Harada et al., 2013;Seidler et al., 2010). Further understanding may improve our ability to counteract age-related cognitive decline through healthcare or other measures (Hillman et al., 2008).
Altered structure and function of the corpus callosum (CC) has been identified to be a key factor with regards to cognitive aging (Reuter-Lorenz and Stanczak, 2000). A widespread impact across domains is plausible, as the CC allows for the integration of cognitive and sensorymotor processing across both hemispheres. We recently discussed its vital role in this context and demonstrated age-related increase of interhemispheric transfer time (IHTT), an estimation of the speed of transmission of information across the CC (Riedel et al., 2022).
Ideally, IHTT is calculated as the difference between event-related potentials (ERP) evoked by lateralized stimuli at homologous electrode sites. Lateralization ensures that the stimuli are initially only perceived through one hemisphere and subsequent processing is transferred to the opposite hemisphere, which may be reflected by the difference in latencies between ipsi-and contralateral ERPs. This idea is backed up by findings of non-transfer of ERPs in acallosal patients, which indicates the important role of the CC in this context (Brown et al., 1999). While further research is needed in order to estimate its direct impact on cognitive performance, there has been some indication of a correlation between IHTT and structural properties such as white matter integrity of the CC (Whitford et al., 2011). In this study, fractional anisotropy of visual fibers, indicating structural integrity of the CC, was strongly related to IHTT. This may be of particular interest in the context of aging, as structural degradation of the CC is largely acknowledged to occur at advanced age (Sullivan and Pfefferbaum, 2006). Therefore, lengthening of IHTT may be attributable to decreased white matter integrity of the CC related to normal aging (Riedel et al., 2022), potentially indicating structural integrity as a mediator for impaired CC functioning. Thus, IHTT may serve as a useful indicator for age-related degradation of the CC (Sullivan and Pfefferbaum, 2006).
At the same time, IHTT has been indicated to be modulated by sex, especially in the context of aging. An age-related increase of IHTT based on reaction times has been shown to be mainly driven by the women of the respective sample (Jeeves and Moes, 1996). Similarly, the negative relationship between IHTT and age was more pronounced in women at an age range of 60-81 years in a recent study (Riedel et al., 2022). Again, similar differential effects based on sex have been observed in the context of structural integrity of the CC with women showing increased degradation through aging (Kumar et al., 2013;Salat et al., 1997). Furthermore, differences in IHTT have been linked to alterations in sex hormone levels explicitly (Hausmann et al., 2013). This indicates that in the context of aging menopause may play a primary role through the effect of altered sex hormone levels on IHTT in women. Therefore, sex should be considered a potential factor, whenever researching IHTT.
Age-related decline of cognitive performance can be counteracted or even reversed through a physically active lifestyle (Hillman et al., 2008). Intervention studies clearly indicate beneficial effects of aerobic fitness training on cognitive performance (Angevaren et al., 2008;Colcombe and Kramer, 2003;Kramer and Colcombe, 2018;Voss et al., 2011), even in the context of dementia and Alzheimer's disease (Fratiglioni et al., 2004;Heyn et al., 2004). Interestingly, this positive effect of fitness training broadly influences the majority of different cognitive domains, with executive functions benefitting the most (Colcombe and Kramer, 2003). Although the underlying mechanisms are not fully understood, this broad influence is reminiscent of the negative impact the deterioration of the structure and function of the CC is expected to exhibit. Therefore, maintaining structural and functional health of the CC may be of central importance to maintaining cognitive performance in the context of aging (O' Sullivan et al., 2001).
Again, sex-related differences with regards to the beneficial effects of physical activity or fitness on age-related cognitive decline have been observed (Barha and Liu-Ambrose, 2018;Colcombe and Kramer, 2003;Hillman et al., 2008). A recent review argues that sex-related physiological differences in turn cause differential effects of physical activity making sex an underestimated modulator of the relationship between physical fitness and cognitive performance, particularly executive function, in the context of aging (Barha et al., 2019). The neuroprotective effect of female sex hormones (Garcia-Segura et al., 2000) in combination with their age-related decline may be one reason for the greater benefit of fitness training on cognition in women than in men. For example, hormonal replacement therapy has been shown to enhance the beneficial effects of increased fitness levels on executive function in the context of cognitive aging in women . Thus, even besides the apparent differences with regards to brain structure and function, sex should be considered an important factor in the relationship between cognition and physical activity or fitness.
A number of potential mechanisms have been identified to explain the relationship between physical activity (PA) as well as cardiorespiratory fitness (CRF) and cognition in older adults. These include neuro-, synapto-and angiogenesis as well as molecular mechanisms involving pathways with regards to brain-derived (BDNF) or other neurotrophic factors and neurotransmitters (Lista and Sorrentino, 2010). Thus, previous findings as well as theoretical implications indicate the positive effect of PA/CRF in the context of age-related cognitive decline and brain health.
A recent review demonstrated, that structural as well as functional properties of the CC benefit from exercise and CRF as shown by various cross-sectional and longitudinal investigations (Loprinzi et al., 2020). In this case the authors found most of the studies correlating white matter integrity with exercise to reveal a positive relationship across a wide range of age groups. For example, changes in diffusivity were related to exercise in obese participants (Mueller et al., 2015), CRF correlated positively with fractional anisotropy in the CC in healthy older adults (Hayes et al., 2013;Johnson et al., 2012) or group differences are detectable between high and low fit adolescents employing tract-based spatial statistic in the CC (Herting et al., 2014). Furthermore, although most prominent in the body, this effect appears to be exerted across the entire CC to some degree (Loprinzi et al., 2020). The authors suggest that exercise may exhibit direct effects on the CC through neurotrophic factors, vasculo-, neuro-and synaptogenesis as well as reduction of inflammatory markers. Interestingly, it is further suggested, that more open-skilled exercise with less predictable varying movements such as dancing may be most beneficial. As IHTT may be associated with the structural integrity of the CC, these findings clearly raise the question, whether PA/CRF may also benefit IHTT, especially in the context of aging.
While often used interchangeably it is important to clearly distinguish between PA and CRF. The World Health Organization refers to PA as "any bodily movement produced by skeletal muscle that requires energy expenditure", while fitness generally describes the ability to perform a task without undue exhaustion (World Health Organization, 2018). Thus, "CRF is related to the ability to perform large muscle, dynamic, moderate-to-vigorous intensity exercise for prolonged periods of time" (American College of Sports Medicine et al., 2018). As a result, PA is often increased through extensive low intensity movement in daily life, while CRF is more likely to be improved by structured exercise regimes at higher intensity for shorter periods of time. Clear distinction is also necessary, because some effects of PA have differed from the ones of CRF in the context of brain health. For example, one study found a significant relationship between white matter integrity and CRF but no link to PA in adolescents, suggesting unequal contributions to structural properties of the CC (Ruotsalainen et al., 2020). Similarly, functional connectivity within networks prone to age-related changes has been associated with CRF independently of PA (Voss et al., 2015). On the other hand, local functional connectivity has been linked to PA, but not CRF in adolescents (Ruotsalainen et al., 2021). Clearly, PA and CRF can exert differential effects in the context of brain health and both need to be taken into account. Again, detailed understanding of the underlying mechanisms with regards to each factor may allow for more effective prevention programs.
Theoretical as well as empirical considerations indicate that PA and CRF are beneficial in the context of cognitive aging through protective effects on brain structure and function (Burzynska et al., 2014). This extends to the structural and functional properties of the CC (Loprinzi et al., 2020). Considering the impact this structure may have in this context, IHTT may be a promising indicator of the respective decline and potential positive effects of PA and CRF. Thus, the present study aims to estimate the relationship between IHTT estimated from ERPs and PA determined by accelerometry as well as CRF assessed through graded exercise testing. Additionally, exploratory analyses are presented investigating women and men differentially as previous findings have indicated sex-related differences in the context of IHTT and aging (Riedel et al., 2022).

Materials and methods
The present data was collected at the German Sport University Cologne as part of the AgeGain study funded by the German Federal Ministry of Education and Research (BMBF, 01GQ1425C), but extended by internal funding (Riedel et al., 2022;Wolf et al., 2018). The present investigation was approved by the ethics committees of the University of Cologne and of the German Sport University Cologne and extends the data and findings of previous investigations (Riedel et al., 2022). Further details on the AgeGain study, which was primarily focused on mechanisms and modulators of cognitive transfer, have been published elsewhere (Wolf et al., 2018).

Subjects
107 subjects (m: 64, f: 43) aged 67.69 ± 5.18 years were drawn from volunteers of the AgeGain Study based on data availability as well as inclusion criteria and included into the present investigation. AgeGain included 235 subjects across multiple centers. The present sample was primarily recruited through newspaper adverts and flyers, however, direct contact through other participants or from public talks was another source. Written informed consent was given by the participants. After the initial contact a brief telephone interview was conducted. The diagnostic expert system for psychiatric disorders -Stamm Screening Interview (Wittchen and Pfister, 1997) as well as the International Diagnostic Checklists for ICD− 10 and DSM-IV (Hiller et al., 1995) were completed in the course of this screening. Volunteers had to be 60 years of age or older, right-handed and without current or history of cognitive, neurological, psychiatric or cardiovascular illnesses. The estimate of intelligence conducted at a later stage using HAWIE-R for 89 of the subjects as part of the AgeGain study (Wolf et al., 2018) revealed an IQ of 116.9 ± 11.1 (Tewes, 1991). The Edinburgh Handedness Inventory (Oldfield, 1971) was employed to confirm right-handedness as suggested previously (Bourne, 2006;Marzi, 2010). Another prerequisite was normal or corrected to normal eye-sight determined by Landolt broken rings (Rohrschneider et al., 2019). Participants had to be able to complete all testing relevant to this investigation within four weeks while each test was conducted on a separate day.

Estimation of IHTT
The methods used to estimate IHTT have been described in detail elsewhere (Riedel et al., 2022). Generally, data collection was based on recommendations on divided visual field paradigms and concurrent EEG recording (Bourne, 2006). Subjects were asked to complete a wellestablished Dimond-Task (Brown et al., 1994;Clawson et al., 2013;Hagelthorn et al., 2010;Larson and Brown, 1997;Moes et al., 2007) using the same equipment and approach as previously described (Riedel et al., 2022). This letter matching task employed lateralized stimuli in order to induce interhemispheric transfer of visual information represented by ERPs. A 64-channel EEG system was used with two extra electrodes recording horizontal eye movements as well as a light sensor precisely detecting stimulus onset. Band-pass filters between 0.5 and 30 Hz as well as notch filter at 50 Hz were used and bad channels were interpolated. Trials were stimulus locked and after artifact rejection 164 ± 26 segments were passed into independent component analysis. Correction was done for components clearly corresponding to eye movements, the light sensor or the response pad. Global re-referencing and baseline correction were applied. Finally, the N170 peak of the PO7 and PO8 electrodes representing each hemisphere were extracted. Only clearly identifiable ERP peaks were included into the analyses. The difference between ipsi-and contralateral ERP latencies yielded discrete values for IHTT from left to right and vice versa.

Accelerometry
Subjects were asked to wear triaxial accelerometers (Geneactiv, Kimbolton UK) for 7 consecutive days at all times. Exercise testing was not conducted within this week. These devices are validated (Esliger et al., 2011) and were found to be comparable to the well-established ActiGraph (ActiGraph, Pensacola, USA) (Hildebrand et al., 2014). The raw data was extracted by GENEActiv Software Version 3.2 as provided by the manufacturer and all subsequent analyses were performed using R package GGIR version 1.9-1 (van Hees et al., 2019) in RStudio Version 1.0.136 (RStudio Team, 2015). These included autocalibration  extraction of the Euclidean Norm minus 1 (ENMO), a metric of the overall acceleration signal subtracted by the gravitational component (van Hees et al., 2013), identification and imputation of potential non-wear time as well as calculation of time spent at moderate/vigorous activity levels (MVPA) . This level was defined such that 80 % of 5s segments of 60s bouts had to exceed the ENMO threshold of 100 mg (Menai et al., 2017). As a representation of overall PA, ENMO was used while MVPA reflected the time spent at higher PA levels.

Exercise testing
Prior to exercise testing the participants' eligibility with regards to physical ability and safety when performing exercise had to be certified by a physician. Additionally, a physician was always at disposal during testing. Considering the additional risks involved in testing older adults, submaximal field testing was used as suggested by the ACSM Guidelines (American College of Sports Medicine et al., 2018). All testing was conducted on a standard 400 m running track. A graded protocol was employed with subjective termination criteria, which corresponded to a perceived exertion of 17 or above on the Borg Scale ("very hard") (Borg, 1998). Furthermore, heart rate and general signs of physical exertion were closely monitored by experts. The test consisted of walking and running at increasing speeds set by an accompanying investigator. Initial speed was chosen at 1.2 m/s and increased at 0.2 m/s per increment. The duration of each stage varied between 3:40 mins and 5:32 mins depending on the current speed due to a pre-determined location for sample collection. At rest as well as after each stage 20 μl capillary blood samples were taken from the earlobe and blood lactate concentrations extracted. Subsequently, these values combined with the respective speeds were used to interpolate walking/running speed at 4 mmol/l blood lactate concentration (v4), which is based on a common onset of lactate accumulation threshold (Heck et al., 1985;Ji et al., 2021). This speed was used as an estimator of CRF.

Statistical analyses
Python 3.8 (Python Foundation, 2020) as well as JASP (JASP Team, 2020) were used for statistical analyses. Significance was assumed at p < .05. Outliers were excluded in case of exceedance of 1.5-times the interquartile range below the first or above the third quartile. Previous analyses (Riedel et al., 2022) have confirmed the concept of IHTT in this sample and, therefore, discrete values (IHTT left→right and IHTT right→left ) were used along with ENMO, MVPA and v4. Additionally, the group was split into male and female participants as previous results indicate differential effects based on sex. Normal distribution was tested using the Shapiro-Wilk-Test. Correlation analyses between IHTT and the PA/CRF variables were conducted accounting for the effect of age through partial correlation. Pearson's product-moment partial correlation was employed if normal distribution could be assumed for all variables and spearman's rank partial correlation was used otherwise. The resulting pvalues were adjusted for multiple testing using the Benjamini-Hochberg false discovery rate correction (Benjamini and Hochberg, 1995). If applicable, correlation coefficients were compared using Fisher's r-to-ztransformation. Table 1 provides an overview of the descriptive data including distribution and data availability. Results of the correlation analyses are presented in Table 2. The varying sample sizes are a consequence of outliers, unclear ERPs, invalid data and not reaching the required 4 mmol/l blood lactate threshold. The requirement of unequivocal ERP peaks may lead to different sample sizes between IHTT directions.

Results
Correlation analyses across all subjects controlling for age revealed significant relationships between IHTT right→left and ENMO (r Spearman = − 0.331*, p = .018) as well as MVPA (r Spearman = − 0.343*, p = .018). No other significant relationship was found although correlation coefficients were negative for all analyses. Scatterplots are provided in Fig. 1.
Correlations with regards to the other direction or v4 were nonsignificant. Fig. 2 provides scatterplots illustrating the correlation between IHTT in both directions and the variables associated with PA and CRF split by sex.
Comparisons of the correlation coefficients between women and men are provided in Table 3. A significant difference between the relationships was found for IHTT right→left and v4 (z = − 2.48, p = .01) between the female and male subgroups.

Discussion
The correlation analyses generally indicate a negative relationship between IHTT and PA as well as CRF. However, significant relationships across the entire sample are only found between IHTT right→left and the parameters reflecting PA. As the majority of participants were men, similar results are revealed for the male subgroup. In women, a clear negative correlation was found between IHTT left→right and CRF. This relationship significantly differed from the one in men. While showing different patterns between the sexes, the other correlation analyses showed no statically significant differences between the correlation coefficients. As, to the best of our knowledge, this is the first study to estimate the relationship between IHTT and PA/CRF, comparison to previous studies is limited. It is widely accepted, that PA/CRF is beneficial to cognition and brain health overall, especially in the context of aging (Hillman et al., 2008;Kramer and Colcombe, 2018;Voss et al., 2011). A recent review summarizes strong evidence, that this relationship extends to the CC with a number of studies showing an association between CRF and white matter integrity of the CC (Loprinzi et al., 2020). In the light of a potential relationship between structural integrity of the CC and IHTT (Whitford et al., 2011), the present results appear plausible. While not across all subgroups and conditions significant relationships were found, the potential for a negative relationship between IHTT and PA/CRF is indicated. However, the differential effects with regards to sex and direction of IHTT as well as interaction effects with regards to PA and CRF have to be taken into account.
More men (N = 64) than women (N = 43) were investigated, which explains, why the results of the entire sample reflect the outcome of the male subgroup. Among women, a strong, significant relationship between IHTT and CRF was found, but none between IHTT and PA. With regards to the specificity to CRF, this latter result is reminiscent of previous investigations researching the relationship of PA and CRF with functional integrity in healthy older adults, among others in the anterior CC (Voss et al., 2015). As noted by the authors, this supports the idea, that CRF is the key factor promoting brain health. On the other hand, men revealed a significant negative relationship between IHTT and PA, but not CRF. This indicates that sex may be an important modulator of the influence PA/CRF can have on IHTT, as has been noted in the context of overall brain health (Barha et al., 2019).
Generally, differential effects between women and men with regards to the influence of PA/CRF on brain health and cognition in the context of aging have been reported previously. For example, beneficial alterations of plasma biomarkers and brain volume related to exercise were found to be more pronounced in women (Castells-Sánchez et al., 2021). Similarly, the relationship between CRF and fMRI-based estimates of network integration was stronger in men, leading the authors to point to the importance of sex as factor with regards to the relationship between fitness and brain function (Dimech et al., 2019). A recent review has identified biological sex to be an important moderator of the beneficial effects of PA/CRF in this context (Barha et al., 2019), discussing sex differences in neuroplasticity, neurotrophic factors and physiological effects of exercise as potential underlying mechanisms, why women may benefit more from CRF than men (Barha and Liu-Ambrose, 2018). While more specific research is required, IHTT may also be differentially affected. Greater benefits of CRF on cognition in women than men have been observed (Kramer and Colcombe, 2018), which may be a result of similar underlying mechanisms. Generally, this might point to a mediating effect of hormones, which have been suggested to contribute to the protective effects of PA/CRF (Lista and Sorrentino, 2010). Accordingly, added benefit was found to be related to short term hormone replacement therapy with regards to the positive effect of CRF on brain volume and executive control in postmenopausal women . This indicates that among potentially other sex hormones estrogen may beneficially interact with and enhance the positive effect of CRF on brain health . Upregulation of growth hormones and neurotrophic factors depends on the intensity of PA/CRF (Copeland  , 2004) and, thus, differs between our estimates of PA and CRF. Considering sex to act as a modulator, this may in turn lead to different effects of PA and CRF on the CC between women and men. However, this relationship may be especially complex, considering the substantial alterations in endocrine regulation during menopause and is beyond the scope of this study. Additionally, a direct effect of sex hormones on IHTT has been observed among women with the menstrual cycle and related hormonal alterations affecting IHTT significantly (Hausmann et al., 2013). In this example, elongated IHTT was observed during the luteal phase, when progesterone and estradiol levels tend to be increased. This indicates that even short alterations of IHTT may be related to changes of sex hormone levels. This may also result in differences between women and men (Riedel et al., 2022) and may extend to the modulating impact of PA/CRF. Future studies may wish to monitor hormonal status in order to estimate its mediating effect. The present results suggest, that IHTT in women is related more strongly to CRF, while in men it correlates with PA. It is also highlighted, that PA and CRF have to be treated as separate factors when investigating their influence on cognition and brain health in aging. Different adaptive responses to overall PA versus increased CRF through structured exercise regimes appear to extend to their protective effect on brain health in the context of aging (Voss et al., 2015). Differences between directions of IHTT are often investigated in the context of asymmetric interhemispheric communication, with IHT-T right→left usually being shorter than IHTT left→right (Brown et al., 1994). Thus, asymmetric interhemispheric communication refers to the comparison between the directions of IHTT as opposed to differences in correlations with PA/CRF as reported in the present study. However, the underlying mechanisms of this asymmetry are largely unknown (Marzi, 2010) and similar theories explaining it may be applicable to the relationship with PA/CRF as well. For example, it has been hypothesized, that more axons are projected from the right towards the left hemisphere than vice versa (Marzi et al., 1991). As an increase in myelination through PA/CRF has been reported repeatedly (Loprinzi et al., 2020), these positive effects may be more beneficial from right to left as well. Of course, this does not explain, how differential effects of the beneficial effects of CRF in women oppose this idea, however, the complex interaction with regards to underlying mechanisms, the role of sex hormones and the impact of menopause in the current sample make it difficult to propose a suitable model considering the little data available today. Future studies should consider potential differences between IHTT directions for their analyses.

Limitations
Methodological limitations with regards to the estimation of IHTT have been described elsewhere (Riedel et al., 2022) and are applicable to the present study. These include that PO7 and PO8 electrodes are not entirely representative of cortex areas related to visual processing, the lack of control for eye dominance (Chaumillon et al., 2018) and the use of simple peak detection while more elaborate methods may be suitable (Kiesel et al., 2008).
While the estimation of PA was done objectively using a validated accelerometer as well as an established algorithm, there is some debate over which approach is most suitable for older adults, mainly with regards to intensity thresholds (Rejeski et al., 2016). Therefore, analyses were conducted using both MVPA reflecting time spent at higher intensity PA using a previously applied algorithm as well as the ENMO metric, estimating overall bodily motion. The results differed very little, indicating a more general relationship between IHTT and PA, rather than being specific to PA intensities.
The criterion measure for the estimation of CRF is considered to be maximal oxygen uptake (American College of Sports Medicine et al., 2018). Instead, we used graded field testing estimating CRF based on submaximal blood lactate concentrations. Prior tests showed that maximal effort is not feasible considering the experience and average age of the present sample. Using running speed at 4 mmol/l blood lactate concentration is commonly used to reflect some capacity threshold in endurance testing, however, in this case it is only supposed to provide some reference for submaximal effort. Although it may not be considered the gold standard in sports science in general, it may be a useful method to estimate CRF in older or less experienced participants.
The sample size of the female group was smaller compared to the male group. This results in a difference in explanatory power. While at least 27 participants were included into any analysis this difference has to be taken into account. Including additional subjects as well as considering a longitudinal approach may add to that power and provide further insights into the causal relationship between IHTT and PA/CRF. Finally, a potential effect of hormone replacement therapy was not considered in the present study. As only two female subjects received some sort of hormone therapy for medical reasons, no respective influence could be detected.

Conclusion and future directions
To the best of our knowledge, this is the first study to present results indicating a potential negative relationship between IHTT and PA/CRF in healthy older adults. However, this relationship appears to be modulated by sex and to depend on the direction of IHTT. These findings can generally be considered in line with the extensive literature ascribing a protective effect of PA/CRF on brain health in the context of aging. In this context, IHTT may be shortened by increased white matter integrity of the CC (Whitford et al., 2011), which has in turn been associated with increased PA/CRF (Loprinzi et al., 2020). Thus, the present findings highlight the importance of investigating functionality of the CC and the overall brain besides their structure. In this context, IHTT has proved a useful parameter in this regard (Whitford et al., 2011). Furthermore, the importance of PA and CRF with regards to functional brain health and aging has been demonstrated while providing insights into the underlying mechanisms and modulators of this relationship. However, further research is required in order to identify the precise mechanisms involved as well as to understand the  Fig. 1. Correlation analyses among all participants are illustrated for ENMO, MVPA and v4 as well as both IHTT directions. Significant relationships were found for IHTT right→left and ENMO as well as for IHTT right→left and MVPA. (*p < .05).

Fig. 2.
Correlation analyses grouped by sex for female (gray) as well as male (black) participants are displayed for ENMO, MVPA and v4 as well as both IHTT directions. The only significant relationship in women was found for IHTT left→right and v4 (*p < .05) while significant relationships were found for IHTT right→left and ENMO as well as IHTT right→left and MVPA in men. (*p < .05).