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Cardiac activity impacts cortical motor excitability [1]

['Esra Al', 'Department Of Neurology', 'Max Planck Institute For Human Cognitive', 'Brain Sciences', 'Leipzig', 'Mindbrainbody Institute', 'Berlin School Of Mind', 'Brain', 'Humboldt-Universität Zu Berlin', 'Berlin']

Date: 2023-12 

Human cognition and action can be influenced by internal bodily processes such as heartbeats. For instance, somatosensory perception is impaired both during the systolic phase of the cardiac cycle and when heartbeats evoke stronger cortical responses. Here, we test whether these cardiac effects originate from overall changes in cortical excitability. Cortical and corticospinal excitability were assessed using electroencephalographic and electromyographic responses to transcranial magnetic stimulation while concurrently monitoring cardiac activity with electrocardiography. Cortical and corticospinal excitability were found to be highest during systole and following stronger neural responses to heartbeats. Furthermore, in a motor task, hand–muscle activity and the associated desynchronization of sensorimotor oscillations were stronger during systole. These results suggest that systolic cardiac signals have a facilitatory effect on motor excitability—in contrast to sensory attenuation that was previously reported for somatosensory perception. Thus, it is possible that distinct time windows exist across the cardiac cycle, optimizing either perception or action.

Data Availability: The experimental code and analysis scripts are available at https://github.com/Esra-Al/Cardiac_Motor_TMS_EEG . Access to the data and code for all analytical figures can be obtained at the following link: https://osf.io/eg8dz?view_only=7edb12b6e50e4c709ad60579bf5ebd62 . The datasets generated during the current study are available from the corresponding author on reasonable request. Due to a lack of explicit consent on the part of the participants to data sharing, structural MRI and EEG data cannot be shared publicly. Such data can only be shared if data privacy can be guaranteed according to the rules of the European General Data Protection Regulation. If the corresponding author is not reachable for data request, info@cbs.mpg.de can be contacted.

In the present study, we systemically examine whether cortical and corticospinal excitability change across the entire cardiac cycle and whether they interact with HEPs. Additionally, to comprehensively evaluate cardiac-related activity, we investigated variations in heart rate following TMS stimulation throughout the cardiac cycle. Neuronavigated TMS was used in combination with multichannel EEG, in order to comprehensively investigate both cortical and peripheral TMS-evoked responses. If systolic activity attenuates motor excitability, similar to somatosensory perception, TMS pulses during systole would be expected to produce weaker MEPs in the hand muscle and weaker TMS-evoked potentials (TEPs) in the motor cortex. Similarly, increases in HEPs would be expected to attenuate upcoming motor excitability. Alternatively, if behavioral observations of motor facilitation during systole are correct [ 18 , 21 , 23 , 24 ], stronger MEPs and TEPs should be observed. Supporting this latter hypothesis, we found that both peripheral and central TEPs were in fact higher during systole. Moreover, stronger HEPs preceded increases in excitability. In line with these findings, hand–muscle activity and associated desynchronization of sensorimotor oscillations in a motor pinch task were strongest during the systolic heart phase. In addition, in an exploratory analysis, we found a specific influence of TMS on heart rate depending on the cardiac phase, which could be relevant for clinical studies. Taken together, our results reveal that there is a facilitatory effect of systolic activity on motor excitability, possibly connected with an optimal window for action initiation during the cardiac cycle.

One possibility is that cardiac activity exerts its effects through alterations of neuronal excitability in different parts of the brain. A few previous studies have investigated this hypothesis using transcranial magnetic stimulation (TMS) over the primary motor cortex, which induces motor-evoked potentials (MEPs), an indicator of corticospinal excitability. However, so far, no main effect of the cardiac phase on excitability levels has been observed [ 26 – 29 ]. Otsuru and colleagues [ 28 ] showed corticospinal excitability 400 ms after R-peak to be significantly higher in poor compared to good interoceptive perceivers, but the authors did not observe a significant main effect of cardiac phase on motor excitability. There are several possible methodological reasons for these findings. Importantly, the examination of excitability was limited to specific time intervals (only up to 400 ms after R-peak), rather than across the entire cardiac cycle including both systolic and diastolic window. Furthermore, individual brain anatomy was not taken into consideration, possibly resulting in higher variability of the stimulated brain regions. Lastly, these previous studies only included peripheral measures of corticospinal excitability without direct measurement of cortical excitability via concurrent electroencephalographic (EEG) recordings. This approach requires considering multiple concomitant factors to minimize TMS artifacts (see a recent review [ 30 ]). To address this limitation, stimulation intensity needs to be minimized by carefully determining the motor threshold, the effects of TMS clicks should be minimized to avoid acoustic stimulation, the experiment should have a sham condition to account for bone-conducted sound from the coil vibration [ 31 ] and thorough data cleaning to remove TMS artifacts using spatial (for instance, ICA) and temporal filters.

How we perceive and engage with the world is influenced by the dynamic relationship between the brain and the rest of the body including respiratory, digestive, and cardiac systems [ 1 – 6 ]. For example, cardiac activity has been found to influence visual and auditory perception [ 7 – 9 ]. In the domain of somatosensation and pain, perception and neural processing of stimuli have been reported to decrease during the systolic compared to the diastolic phase of the cardiac cycle [ 10 – 13 ]. An overall systolic dampening of cortical processes was suggested to be due to baroreceptor activation during systole [ 14 ]. In support of this view, reaction times to auditory, visual, and tactile stimuli have been shown to be slower for systolic presentation [ 15 , 16 ]. Furthermore, when touch was initiated during systole, the duration of active sensation was longer [ 17 ]. However, for some other motor activities, a facilitatory effect of systole has been observed, for instance, self-initiated movements occurred more frequently during systole [ 17 , 18 ] or around the R-peak [ 19 ]; but see [ 20 ]. Similarly, an effect of the cardiac cycle was also observed in gun shooting, with shooters preferentially triggering a gun in a cardiac window that included a large part of systole and the initial part of diastole [ 21 ]; but also see an opposite effect for elite shooters [ 22 ]. Furthermore, (micro)saccades occur more often during systole whereas fixations during diastole [ 23 , 24 ]. One possible explanation for these effects can be related to blood movement within the body (peripheral), rather than being driven by top-down neural mechanisms (central) [ 23 ]. In addition to cardiac phase effects, stronger neural responses to heartbeats, i.e., heartbeat-evoked potentials (HEPs), are followed by increases in visual perception and decreases in somatosensory detection [ 11 , 13 , 25 ]. These results, therefore, suggest that cardiac activity could interact with both perception and action. However, it is not known whether a central/cortical mechanism underlies these cardiac effects.

Next, we investigated whether our findings of larger motor excitability during systole might have been related to the displacement of the cortex due to blood hemodynamics (as a result of cardiac activity). Previous research has shown that the mechanical displacement of the cortex follows an inverse u-shaped pattern across the cardiac cycle and reaching its maximum at 450 to 500 ms after the R-peak [ 33 ]. As the electric field induced by a TMS pulse is stronger when the coil is closer to the brain [ 34 ], any heart phase–dependent modulation of MEPs could potentially be influenced by cortical tissue movement towards the skull. If this was the case, we would expect a stronger TMS stimulation at the peak of the displacement. Therefore, we examined whether our findings displayed a similar temporal pattern as observed in the displacement of cortical tissue to shed light on this aspect. To investigate whether MEP amplitudes followed a similar pattern across the cardiac cycle, we first visualized MEP amplitudes across 50 ms bins following the previous R-peak ( S3 Fig ). This demonstrated that MEPs were maximal during the first 50 ms and gradually decreased across the cardiac cycle. To statistically test the relationship between MEP amplitudes and the distance from the previous heartbeat, linear-mixed-effects model regressions were fit on the single-trial level. The linear regression that included the cardiac distance (MEP ~ distance + (1 | participant)) explained the empirical data better than the null model, i.e., a model with no relationship assumed (MEP ~ (1 | participant); χ 2 = 4.67, p = 0.03). Crucially, this linear model also showed a better fit than a second-degree polynomial model (MEP ~ distance + distance^2+ (1 | participant), χ 2 = 0.34, p = 0.6). This result indicates that the changes in MEP amplitudes do not follow a u-shaped pattern across the cardiac cycle and are thus not likely to be explained by the displacement of the cortex due to blood influx or efflux.

To test whether these effects are induced by overall changes in cardiac activity during TMS stimulation, we further tested the differences in HEP activity during TMS stimulation and resting-state condition (without TMS stimulation). No significant differences in HEP amplitudes during TMS and resting-state were observed (no clusters were found; S2 Fig ). Overall, these analyses show that increases in HEP amplitudes lead to stronger motor excitability levels, which again stands in contrast to the previous HEP findings in somatosensory perception.

( a ) To assess relationship between HEPs and motor excitability, single trials were sorted according to MEP amplitudes and split into 3 equal bins for each participant. HEP amplitudes between 304 and 328 ms following the R-peak (the highlighted gray area) were higher preceding strong compared to weak MEPs across the centroparietal electrodes. The topography contrast represents HEP amplitude difference preceding strong versus weak MEPs between 304 and 328 ms. ( b ) (left) The neural sources of HEP differences preceding strong and weak MEPs are visualized. (right) Same as the left figure but displaying the strongest generators only (thresholded at 85% of the maximum activity and clusters sizes of at least 5 vertices). *p < 0.05, ***p < 0.0005.

The analysis of cardiac phase effects on motor excitability showed a contrasting pattern to the previous findings on somatosensory perception. Here, we asked whether a similar contrast would be observed for another aspect of heart–brain interactions, which is the cortical responses to heartbeats, so-called heartbeat-evoked potentials (HEPs). Therefore, we analyzed the relationship between HEPs and motor excitability levels. To be able to distinguish cardiac and TMS-related neural processing, we first only chose trials in which the TMS stimulation occurred at least 400 ms after the preceding R-peak in line with the previous studies [ 11 , 13 ]. This allowed us to investigate the relationship of HEPs (during systole) with MEPs (during diastole) within the same cardiac cycle. For this purpose, we sorted individual trials based on their MEP amplitudes, ranging from weak to strong, and divided them into 3 equal bins for each participant. The sorting was based on MEP amplitudes since they were present in every single trial included in the analysis. Subsequently, we compared the prestimulus HEP amplitudes preceding weak (first bin) and strong (third bin) MEP levels. This comparison was conducted using a cluster-based permutation t test within the time window of 296 to 400 ms post R-peak, focusing on the centroparietal electrodes as identified in previous studies [ 11 , 13 ]. HEPs were significantly higher preceding strong compared to weak MEP amplitudes, between 304 and 324 ms over the centroparietal electrodes (p cluster = 0.021 corrected for multiple comparisons in space and time; Cohen’s d = 0.48; Fig 6A and 6B ). We then asked whether MEP amplitudes during the first 400 ms of the cardiac cycle are influenced by HEP activity in response to the previous cardiac cycle. This analysis showed that HEP amplitudes were more positive between 362 and 394 ms at centroparietal electrodes preceding strong compared to weak MEP amplitudes (p cluster = 0.018 corrected for multiple comparisons in space and time; Cohen’s d = 0.53; S1 Fig ).

To control whether these heart rate changes were due to genuine effects of TMS rather than artifacts (for instance, auditory, somatosensory) induced by TMS application, heart rate across time was subtracted with the heart rate during the sham TMS condition individually for each time interval and cardiac phase. This analysis again showed a similar main effect of time (F 2, 70 = 7.42, p = 1⋅10 −3 , ges = 4⋅10 −3 ) and an interaction of time and cardiac phase (F 1.56, 54.64 = 3.88, p = 0.03, ges = 3⋅10 −3 ) on heart rate. These results suggest that heart rate is influenced by TMS only when administered during systole but not during diastole.

Previous research suggests that TMS stimulation has significant effects on heart rate [ 32 ]. However, it is not known whether this effect depends on the cardiac phase of the TMS stimulation. Therefore, in an exploratory analysis, we investigated the changes of the heart rate in response to TMS stimulation during systole and diastole. As a measure of heart rate, we calculated the length of interbeat intervals in the cardiac cycles before TMS (pre-TMS), during TMS, and post-TMS stimulation. The analysis showed a main effect of time (F 2, 70 = 23.11, p = 2⋅10 −8 , ges = 2⋅10 −4 ) and an interaction of time and cardiac phase (F 2, 70 = 10.30, p = 1⋅10 −4 , ges = 2⋅10 −4 ) on heart rate. Comparison of heartbeat intervals preceding TMS and concurrent with TMS revealed a significant cardiac deceleration when TMS stimulation occurred during systole (t 35 = −5.73, p = 2⋅10 −6 , Cohen’s d = 0.96). This was followed by a cardiac acceleration (from TMS to post-TMS; t 35 = 8.58, p = 4⋅10 −10 , Cohen’s d = 1.43; Fig 5 ). No significant changes were observed for stimulations during diastole (from pre-TMS to TMS, t 35 = 0.75, p = 0.5 and from TMS to post-TMS, t 35 = 0.42, p = 0.68; Fig 5 ). Post hoc t tests showed that there was no significant difference in heart rate before TMS stimulation between systole and diastole (t 35 = 1.83, p = 0.075), whereas the heart rate difference was significant during TMS stimulation (t 35 = 2.10, p = 0.043, Cohen’s d = 0.35). This difference was no longer statistically significant in the post-TMS window (t 35 = 1.80, p = 0.080).

Following the analysis of the muscle activity in the periphery, we also tested whether sensorimotor oscillations in the motor areas desynchronize differently following the initiation of the pinch during systole and diastole. This analysis demonstrated that the desynchronization of sensorimotor oscillations in the range of 8 to 25 Hz was stronger between 0 and 726 ms following pinch onset during systole as compared to diastole (p cluster = 0.012, Cohen’s d = 0.37; Fig 4B and 4C ). To investigate whether this finding was influenced by cardiac-related artifacts, we again sampled systolic and diastolic windows during the resting state and tested the differences in sensorimotor oscillations between systole and diastole. Also, in this control analysis, no significant differences were found (p cluster = 0.12). Thus, these results indicate that both peripheral muscle activity and its central correlates are stronger when the movement starts during systole as compared to diastole.

( a ) Muscle force, measured by the linear envelope of EMG activity in the left hand, was significantly higher from 340 to 454 ms following pinch onset (at 0 ms) during systole compared to diastole. ( b ) Similarly, systolic and diastolic sensorimotor oscillations were analyzed in the range of 8–30 Hz in the sensorimotor electrodes to quantify event-related desynchronization following the muscle activation. Cluster statistics revealed that when participants started the pinch during systole, the desynchronization of sensorimotor oscillations was higher in the frequency range of 8–25 Hz between 0 and 726 ms following pinch onset. The raster plot shows the contrast between systole and diastole. ( c ) The topography of the significant contrast between systole and diastole.

To determine whether changes in motor excitability during systole facilitate muscle activity in the absence of TMS stimulation, we analyzed cardiac effects on muscle activity in a follow-up motor pinch task. During the task, participants were asked to pinch a dynamometer with their index finger and thumb, while we recorded EMG, EEG, and ECG signals ( Fig 4A ). To estimate peripheral muscle force, we calculated the envelope of EMG activity when participants initiated the pinch during systole and diastole (see EMG envelope in the Methods section). Cluster statistics revealed a significant increase in the EMG envelope from 340 to 454 ms after the onset of the pinch during systole compared to diastole (p cluster = 0.02, Cohen’s d = 0.44; Fig 4A ). To test whether this finding might have been related to blood circulation–related changes in the fingers, we sampled systolic and diastolic EMG activity during the resting state condition. This analysis did not reveal any significant difference in the resting EMG envelope between systole and diastole (no significant clusters were found). This indicates that there was no influence of cardiac-related artifacts on the EMG signal across the cardiac cycle.

( a ) TEPs, in response to TMS stimulation, at the electrodes closest to the motor hotspot (C4; CP4; C6; CP6). Early TEPs were significantly larger during systole compared to diastole in motor areas between 22 and 60 ms. The contrast between systole and diastole in this time window is shown in the topography plot. ( b ) Same as in ( a ), for the sham TMS condition. No significant differences between systole and diastole were observed here. ( c ) The difference curve between real TMS and sham, for systole and diastole (sham-corrected TEP contrast). After correcting for the TMS and physiological artifacts, TEPs during systole and diastole were significantly different between 24 and 60 ms. ( d ) The source reconstruction of the corrected TEP contrast (systole minus diastole) between 24 and 60 ms (left), and same displaying the strongest generators only (thresholded at 85% of the maximum activity and clusters sizes of at least 5 vertices; right).

In addition to corticospinal excitability, we also aimed to test differences of purely cortical responses to the TMS pulse between the systole and diastole phases of the cardiac cycle. Cortical excitability was probed by early TEPs (15 to 60 ms post-TMS) measured from a cluster of electrodes (C4, CP4, C6, CP6) over the right motor cortex (hotspot). By focusing on this time window, we prevented a possible contamination of cranial muscle artefacts in the very early peaks as well as sensory-evoked potentials in the later time windows [ 30 ]. TEP amplitudes between 22 and 60 ms following the TMS stimulation were stronger during systole as compared to diastole (cluster-based permutation t test, p cluster = 0.009; Cohen’s d = 0.41; Fig 3A ). To test whether these results were indeed related to neural activity of the cortex, rather than reflecting TMS and cardiac artifacts, we contrasted them with the sham TMS condition. During the sham condition, a plastic block between the coil and the participant’s head was placed to keep air- and bone-conducted auditory and somatosensory sensations similar to the real TMS [ 31 ]. Additionally, pulse-related artifacts in the EEG were expected to be similar to the real TMS stimulation. Therefore, if the cardiac cycle effect on TEPs is a genuine modulation of evoked neuronal responses to TMS, it should not be present in the sham condition. A cluster-based permutation test did not reveal any significant difference in TEPs in response to sham TMS during systole and diastole (p cluster = 0.2; Fig 3B ). Furthermore, to account for physiological and stimulation artifacts, TEPs during sham were subtracted from those in the real TMS condition. The TEP difference was significantly higher between 24 and 60 ms during systole relative to diastole (p cluster = 0.008, Cohen’s d = 0.41; Fig 3C ). The corresponding neural sources of the TEP difference between systole and diastole were observed to be maximal around the right primary motor cortex ( Fig 3D ). These results show that similar to corticospinal excitability, purely cortical excitability increases during systole, suggesting increased neuronal excitability in the motor system.

( a ) Schematic of the cardiac cycle. The systolic phase (indicated in red) starts with the R-peak and reflects the ventricular contraction of the heart (leading to blood ejection), whereas the diastolic phase (indicated in blue) represents the relaxation phase during which the heart refills with blood. To equate the probability of a stimulation event occurring in either of the 2 phases, equal lengths of systole and diastole were defined. ( b ) MEP amplitudes of the first dorsal interosseus muscle in the left hand are higher in response to TMS stimulation during systole (red) compared to diastole (blue). The individual points indicate the mean MEP amplitudes for each participant. *p < 0.05. Access to the data and code for all analytical figures can be obtained at the following link: https://osf.io/eg8dz?view_only=7edb12b6e50e4c709ad60579bf5ebd62 .

( a ) TMS was applied over the right primary motor cortex of the participants. The motor response to TMS in their left hand, i.e., MEP, was measured by bipolar EMG. Their cortical responses to TMS, the TEP, as well as to heartbeats, the HEP, were measured using multichannel EEG. The heart activity was recorded via ECG. ( b ) After determining the individual RMT, participants underwent a resting-state EEG measurement. Thereafter, 416 single TMS pulses with an intensity of 120% of the RMT were applied in 4 blocks. There were also 4 blocks of sham conditions, in which a plastic block was placed between the TMS coil and the head of the participant. The pairs of real and sham TMS blocks were randomized across the participants. At the end of the TMS blocks, participants performed a motor pinch task. In this task, they were instructed to squeeze a pinch gauge with their left thumb against the index finger while a red circle was presented in the middle of the monitor. When the circle became green, they relaxed their fingers. In this order, participants performed 30 trials. ECG, electrocardiography; EEG, electroencephalography; EMG, electromyography; HEP, heartbeat-evoked potential; MEP, motor-evoked potential; RMT, resting motor threshold; TEP, TMS-evoked potential; TMS, transcranial magnetic .stimulation

We first aimed to determine whether corticospinal excitability changes systematically over the phases of the cardiac cycle. For this purpose, we applied TMS to the right primary motor area at random time points across the cardiac cycle and recorded MEPs of the first dorsal interosseus muscle in the left hand in 36 participants. Following the TMS administration, the corresponding cardiac phase was determined posteriori (see Methods for the details; Fig 1 ). Consistent with the notion of corticospinal excitability changes across the cardiac cycle, MEP amplitudes were significantly higher during systole to diastole (Wilcoxon signed rank test, V = 463, p = 0.040, Cohen’s d = 0.341; Fig 2 ). As an additional control of a potential effect of ECG artefact on EMG activity, systolic and diastolic EMG activity during the sham condition was subtracted from real TMS activity. After this control analysis, MEP amplitudes remained significantly higher during systole (V = 463, p = 0.041, Cohen’s d = 0.340). So, these results suggest that corticospinal excitability is higher during systole compared to diastole.

Discussion

Using simultaneous recordings of brain activity, heart activity, and muscle activity, this study discovered that the timing of heartbeats and their neural processing were linked to changes in the excitability of the motor system. Our findings build upon previous evidence showing that somatosensory perception is affected during the systolic phase of the cardiac cycle and when heartbeats evoke stronger cortical responses. To delve deeper into these cardiac effects, we examined whether they arise from overall changes in cortical excitability. For this, we performed simultaneous recordings of cortical and corticospinal excitability using electroencephalography (EEG) and electromyography (EMG) responses to TMS, along with concurrent monitoring of cardiac activity using electrocardiography (ECG). As a result, we observed multiple complementary effects of cardiac signals on motor activity. Specifically, we discovered that cortical and corticospinal excitability reached their highest levels during systole and were enhanced following stronger neural responses to heartbeats. Additionally, in a motor task, we observed that hand–muscle activity and the associated desynchronization of sensorimotor oscillations were more pronounced during systole. These findings suggest that systolic cardiac signals exert a facilitatory effect on motor excitability, which contrasts with the sensory attenuation previously reported in somatosensory perception. Therefore, our study sheds light on the existence of distinct time windows across the cardiac cycle that potentially optimize perception and action.

Importance of methodology for current findings Methodological differences are likely to explain the absence of cardiac modulation of motor excitability in previous TMS studies [26–28]. In those studies, time resolution across the cardiac cycle was rather limited. Unlike in our study, TMS stimulations were not presented throughout the entire cardiac cycle, they were rather presented up to 400 or 600 ms after the heartbeats and at specific time points (for instance, 100 ms after R-peak). Since our study revealed a linear decrease in motor excitability throughout the cardiac cycle, previous studies might not have been able to sample the decrease towards the end of the cardiac cycle. Furthermore, combining a neuronavigational system with individual brain scans provided us with a higher spatial specificity for the stimulation location, in comparison to previous studies. In addition, our study had the advantage of a larger sample size and trial numbers, which contributed to higher statistical power to detect the cardiac-cycle effects on motor excitability [26–28]. Since the observed MEP effect was rather small in our study, a larger set of participants (as in the present study) would indeed facilitate a statistical detection of differences. Finally, previous studies only tested cardiac effects on peripheral MEPs without concurrent cortical recordings. Yet, it is known that peripheral MEPs reflect excitability changes at both cortical and spinal cord levels and special measures should be taken (such as H-reflex) in order to disentangle excitability changes between these 2 levels [35]. On the other hand, TEPs directly reflect changes in cortical excitability, especially at early latencies [36]. This can also explain why we observed a stronger effect size for the cardiac modulation of TEPs as compared to MEPs.

Central and peripheral changes of motor excitability across the cardiac cycle Cardiac cycle effects on motor excitability are consistent with previous findings of increased frequency of muscle movement during systole as compared to diastole [18,21,23,24]. Here, we showed that TMS during systole is associated with higher corticospinal and cortical excitability in motor areas. Thus, motor-related activity seems to be facilitated during systole. This, in turn, may also explain why eye movements [23,24], for instance, (micro)saccades, and voluntary hand movements [21], for instance, firing a gun, have been found to occur more often during systole. One could also argue that the effects we found were merely due to the fact that the distance of the brain to the skull (and, thus, the TMS coil) changes due to fluctuations in intracranial pressure throughout the cardiac cycle [37]. This, in turn, should affect the induced electric field from TMS. However, our control analyses did not support this argument. More specifically, the movement of the brain follows an inverse u-shaped pattern across the cardiac cycle and reaches a maximal distance at about 450 to 500 ms after the previous heartbeat [33]. If the cortical movement across the cardiac cycle was responsible for the cardiac phase effects, then MEPs would be expected to follow a similar pattern across the cardiac cycle. However, MEP amplitudes decreased rather linearly across the cardiac cycle, differently than effects that would be expected due to cortical movement. This result indicates that the changes in MEP amplitudes are not likely to be explained by the displacement of the cortex across the cardiac cycle. Another possible artifact, which can influence the amplitude of the evoked activity, are muscle-related far-fields from the cardiac activity (typically referred to as “cardiac artifacts” in the EEG). To control for those, we included a sham condition, in which auditory, tactile, and cardiac artifacts were comparable. After the correction of real TMS recordings with the sham condition, cortical excitability was still significantly higher during systole as compared to diastole. Overall, we found that the excitability in the sensorimotor cortex is increased in systole and correspondingly such increase is mirrored in the strength of the motor output. However, the strength of the motor output is not the only parameter important for motor control. The timing of the movement initiation as well as the coordination between different muscle groups could be equally important for the functionally relevant motor output. These aspects should be investigated in future studies. The cardiac cycle was also observed to affect muscle activity in a motor task, where participants were asked to pinch and release a dynamometer with their left index finger and thumb. When the pinch was initiated during systole, compared to diastole, muscle activity was transiently stronger, suggesting a systolic increase in the applied force [38]. In addition to the peripheral activity, we analyzed cardiac effects on the central neural activity during the motor task. Previous studies have shown that following muscle contractions, sensorimotor oscillations desynchronize in the motor regions, which is reflected as an amplitude decrease in the alpha and beta range [39,40]. Here, we found that this desynchronization transiently increased when the pinch was initiated during systole. Furthermore, these cardiac effects on the muscle-related activity are not likely due to cardiac artifacts, since no significant differences in muscle and neural activity were observed across the cardiac cycle while participants were resting. Overall, these findings suggest that muscle activity is stronger when movement is initiated during systole due to an increase in motor excitability.

Underlying mechanisms and the link to perception The increased motor excitability during systole seems to be at odds with the previously shown cardiac effects on perception. For example, we recently demonstrated that somatosensory percepts and their neural processing are attenuated during systole [11,13]. To compensate for this reduced perceptual sensitivity, a recent study revealed that touches initiated in the systole phase were held for longer periods of time [17]. These findings could be explained by an interoceptive predictive coding account, which postulates that rhythmic cardiac signals are predicted and suppressed from entering conscious perception. This mechanism was suggested to additionally inhibit the perception of coincident weak external stimuli [11,13]. Furthermore, this suppression of nonsalient sensory stimuli was suggested to lead to a greater uncertainty about threatening factors in the environment [41]. To compensate for it, the organism might increase expectation for a “risk” and use its limited resources for a “flight or fight” motor response, which can be potentially mediated by increased baroreceptor activity during systole. Therefore, it is possible that the increased motor activity during systole might provide a survival advantage. Hence, this would suggest that there are different optimal windows for action and perception throughout the cardiac cycle. This idea also fits well with previous studies on “sensory gating,” in which somatosensory perception and evoked potentials were shown to be attenuated during movement [42–44]. This would also explain why eye movements occur more often during systole, whereas eyes fixate on visual stimuli more often during diastole [23]. Given that action has an inhibitory effect on perception, it is plausible that systolic facilitation of action is indeed consistent with inhibition of perception during the systolic phase of the cardiac cycle. It is also important to note that different cardiac effects occur within the systolic and diastolic cardiac phases. During systole, in response to changes in blood pressure, baroreceptors become maximally active approximately 300 ms after R-peak [45]. This change in baroreceptor activity has been suggested to be the driving force of the cardiac effects on perception. For example, during this time window, the processing of somatosensory and pain stimuli is shown to be minimal [11,13,46]. These findings were in line with the idea that activation of baroreceptors cause an overall decrease in cortical excitability [14,47,48]. However, in the current study, we observed that motor excitability was strongest during the pre-ejection period of the systole, before arterial pressure starts to increase and activate baroreceptors. Therefore, the cardiac-related effects on the motor domain might not be mediated primarily by baroreceptor activity but rather via a direct neural pathway involving cardiac afferent neurons. These neurons receive inputs from sensory receptors within the heart and transmit signals to coordinate heart rate and other cardiac functions. They fire at specific phases of the ECG signal, such as around the R or T-waves, depending on their location and transduction characteristics. Importantly, they have a fast conduction velocity leading to a rapid cortical activation [49]. Future studies could investigate this idea by using animal models.

Possible clinical relevance of heart rate changes following TMS stimulation Cortical excitability changes have been associated previously with epilepsy, disorders of consciousness, stroke, and depression [50,51]. To counterbalance these abnormalities in cortical excitability, therapeutic applications of TMS have been introduced, for instance, for treating depression [51] or facilitating motor recovery during neurorehabilitation in stroke [50]. Our results on cardiac modulations of cortical excitability raise some important questions for these clinical populations using different TMS protocols. For example, it remains unknown how cortical excitability over the cardiac cycle is modulated in those pathological conditions. Furthermore, our observation that TMS induces changes of the heart rate during systole, i.e., when the cortical processing of heartbeats occurs, but not during diastole, can have important implications for the clinical use of TMS. For instance, in case the changes in heart rate during TMS application are of clinical concern for patients, our results, based on single pulse TMS, suggest that stimulation during diastole may help mitigate these undesired effects. Addressing these questions in future research could provide valuable insights for patients undergoing TMS in clinical settings.

Relationship between heartbeat-evoked potentials and motor excitability levels Another effect of cardiac activity on motor excitability was found on the cortical level. We observed that HEPs, during systole, showed higher positivity over centroparietal electrodes between 304 and 328 ms preceding strong as compared to weak corticospinal excitability (as measured by TMS-induced MEPs). These results again diverge from our previous results on somatosensory perception, in which we observed higher HEPs preceding attenuated somatosensory processing. We previously explained increases in HEPs as a result of an attentional switch from the external world to internal bodily signals, such as heartbeats [11]. This was further supported by higher HEP amplitudes when participants were resting compared to engaging in an external task [13]. If internal attention levels changed in the current study during the TMS condition compared to rest, we would expect lower HEPs during the TMS condition. However, in the current study, there was no significant change in HEPs during the TMS application in comparison to the resting state of the participants. This was probably related to the absence of an external task during the TMS condition. Another factor, which can positively influence HEP amplitude, is arousal [52]. Increases in arousal are also known to increase motor excitability [53] as well as heart rate [1,54]. Supporting a possible involvement of arousal in our study, we observed that heart rate became higher as motor excitability increased. Therefore, we suggest that increases in arousal might be responsible for increases in HEP amplitudes for stronger motor excitability. It is also possible that since this analysis involves HEPs and MEPs, which were close in time, there was a similar cortical state for both responses due to intrinsic neuronal dynamics. If the magnitude of both HEPs and MEPs reflects increased cortical excitability, then a positive correlation would be expected, since cortical excitability changes on many time scales [55], including a period covering both pre- and immediate post-stimulus intervals.

Limitations While the present study provides valuable insights into the influence of cardiac oscillations on motor excitability, there are several limitations that should be acknowledged. Firstly, the study sample consisted of young white individuals between the ages of 18 and 40. Although we anticipate that our findings may extend to the broader population, it is crucial for future studies to investigate the effects of cardiac oscillations in more diverse participant populations across different racial groups. Secondly, we only stimulated the right motor cortex. Further research should examine whether similar cardiac effects on motor excitability can be observed for left-hemispheric stimulation. Finally, we did not examine the potential impact of respiratory oscillations on the observed results. As respiration has been shown to organize neural dynamics [56] and modulate cortical excitability [57], it would be important for future studies to investigate how respiratory phase (i.e., inhale and exhale) during TMS stimulation and movement initiation might influence the effects of cardiac oscillations.

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002393

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