Changes in resting vmHRV predicting changes in SSRTs
Our linear regression model revealed that there were no significant associations between changes in resting vmHRV and changes in SSRTs,β = .53, SE = .39, t (62) = 1.34, p = .18 (see Table 5). As already observed in a previous linear regression model, we found a significant effect of age on the changes in SSRTs from the first to the second ESST, β = 4.18, SE = 1.85,t (62) = 2.26, p < .05.
Discussion
Based on a vast amount of evidence demonstrating correlations between cognitive functioning as well as emotional well-being and vmHRV, current theories in the fields of autonomic neuroscience and psychophysiology (see Laborde et al., 2018; Smith et al., 2017; Thayer & Lane, 2000) suggest the regulation of cognitive-affective and autonomic processes to be highly linked to each other. Accordingly, this connection is established by a shared neural network consisting of widespread cortical and subcortical regions. Meta-analytical evidence indicates the PFC to be a key hub within this network, showing that higher prefrontal activity is associated with higher levels of vmHRV (Thayer et al., 2012). However, since these results are correlational in nature, they do not allow to draw any causal inferences regarding the mechanism underlying these relationships. In this study, we used rTMS (i.e., cTBS and iTBS) over the left dlPFC to test the proposed links between PFC activity, cognitive-affective processing, and vmHRV. As such, the goal of the present study was threefold. First, we aimed to replicate our previous findings indicating that resting vmHRV, vmHRV reactivity as well as the interaction between both predicts cognitive-affective processing in an ESST (Schmaußer & Laborde, 2023); second, to investigate the effects of cTBS and iTBS on cognitive-affective processing as well as on resting vmHRV, vmHRV during performance of the ESST, and vmHRV reactivity; and third, to examine whether stimulation-induced changes in vmHRV directly predict changes in cognitive-affective processing operationalized as SSRT.
In regards of our assumptions concerning the predictive value of resting vmHRV and vmHRV reactivity in relation to cognitive-affective processing, the results of this study provide partial support for our hypotheses. While there were no significant associations between neither resting vmHRV nor vmHRV reactivity and task performance in the first ESST trial (see Table 2), such links could be found for the execution of the ESST after stimulation (see Table 3). As such, we found that vagal withdrawal during the execution of the ESST after stimulation was associated with slower SSRTs, whereas increase of vagal activity predicted faster SSRTs. Decreases of vmHRV, as a marker of vagal withdrawal, have been widely associated with increased arousal as part of the physiological fight or flight response (Appelhans & Luecken, 2006; Hildebrandt et al., 2016). In line with our results, previous research indicates that increased arousal (e.g., as a consequence of acute stress or anxiety) leads to increased early sensory processing (Shackman et al., 2011) as well as to a more sensitive, though relatively indiscriminate, processing of biologically salient stimuli within the amygdala (van Marle et al., 2009). Employing a predictive coding approach, Cornwell et al. (2017) suggest that heightened arousal increases primary cortical excitability and decreases prefrontal feedback modulation (i.e., decreasing precision of prior goal representations), thereby amplifying prediction errors. Consequently, sensory-perceptual processes may depend exclusively on local stimulus variations, supporting a rapid and direct sequence between detection and response to potentially threatening stimuli. However, according to Cornwell et al., (2017) these mechanisms, though promoting self-preservation under dangerous conditions, may have profound, downstream effects on cognitive processes that rely on more complex perceptual processing and controlled behavioral responding, such as working memory and response inhibition. Increases in vmHRV, on the other hand, may be associated with increases in the precision of goal representations, thereby facilitating cognitive processes critical for goal-directed behavior, such as working memory and response inhibition.
As hypothesized, effects of vmHRV reactivity on ESST performance were more pronounced in participants showing low levels of vmHRV at rest compared to those with high levels of resting vmHRV. Given that, contrary to our expectations, higher resting vmHRV was not found to be linked with faster SSRTs, our results suggest that higher resting vmHRV may contribute to enhanced cognitive processing stability under demanding situations rather than predicting a heightened degree of goal-relevant processing per se. These findings are in line with recent evidence from Spangler and MCGinley (2020) who found that higher resting vmHRV was not associated with mean inhibition performance in a stroop task, but with performance stability across different stroop conditions including different kinds of emotional auditory distractors.
Another aim of this study was to investigate the effects of two rTMS protocols, namely cTBS and iTBS, on both vmHRV and cognitive-affective processing. Based on an extensive theoretical background suggesting the role of the PFC in regulating autonomic processing (Smith et al., 2017; Thayer et al., 2009), as well as recent meta-analytic evidence (Makovac et al., 2017; Schmaußer et al., 2022), we hypothesized that increasing the excitability of the left dlPFC by iTBS will lead to increased vmHRV at rest and during task performance. Given the supposed inhibitory effects of cTBS, we expected the use of cTBS to produce opposite outcomes. While we found no effects of stimulation on neither on-task vmHRV nor vmHRV reactivity during task performance, a significant effect of stimulation was found on resting vmHRV. In accordance with our assumptions, we observed that cTBS lead to a significant decrease in vmHRV at rest compared to iTBS and sham stimulation. Within theNeurovisceral Integration Model , it is proposed that activity within the PFC constantly exerts inhibitory effects on cardioacceleratory circuits within the CAN (Smith et al., 2017; Thayer et al., 2009). In line with these assumptions, we suggest that cTBS over the left dlPFC reduced prefrontal activity, leading to disinhibition of the circuits mentioned above, thereby decreasing vmHRV. However, contrary to our hypotheses, our results yielded no effect of iTBS compared to sham on resting vmHRV. Whereas we had expected iTBS to increase prefrontal activity and thus vmHRV at rest, our results suggest that iTBS elicited rather variable responses instead of a constant increase in resting vmHRV (see Figure 3). By including levels of state anxiety as covariate in our statistical models, we were able to rule out that these variable responses were driven by the effects of state anxiety which have been found previously (Poppa et al., 2020). Another possible explanation for this response pattern lies in the nature of iTBS. Previous evidence has demonstrated high variation in the neural response to standard iTBS (Hamada et al., 2014; López-Alonso et al., 2014). Consequently, there may have been a high inter-individual variability in how iTBS affected neuronal dynamics within the CAN, thereby producing variable responses in vmHRV. As recent attempts have demonstrated the efficacy of individualized iTBS in decreasing variance in induced neuronal responses (Chung et al., 2019), we want to stimulate future research to investigate the effects of individualized rTMS protocols on the robustness of TMS-induced responses in vmHRV.
In addition to the effects of TBS on vmHRV, we also aimed to investigate the effects of TBS on cognitive-affective processing in an ESST (Allen et al., 2021). As hypothesized, we found a significant effect of stimulation on ESST performance with iTBS leading to a more pronounced decrease in SSRTs compared to sham stimulation. This result adds to a substantial body of evidence demonstrating iTBS over the left dlPFC to exert amplifying effects on cognitive and affective processes (Pabst et al., 2022). Given the role of the dlPFC in the maintenance of contextual goal representations (Curtis & D’Esposito, 2003), we assume that the positive effects of iTBS on ESST performance may act by strengthening ESST-related goal representations (i.e., inhibition of motor response), thereby counteracting stimulus-driven action tendencies. Interestingly, the decrease in SSRTs did not differ between iTBS and cTBS. Furthermore, contrary to our assumptions, SSRTs decreased more in participants that received cTBS compared to those that received sham stimulation, though this effect was not significant. While prevailing literature largely denotes inhibitory outcomes of cTBS over the left dorsolateral prefrontal cortex (dlPFC) on cognition, there have been sporadic cases reporting ameliorative effects (Ngetich et al., 2020). These contradictory effects have been suggested to be a result of so-called addition-by-subtraction (Luber & Lisanby, 2014). Followingly, cTBS may inhibit competing or distracting cognitive processes, hence improving task-performance. Therefore, it seems plausible that the noted enhancement in ESST performance subsequent to cTBS may arise from the disruption of cognitive processes that either compete with or distract response inhibition.
Finally, based on the presumed shared role of the PFC in both cognitive-affective and autonomic processing, we expected a direct link between the effects of TBS on vmHRV and on ESST performance. In detail, we hypothesized that increases in resting vmHRV after stimulation will predict improved ESST performance and vice versa. Nevertheless, our analyses detected no such link between changes in vmHRV and ESST performance (see table 5). The absence of significant findings in this context may be explained by prior literature emphasizing the dynamic involvement of the dlPFC in neurovisceral integration. As such, previous research proposes that the influence of dlPFC on cardiac vagal activity may strongly depend on situational demands. Notably, McIntosh et al. (2020) demonstrated stronger connectivity of dlPFC with the middle frontal gyrus to be linked with higher vmHRV during resting state in a large sample of 271 individuals. Additionally, dlPFC was found to exhibit a positive correlation with vmHRV during experimental emotion induction (Lane et al., 2009) and cognitive emotion regulation (Neacsiu et al., 2022), yet no such associations emerged in an emotional counting Stroop task (Lane et al., 2013; Smith et al., 2014) and dietary self-control challenges (Maier & Hare, 2017). Intriguingly, despite the emotional or motivational aspect across tasks, differences in participant instruction regarding cognitive resource direction were apparent. Whereas dlPFC activity correlated with vmHRV when participants were explicitly directed to engage with emotional stimuli, no such connection was evident when no deeper cognitive processing of the emotional stimuli was emphasized. In this context, Lane et al. demonstrated that during emotion induction, dlPFC activity was linked to vmHRV in both emotional and neutral conditions, while they found no emotion-specific association between dlPFC activity and vmHRV. Since the authors explicitly asked participants to uphold the goal of preserving the intended emotion or neutral state throughout each scan, they posited that dlPFC activity reflects emotional state maintenance in working memory, thereby influencing vmHRV. Consistent with these observations, Smith et al. (2017) have recently posited, within a hierarchical model of neurovisceral integration, that connectivity among distinct regions contributing to ANS activity can be dynamically modulated. Consequently, the impact of higher-level regions such as the dlPFC on vagal output is engaged selectively in situations demanding their influence.
Building upon this line of evidence, we assume the absence of a significant association between stimulation-induced changes in resting vmHRV and ESST performance in our study to be a result of dynamic dlPFC recruitment in the regulation of vmHRV. In this light, our findings indicate that TBS administered to the dlPFC resulted in alterations of dlPFC activity, influencing vmHRV during resting state but not during the execution of the ESST. This explanation further provides insight into why, in contrast to our hypotheses, stimulation effects were absent on task-related vmHRV and vmHRV reactivity, while still resulting in a significant impact on ESST performance. Nonetheless, it has to be noted that the ESST version used in this study did contain emotional stimuli which need to be processed. However, we contend that the particular nature of the ESST employed in this study recruits dlPFC activity primarily for maintaining the goal representation concerning response inhibition within working memory. In contrast, the evaluation of emotional stimuli (positive vs. negative) rather demands sensory-perceptual processing than the retention of emotional evaluation within working memory. As we are aware of the speculative nature in which we interpret our results in this regard, we know that future research is highly warranted in order to test our assumptions. Hence, to validate our assumptions, we suggest investigating whether changes in vmHRV via dlPFC stimulation distinctly predict performance shifts in tasks that exhibit varying levels of dlPFC engagement in regulating emotional and autonomic processes.
Limitations
Despite its strengths, certain limitations of this study should be acknowledged. First, it should be noted that the experimental session, including stimulation, as well as the statistical analysis were conducted by the first author in an unblinded manner. Hence, it remains plausible that potential experimenter expectation effects might have unintentionally influenced the experimenter’s conduct throughout both the experimental session and statistical analyses, even though we tried to counteract such effects by a strict experimental protocol. Another limitation concerns the interpretation and categorization of our results. While our results indicate a different contribution of the left dlPFC to autonomic regulation at rest and during ESST execution, they do not allow insights into the neural underpinnings of this phenomenon. We believe that integrating the methods employed in this study with imaging techniques such as fMRI and EEG will enable the assessment of contextual shifts in neuronal dynamics and functional connectivity among brain regions. Consequently, this attempt may hold potential to improve our understanding of the complex interplay between cognitive-affective, autonomic, and neuronal processes.
Conclusion
Overall, our findings build upon existing evidence highlighting the role of the left dlPFC in regulating cognitive-affective and autonomic processing. While we found TBS effects on both ESST performance and vmHRV, our results also demonstrate the substantial intra-individual variability within TBS outcomes reported in current literature. Further, our findings reveal no significant correlation between changes in vmHRV and ESST performance, alongside distinct effects of TBS on these two measures. These results can be interpreted within the framework of a hierarchical model of neurovisceral integration, suggesting that the recruitment of higher-order cortical areas, such as the left dlPFC, to autonomic regulation proceeds flexibly in accordance with situational demands. While more research in this regard is highly warranted, these findings represent an important step in uncovering the complex interactions between cognitive-affective processes, autonomic control, and cortical dynamics.