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.