Edited by: Tilmann A. Klein, Max Planck Institute for Human Cognitive and Brain Sciences, Germany
Reviewed by: Redmond O'Connell, Trinity College Dublin, Ireland; Sören Enge, Technische Universität Dresden, Germany
*Correspondence: Erik M. Mueller, Department of Psychology, Philpps-Universität Marburg, Gutenbergstrasse 18, 35032 Marburg, Germany. e-mail:
This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
External and internal performance feedback triggers neural and visceral modulations such as reactions in the medial prefrontal cortex and insulae or changes of heart period (HP). The functional coupling of neural and cardiac responses following feedback (cortico-cardiac connectivity) is not well understood. While linear time-lagged within-subjects correlations of single-trial EEG and HP (cardio-electroencephalographic covariance tracing, CECT) indicate a robust negative coupling of EEG magnitude 300 ms after presentation of an external feedback stimulus with subsequent alterations of heart period (the so-called N300H phenomenon), the neurotransmitter systems underlying feedback-evoked cortico-cardiac connectivity are largely unknown. Because it has been shown that acute tryptophan depletion (ATD), attenuating brain serotonin (5-HT), decreases cardiac but not neural correlates of feedback processing, we hypothesized that 5-HT may be involved in feedback-evoked cortico-cardiac connectivity. In a placebo-controlled double-blind cross-over design, 12 healthy male participants received a tryptophan-free amino-acid drink at one session (TRP−) and a balanced amino-acid control-drink (TRP+) on another and twice performed a time-estimation task with feedback presented after each trial. N300H magnitude and plasma tryptophan levels were assessed. Results indicated a robust N300H after TRP+, which was significantly attenuated following TRP−. Moreover, plasma tryptophan levels during TRP+ were correlated with N300H amplitude such that individuals with lower tryptophan levels showed reduced N300H. Together, these findings indicate that 5-HT is important for feedback-induced covariation of cortical and cardiac activity. Because individual differences in anxiety have previously been linked to 5-HT, cortico-cardiac coupling and feedback processing, the present findings may be particularly relevant for futures studies on the relationship between 5-HT and anxiety.
We rapidly process internal and external feedback signals in order to optimally interact with our environment. Neural signatures of error or negative feedback processing (e.g., event-related potentials, fMRI activation) are often accompanied by changes of behavior (Debener et al.,
Consistent with this proposal Mueller et al. (
The finding that feedback-locked EEG with a latency of 300 ms relates to heart period modulations converges with prior work on the P300 event-related potential component. It has long been speculated that P300 and evoked changes in autonomic activity are linked to each other, for example as different correlates of the orienting response which may function to facilitate information processing and/or action preparation (Graham and Clifton,
The neurotransmitter systems involved in this feedback-related cortico-cardiac connectivity phenomenon are currently unknown. Given the plethora of brain structures involved in feedback processing and the neurogenic modulation of peripheral responses to external stimuli (Benarroch,
In line with this assumption, van der Veen et al. (
One explanation of these findings is, that a cortical feedback-related process, which is not captured by the FRN but associated with the cardiac response is attenuated by 5-HT. In addition, the findings by van der Veen et al. (
Data of 12 healthy male participants (mean age: 22.5 years; SD = 5 years) with complete EEG and ECG data for both sessions (TRP+ and TRP−) was available from the study previously published by van der Veen et al. (
Participants performed a time estimation task based on a paradigm developed by Miltner et al. (
Participants were tested in a randomized double-blind cross-over design and details are described elsewhere (van der Veen et al.,
As described in detail elsewhere (van der Veen et al.,
To compute CECTs, the continuous EEG was first segmented into epochs from 0 to 500 ms relative to the feedback stimulus and baseline corrected for the preceding 500 ms. EEG epochs were then binned into 50 bins of 10 ms each (corresponding to a sampling rate of 100 Hz) and mean voltage magnitudes were determined for each bin. With this data, for each participant and each channel an EEG matrix for subsequent CECT analyses was constructed which consisted of about 200–240 rows (depending on the number of artifact-free trials) and 50 columns (corresponding to the 50 bins per epoch). In analogy to the EEG, the continuous IBI-trace was segmented into epochs from 0 to 2500 ms relative to the feedback stimulus and baseline corrected for the preceding 250 ms. IBI epochs were binned into 10 bins of 250 ms each (4 Hz) and mean IBI values were determined for each bin. For each participant an IBI matrix for CECT analyses was constructed that consisted of about 200–240 rows (trials) and 10 columns (bins). CECT matrices were computed for each participant and channel, separately by correlating each column of the corresponding EEG matrix with each column of the IBI matrix. Thus, for every CECT matrix 10 × 50 within-subject correlations were computed (correlations over trials). These were now structured in a 10 × 50 correlation matrix in which each row represents one particular IBI bin and each column represents one particular EEG bin. To illustrate the interpretation of CECT matrices, a correlation displayed in column 1, row 2, reflects how much the EEG magnitude from 0 to 10 ms (EEG bin 1) after a feedback stimulus correlates with the change in IBI from 250 to 500 ms after a feedback stimulus (IBI bin 2).
Grand average CECTs (as displayed in Figure
As expected and as previously reported for the entire sample, the oral intake of the tryptophan-deficient amino-acid mixture reduced the levels of free tryptophan concentrations in blood plasma from
On average, participants had 112 correct responses, 40 under-estimations and 88 over-estimations of the 1 s epoch (the window was continuously adapted to provide about equal amounts of positive and negative feedback). There was no effect of ATD on the number of correct responses, under-estimations or over-estimations (
Feedback-evoked a P300-like deflection, which extended from 200 to 500 ms (peak at 360 ms, channel Cz) and a triphasic cardiac response (0–1000 ms: deceleration; 1000–2000 ms: acceleration; 2000–2500 ms: deceleration). ATD did not influence the P300 amplitude (
A paired samples
Because ATD affected the overall CECT, separate CECTs for each session were tested for N300H. As shown in Figures
Of relevance, in the TRP− session an unexpected, temporally less specific
Mean N300H values in the time window from 150 to 300 ms in the EEG time domain and from 250 to 1750 ms in the EEG time domain were significantly different from zero for positive (
In addition to these group effects, we examined the association between plasma tryptophan level and N300H aiming to probe whether interindividual variations of tryptophan level are also related to N300H. The tryptophan level was measured at two occasions (
To rule out the alternative explanation that ATD reduced cortico-cardiac within-subject correlations by affecting trial-to-trial variation of cardiac responses we tested whether there was a difference in the cross-trial variance of feedback-locked IBI (from 250 to 1750 ms) between TRP+ and TRP−. However, this was not the case (
The goal of the present study was to test whether a manipulation of central 5-HT would influence cortico-cardiac connectivity evoked by feedback stimuli. Central 5-HT was manipulated through administration of drinks that either contained no tryptophan (TRP−), serving to deplete this precursor of 5-HT synthesis, or elevated tryptophan levels (TRP+) in two separate sessions (double-blind cross-over design). Five hours later, when plasma levels of tryptophan were reduced in the TRP− vs. TRP+ session, participants conducted a time estimation task in which feedback was given after each trial. To measure cortico-cardiac connectivity, CECT-analyses were conducted, in which feedback-evoked-changes in single-trial EEG magnitudes are systematically correlated with time-lagged feedback-evoked changes in heart period. Importantly, overall CECTs were significantly different between the TRP+ and TRP− session. In the TRP+ session, we replicated a previously reported phenomenon (N300H), indicating a significant coupling between centromedial EEG magnitude about 300 ms after feedback presentation and subsequent accelerations of heart rate (i.e., smaller IBIs). Of particular relevance, N300H was absent following TRP−, indicating that a pharmacological downregulation of 5-HT synthesis attenuated the negative covariation of feedback-evoked EEG and heart period changes or even induced a positive covariation (as indicated by the red spots in Figures
As outlined in Figure
In the present study CECTs indicated a covariation of feedback-evoked single-trial EEG at 300 ms and changes in IBI from 250 to 1750 ms in the TRP+ session (N300H). Because the EEG in the TRP+ session thus correlated with an earlier proportion of IBI than in the Mueller et al. (
CECTs provide a method to measure cortico-cardiac coupling with higher temporal precision than neuroimaging-based approaches. However, when interpreting the latencies of N300H in the present study, it should be considered, that IBI values only change with every heartbeat, and that an IBI value at a given time (e.g., at 250 ms) is determined by the latency of the subsequent heart beat (which may occur several 100 ms later). Thus, the temporal resolution in the IBI domain is somewhat blurred. Nevertheless, under the assumption that N300H is driven by the combined paths (a), (b), and (c), the present findings indicate that it took less than 1500 ms (i.e., 1750 ms minus 300 ms) for the feedback signal to be transmitted from the cortex to the heart (or alternatively, to be simultaneously transmitted from a third region to the cortex and the heart). Thus, the cortical response 300 ms after a given feedback stimulus predicts how much the heart accelerates about one to two beats later.
As outlined in the introduction the N300H and the P300 event-related potential show overlap with regard to latency and scalp topography. However, it should be emphasized that they are not the same phenomenon. The P300 reflects the
In the present study, we were predominantly interested in the effect of 5-HT on cortico-cardiac connectivity in feedback processing. Following TRP− vs. TRP+, we found relatively lower N300H, which explains the previously reported finding in the same data, namely that ATD had no effect on cortical feedback-related signatures but attenuated the cardiac concomitants of feedback processing. These findings are consistent with a predominant role of 5-HT for path (c), which has been demonstrated in studies with cats and rats before (Jordan,
In the TRP+ session, the tryptophan level predicted the amplitude of N300H. Individuals with higher plasma tryptophan levels, possibly associated with higher levels of 5-HT, showed a stronger covariation of cortical and cardiac activity after feedback stimuli. Accordingly, individual differences in cortico-cardiac connectivity may be biologically linked to 5-HT. Interestingly, both, 5-HT and cortico-cardiac connectivity may be of high relevance for individual differences in trait anxiety. For example, the short allele of the 5-HT transporter polymorphism (5-HTTLPR) predicts high levels of extracellular 5-HT and is associated with elevated risk for high trait anxiety and negative emotionality (Lesch et al.,
It is worth noting, that the effects of ATD on evoked cardiac response are significant for the initial deceleratory (0–1250 ms) but not for the acceleratory phase, while the N300H, which is also affected by ATD, suggests an association between EEG and heart period from 250 to 1750 ms. At the moment, detailed mechanistic explanations for this dissociation between evoked IBI and CECTs would be speculative. However, it should be noted, that cardiac responses are influenced by a variety of more or less opposing processes, which may occur in parallel. Accordingly, the observed cardiac response pattern (deceleration—acceleration—deceleration) may reflect the overall net effect of several (cortical and non-cortical) processes while the CECT only captures heart period fluctuations that covary with feedback-evoked cortical activity. The present N300H findings indicate that increased (positive) EEG around 300 ms covaries with a
Consistent with the assumption of parallel partially opposing brain-heart processes there appeared to be a positive correlation between feedback-evoked EEG and IBI in the TRP− session. Unlike the N300H, this association did not show a precise temporal or spatial localization, although the largest correlation cluster at Cz appeared from 300 to 400 ms. One could speculate, that while earlier feedback-evoked centromedial brain activity (i.e., 200–300 ms) is linked to cardiac acceleration, for example to prepare the organism for subsequent actions, more widespread brain activity with a later onset is linked to cardiac deceleration, possibly associated with information intake. If 5-HT differently contributes to these cortico-cardiac processes the polarity of the net CECT could be modulated by ATD as in the present study. However, it should be emphasized that this cortico-cardiac covariation in the TRP− session was unexpected with regard to polarity, spatial, and temporal localization. The current interpretations thus remain speculative until this pattern is replicated in a larger independent sample.
Two limitations deserve attention. First of all, the present study investigated a relatively small sample. Thus, although an N300H-like phenomenon was detected after TRP+, this component was not significantly different from zero after rigorously controlling for
Despite these limitations, we showed for the first time, that the covariation of cortical and cardiac activity following external feedback presentation in humans is affected by plasma tryptophan availability, which determines the rate of central 5-HT synthesis. Our findings thereby provide indirect evidence that 5-HT is of relevance for the interaction between the brain and the heart following feedback presentation.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This study was supported by a TOP grant (912-02-050) from ZonMW-NWO to Dr. Evers and a DFG grant DFG WA 2593/2-2 to Dr. Wacker.