Accepted Manuscript

The frontal cortex is a heart-brake: Reduction in delta oscillations is associated with

heart rate deceleration

Elisabetta Patron, Rocco Mennella, Simone Messerotti Benvenuti, Julian F. Thayer

PII: S1053-8119(18)32179-7
DOI: https://doi.org/10.1016/j.neuroimage.2018.12.035
Reference: YNIMG 15503

To appear in: NeuroImage

Received Date: 21 September 2018

Revised Date: 1 December 2018
Accepted Date: 16 December 2018

Please cite this article as: Patron, E., Mennella, R., Messerotti Benvenuti, S., Thayer, J.F., The frontal
cortex is a heart-brake: Reduction in delta oscillations is associated with heart rate deceleration,
NeuroImage (2019), doi: https://doi.org/10.1016/j.neuroimage.2018.12.035.

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 ACCEPTED MANUSCRIPT

1 The frontal cortex is a heart-brake: Reduction in delta oscillations is associated with heart rate

2 deceleration

3 Elisabetta Patron, Ph.D.a 1, Rocco Mennella, Ph.D.b 1, Simone Messerotti Benvenuti, Ph.D,a,

4 Julian F. Thayer, Ph.D.c

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6 Department of General Psychology, University of Padua, Padua, Italy.
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7 Laboratoire de neurosciences cognitives, Département d’études cognitives, École normale supérieure,

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8 INSERM, PSL Research University, Paris, France.
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9 Department of Psychology, The Ohio State University, Columbus, OH, United States.

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11 These authors contributed equally to this work

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13 Correspondence:
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14 Elisabetta Patron, Ph.D., Department of General Psychology, University of Padua, Via Venezia, 8, I-
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15 35131 - Padua. Tel.: +39 049-8276957; Fax: +39 049-8276600, E-mail: elisabetta.patron@unipd.it

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1 Abstract

2 Prefrontal brain regions have been proposed to modulate vagally mediated heart rate variability (HRV)

3 through their action on subcortical structures. This study aimed at investigating the beat-to-beat

4 influence of the brain cortex over the heart through a high temporal resolution estimation of brain-heart

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5 coupling. Electrocardiogram (ECG) and electroencephalogram (EEG) from 32 scalp positions were

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6 recorded at rest for five minutes in 38 participants. To assess beat-to-beat cortical control on vagal

7 activity, the longest and shortest inter-beat intervals (IBIs) were identified for each participant. Then,

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8 the EEG activity was time-locked to R waves in the ECG signal and analyzed using a time-frequency

9 approach. Logistic regression models were applied to predict the trial-by-trial occurrence of long and

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short IBIs from cardiac-related EEG activity. Delta power reduction over prefrontal and frontocentral
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11 areas preceding the R-wave increased the probability for a long IBI to occur, as compared to a short

12 one. Moreover, reduced prefrontal delta power preceding the R wave was correlated to higher cardiac
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13 vagal control, as reflected by the High Frequency (HF) power of HRV calculated on the whole
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14 recording time. The present results support the hypothesis that phasic activation/deactivation of
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15 prefrontal areas modulates vagal control of heart rate at rest.

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17 Keywords

18 Cardiac vagal control; Delta activity; EEG; Heart rate variability; Prefrontal cortex
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1 Introduction

2 Heart rate (HR) is directly controlled by the synchronous activity of the sympathetic and

3 parasympathetic (vagal) branches of the Autonomic Nervous System (ANS). While sympathetic

4 postganglionic fibres innervate the sinoatrial and atrioventricular nodes, most of the parasympathetic

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5 preganglionic fibres reside in the nucleus ambiguous and in the dorsal motor nucleus of the vagus. The

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6 distinct and interactive activity of both sympathetic and parasympathetic systems on the heart has been

7 consistently demonstrated in animal and human studies. On the one hand, sympathetic activation

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8 increases both HR and ventricular contractility in response to internal and/or external stimulation. It has

9 been shown that parasympathetic blockade determined HR increases in dogs, which has been attributed

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to sympathetically mediated increase in ventricular contractility (Glick and Braunwald, 1965). The
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11 same effect was replicated by directly stimulating the stellate ganglions of the sympathetic system in

12 dogs (Levy and Zieske, 1969). On the other hand, parasympathetic activation tonically slows down HR
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13 in resting conditions, by inhibiting the natural firing rate of the sinoatrial node cells. Sympathetic
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14 blockade by beta-adrenergic blocking agent propranolol produced an HR reduction in humans

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15 (Robinson et al., 1966). In addition, it has been shown that direct stimulation of the vagus nerve

16 produced HR decreases in dogs (Levy and Zieske, 1969). Importantly, the general balance between
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17 sympathetic and parasympathetic nervous system effects on the heart is responsible for the Heart Rate

18 Variability (HRV), which is the physiological variation in time intervals between heartbeats.
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19 Accordingly, there is large evidence showing that a high HRV represents an important index of an
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20 effective sympathovagal balance (Bootsma et al., 1994) and, therefore, of cardiac health (Thayer et al.,

21 2010).

22 However, several authors proposed that HRV, and in particular the vagally mediated part of

23 HRV as reflected by the high frequency power (HF-HRV), ought to be considered as more than a mere

24 index of cardiac health (Beauchaine and Thayer, 2015). Such a claim is supported by the evidence that
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1 high HF-HRV is associated with positive affect (Geisler et al., 2010), lower probability to experience

2 negative emotional arousal during stressful situations (Fabes and Eisenberg, 1997), adequate emotional

3 regulation in patients after cardiac surgery (Patron et al., 2013), and high cognitive performance

4 (Hansen et al., 2004, 2003; Luft et al., 2009; Scrimin et al., 2017). Accordingly, reduced HF-HRV has

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5 been linked to several psychopathological conditions, including anxiety (Chalmers et al., 2014), clinical

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6 depression (Kemp et al., 2010), depressive symptoms after cardiac surgery (Patron et al., 2012), and

7 trait hostility (Sloan et al., 1994). In light of these findings, HRV has been proposed to serve as a

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8 peripheral index of the integrity of cortical (prefrontal) networks that support goal-directed behaviour,

9 executive functions, affect regulation, and other high-order brain functions (Benarroch and Bennaroch,

10 1993; Thayer et al., 2009; Thayer and Lane, 2009).

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11 Consistent with this hypothesis, prefrontal areas involved in cognitive and affective regulation,

12 such as the medial prefrontal cortex (mPFC) and ventromedial prefrontal cortex (vmPFC), have been
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13 shown to directly modulate the parasympathetic branch of the ANS in rats (Ter Horst and Postema,
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14 1997), as well as in primates and in humans (for a review see Neafsey, 1991). This cortical control over
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15 ANS responses is thought to be possible given that the mPFC and vmPFC, along with the insular

16 cortex and anterior cingulate cortex, form an interconnected network with core regulatory subcortical
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17 nuclei, one of the most important being the amygdala. In general, the activation of the central nucleus

18 of the amygdala can lead to increased HR and reduced HRV by three routes: 1) inhibition of the
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19 nucleus of the solitary tract, which, in turn, leads to inhibition of vagal neurons in the dorsal motor
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20 nucleus and in the nucleus ambiguus, the main vagal connections with the sinoatrial node; 2)

21 disinhibition of tonically active neurons in the caudal ventrolateral medulla which, in turn, leads to

22 activation of tonically active sympathoexcitatory neurons in the rostral ventrolateral medulla; 3) direct

23 sympathoexcitatory connections with the rostral ventrolateral medulla (Matthews et al., 2004; Thayer

24 and Lane, 2000; Wong et al., 2007). By downregulating amygdala activity, activation of PFC leads to
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1 longer inter-beat intervals (IBIs), that is, slower HR (Balaban and Thayer, 2001; Matthews et al., 2004;

2 Thayer and Lane, 2000; Wong et al., 2007). Notably, increased PFC tonic activity is associated with

3 higher parasympathetic than sympathetic cardiac influence; on the contrary, decreased PFC tonic

4 activity leads to lower parasympathetic than sympathetic inputs on the heart (Lane et al., 2009; Ruiz

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5 Vargas et al., 2016).

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6 Several functional Magnetic Resonance Imaging (fMRI) studies provided support for this

7 model reporting positive correlations between the activation in prefrontal and subcortical areas and HF-

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8 HRV in resting state (Jennings et al., 2016), during cognitive (Critchley et al., 2003; Gianaros et al.,

9 2004; Gillie et al., 2014; Nugent et al., 2011) and emotional (Lane et al., 2009; O’Connor et al., 2007)

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tasks, and volitional exercise (Shoemaker et al., 2015). These findings are in line with the view that a
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11 common network involving prefrontal and subcortical areas is activated when vagal autonomic

12 modulation is needed, such as during cognitive and emotional tasks. It has to be noted that a more
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13 extended network of cortical regions, including the prefrontal cortex along with the medial frontal
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14 cortex and more posterior areas, such as the parietal cortex, has been also found to be involved in
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15 autonomic control. For instance, during a heartbeat detection task, activation was reported in the insula,

16 inferior/middle frontal gyrus, medial frontal/dorsal cingulate gyrus, thalamic nuclei, and right inferior
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17 parietal lobule (Pollatos et al., 2007). Furthermore, Critchley and colleagues (2003) found that activity

18 in the dorsal anterior cingulate cortex, medial orbitofrontal cortex, insula, hypothalamus, and medial
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19 parietal lobe was associated with higher HRV. HF-HRV was also found to correlate with blood flow in
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20 the right superior prefrontal cortex, the left rostral anterior cingulate cortex, the right dorsolateral

21 prefrontal cortex, and the right parietal cortex during emotional states induced by film clips (Lane et

22 al., 2009).

23 However, although neuroimaging studies conducted so far have provided valuable information

24 on cortical and subcortical structures involved in HRV modulation, they did not examine fast variations
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1 (in terms of milliseconds) in the brain control over the heart due to poor temporal resolution. Indeed, in

2 the majority of the studies, both HRV and neural indexes are calculated over several seconds or

3 minutes and represent a single steady-state measurement. These are important limitations if one

4 considers that parasympathetic control over the heart is rapid (< 1 sec; Nunan et al., 2010; Smith,

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5 1974), and cortical areas implicated in parasympathetic modulation are more likely to be involved in

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6 moment-by-moment rather than long-lasting cardiac adjustments.

7 Electroencephalography (EEG) overcomes the temporal limitations of other brain imaging

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8 techniques. A wide literature has employed EEG - but also magnetoencephalography (MEG: Babo-

9 Rebelo et al., 2016; Park et al., 2014), intracranial EEG (iEEG: Babo-Rebelo et al., 2016b; Park et al.,

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2018), and intracranial electrocorticographic recordings (Kern et al., 2013) - to investigate the brain
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11 responses subsequent to a heartbeat (Heartbeat Evoked Potentials; HEP). At each heartbeat,

12 information about heart contraction is transmitted, through vagal and spinal pathways, to the neocortex
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13 (Critchley and Harrison, 2013), where it elicits transient HEP reflecting the influence of bottom-up
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14 visceral information on the brain (Katkin et al., 1991; Leopold and Schandry, 2001; Montoya et al.,
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15 1993; Müller et al., 2015; Pollatos et al., 2005; Pollatos and Schandry, 2004; Schandry et al., 1986;

16 Terhaar et al., 2012; Werner et al., 2009; Wiens et al., 2000). Nonetheless, despite the bi-directionality
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17 of the brain-heart communication, fewer EEG studies have investigated the top-down influence of the

18 brain on the heart or, in other words, the changes in cardiac activity which follow modifications in the
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19 EEG activity. Among these, Mueller and colleagues investigated brain-heart coupling during tasks
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20 involving feedback to task performance. Intriguingly, they found that feedback-evoked modifications

21 in frontocentral EEG activity predicted subsequent cardiac modulations (Mueller et al., 2010; Panitz et

22 al., 2013). Slow wave bands, particularly frontal theta and delta power, have been associated with

23 cardiac vagal control (Kubota et al., 2001; Liou et al., 2014). However, those results derived from

24 simple correlation analyses between EEG and ECG signals conducted over long-lasting recordings
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1 (typically 1 to 5 minutes), thus providing only a “static” picture of brain-heart coupling. The few

2 studies examining EEG correlates of fast variations in the cardiac rhythm found that increases in EEG

3 slow wave activity were associated with higher sympathetic activity on the heart in preterm infants

4 (Pfurtscheller et al., 2008) and in children with temporal lobe epilepsy (Piper et al., 2014). To our

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5 knowledge, only one recent study applied a time-frequency approach on EEG data to investigate

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6 moment-by-moment electrocortical correlates of cardiac activity during daytime sleep (i.e., nap; Naji et

7 al., 2017). Specifically, Naji et al. calculated changes in slow wave EEG (i.e., delta band) time-locked

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8 to heart rate bursts (i.e., two standard deviations [SDs] below the mean of all IBIs). The results showed

9 that increases in low-frequency oscillations (including delta activity) precede successive bursts of

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increased HR (shorter IBIs). Intriguingly, the coupling between central and autonomic activity during
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11 sleep has been reported to improve learning in a non-declarative memory task, suggesting that an

12 efficient cortical control of the cardiac sympathovagal balance is associated with improved cognitive
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13 functioning (Naji et al., 2017).

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14 In addition, even though brain-heart coupling has been consistently reported, the majority of
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15 fMRI and EEG studies in this field mainly relied on a correlational method. However, correlation limits

16 the possibility of examining the direction of the brain-heart coupling, which is of relevance since
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17 bottom-up influences from the heart to the brain have been reported in the abovementioned HEP

18 literature. Also, increased cardiac vagal control (as measured by HF-HRV) has been showed to
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19 modulate the activity of higher level integrative neural networks through baroreflex activity (Grossman
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20 and Taylor, 2007; Porges, 2007). A novel method to investigate top-down control of beat-to-beat

21 variability exerted by brain cortex is to compare very long and very short heartbeats in terms of the

22 EEG activity that precedes them. Indeed, long beats in the resting condition indicate increased vagal

23 control on the heart (see for instance the NN50 index of HRV; Malik et al., 1996), as compared to short

24 ones, which, in turn, reflect reduced cardiac vagal control. Given that brain cortex modulation of
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1 cardiac vagal tone occurs in a short time range (Nunan et al., 2010; Smith, 1974), a difference could be

2 expected in the EEG activity preceding long (high vagal control) and short (low vagal control)

3 heartbeats, especially over prefrontal areas as suggested by the Neurovisceral Integration Model

4 (Thayer and Lane, 2009, 2000).

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5 In light of these considerations, the present study investigated the role of brain oscillations as

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6 recorded by scalp EEG in controlling beat-to-beat variability at rest through a high temporal precision

7 approach. It was hypothesized that a reduction in EEG oscillations in the low-frequency range (i.e.,

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8 delta and theta bands) over prefrontal areas preceding, and time-locked to, the following heartbeat

9 would be predictive of increased beat-to-beat vagal control on the heart, as indexed by the occurrence

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of long IBIs (here defined as intervals between R waves of the ECG). Since reduced slow wave EEG
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11 activity preceding long vs. short IBIs would reflect greater phasic vagal control over the heart, it was

12 also hypothesized that average prefrontal slow wave activity would be negatively correlated with tonic
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13 vagal control as calculated with frequency-domain analysis (i.e., HF-HRV calculated over the whole
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14 recording period). Therefore, individuals with a greater reduction in prefrontal slow wave activity
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15 occurring prior to longer IBIs were expected to show greater tonic vagal control.

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17 Method

18 Participants
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19 Forty-three healthy undergraduates (35 females; mean age: 22.81 ± 2.11 years; mean education:
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20 16.30 ± 1.28 years) from the University of Padua volunteered for the study. Cardiovascular or

21 neurological diseases, as well as drugs intake, were exclusion criteria. All participants were right-

22 handed and had normal or corrected-to-normal vision. They were asked to refrain from alcohol in the

23 12 hours before the study and from caffeinated substances and smoking three hours before the study.

24 Data from five participants were excluded on account of artefacts in the electrophysiological data,

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1 specifically due to environmental electrical noise in high frequencies (around 30 Hz). Thus, the final

2 sample consisted of 38 individuals medically healthy and free of medication (31 females; mean age:

3 22.95 ± 2.14 years; mean education: 16.37 ± 1.30 years). The study was approved by the ethics

4 committee of the University of Padua and all volunteers gave written consent prior to participation. The

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5 study was conducted in accordance with the Declaration of Helsinki.

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7 Procedure

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8 Upon arrival at the laboratory, participants received general information about the experiment,

9 and read and signed an informed consent (duration about 10 minutes). Then, each participant was

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seated in a comfortable armchair in a sound-attenuated, dimly-lit room, and sensors were attached. An
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11 elastic cap embedded with 32 EEG electrodes was applied and ECG electrodes were attached (duration

12 of about 20 minutes); then, after an adaptation period of 15 minutes, each participant completed a five-
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13 minute resting-state recording. Participants were instructed to stay still and to keep their gaze on a
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14 central fixation cross during the electrophysiological recording in order to minimize eye movements.
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16 Electrophysiological data recording and processing

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17 ECG

18 Ag/AgCl surface electrodes were positioned on the participant’s chest in a modified lead II
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19 configuration to register the ECG. The raw signal was amplified with a gain of 150, bandpass filtered
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20 (0.3–100 Hz) and digitized at 500 Hz (16 bit A/D converter; resolution 0.559 µV/LSB). Time-series of

21 IBIs were obtained applying a digital trigger to the R-waves. Specifically, an automatic detection

22 function was applied which allows to identify and mark each R peak from the ECG signal, and

23 calculate the interval in ms between each R wave. The signal was visually inspected. Then, IBIs series

24 were exported and analyzed using Kubios HRV Analysis Software 2.2 (The Biomedical Signal
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1 Analysis Group, Department of Applied Physics, University of Kuopio, Finland), fast Fourier spectral

2 analysis was applied on the IBIs series to compute frequency domain indexes, in particular: 1) HRV

3 total power in ms2, reflecting the variance of all IBIs (Malik et al., 1996); 2) HF-HRV power (0.15–

4 0.40 Hz) in ms2, which primarily reflects cardiac parasympathetic tone (Malik et al., 1996). Frequency

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5 domain indexes were logarithmically transformed to normalize their distribution.

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7 EEG

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8 The EEG signal was collected using an elastic cap with tin electrodes (Electro-cap International,

9 Inc.) from 32 scalp positions (i.e., Fp1, Fpz, Fp2, F7, F3, Fz, F4, F8, FT7, FC3, FCz, FC4, FT8, T3,

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C3, CZ, C4, T4, TP7, CP3, CPz, CP4, TP8, P7, P3, Pz, P4, P8, O1, Oz, O2 and A2 [right mastoid]),
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11 referenced online to A1 (left mastoid). Both vertical and horizontal electrooculograms (EOGs) were

12 recorded using a bipolar montage to monitor eye-movements and eye-blinks. The electrode pairs were
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13 placed at the supra- and suborbit of the right eye and at the external canthi of the eyes, respectively. All
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14 electrophysiological signals were amplified with Neuroscan Synamps (El Paso, TX, USA), and stored
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15 on to a Pentium IV computer. All electrode impedances were kept below 5 kΩ.

16 The EEG signal was bandpass filtered online (EEG filter = 0.1-70 Hz), digitized at 500 Hz (16
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17 bit AD converter, accuracy 0.034 µV/bit). Offline the EEG was re-referenced to a linked mastoids

18 montage, corrected for eyeblink artefacts using a regression-based algorithm (Scan 4.1 software), and
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19 low-pass filtered at 30 Hz. Filtering and further EEG processing were run in Brainstorm (Tadel et al.,
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20 2011).

21 As an index of beat-to-beat parasympathetic vagal influence on the sinoatrial node, the longest

22 IBIs were identified for each participant, assuming that in the resting condition sympathetic activation

23 is at its minimum and that variations in HR are mainly driven by vagal firing over the sinoatrial node

24 (Robinson et al., 1966). First, outliers in the IBIs series (IBIs exceeding ±3 SDs from the individual
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1 average) were detected and excluded from the following computations. Long IBIs were defined as the

2 intervals equal to or above the 85th percentile of each participant’s distribution, intervals equal to or

3 below the 15th percentile were defined as short IBIs. The threshold choices represent a compromise

4 between obtaining a sufficient number of EEG epochs time-locked to R-waves to perform statistical

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5 analyses and ensuring separation between long and short IBIs. At the group level, average long IBIs

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6 significantly differed from short IBIs (Mlong = 0.85 sec, SDlong = 0.11 sec; Mshort = 0.69 sec, SDshort =

7 0.09 sec; t(37) = -20.30, p < .001, 95% CI Long -Short = {-0.17 -0.14}; see also Figure 1a). To further

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8 control that the distributions of long and short IBIs were uniform throughout the five-minute recording

9 session (and not clustered at the beginning and/or at the end of the recording as a possible consequence

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of modifications in arousal state during the recording), frequency distributions were plotted. As shown
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11 in Figure 1b, the two categories of IBIs are evenly distributed over the entire 300 sec.

12 The EEG signal was then time-locked to the R-waves corresponding to long and short IBIs and
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13 epoched with a -2000 ms to +2000 ms interval to prevent potential boundary effects in the time-
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14 frequency decomposition. This window allowed a sufficient representation of slow waves activity,
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15 including four cycles of delta activity at 1 Hz. Artefact rejection procedures included the automatic

16 rejection of epochs in which the signal exceeded ±70 µV amplitude and visual inspection of the
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17 remaining epochs for residual artefacts. Then, Morlet wavelet transformation on individual trials was

18 applied for each 1 Hz frequency bin between 1 and 30 Hz, using a mother wavelet at 1 Hz with 3
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19 seconds time-resolution (as calculated by the Full Width at Half Maximum; FWHM). Time-frequency
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20 approach was selected because it allows to preserve any time-locked activity irrespective of its phase,

21 whereas Event Related Potentials (ERPs) averaging procedure preserves event related time-locked

22 activity canceling out all the activity not aligned in phase (Herrmann et al., 2014). This is of particular

23 importance when studying spontaneous oscillations whose phase is not dependent on the occurrence of

24 a stimulus, like in the present case.

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2 Statistical analysis

3 Following a method proposed in recent EEG studies (e.g., El Zein et al., 2015), we performed

4 single-trial general linear regression models (GLM) to analyze the data. A logistic model was applied,

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5 where EEG power at each electrode, frequency and time point, before and after stimulus onset (from

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6 1240 ms before to 1240 ms after stimulus onset, after cutting out the extremes of the epoch

7 contaminated by the edge effect), was introduced as a trial-per-trial predictor of heartbeat length (see

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8 equation).

ℎ(1 = ;0 = ℎ )~ ( )

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The resulting parameter estimates of the regression, reported in arbitrary units, were measured
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10 per participant. The time course of the parameter estimates describes the log-odds of the probability of

having a long vs. short heartbeat for each unit increment in EEG power. Positive values indicate that an
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12 increment in EEG power predicts an increment of the probability of having a long vs. short heartbeat in
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13 that trial.
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14 All regression-based analyses of the EEG data were performed independently for each

15 participant. Then, analyses at the group level were employed to test the significance of the observed
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16 effects across participants. Namely, standard parametric tests against zero were run, controlling for the

17 type I error rate arising from multiple comparisons across electrodes, frequencies and time points
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18 through non-parametric cluster-level statistics (Maris and Oostenveld, 2007). Despite having an a
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19 priori hypothesis on the role of low frequency oscillations at anterior sites in the control of cardiac

20 activity, due to the novelty of our approach to the investigation of brain-heart coupling, a conservative

21 whole-brain analysis was applied in order to test the possible role of all electrodes, frequencies and

22 time-points, correcting over all these dimensions. The pairing between the experimental condition and

23 zero was shuffled pseudo-randomly 1000 times, and the maximal cluster-level statistics (the sum of t-
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1 values across contiguously significant electrodes, frequencies and time points at a threshold level of

2 0.005) were extracted for each shuffle to compute a “null” distribution of effect size across the whole-

3 time window. The proportion of clusters in the null distribution whose statistics exceeded the one

4 obtained for each significant cluster in the original (non-shuffled) data was computed, resulting in its

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5 cluster-corrected p-value.

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6 To further confirm that the parameter estimates of the regression were associated to

7 parasympathetic control over the sinoatrial node, one-tailed Pearson correlations were computed

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8 between the average of the parameter estimates for each participant in the significant cluster

9 frequencies and times at each electrode, and the average individuals’ cardiac parameters calculated

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over five minutes (i.e., IBIs, total lnHRV, and lnHF). For illustrative purposes, the time course of the
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11 correlations was also plotted (see Figure 3a).

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13 Results
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14 Cluster-based EEG analysis highlighted the presence of a significant cluster (pcorr = 0.01),
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15 ranging from -1240 to -260 ms and relative to the 2 to 3 Hz (i.e., delta) frequency range (Figure 2).

16 This result indicates that for this specific cluster of both prefrontal (i.e., Fp1, Fp2, F3, Fz, F4,) and
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17 frontocentral (F8, FC3, FCz, FC4, FT8, Cz) electrodes, frequencies and time points, the parameter

18 estimates of the logistic regression were significantly lower than zero, indicating that as delta power
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19 decreases the probability of a subsequent long heartbeat to occur increases, compared to the probability
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20 of a short one.

21 As depicted in Figure 3a, regression parameter estimates in the delta range revealed a negative

22 association with both lnHF and total lnHRV values during the time period preceding the heartbeat.

23 Specifically, as shown in Figure 3b, parameter estimates averaged over cluster’s significant frequencies

24 (i.e., 2-3 Hz) and time (i.e., from -1240 to -260 ms before R wave) significantly correlated with lnHF at
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1 Fz (r = -0.29, p = .04) and marginally significantly at F3 (r = -0.25, p = 0.06) and F4 (r = -0.26, p =

2 .05). Parameter estimates in the delta range also correlated significantly with lnHRV at Fz (r = -0.34, p

3 = .02), F4 (r = -0.31, p = .03), FC3 (r = -0.30, p = .03), and FCz (r = -0.30, p = .03). Interestingly, this

4 correlation pattern did not emerge for IBIs (all p’s > .05), strengthening the specificity of the

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5 association between prefrontal delta power and vagally mediated tonic HRV. However, it should be

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6 noted that none of the significant correlations survived correction for multiple comparisons (i.e.,

7 electrodes).

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8

9 Discussion

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The main aim of the present study was to evaluate the possibility of predicting beat-to-beat
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11 cardiac vagal activation from EEG activity using a high temporal precision approach. A reduction in

12 EEG oscillations in the low-frequency range (i.e., delta and theta bands) over prefrontal areas
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13 preceding, and time-locked to, the following heartbeat was hypothesized to be predictive of increased
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14 beat-to-beat vagal control on the heart. The results supported this hypothesis showing that the
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15 occurrence of long vs. short IBIs was preceded by a reduction in delta activity over prefrontal and

16 frontocentral areas.
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17 Since the reduction in delta activity over anterior scalp sites has been associated with higher

18 cortical activity over prefrontal brain regions (Kilner et al., 2005), it could be proposed that increased
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19 prefrontal activity triggers high cardiac vagal control. In this fashion, the waxing and waning of the
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20 prefrontal cortex activity, as reflected in delta oscillations, seems to act as a dynamic brake on the

21 cardiac rhythm. This claim is further supported by the beat-to-beat nature of the effect described by the

22 present results, which is in line with fast (< 1 sec; Levy et al., 1970; Smith, 1974) regulation of HR

23 modulated by vagal, but not sympathetic, control (Warner and Cox, 1962).

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1 The present findings are in line with those of previous fMRI studies reporting that increased

2 prefrontal activity is associated with higher vagal control over the heart (Gillie et al., 2014; Lane et al.,

3 2009; Ruiz Vargas et al., 2016; Shoemaker et al., 2015). It has to be noted that not only prefrontal (i.e.,

4 Fp1, Fp2, F3, Fz, F4,), but also frontocentral sites (i.e., F8, FC3, FCz, FC4, FT8, Cz) were part of the

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5 cluster, in line with a previous EEG study reporting an association between activity in frontocentral

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6 sites and autonomic reactivity (i.e., greater HR deceleration) during a gambling task (Mueller et al.,

7 2010). Accordingly, there is converging evidence that activation in both prefrontal and mediofrontal

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8 brain regions is related to autonomic control (Critchley et al., 2003; Gianaros et al., 2004; Jennings et

9 al., 2016; Lane et al., 2009; Wager et al., 2009).

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Correlation analyses confirmed that the degree of brain-heart coupling was associated with both
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11 lnHF power, which is a well-established parameter reflecting vagally mediated HRV, and lnHRV

12 power, which includes vagally mediated HRV and other sources of variability (e.g., sympathetic and
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13 baroreflex activity; Berntson et al., 1997; Malik et al., 1996). Specifically, vagally mediated HRV
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14 negatively correlated with parameter estimates in the delta range at prefrontal electrodes. Furthermore,
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15 total HRV correlated inversely with parameter estimates in the delta range at both prefrontal and

16 frontocentral electrodes. Accordingly, it could be argued that delta oscillations at prefrontal areas
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17 mainly reflect cortical modulation of vagal input to the sinoatrial node. EEG oscillations in the low-

18 frequency range at frontocentral sites may index both vagal control and other sources of cardiac
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19 variability. Of note, the average HR (as inversely reflected by mean IBIs), did not correlate with delta
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20 activity at any sites. However, due to the limited number of EEG channels employed, any statement

21 with regard to precise cortical generators within the frontal lobe is speculative. Future studies using

22 techniques which allow high temporal resolution and better spatial resolution (e.g., high-density EEG,

23 MEG, iEEG) are warranted in order to accurately identify cortical regions involved in beat-to-beat

24 cardiac control.
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1 Results from the present study showed that activity in theta band (4-8 Hz) and activity in other

2 EEG bands were unrelated to autonomic control of HR. Slow wave oscillations (including both delta

3 and theta band activity) have been associated with autonomic control and long-range

4 communication/modulation between brain areas (Knyazev, 2012; Tang et al., 2009). Specifically,

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5 frontal theta activity has been linked to increases in sympathetic and parasympathetic activity on the

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6 heart during a task inducing a state of relaxed concentration (Kubota et al., 2001). Therefore, it could

7 be speculated that delta and theta activity may be differentially involved in autonomic modulation of

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8 HR. In particular, delta activity may specifically index cortical modulation of beat-to-beat cardiac vagal

9 control, whereas theta activity may reflect both sympathetic and parasympathetic cardiac modulation.

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Consistent with this hypothesis, delta band activity has been proposed to be crucial for the
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11 synchronization of brain activity with autonomic functions, such as heartbeat and breathing (Knyazev,

12 2012). Accordingly, it has been recently shown that increases in EEG delta oscillations predict bursts
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13 of increased HR (Naji et al., 2017), thus supporting the hypothesis of delta activity as an EEG indicator
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14 of brain-heart coupling.
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15 The present results are also consistent with previous findings reporting a positive association

16 between tonic cardiac vagal control (as indexed by HF-HRV) and phasic HR response to emotional
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17 stimuli (Ruiz-Padial et al., 2017; Thayer et al., 2000). This has important implications for better

18 understanding cortical processes underlying the relation between tonic HRV measures and phasic vagal
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19 control of the heart. Greater phasic vagally mediated response has been suggested to index the integrity
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20 of neuroregulatory processes involved in organism-environment regulation, and tonic HRV can be an

21 indicator of flexible responsiveness to environmental demands (Goldberger, 1991). Therefore, these

22 findings are interesting from a clinical perspective. A wide range of psychopathological syndromes has

23 been linked to both central and peripheral alterations. Indeed, reduced activity in PFC, particularly

24 vmPFC and dorsolateral PFC, and decreased HF-HRV have been reported in individuals with
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1 psychopathology, including depression (Rottenberg et al., 2007, 2005), anxiety (Åhs et al., 2009;

2 Hastings et al., 2008; Kemp et al., 2014) and schizophrenia (Clamor et al., 2016). Consistent with these

3 findings, a disruption in top-down PFC control mediated by an increased activation in the ventral

4 portion of the anterior cingulate cortex has been proposed to characterize individuals with

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5 psychopathology and, more intriguingly, to confer vulnerability to psychopathology (Beauchaine and

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6 Thayer, 2015). Given that increased slow wave EEG activity at rest has been reported in depression

7 (Bjørk et al., 2008; Gatt et al., 2008; Korb et al., 2008), anxiety disorders (Gauthier et al., 2009;

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8 Velikova et al., 2010) and schizophrenia (Alfimova and Uvarova, 2003; Bates et al., 2009; Boutros et

9 al., 2008), it can be speculated that the reduced integrity in the brain-heart network may be reflected by

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disrupted delta-HRV coupling in individuals with psychopathology. Clearly, future studies are
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11 warranted to test whether individuals with psychopathology, particularly those suffering from anxiety

12 and depressive disorders, are characterized by abnormal delta-HRV coupling.

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13 The present study is, to our knowledge, the first to evaluate beat-to-beat EEG correlates of
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14 resting heart rate modulation with a time-frequency approach.

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15 The GLM statistical approach applied allowed an accurate estimation of the probability of

16 increased vagal control on the heart (i.e., the occurrence of a long heartbeat) from each electrode, time-
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17 point and frequency, providing a powerful trial-by-trial measure of the impact of brain activity on the

18 heart rhythm. Combined with cluster-based multiple comparison correction, this method allowed a
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19 conservative data-driven approach, which did not require any a-priori assumption on the scalp sites,
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20 frequencies and time points implied in the EEG-ECG coupling.

21 The current findings ought to be interpreted in light of some limitations. First, the sample is

22 only representative of a young and healthy population, limiting the generalizability of the results.

23 Second, the possibility of an influence of ECG artefacts on the results cannot be completely ruled out.

24 Nevertheless, the ICA procedure run to identify this artefact over the EEG signal was ineffective, since
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1 the artefact was hardly visible in the majority of the participants. Therefore, no correction was applied

2 in order to avoid the risk of removing meaningful physiological EEG signal. It has to be noted that the

3 typical frequency range of ECG artefact (~15-35 Hz; Jiang et al., 2007) is clearly separate from the

4 frequency range reported in this study (2-3 Hz). Thus, the findings reported in delta activity are

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5 unlikely to be explained by ECG artifacts. Future studies should better control for this possible

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6 confound by using recording techniques that allow clear identification of ECG artifacts, such as MEG.

7 Finally, MEG, high-density EEG, and iEEG studies may help clarify the neural generators of prefrontal

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8 and frontocentral delta activity preceding heartbeats. This would be a critical step toward a more

9 detailed comparison with findings obtained by fMRI studies, which reported specific cortical regions

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(e.g., the vmPFC) to be associated with vagal control on the heart.
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11 In conclusion, the present findings support the hypothesis that phasic activation/deactivation of

12 prefrontal and frontocentral areas modulates vagal control of heart rate at rest, supporting the
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13 assumptions made by the Neurovisceral Integration Model. Specifically, the utilization of a high
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14 temporal resolution approach revealed that a reduction in delta activity over the prefrontal and
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15 frontocentral electrodes, presumably indicating activation in these cortical areas, predicted an

16 immediate increase in vagal control on the sinoatrial node. Future studies on beat-to-beat brain-heart
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17 coupling disruption could shed light on the risks for psychopathology.

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1 Funding

2 This research did not receive any specific grant from funding agencies in the public,

3 commercial, or not-for-profit sectors.

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1 Figure captions

3 Figure 1. Panel a. Plot of means for short IBIs and long IBIs for each participant. Panel b.

4 Distributions of short (red area) and long (blue area) IBIs throughout the five-minute recording session.

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5

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6 Figure 2. Panel a. Mean of t-values over frequency and time in the significant cluster. Panel b.

7 Average of beta values in the significant cluster (time 0 corresponds to the R-wave). The blue square

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8 represents significance in time and frequency. The negative beta values displayed in the square indicate

9 that a decrease in delta activity preceding the heartbeat increases the log odds of having a long vs. short

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heartbeat. A decrease in delta activity is associated with higher probability of the following IBI to be a
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11 long one, indicating higher vagal control. Panel c. Odds ratios in the delta band over time (blue line

12 represents the mean, orange line represents the median, blue shade represents 95% interval of
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13 confidence).
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14
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15 Figure 3. Panel a. Correlations between regression parameter estimate in the delta range at time points

16 before and after each heartbeat (0 corresponds to the occurrence of the R wave) and HRV parameters
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17 (lnHF, lnHRV, and IBIs). Panel b. Correlations (one-tailed) between averaged parameter estimates in

18 delta activity in the time range that resulted predictive of long vs. short heartbeat (i.e., from -1240 to -
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19 260 ms before R wave) and HRV parameters (lnHF, lnHRV, and IBIs). White dots represent electrodes
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20 where significant correlations (p < .05) emerged. lnHF: natural logarithm of High-Frequency power

21 spectrum; lnHRV: natural logarithm of the total power of Heart Rate Variability; IBIs: Inter-Beat

22 Intervals.

23

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