Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

Conscious processing of global and local auditory irregularities causes differentiated heartbeat-evoked responses.

Recent research suggests that brain-heart interactions are associated with perceptual and self-consciousness. In this line, the neural responses to visceral inputs have been hypothesized to play a leading role in shaping our subjective experience. This study aims to investigate whether the contextual processing of auditory irregularities modulates both direct neuronal responses to the auditory stimuli (ERPs) and the neural responses to heartbeats, as measured with heartbeat-evoked responses (HERs). HERs were computed in patients with disorders of consciousness, diagnosed with a minimally conscious state or unresponsive wakefulness syndrome. We tested whether HERs reflect conscious auditory perception, which can potentially provide additional information for the consciousness diagnosis. EEG recordings were taken during the local-global paradigm, which evaluates the capacity of a patient to detect the appearance of auditory irregularities at local (short-term) and global (long-term) levels. The results show that local and global effects produce distinct ERPs and HERs, which can help distinguish between the minimally conscious state and unresponsive wakefulness syndrome patients. Furthermore, we found that ERP and HER responses were not correlated suggesting that independent neuronal mechanisms are behind them. These findings suggest that HER modulations in response to auditory irregularities, especially local irregularities, may be used as a novel neural marker of consciousness and may aid in the bedside diagnosis of disorders of consciousness with a more cost-effective option than neuroimaging methods.

Interoceptive rhythms in the brain.

Sensing internal bodily signals, or interoception, is fundamental to maintain life. However, interoception should not be viewed as an isolated domain, as it interacts with exteroception, cognition and action to ensure the integrity of the organism. Focusing on cardiac, respiratory and gastric rhythms, we review evidence that interoception is anatomically and functionally intertwined with the processing of signals from the external environment. Interactions arise at all stages, from the peripheral transduction of interoceptive signals to sensory processing and cortical integration, in a network that extends beyond core interoceptive regions. Interoceptive rhythms contribute to functions ranging from perceptual detection up to sense of self, or conversely compete with external inputs. Renewed interest in interoception revives long-standing issues on how the brain integrates and coordinates information in distributed regions, by means of oscillatory synchrony, predictive coding or multisensory integration. Considering interoception and exteroception in the same framework paves the way for biological modes of information processing specific to living organisms.

Interoception: Probing internal state is inherent to perception and cognition.

Interoception, i.e. the perception of the organism physiological state, jointly operates with perception and cognition, including when homeostatic balance is not particularly challenged. Studying interoception offers new leads to understanding the link between internal state, neural activity, and behavior.

Whose emotion is it? Perspective matters to understand brain-body interactions in emotions.

Feeling happy, or judging whether someone else is feeling happy are two distinct facets of emotions that nevertheless rely on similar physiological and neural activity. Differentiating between these two states, also called Self/Other distinction, is an essential aspect of empathy, but how exactly is it implemented? In non-emotional cognition, the transient neural response evoked at each heartbeat, or heartbeat evoked response (HER), indexes the self and signals Self/Other distinction. Here, using electroencephalography (n = 32), we probe whether HERs' role in Self/Other distinction extends also to emotion - a domain where brain-body interactions are particularly relevant. We asked participants to rate independently validated affective scenes, reporting either their own emotion (Self) or the emotion expressed by people in the scene (Other). During the visual cue indicating to adopt the Self or Other perspective, before the affective scene, HERs distinguished between the two conditions, in visual cortices as well as in the right frontal operculum. Physiological reactivity (facial electromyogram, skin conductance, heart rate) during affective scene co-varied as expected with valence and arousal ratings, but also with the Self- or Other- perspective adopted. Finally, HERs contributed to the subjective experience of valence in the Self condition, in addition to and independently from physiological reactivity. We thus show that HERs represent a trans-domain marker of Self/Other distinction, here specifically contributing to experienced valence. We propose that HERs represent a form of evidence related to the 'I' part of the judgement 'To which extent do I feel happy'. The 'I' related evidence would be combined with the affective evidence collected during affective scene presentation, accounting at least partly for the difference between feeling an emotion and identifying it in someone else.

The topological space of subjective experience.

Subjective experiences often feel rich, yet are most often quantified with simple metrics, such as a few levels on a predefined scale. What are the dimensions and topological organization of subjective experience? How do they relate to behavioral output? And how do they map onto the classical cognitive domains?

Consciousness matters: phenomenal experience has functional value.

'Why would we do anything at all if the doing was not doing something to us?' In other words: What is consciousness good for? Here, reversing classical views, according to many of which subjective experience is a mere epiphenomenon that affords no functional advantage, we propose that subject-level experience-'What it feels like'-is endowed with intrinsic value, and it is precisely the value agents associate with their experiences that explains why they do certain things and avoid others. Because experiences have value and guide behaviour, consciousness has a function. Under this hypothesis of 'phenomenal worthiness', we argue that it is only in virtue of the fact that conscious agents 'experience' things and 'care' about those experiences that they are 'motivated' to act in certain ways and that they 'prefer' some states of affairs vs. others. Overviewing how the concept of value has been approached in decision-making, emotion research and consciousness research, we argue that phenomenal consciousness has intrinsic value and conclude that if this is indeed the case, then it must have a function. Phenomenal experience might act as a mental currency of sorts, which not only endows conscious mental states with intrinsic value but also makes it possible for conscious agents to compare vastly different experiences in a common subject-centred space-a feature that readily explains the fact that consciousness is 'unified'. The phenomenal worthiness hypothesis, in turn, makes the 'hard problem' of consciousness more tractable, since it can then be reduced to a problem about function.

The Sensory and Motor Components of the Cortical Hierarchy Are Coupled to the Rhythm of the Stomach during Rest.

Bodily rhythms appear as novel scaffolding mechanisms orchestrating the spatiotemporal organization of spontaneous brain activity. Here, we follow-up on the discovery of the gastric resting-state network (Rebollo et al., 2018), composed of brain regions in which the fMRI signal is phase-synchronized to the slow (0.05 Hz) electrical rhythm of the stomach. Using a larger sample size (n = 63 human participants, both genders), we further characterize the anatomy and effect sizes of gastric-brain coupling across resting-state networks, a fine grained cortical parcellation, as well as along the main gradients of cortical organization. Most (67%) of the gastric network is included in the somato-motor-auditory (38%) and visual (29%) resting state networks (RSNs). Gastric brain coupling also occurs in the granular insula and, to a lesser extent, in the piriform cortex. Thus, all sensory and motor cortices corresponding to both exteroceptive and interoceptive modalities are coupled to the gastric rhythm during rest. Conversely, little gastric-brain coupling occurs in cognitive networks and transmodal regions. These results suggest not only that gastric rhythm and sensory-motor processes are likely to interact, but also that gastric-brain coupling might be a mechanism of sensory and motor integration that mostly bypasses cognition, complementing the classical hierarchical organization of the human brain.SIGNIFICANCE STATEMENT While there is growing interest for brain-body communication in general and brain-viscera communication in particular, little is known about how the brain interacts with the gastric rhythm, the slow electrical rhythm continuously produced in the stomach. Here, we show in human participants at rest that the gastric network, composed of brain regions synchronized with delays to the gastric rhythm, includes all motor and sensory (vision, audition, touch and interoception, olfaction) regions, but only few of the transmodal regions associated with higher-level cognition. Such results prompt for a reconsideration of the classical view of cortical organization, where the different sensory modalities are considered as relatively independent modules.

Neuronal correlates of the subjective experience of attention.

The effect of top-down attention on stimulus-evoked responses and alpha oscillations and the association between arousal and pupil diameter are well established. However, the relationship between these indices, and their contribution to the subjective experience of attention, remains largely unknown. Participants performed a sustained (10-30 s) attention task in which rare (10%) targets were detected within continuous tactile stimulation (16 Hz). Trials were followed by attention ratings on an 8-point visual scale. Attention ratings correlated negatively with contralateral somatosensory alpha power and positively with pupil diameter. The effect of pupil diameter on attention ratings extended into the following trial, reflecting a sustained aspect of attention related to vigilance. The effect of alpha power did not carry over to the next trial and furthermore mediated the association between pupil diameter and attention ratings. Variations in steady-state amplitude reflected stimulus processing under the influence of alpha oscillations but were only weakly related to subjective ratings of attention. Together, our results show that both alpha power and pupil diameter are reflected in the subjective experience of attention, albeit on different time spans, while continuous stimulus processing might not contribute to the experience of attention.

Does stroke volume influence heartbeat evoked responses?

We know surprisingly little on how heartbeat-evoked responses (HERs) vary with cardiac parameters. Here, we measured both stroke volume, or volume of blood ejected at each heartbeat, with impedance cardiography, and HER amplitude with magneto-encephalography, in 21 male and female participants at rest with eyes open. We observed that HER co-fluctuates with stroke volume on a beat-to-beat basis, but only when no correction for cardiac artifact was performed. This highlights the importance of an ICA correction tailored to the cardiac artifact. We also observed that easy-to-measure cardiac parameters (interbeat intervals, ECG amplitude) are sensitive to stroke volume fluctuations and can be used as proxies when stroke volume measurements are not available. Finally, interindividual differences in stroke volume were reflected in MEG data, but whether this effect is locked to heartbeats is unclear. Altogether, our results question assumptions on the link between stroke volume and HERs.

Coupling between the phase of a neural oscillation or bodily rhythm with behavior: Evaluation of different statistical procedures.

Growing experimental evidence points at relationships between the phase of a cortical or bodily oscillation and behavior, using various circular statistical tests. Here, we systematically compare the performance (sensitivity, False Positive rate) of four circular statistical tests (some commonly used, i.e. Phase Opposition Sum, Circular Logistic Regression, others less common, i.e., Watson test, Modulation Index). We created semi-artificial datasets mimicking real two-alternative forced choice experiments with 30 participants, where we imposed a link between a simulated binary behavioral outcome with the phase of a physiological oscillation. We systematically varied the strength of phase-outcome coupling, the coupling mode (1:1 to 4:1), the overall number of trials and the relative number of trials in the two outcome conditions. We evaluated different strategies to estimate phase-outcome coupling chance level, as well as significance at the individual or group level. The results show that the Watson test, although seldom used in the experimental literature, is an excellent first intention test, with a good sensitivity and low False Positive rate, some sensitivity to 2:1 coupling mode and low computational load. Modulation Index, initially designed for continuous variables but that we find useful to estimate coupling between phase and a binary outcome, should be preferred if coupling mode is higher than 2:1. Phase Opposition Sum, coupled with a resampling procedure, is the only test retaining a good sensitivity in the case of a large unbalance in the number of occurrences of the two behavioral outcomes.

Responses to Heartbeats in Ventromedial Prefrontal Cortex Contribute to Subjective Preference-Based Decisions.

Forrest Gump or The Matrix? Preference-based decisions are subjective and entail self-reflection. However, these self-related features are unaccounted for by known neural mechanisms of valuation and choice. Self-related processes have been linked to a basic interoceptive biological mechanism, the neural monitoring of heartbeats, in particular in ventromedial prefrontal cortex (vmPFC), a region also involved in value encoding. We thus hypothesized a functional coupling between the neural monitoring of heartbeats and the precision of value encoding in vmPFC. Human participants of both sexes were presented with pairs of movie titles. They indicated either which movie they preferred or performed a control objective visual discrimination that did not require self-reflection. Using magnetoencephalography, we measured heartbeat-evoked responses (HERs) before option presentation and confirmed that HERs in vmPFC were larger when preparing for the subjective, self-related task. We retrieved the expected cortical value network during choice with time-resolved statistical modeling. Crucially, we show that larger HERs before option presentation are followed by stronger value encoding during choice in vmPFC. This effect is independent of overall vmPFC baseline activity. The neural interaction between HERs and value encoding predicted preference-based choice consistency over time, accounting for both interindividual differences and trial-to-trial fluctuations within individuals. Neither cardiac activity nor arousal fluctuations could account for any of the effects. HERs did not interact with the encoding of perceptual evidence in the discrimination task. Our results show that the self-reflection underlying preference-based decisions involves HERs, and that HER integration to subjective value encoding in vmPFC contributes to preference stability.SIGNIFICANCE STATEMENT Deciding whether you prefer Forrest Gump or The Matrix is based on subjective values, which only you, the decision-maker, can estimate and compare, by asking yourself. Yet, how self-reflection is biologically implemented and its contribution to subjective valuation are not known. We show that in ventromedial prefrontal cortex, the neural response to heartbeats, an interoceptive self-related process, influences the cortical representation of subjective value. The neural interaction between the cortical monitoring of heartbeats and value encoding predicts choice consistency (i.e., whether you consistently prefer Forrest Gump over Matrix over time. Our results pave the way for the quantification of self-related processes in decision-making and may shed new light on the relationship between maladaptive decisions and impaired interoception.

Neural Responses to Heartbeats Detect Residual Signs of Consciousness during Resting State in Postcomatose Patients.

The neural monitoring of visceral inputs might play a role in first-person perspective (i.e., the unified viewpoint of subjective experience). In healthy participants, how the brain responds to heartbeats, measured as the heartbeat-evoked response (HER), correlates with perceptual, bodily, and self-consciousness. Here we show that HERs in resting-state EEG data distinguishes between postcomatose male and female human patients (n = 68, split into training and validation samples) with the unresponsive wakefulness syndrome and in patients in a minimally conscious state with high accuracy (random forest classifier, 87% accuracy, 96% sensitivity, and 50% specificity in the validation sample). Random EEG segments not locked to heartbeats were useful to predict unconsciousness/consciousness, but HERs were more accurate, indicating that HERs provide specific information on consciousness. HERs also led to more accurate classification than heart rate variability. HER-based consciousness scores correlate with glucose metabolism in the default-mode network node located in the right superior temporal sulcus, as well as with the right ventral occipitotemporal cortex. These results were obtained when consciousness was inferred from brain glucose met`abolism measured with positron emission topography. HERs reflected the consciousness diagnosis based on brain metabolism better than the consciousness diagnosis based on behavior (Coma Recovery Scale-Revised, 77% validation accuracy). HERs thus seem to capture a capacity for consciousness that does not necessarily translate into intentional overt behavior. These results confirm the role of HERs in consciousness, offer new leads for future bedside testing, and highlight the importance of defining consciousness and its neural mechanisms independently from behavior.

Electrogastrography for psychophysiological research: Practical considerations, analysis pipeline, and normative data in a large sample.

Electrogastrography (EGG) is the noninvasive electrophysiological technique used to record gastric electrical activity by means of cutaneous electrodes placed on the abdomen. EGG has been so far mostly used in clinical studies in gastroenterology, but it represents an attractive method to study brain-viscera interactions in psychophysiology. Compared to the literature on electrocardiography for instance, where practical recommendations and normative data are abundant, the literature on EGG in humans remains scarce. The aim of this article is threefold. First, we review the existing literature on the physiological basis of the EGG, pathways of brain-stomach interactions, and experimental findings in the cognitive neuroscience and psychophysiology literature. We then describe practical issues faced when recording the EGG in young healthy participants, from data acquisition to data analysis, and propose a semi-automated analysis pipeline together with associated MATLAB code. The analysis pipeline aims at identifying a regular rhythm that can be safely attributed to the stomach, through multiple steps. Finally, we apply these recording and analysis procedures in a large sample (N = 117) of healthy young adult male and female participants in a moderate (<5 hr) to prolonged (>10 hr) fasting state to establish the normative distribution of several EGG parameters. Our results are overall congruent with the clinical gastroenterology literature, but suggest using an electrode coverage extending to lower abdominal locations than current clinical guidelines. Our results indicate a marginal difference in EGG peak frequency between male and female participants, and that the gastric rhythm becomes more irregular after prolonged fasting.

Visceral Signals Shape Brain Dynamics and Cognition.

Most research in cognitive neuroscience explores how external stimuli are processed by the brain. However, the brain also receives input from the internal body. We discuss here how the heart and gastrointestinal (GI) tract intrinsically generate their own electrical activity, thereby continuously sending information to the brain. These ongoing ascending signals actively shape brain dynamics at rest, complementing canonical resting-state networks (RSNs). Cardiac signals also influence the processing of external sensory information and the production of spontaneous, internal cognition. These findings are discussed in relation to interpretative frameworks regarding the functional role of visceral inputs. This active field of research offers a unique opportunity to draw new theories blurring the border between cognition, emotion, and consciousness, as well as between mind and body.

Resting-State Neural Firing Rate Is Linked to Cardiac-Cycle Duration in the Human Cingulate and Parahippocampal Cortices.

Stimulation and functional imaging studies have revealed the existence of a large network of cortical regions involved in the regulation of heart rate. However, very little is known about the link between cortical neural firing and cardiac-cycle duration (CCD). Here, we analyze single-unit and multiunit data obtained in humans at rest, and show that firing rate covaries with CCD in 16.7% of the sample (25 of 150). The link between firing rate and CCD was most prevalent in the anterior medial temporal lobe (entorhinal and perirhinal cortices, anterior hippocampus, and amygdala), where 36% (18 of 50) of the units show the effect, and to a lesser extent in the mid-to-anterior cingulate cortex (11.1%, 5 of 45). The variance in firing rate explained by CCD ranged from 0.5 to 11%. Several lines of analysis indicate that neural firing influences CCD, rather than the other way around, and that neural firing affects CCD through vagally mediated mechanisms in most cases. These results show that part of the spontaneous fluctuations in firing rate can be attributed to the cortical control of the cardiac cycle. The fine tuning of the regulation of CCD represents a novel physiological factor accounting for spontaneous variance in firing rate. It remains to be determined whether the "noise" introduced in firing rate by the regulation of CCD is detrimental or beneficial to the cognitive information processing carried out in the parahippocampal and cingulate regions.SIGNIFICANCE STATEMENT Fluctuations in heart rate are known to be under the control of cortical structures, but spontaneous fluctuations in cortical firing rate, or "noise," have seldom been related to heart rate. Here, we analyze unit activity in humans at rest and show that spontaneous fluctuations in neural firing in the medial temporal lobe, as well as in the mid-to-anterior cingulate cortex, influence heart rate. This phenomenon was particularly pronounced in the entorhinal and perirhinal cortices, where it could be observed in one of three neurons. Our results show that part of spontaneous firing rate variability in regions best known for their cognitive role in spatial navigation and memory corresponds to precise physiological regulations.

Neural responses to heartbeats distinguish self from other during imagination.

Imagination is an internally-generated process, where one can make oneself or other people appear as protagonists of a scene. How does the brain tag the protagonist of an imagined scene as being oneself or someone else? Crucially, during imagination, neither external stimuli nor motor feedback are available to disentangle imagining oneself from imagining someone else. Here, we test the hypothesis that an internal mechanism based on the neural monitoring of heartbeats could distinguish between self and other. 23 participants imagined themselves (from a first-person perspective) or a friend (from a third-person perspective) in various scenarios, while their brain activity was recorded with magnetoencephalography and their cardiac activity was simultaneously monitored. We measured heartbeat-evoked responses, i.e. transients of neural activity occurring in response to each heartbeat, during imagination. The amplitude of heartbeat-evoked responses differed between imagining oneself and imagining a friend, in the precuneus and posterior cingulate regions bilaterally. Effect size was modulated by the daydreaming frequency scores of participants but not by their interoceptive abilities. These results could not be accounted for by other characteristics of imagination (e.g., the ability to adopt the perspective, valence or arousal), nor by cardiac parameters (e.g., heart rate) or arousal levels (e.g. arousal ratings, pupil diameter). Heartbeat-evoked responses thus appear as a neural marker distinguishing self from other during imagination.

Stomach-brain synchrony reveals a novel, delayed-connectivity resting-state network in humans.

Resting-state networks offer a unique window into the brain's functional architecture, but their characterization remains limited to instantaneous connectivity thus far. Here, we describe a novel resting-state network based on the delayed connectivity between the brain and the slow electrical rhythm (0.05 Hz) generated in the stomach. The gastric network cuts across classical resting-state networks with partial overlap with autonomic regulation areas. This network is composed of regions with convergent functional properties involved in mapping bodily space through touch, action or vision, as well as mapping external space in bodily coordinates. The network is characterized by a precise temporal sequence of activations within a gastric cycle, beginning with somato-motor cortices and ending with the extrastriate body area and dorsal precuneus. Our results demonstrate that canonical resting-state networks based on instantaneous connectivity represent only one of the possible partitions of the brain into coherent networks based on temporal dynamics.

Neural Sources and Underlying Mechanisms of Neural Responses to Heartbeats, and their Role in Bodily Self-consciousness: An Intracranial EEG Study.

Recent research has shown that heartbeat-evoked potentials (HEPs), brain activity in response to heartbeats, are a useful neural measure for investigating the functional role of brain-body interactions in cognitive processes including self-consciousness. In 2 experiments, using intracranial electroencephalography (EEG), we investigated (1) the neural sources of HEPs, (2) the underlying mechanisms for HEP generation, and (3) the functional role of HEPs in bodily self-consciousness. In Experiment-1, we found that shortly after the heartbeat onset, phase distributions across single trials were significantly concentrated in 10% of the recording sites, mainly in the insula and the operculum, but also in other regions including the amygdala and fronto-temporal cortex. Such phase concentration was not accompanied by increased spectral power, and did not correlate with spectral power changes, suggesting that a phase resetting, rather than an additive "evoked potential" mechanism, underlies HEP generation. In Experiment-2, we further aimed to anatomically refine previous scalp EEG data that linked HEPs with bodily self-consciousness. We found that HEP modulations in the insula reflected an experimentally induced altered sense of self-identification. Collectively, these results provide novel and solid electrophysiological evidence on the neural sources and underlying mechanisms of HEPs, and their functional role in self-consciousness.