The Fundamental Basis of Palpitations: A Neurocardiology Approach

Abstract

Background and Objective

Palpitations are a common symptom that may indicate cardiac arrhythmias, be a somatic complaint in anxiety disorders, and can be present in patients without either condition. The objective of this review was to explore the pathways and fundamental mechanisms through which individuals appreciate palpitations.

Observations

Cardiac afferents provide beat-to-beat sensory information on the heart to the spinal cord, brain stem, and higher brain centers. Cardioception, a subset of interoception (‘the physiological sense of the condition of the body’), refers to sensing of the heartbeat. High cardioception is present in persons with lower body mass index, lower percentages of body fat, and anxiety disorders. Low cardioception (lower interoceptive awareness) is associated with psychiatric disorders, such as depression, personality disorders, and schizophrenia. CNS sites associated with heartbeat detection have been identified by functional magnetic resonance imaging studies and heartbeat-evoked electroencephalogram potentials. The right insula, cingulate gyrus, somatomotor and somatosensory cortices nucleus accumbens, left subthalamic nucleus, and left ventral capsule/striatum are implicated in both palpitations and heartbeat detection. Involvement of the brain as a primary modulator of palpitations rests on the data that various areas of the brain are activated in association with cardioception, the ability of focal brain stimulation to induce palpitations, the ability of central alpha receptor agonists and antagonists to modulate palpitations, and suppression of palpitations by transcranial repetitive magnetic stimulation (rTMS).

Conclusions

Palpitations should be viewed as a pathway extending from the heart to the brain. Palpitations are, in part, a reflection of an individual’s cardioception awareness, which is modulated by body size, percentage of body fat, and psychological or psychiatric conditions. Palpitations can originate in the brain and involve central neurotransmitters. Treatment of palpitations unrelated to cardiac arrhythmias or anxiety disorders should consider the use of central alpha-2 agonists and possibly rTMS.

1. INTRODUCTION

Palpitations are a common symptom that may indicate cardiac arrhythmias, or they might be a somatic complaint in some patients with anxiety disorders or panic attacks. In addition, there is a high proportion of patients with palpitations in whom no psychiatric or cardiologic cause is found [1]. Palpitation without a defined cardiac etiology can be ‘persistent and disturbing’ with impairment in occupational functioning and increased health care utilization [1]. A fundamental question is how an individual perceives palpitations. This question generates several specific questions, namely, what is the afferent limb of the sensory pathway presumably involving cardiac afferent nerves and their course to the brain, what brain centers process these signals, and in turn, what brain centers are activated to elicit the symptom of palpitations in the absence of cardiac arrhythmias. An understanding of these processes would provide a biological basis for the interpretation of this important symptom and guide potential treatment options.

2. APPRECIATION OF HEARTBEAT

The heart is richly innervated by the autonomic nervous system, which has been categorized into central, intrathoracic extra-cardiac, and intrinsic cardiac components [2]. The intrathoracic extrinsic cardiac nervous system connects the intrinsic cardiac nervous system within the heart to the central nervous system [2]. Complex inter-neuronal interactions exist between intracardiac neurons and other intrathoracic and central nervous system neurons [3]. Cardiac afferents provide beat-to-beat sensory information on cardiac function and microenvironment to the spinal cord, brain stem, and higher brain centers [2-4]. Central nervous system neurotransmitters can modulate cardiac arrhythmias [5, 6].

Interoception, defined as ‘the physiological sense of the condition of the body,’ involves the ascending pathway to the cortex from body tissues and their integration with the ‘central autonomic network’ and with cerebral centers involved with emotions [7-14]. With respect to palpitations, interoception represents sensing of the heartbeat. A common method of testing an interoceptive process is heartbeat detection, labelled cardioception [9, 15-17].

3. FACTORS MODULATING CARDIOCEPTION

The association between anxiety disorders and ‘cardiac’ symptoms in persons without a cardiac cause may be traced back to the James-Lange theory, which states that a bodily change or a perception of bodily changes subsequent to an emotional stimulus is a manifestation or representation of that emotion [18, 19]. As a result, many studies have attempted to identify the link between experiencing symptoms, such as palpitations, and neurotransmitter release or anatomical activation in the central nervous system.

There are a number of lines of evidence that implicate the brain as a key component and even the primary originator of palpitations in the absence of cardiac arrhythmias. One of these involves brain adrenergic neurotransmitters, specifically central alpha-2 adrenoreceptors. These are autoreceptors or presynaptic membrane receptors that are located on and are sensitive to the same neurotransmitters that are released by the neuron that releases the neurotransmitter. In the case of the central alpha-2 adrenoreceptor, the autoreceptor inhibits the release of norepinephrine through a negative feedback mechanism [20]. Central alpha-2 adrenoreceptors have well-known effects on cardiovascular regulation [21]. It has been posited that patients with panic disorder have more ‘sensitive’ central alpha-2 adrenergic receptors [22-24]. To test this hypothesis, patients with panic disorder have been treated with alpha-2 agonists (e.g., clonidine and guanabenz) or alpha-2 antagonists (e.g., yohimbine) in order to assess the effect on palpitations.

Central alpha-2 adrenoreceptor stimulation with clonidine is more effective than the tricyclic antidepressant doxepin in alleviating palpitations in opiate-dependent patients experiencing withdrawal symptoms [25]. Patients who had received clonidine developed palpitations upon its discontinuation and the symptom resolved after reinstating therapy [25]. The same results were reported with guanabenz therapy [26].

Alpha-2 antagonists induce palpitations, presumably by increasing the amount of norepinephrine in the synaptic cleft. Yohimbine significantly increased the number of palpitations in patients with panic disorder with or without agoraphobia [22, 27-29]. Yohimbine-induced palpitations were noted even in patients treated with imipramine or fluvoxamine [27, 28]. The ability of yohimbine to accentuate palpitations was also found in placebo-controlled studies of healthy individuals and patients with major depression [30, 31]. Taken together, these data suggest that brain neurotransmitters can play a role to induce, stop or modulate palpitations.

4. PALPITATIONS AND BRAIN REGIONS

Isoproterenol, a non-specific beta-adrenergic agonist, can produce sensations of palpitations and dyspnea [32]. Isoproterenol inducing palpitations in healthy participants produce activation in the right mid-dorsal and posterior insula as well as the left medial frontal gyrus (premotor cortex) as seen on functional magnetic resonance imaging (fMRI) [33, 34]. The anticipation period prior to isoproterenol administration was noted to activate the mid-anterior regions of the right insula, right postcentral gyrus, and left inferior parietal lobule [33]. Positron emission tomography (PET) has identified that isoproterenol is associated with increased cerebral glucose metabolism in the medial portion of the cingulate gyrus and right insular cortex [35].

In addition to the cingulate and insular cortices, isoproterenol-induced palpitations have been associated with increased cerebral glucose metabolism, measured via PET, in the left primary somatosensory cortex [35].

There is much overlap between activation of brain regions associated with cardioception and isoproterenol-induced palpitations. This includes the right insular cortex, cingulate gyrus, and the somatosensory cortex [33-35].

The insula, bilaterally, plays a role in visceral interoception, and it appears that parasympathetic activity is usually represented in the dominant (left) hemisphere, whereas sympathetic activity is represented in the non-dominant (right) hemisphere [12].

Deep brain stimulation has also been associated with palpitations, as evidenced by bilateral stimulation at the level of the nucleus accumbens [36], subthalamic nucleus [37], and left ventral capsule/ventral striatum [38].

5. CARDIOCEPTION AND BRAIN REGIONS

fMRI studies directly measured brain region activation associated with a heartbeat detection task, an interoceptive process [9, 15-17]. The heartbeat detection task is primarily done by having patients tapping or silently counting their heartbeat compared to an exteroceptive condition, which typically consists of counting auditory external tones [9, 39]. These tasks are easily measured due to the frequency and distinctiveness of heartbeats [40]. The heartbeat detection task is a close representation of the increased awareness of the heartbeat (i.e., palpitation) as the heartbeat is an interoceptive sensation. Cardioceptive tasks produce larger signals in the bilateral insula as compared to exteroceptive conditions [9, 41-44]. Isolated activity in the right insula [45, 46], left insula [47, 48], and in the right inferior frontal operculum [surrounding the anterior insula] have been associated with heartbeat detection tasks [45, 46, 49]. Neural activity in the right insular and opercular cortex predicts an individual’s accuracy in heartbeat detection [41, 50, 51].

Activity in the cingulate cortex, detected by fMRI, has also been associated with heartbeat detection [9, 41, 42, 46, 47, 51]. Among interoceptive tasks, there is greater activity in the anterior cingulate cortex, mid and anterior insula when heartbeat detection tasks are performed compared to skin temperature detection tasks in healthy patients [44].

Measuring heartbeat-evoked potentials (HEP), which are electroencephalogram (EEG) segments synchronized to the heartbeat during a heartbeat perception task, identifies higher HEP amplitudes over frontal and fronto-central electrode locations [52]. This coincides with previous studies [53-57] and is thought to have reflected activity in the insular, anterior cingulate, and somatosensory cortices [52, 56]. BESA dipole-source analysis, which allows spatiotemporal modeling of multiple dipoles to identify areas associated with HEP amplitudes, found that heartbeat detection was associated with activation in the right insula and anterior cingulate cortex [52], with good heartbeat perceivers showing significantly higher HEP amplitudes and higher dipole strengths than poor perceivers [52]. Inhibiting the right anterior insula via repetitive transcranial magnetic stimulation reduced interoceptive accuracy as well as the HEP amplitude over frontocentral locations [52].

Seeley et al. labelled a network, the salience network, consisting of the insula, anterior cingulate cortex, and subcortical regions such as the ventral striatum, amygdala, ventral tegmental area, and midbrain [58]. fMRI data have shown positive correlations between heartbeat counting scores and salience network connectivity in the right posterior insula and a trend towards positive correlation in the left posterior insula [59].

In addition to fMRI studies, inhibition of brain regions has also been performed to assess interoception. Inhibition of the insula via transcranial direct current stimulation (tCDS), has reduced interoceptive accuracy as compared to sham treatment in both the left and right insula [60]. Neoplastic lesions affecting the right insula reduce but do not completely compromise heartbeat awareness [61].

5.1. The Smatosensory and Somatomotor Cortices in Cardioception

In addition to the insular cortex and the anterior cingulate cortex, somatosensory cortices may influence viscero-sensation as they have a plethora of connections with the insula, and its activity has been associated with heartbeat detection tasks [9, 45, 51, 62, 63]. In addition to the insular and anterior cingulate cortex pathway of interoception, there exists another that involves the secondary somatosensory cortex [9, 51, 64]. In a patient with a left ventricular assist device (LVAD), heartbeat detection responses followed the external pump rather than cardiac tissue, suggesting that a separate secondary somatosensory cortex (S2) pathway is prominent in interoception and not only the insular cortex/anterior cingulate cortex pathway [64]. Individuals with lower body mass index and lower percentages of body fat are better heartbeat detection performers, suggesting that skin receptors involved with the somatosensory pathway may also play a role in cardiac interoceptive awareness [15, 65].

fMRI studies have suggested that interoceptive heartbeat perception tasks are associated with activation in the somatosensory cortices, including the primary somatosensory, secondary somatosensory cortices, and the somatosensory association cortex (areas associated with the S2 pathway) [41, 44, 47, 49, 51] and the somatomotor cortices (including the primary motor, supplementary motor and premotor cortices) [9, 41, 44, 45]. When comparing heartbeat detection versus skin temperature detection, there was greater activity in the supplementary motor area and precentral and inferior frontal gyri associated with heartbeat awareness [44].

BESA dipole-source analysis of HEPs has shown HEP associated with activation in the prefrontal cortex and left secondary somatosensory cortex in addition to the anterior cingulate cortex, right insula [66]. Studying interoceptive awareness via heartbeat counting with high-density electroencephalography (EEG) has shown that high interoceptive awareness was associated with overall higher activation levels in the prefrontal cortex and the somatosensory cortices [67]. Inhibiting the right somatosensory cortex via repetitive transcranial magnetic stimulation produced a significant decline in cardiac interoceptive accuracy as compared to occipital stimulation [66].

A patient with complete bilateral damage to the insular and anterior cingulate cortices but an intact bilateral primary somatosensory cortex showed dose-dependent changes in interoceptive awareness in response to isoproterenol that were comparable, albeit delayed, to healthy participants [68]. Applying a topical anesthetic to the region of maximal heartbeat sensation resulted in a significantly impaired interoceptive awareness as compared to controls [68].

A summary of neural afferent and efferent pathways can be seen in Fig. (1). A summary of brain regions activated during cardioception can be seen in Table 1 and Fig. (2).

Fig. (1).

Proposed pathways identified with respect to cardiac interoception/palpitations. The visceral afferent pathway carried by the vagus nerve (CN X) is identified in red. The visceral afferent pathway with cell bodies in the dorsal root ganglion (DRG) is identified in blue. In addition to the insula (INS) and anterior cingulate cortex (ACC), the afferent pathway also terminates in the somatosensory cortex (SC). The efferent pathway (black, dashed) has contributing inputs from the brainstem reticular formation (BSRF). PC = paravertebral chain, NTS = nucleus of the solitary tract, PBN = parabrachial nucleus, PAG = periaqueductal gray matter, THAL = thalamus NG is nodose ganglion (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Table 1.

Summary of anatomical brain regions associated with cardioception and palpitations.

Brain Region	Reference (Cardioception)	Reference (Palpitations)
Bilateral insula	Avery et al., 2017 (42); Caseras et al., 2013 (41); Critchley et al., 2004 (9); Ernst et al., 2013 (43); Stern et al., 2017 (44); Pollatos, Schandry et al. 2007(51); Sagliano et al. 2019 (60); Khalsa et al., 2009 (68)
Right insula	Kuehn et al., 2016 (45); Pollatos et al. 2005 (52); Zaki et al. 2012 (46); Pollatos et al. 2016 (66); Ronchi et al. 2015 (61); Chong et al., 2017 (59)	Hassanpour et al. 2016 (33); Hassanpour et al. 2018 (34); Cameron & Minoshima, 2002 (35)
Left insula	Wiebking et al. 2014 (48); Tan et al. 2018 (47)
Anterior cingulate cortex	Avery et al., 2017 (42); Caseras et al., 2013 (41); Critchley et al., 2004 (9); Tan et al., 2018 (47); Pollatos et al., 2005 (52); Khalsa et al., 2009 (68)	Cameron & Minoshima, 2002 (35)
Middle/posterior cingulate cortex	Zaki et al., 2012 (46); Pollatos, Schandry et al., 2007 (51)	Cameron & Minoshima, 2002 (35)
Somatomotor cortices (primary motor cortex, supplementary motor area, premotor cortex)	Caseras et al., 2013 (41); Critchley et al., 2004 (9); Stern et al., 2017 (44); Kuehn et al., 2016 (45)	Hassanpour et al., 2018 (34)
Somatosensory cortices (primary somatosensory cortex, secondary somatosensory cortex, somatosensory association cortex)	Caseras et al., 2013 (41); Stern et al., 2017 (44); Couto et al., 2014 (64); Rouse et al., 1988 (65); Pollatos, Gramann et al., 2007 (67); Khalsa et al., 2009 (68); Kuehn et al., 2016 (45); Pollatos et al., 2005 (52); Tan et al., 2018 (47); Blefari et al., 2017 (49); Pollatos, Schandry et al., 2007 (51)	Cameron & Minoshima, 2002(35)
Right thalamus	Avery et al., 2017 (42); Tan et al., 2018 (47); Pollatos, Schandry et al., 2007 (51)
Superior, middle/inferior temporal gyri	Caseras et al., 2013 (41); Stern et al., 2017 (44); Blefari et al., 2017 (49); Pollatos, Schandry et al., 2007 (51)
Inferior frontal cortex	Critchley et al., 2004 (9); Pollatos, Schandry et al., 2007 (51); Kuehn et al., 2016; Zaki et al., 2012 (46); Blefari et al., 2017 (49)
Prefrontal cortex	Pollatos et al., 2005 (52); Zaki et al., 2012 (46); Pollatos, Gramann et al., 2007 (67)
Middle frontal gyrus	Tan et al., 2018 (47); Zaki et al., 2012 (46); Pollatos, Schandry et al., 2007 (51)
Occipital cortex	Stern et al., 2017 (44)
Precuneus	Tan et al., 2018 (47)
Hypothalamus	Zaki et al., 2012 (46)
Nucleus accumbens		Shapira et al., 2006 (36)
Left subthalamic nucleus		Okun et al., 2004 (37)
Left ventral capsule/striatum		Tsai et al., 2014 (38)

Fig. (2).

Brain regions activated in cardioception (blue), palpitations (red) and both (green). Shown is lateral view (top left), sagittal view (top right) and coronal view (bottom). PrFC = prefrontal cortex, iFC = inferior frontal cortex, PC = premotor cortex, SMA = supplementary motor area, PMC = primary motor cortex, RO = Rolandic operculum, PSC = Primary somatosensory cortex, S2 = secondary somatosensory cortex (overlapping with parietal operculum), iPL = inferior parietal lobule, SMG = supramarginal gyrus, MFG = medial frontal gyrus, ACC = anterior cingulate cortex, MCC = middle cingulate cortex, PCC = posterior cingulate cortex, INS = insula, PO = parietal operculum (overlapping with S2) (A higher resolution / colour version of this figure is available in the electronic copy of the article).

5.2. Association of Brain Regions in Cardioception and Anxiety

High interoceptive awareness is associated with anxiety disorders [69-74], and lower interoceptive awareness is associated with psychiatric disorders, such as depression, personality disorders, and schizophrenia [50, 75-77]. Phobic patients showed increased activity in the bilateral insula and anterior cingulate cortex upon symptom provocation (i.e., exposure to spider or blood injection injury [41]).

When comparing signal changes between cardiac interoception and anxiety activation (i.e., focusing on predetermined anxieties), cardiac interoception disproportionally activated the bilateral insular cortex, left precentral gyrus, bilateral supramarginal gyrus, bilateral thalamus, and right supplementary motor area compared with the anxiety condition. Overlapping regions included the left anterior insular cortex, left supplementary motor area, and middle cingulate gyrus [47].

The overlap shown between interoception and anxiety with respect to brain region activation is corroborated by the activation of the insular cortex/anterior cingulate cortex duo during anxious states [78-82]. Indeed, this abnormal activation might coincide with panic patients who cannot accurately discriminate their cardiac stimuli as compared to patients without panic disorders who have palpitations [83].

6. TREATMENT OPTIONS IN PALPITATION IN THE ABSENCE OF CARDIAC OR PSYCHIATRIC CAUSES

Individuals with debilitating palpitations in the absence of cardiac or psychiatric merit consideration for treatment. Pharmacologic treatment could use central alpha-2 agonists such as clonidine or guanabenz, based on the data cited above [25, 26]. Alpha-2 antagonists should be avoided [22, 28, 30, 31]. Interestingly, meditation is not associated with changes in interoceptive awareness [84].

Brain stimulation interventions are an intriguing modality for treatment. Transcranial direct current stimulation (tDCS) over the right or left insula has been demonstrated to significantly alter interoception in healthy young individuals [60]. Transcranial repetitive magnetic stimulation (rTMS), which uses rapid and time-varying magnetic field pulses to produce changes in neural circuits, has demonstrated efficacy in a number of psychiatric conditions [85, 86]. Inhibiting the right anterior insula via repetitive transcranial magnetic stimulation reduced interoceptive accuracy as well as the HEP amplitude over frontocentral locations [52].

rTMS focused on areas of the brain such as the right insula, and cingulate cortex may be helpful in palpitations refractory to other management approaches. The ability of rTMS to affect parasympathetic nerve activity to the heart [87] suggests that it might also modulate afferent pathways involved in cardioception. Investigating the impact of excitatory and inhibitory TMS paradigms on neuro-cardiac pathways may open new treatment paradigms for patients who experience intractable palpitations of non-cardiac origin.

SUMMARY AND CONCLUSIONS

Palpitations should be viewed as a pathway extending from the heart to the brain. Palpitations are, in part, a reflection of an individuals’ cardioception awareness, which is modulated by body size, percentage of body fat, and psychological or psychiatric conditions. Palpitations in the absence of cardiac arrhythmia may have diverse pathophysiology. It may represent a heightened sense of interoception. There are many areas of the brain that participate in this network, processing signals related to palpitations. The right insula, cingulate gyrus, somatomotor and somatosensory cortices are implicated in both palpitations and the heartbeat detection task. Likely, brain regions related to palpitations involve the nucleus accumbens, left subthalamic nucleus, and left ventral capsule/striatum, though only a few studies have confirmed these areas. The frontal, temporal, occipital cortices, in addition to the thalamus and hypothalamus have been shown to be activated in cardioceptive tasks, but not palpitations specifically. The involvement of the brain as a primary modulator of palpitations rests on the data that various areas of the brain are activated in association with cardioception, the ability of focal brain stimulation to induce palpitations, and the ability of central alpha receptor agonists and antagonists to modulate the experience of palpitations. Utilization of drugs that affect CNS modulators and the use of stimulation of brain regions related to palpitations may bring relief to patients with persistent palpitations without a cardiac or psychiatric cause.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

DMB has received research support from the CIHR, NIH, Brain Canada, and the Temerty Family through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd., and he is the principal site investigator for three sponsor-initiated studies for Brainsway Ltd. He receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior.