As expected, bolus isoproterenol infusions elicited rapid and transient dose-dependent increases in heart rate. These increases were evident across the mean as well as peak heart rate responses. Significant increases in mean heart rate were observed at the three highest doses (0.75, 1.0 and 2.0 mcg), whereas increases in peak heart rate were observed at the four highest doses (0.5, 0.75, 1.0 and 2.0 mcg). The calculated CD25 values from the isoproterenol sensitivity tests and the interoceptive rating condition suggest that the levels of bodily change observed in the current study are similar to those commonly reported in the literature (Mills, Dimsdale, Ancoli-Israel, Clausen, & Loredo, 1998
; Yu, Kang, Ziegler, Mills, & Dimsdale, 2007
Concomitant with these changes in peripheral body state, bolus isoproterenol infusions elicited changes in cardiac and respiratory sensations. Increases in interoceptive awareness were observed at increasing doses of isoproterenol, as indexed by retrospective ratings, post infusion wagering, and continuous dial ratings. Interestingly, these increases in interoceptive awareness were indexed to a somewhat different extent by each rating method. Retrospective ratings of interoceptive sensations and post infusion wagering indicated that increased awareness of both heartbeat and breathing sensations occurred at the three highest doses (0.75, 1.0 and 2.0 mcg), perhaps suggesting that these two tasks draw upon a similar type of information when utilized in a retrospective fashion. In contrast, after accounting for the lag time, the cross correlations measured via continuous dial ratings indicated that increases in interoceptive awareness occurred at the four highest doses (0.5, 0.75, 1.0, and 2.0 mcg). Since heart rate changes were observed at the four highest doses of isoproterenol, it appears that the continous dial ratings provided a more sensitive measure for detecting changes in interoceptive awareness than retrospective ratings. This is understandable given that the dial rating method provides a higher resolution scale for reporting momentary and/or subtle changes in interoceptive sensation, over a more nuanced window of time (e.g., continuous online versus single retrospective). Nevertheless, from the observed lag times it also appears that there are significant delays between the objective changes in body state and subjective perceptions of these changes, even for doses that readily elicit increases in interoceptive awareness. These delays are consistent with findings from other modalities of visceral sensation such as gastrointenstinal distension, in which the time course and quality of visceral sensations correlate imperfectly with visceral stimulation (Aziz, et al., 2000
; Cervero, 1985
; Holzl, Erasmus, & Moltner, 1996
). Identifying the neurophysiological mechanisms underlying these multimodal delays in awareness represents an important area for further investigation, one that may yield critical insights into the neural basis of interoceptive awareness.
At the four highest doses of isoproterenol (0.5, 0.75, 1.0 and 2.0 mcg) the majority of participants perceived increased interoceptive sensations, and at the highest dose all participants reported increases in interoceptive sensations. In addition, the degree to which these sensations were perceived was highly correlated with the degree of observed heart rate change at the highest dose. These findings indicate that our method has overcome a major limitation of previous methods, for example, the widely reported finding of less than 40% accuracy rates for resting heartbeat detection tasks. Specifically, our method appears to provide the capacity to reliably manipulate and measure awareness of interoceptive sensations in most if not all participants. Accordingly, instead of examining differences between good and bad heartbeat detectors (or perceivers), the relationship between interoceptive sensations and emotion (or any other variable under investigation) might be measurable in every participant, at varying levels of interoceptive awareness. The fact that the intensity of subjective sensations was highly correlated with the degree of observed heart rate changes also speaks to the efficacy of the current approach, although future studies are needed to examine how performance on this protocol compares with performance on standard heartbeat perception tasks. For example, it would be interesting to examine whether good heartbeat detectors are more aware of isoproterenol induced heartbeat sensations (e.g., generate greater retrospective ratings at lower doses than non detectors and/or greater cross correlations). An additional benefit of the present method relates to improved ecological validity: rather than abstractly comparing heartbeat sensations to tones or counting heartbeats, participants simply indicate the degree to which their interoceptive sensations are changing in real time. Furthermore, they do so in a manner that shares closer phenomenological proximity to the experience of naturally occurring changes in levels of physiological arousal that, notably, also arise within the context of emotional experience.
Isoproterenol doses elicited a small increase in retrospective ratings of physical anxiety but did not elicit increased ratings of mental anxiety or distress, indicating that the effects of the bolus isoproterenol infusions were disproportionately restricted to experiences of physical body sensations. The observed pattern of findings is somewhat different from the ratings reported by Cameron & Minoshima (2002)
, who found that a continuous 30 minute infusion of isoproterenol titrated to a heart rate of 120 bpm resulted in increased ratings of anxiety and distress. Since the current study utilized lower doses of isoproterenol and in a bolus format, few participants’ heart rates ever reached 120 bpm (peak heart rate reached 120 bpm for only 2 of the 15 participants). As a result, participants in the current study experienced smaller changes in arousal and for briefer periods of time. However, these changes were an intended feature of the design: they were aimed at better mimicking the transient aspect of emotions, and were in light of the fact that extreme changes in arousal are not required for an experience to be reported as emotional (Ben-Ze’ev, 2000
; Davidson, 2003
; Hutcherson, et al., 2005
). In the Cameron & Minoshima (2002)
study, the duration and magnitude of the heart rate increase was such that participants may have generated anxiety about being in this state for so long, with potential distress due to the lack of controllability over such an extended elevation in the state of arousal. Thus it is possible that the reported anxiety might have not been the direct reflection of the physiological activation (as would be predicted in a James-Lange theoretical framework), but rather a secondary development of an emotional state. It is interesting to note that in the current study, participants only perceived the intensity of interoceptive sensations as moderate at the maximum dose (on average not exceeding 5 on a scale of 10). Future studies could address whether reports of anxiety or other emotions can be induced at higher doses approximating or even exceeding the heart rate changes observed by Cameron & Minoshima (2002)
In a broader context, the fact that transient changes in peripheral arousal were not sufficient to induce negatively valenced affective states would appear to argue against a literal interpretation of the James-Lange theory. However, the current study was not specifically designed to tackle this issue, and thus our comments here should be taken as speculative. We only mention it as a possibility because the current method provides a powerful tool for evaluating the roles that interoceptive awareness have been proposed to play in the experience of emotional states. Thus, one benefit of this method could allow for investigations of the degree to which the elicited patterns of cardiorespiratory responses are capable of inducing primary and secondary emotions, as suggested by the James-Lange theory. Similarly, by combining the current method with adequate manipulations of emotional context (a la Schacter & Singer, 1962
), novel insights could be generated that refine our understanding of the relative influences of interoceptive and cognitive states on the subjective experience of emotion. Yet another viable area of inquiry relates to the extent to which interoceptive sensations are at all relevant for emotional states (a la Rolls, 2000
; i.e., whether they are a necessary component or are merely a downstream consequence of emotional processing). Beyond basic emotion research, this method could also be used to clarify other putative influences of peripheral body states on cognition, such as the contribution of ‘gut feelings’ to complex decision making (a la the Somatic Marker Hypothesis of Damasio, 1996
Nevertheless, at the most basic level, the current method provides a framework for studying the phenomenology of, and mechanisms underlying interoceptive awareness. For instance, overlap maps of the location of perceived heartbeat sensations indicated that heartbeat sensations induced by isoproterenol were most commonly experienced in the lower left side of the anterior chest, in a region roughly corresponding to the point of maximum impulse (or PMI). The PMI is considered the location where the heart rotates, moves forward and strikes against the chest wall during systole, and is a physical exam sign routinely utilized by physicians to help them determine if an individual has an enlarged heart (in which case the location of the PMI is shifted). However, heartbeat sensations were also commonly perceived in several other body locations including the head, neck, abdomen and arms. Heartbeat sensations have been localized to many of these same regions in previous studies of heartbeat detection (Jones, 1994
; Jones, Jones, Rouse, Scott, & Caldwell, 1987
; Ring & Brener, 1992
, Khalsa et al, unpublished data
), indicating that the observed variability in the present study is reliable. This raises the question of which neural pathways within the body mediate awareness of heartbeat sensations. Possible mechanisms include signal transmission via sensory pathways from receptors in the heart, such as low-threshold mechanosensitive endings on vagal afferent fibers in the atria and venoatrial junction, or mechanosensitive C-fibers in the ventricles (Longhurst, 2004
; Malliani, 1986). Another possibility includes intra-thoracic detection of the force generated by the heart beat on the walls of the great vessels (e.g., via baroreceptors) and in surrounding mechanosensitive thoracic tissues (Eichler & Katkin, 1994
; Schandry, Bestler, & Montoya, 1993
). Yet another possibility includes transmission by cutaneous (dermal and epidermal) mechanosensitive fibers overlying larger arteries. Each of the aforementioned peripheral pathways project to different regions in the brainstem and cerebral cortex (e.g., insula versus primary or secondary somatosensory cortex), and thus have implications for whether heartbeat sensations should be categorized as visceral sensation, cutaneous sensation, or both. An examination of the overlaps from the present study indicates that several of the reported body locations, such as the neck, belly and head share close proximity with major arteries (e.g., common carotid, abdominal aorta and external carotid arteries respectively). This, in combination with the knowledge that individuals with a lower body mass index are better at detecting heartbeat sensations (Rouse, Jones, & Jones, 1988
), suggests that receptors in the skin may play a role in the apprehension of heartbeat sensations. Indeed, Knapp, Ring, & Brener (1997)
reported that vibrotactile sensitivity in the finger accounted for a portion of the variance in a heartbeat detection task, and based on this finding suggested that heartbeat sensations might be mediated via Pacinian corpuscles. Although the present findings are not capable of distinguishing whether the skin or deeper structures in the viscera were mediating heartbeat sensations, it seems plausible that a combination of both is occurring. For example, it is possible that structures within the thoracic cavity relay heartbeat sensations localized to the chest, whereas receptors in the skin may transmit heartbeat sensations experienced in other body locations such as the belly, neck and head.
Another important question is which neuroanatomical structures within the brain mediate awareness of heartbeat sensations. Based on the observed variability in the location of heartbeat sensations and the available sensory pathways within the body, it seems plausible that a combination of visceral and somatosensory structures contribute to the perception of heartbeat sensations. This notion is supported by the findings of Cameron & Minoshima (2002)
, who reported increased regional metabolism of both the insula and midline (truncal) primary somatosensory cortex in participants receiving isoproterenol infusions. However, it is still unclear whether these brain regions truly mediate awareness of heartbeat sensations since functional neuroimaging studies are not capable of determining whether brain regions are required for the ability to experience the sensation of the heartbeat. For example, even though both brain regions show greater metabolism during the experience of heartbeat sensations, it is possible that only one of these is important for the ability feel the heartbeat, or that the two regions provide differential contributions to the heartbeat sensation. These questions could be addressed by adapting the current protocol to human lesion studies, for example, by studying the experience of heartbeat sensations in individuals with damage to insular or somatosensory cortex.
There are several limitations associated with the current study. Since isoproterenol induces ionotropic as well as chronotropic changes in cardiac function, one limitation of the cross correlation method relates to the isolated use of heart rate change for calculating the interoceptive cross correlations. We do not consider this to be a major limitation, though, because cardiac contractility also increases during isoproterenol administration and these changes are closely correlated with changes in heart rate (de Mey, et al., 1992
; De Mey, Erb, Schroeter, & Belz, 1996
). An additional limitation that may be addressed by future studies relates to the absence of a measure of breathing change in the cross correlation, since participants were instructed to rate respiratory as well as cardiac sensations. However, we feel that utilizing the heart rate reflects an acceptable approach for several reasons. Firstly, isoproterenol induced respiratory changes occur concomitantly with cardiac changes. Secondly, the heart rate is the most readily observable and commonly utilized measure of the response to isoproterenol in both clinical and research applications. Finally, in the current study reliable cross correlations were measured using the heart rate alone.
Another important consideration for the current study is the fact that all participants underwent two isoproterenol sensitivity tests prior to the interoceptive rating condition. Thus, each participant was familiar with the particular interoceptive sensations elicited by isoproterenol prior to the measurement of interoceptive awareness. Consequently, the interoceptive ratings could in principle have been biased by a learning effect (in the same vein, it is equally possible that the lack of increases in mental anxiety and distress could have been due to emotional habituation to the subjective experience of isoproterenol). However, this intended feature of the design may have also improved the reliability of each participant’s rating, by reducing the contribution of noise in the ratings related to novelty effects. A separate potentially confounding outcome of this design relates to habituation in the bodily response to isoproterenol. We found little evidence for this possibility, as an analysis of the CD25 values for all three rounds of isoproterenol failed to reveal any differences in sensitivity as exposure to isoproterenol increased. This absence of habituation bodes well for future research studies implementing isoproterenol, as it suggests that repeated administration of the same doses within the same participant will result in similar bodily responses.
A final consideration relates to the use of saline infusions in the current study. A minority of participants reported increases in heartbeat sensations during saline infusions, as indexed by the dial ratings and the overlap map of heartbeat sensations. This outcome is not surprising given the well known existence of the placebo response, and it is interesting to note that the frequency of placebo responses in the current study (30%) is entirely consistent with the rates of placebo responding in the literature (Olshansky, 2007
). A more difficult question to answer may be why some individuals perceived interoceptive sensations during saline infusions. One potential explanation may be found from the literature on heartbeat detection. Since a minority of individuals are good heartbeat detectors at rest, it is likely that several individuals in the current study would also be classified as good detectors if tested on a heartbeat detection paradigm. It seems possible that during several saline infusions this type of individual might have been rating spontaneous cardiac changes occurring during the infusion interval as well as cardiorespiratory changes induced by the manipulation itself, such as cardiac accelerations and decelerations related to infusion administration (Vila et al, 2007
). This question could be addressed in future studies.
The contribution of bodily signals to the experience of emotion has remained a fundamental and unresolved issue in emotion research, primarily due to the lack of suitable methods for manipulating the state of the body. The current findings indicate that bolus isoproterenol infusions provide a reliable method for manipulating and assessing interoceptive awareness. This method reliably demonstrated increases in interoceptive awareness in the majority of participants, thereby overcoming a major limitation of heartbeat perception tasks. The versatility of this approach in inducing brief, rapid and reversible changes in arousal suggests that it may help in providing new understandings of how conscious and subconscious feedback from the body influences the experience of emotion, how these experiences are mediated within the central nervous system, and how they might guide cognition and behavior.