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Psychosomatic Medicine 64:851-861 (2002)
© 2002 American Psychosomatic Society

ORIGINAL ARTICLES

Regional Brain Activation Due to Pharmacologically Induced Adrenergic Interoceptive Stimulation in Humans

Oliver G. Cameron, MD, PhD and Satoshi Minoshima, MD, PhD

From the University of Michigan Medical Center, Ann Arbor, Michigan.

Address reprint requests to: Oliver G. Cameron, MD, PhD, University of Michigan Medical Center, Room C9154, University Hospital, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0120. Email: ocameron{at}umich.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Identifying the brain regions associated with visceral sensory activation and awareness (interoception) was a neglected area of neural science until quite recently despite being essential to a comprehensive understanding of psychosomatic processes, baroreception, and higher brain functions such as fear and anxiety, other emotions, and pain.

METHODS: In this study regional changes in the cerebral metabolic rate for glucose were determined with positron emission tomography in response to cardiovascular-respiratory activation induced in healthy humans by ß-adrenergic stimulation produced with intravenous isoproterenol, which acts predominantly in the periphery because of minimal transport across the blood-brain barrier.

RESULTS: Interoceptive activation raised heart rate to approximately 120 beats per minute, produced somatic and to a lesser extent psychological symptoms, and significantly increased cerebral glucose metabolism in the left primary somatosensory cortex and medial portion of the cingulate gyrus; right insular cortex showed a trend toward an increase that was significant in homogeneous subgroups of right-handed or female subjects.

CONCLUSIONS: These results demonstrate the involvement of specific brain regions as well as hemispheric laterality of function in visceral perception, and they suggest that during emotional reactions involving changes in visceral organ function, activation of some of the brain regions observed could be due specifically to interoceptive processes.

Key Words: interoception, • isoproterenol, • cerebral glucose metabolism, • positron emission tomography, • emotion, • humans.

Abbreviations: ACPC = anterior commissure posterior commissure;; ANOVA = analysis of variance;; CMRglu = cerebral metabolic rate for glucose;; CNS = central nervous system;; FWHM = full-width, half-maximum;; PET = positron emission tomography;; ROI = region of interest.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
There has been a renaissance of interest in the past two decades in the study of emotion (1) and other phenomena at the interface of neural and psychological processes (2), supported in part by the development of techniques of functional brain imaging (3). An essential component of emotions and other motivational states is their associated physiological changes, including visceral-autonomic changes and the sensory awareness that is sometimes part of those changes; the latter is often called interoception (4–9). The most prominent changes are often in cardiac function and related symptoms. Despite the theory going back more than 100 years that these sensory functions are a sine qua non for the experience of emotion (10), systematic study of these interoceptive processes is fairly new, and the data are not familiar to many investigators.

Prior studies have indicated that specific brain regions are involved in interoceptive processes, including the insular cortex (11–14), cingulate gyrus (14–17), somatosensory cortex (18, 19), frontal cortex (11, 15, 16, 20), amygdala (14), and thalamus (11, 15, 16). Other structures implicated at least indirectly include the nucleus of the solitary tract, parabrachial nucleus, locus ceruleus, and periaqueductal gray of the brain stem; the subcortical hippocampus, mamillary bodies, and hypothalamus; the cortical temporal pole and parahippocampal gyrus; and various fiber bundles that connect these structures (9). Many of the studies that have implicated these structures have focused not only on interoceptive processes per se but more broadly on brain regions activated by emotions (18, 21–25), including sadness and depression (26–34), fear (1, 35–37), and anxiety (33, 38–40), and by pain (41, 42), although some studies associated more directly with interoceptive cardiovascular (11, 15, 16), respiratory (11, 13, 14), and alimentary-gastrointestinal tract (11, 43–46) functions (including disgust; Refs. 29, 47, and 48) have also been reported. Many of these studies have observed laterality effects, that is, structures on one side of the brain affected with analogous structures on the opposite side not showing the same effect. Some of these studies have used administration of pharmacological substances to produce the brain activation and interoceptive stimuli (7, 15, 16, 49, 50), similar to the research described here.

This positron emission tomographic (PET) functional imaging study determined brain regions activated by cardiac and respiratory interoception in human subjects with normal cardiovascular and respiratory function. Pharmacological activation with isoproterenol, a nonselective ß-adrenergic receptor agonist with a short half-life in blood (51) that has both chronotropic and inotropic effects on the heart (52) and relaxes bronchial smooth muscle, was used because less than 4% crosses the blood-brain barrier on the first pass after intravenous administration (53). Hence, isoproterenol can be expected to produce minimal acute direct chemical effects on brain. Any observed stimulatory changes in brain function therefore are most likely to be due to afferent sensory nerve input. Thus, isoproterenol administration should provide a highly controllable experimental model of interoceptive processes. Based on the previous studies described above, a priori hypotheses predicted interoceptive stimulation would activate the following regions: insula, cingulate gyrus, amygdala, frontal cortex, thalamus, and somatosensory cortex. These prior studies are most consistent for interoceptive stimulation to activate insula and cingulate, with amygdala activation expected to the extent that fear or anxiety reactions occur and somewhat less consistent support for the other regions.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Eighteen women and six men were studied in one experimental session each of 2 to 3 hours’ duration. Two of the men and two of the women were left-handed. A between-group experimental design was used with stratified random assignment to place each subject in one of two groups, isoproterenol or placebo, with 12 in each, balanced for gender and handedness. Height, weight, and age for the two groups are shown in Table 1. All subjects were healthy and drug free. Specifically, all denied any history of hypertension, other cardiovascular disease, or respiratory disease. The study was approved by the university institutional review board, and after a full description of the study, all subjects gave written informed consent.


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  		TABLE 1. Demographics, Heart Rate, and Pre and Post Symptom Ratingsa
 
Subjects were studied supine in a Siemens 931/08-12 PET scanner. A catheter was inserted in an antecubital vein in the right arm, and electrocardiographic chest leads were attached for continuous heart rate and rhythm monitoring. Eleven symptoms, listed in Table 1, were rated twice by each subject on a scale of 0 to 10 (0 = none, 10 = most ever). The first rating (pre) was a baseline completed before placement in the scanner. The second rating (post) was done retrospectively at the end of the session, based on recall of symptoms experienced during the infusion of isoproterenol or placebo.

After the first symptom ratings, 10 mCi of 18F-flourodeoxyglucose was administered by intravenous bolus in 3 to 5 ml of normal saline. Changes in cerebral metabolic rate for glucose (CMRglu) were studied because isoproterenol might have direct pharmacological effects on the human cerebral vasculature (O. G. Cameron, unpublished observations, 1998; see Discussion).

Immediately after glucose administration, during glucose uptake into brain, the experimental solution was infused continuously for 30 minutes. The study was performed single blind; before infusion subjects were not aware of their group assignment. Isoproterenol in normal saline was infused at a rate that raised heart rate to approximately 120 beats per minute throughout the 30 minutes. This was accomplished by moment-to-moment titration of flow rate, based on continuous heart rate monitoring, out of sight and hearing of the subject. During infusion all subjects closed their eyes, room lights were dimmed, ambient noise was minimized, and subjects were instructed not to sleep.

After 30 minutes of infusion of either isoproterenol or placebo, and glucose uptake into brain, the infusion was stopped and PET data acquisition was initiated. Subjects were scanned for 60 minutes, producing 15 slices with approximately 8 mm full-width, half-maximum (FWHM) between slices. Processing of scans to measure the CMRglu (mg of glucose/min per 100 ml of tissue), normalized to whole brain (54), was performed as described below.

Symptom rating data were analyzed with repeated-measures ANOVAs (grouping variable: isoproterenol vs. placebo infusion; repeated measure; baseline ratings vs. retrospective ratings for time of infusion), based on log-transformed data. Other scan and nonscan variables were compared for the isoproterenol group vs. the placebo group with repeated measures and two-sample t tests. Pearson product-moment correlations were used to assess relationships between symptoms and regions of brain activation.

PET image data were analyzed using statistical parametric mapping techniques developed extensively in our facility (55–58). Emission scans were reconstructed with calculated attenuation correction using a standard ellipse-fitting method (59). All images were transformed to a standard stereotactic coordinate system (based on the human brain atlas of Talairach and Tournoux—"Talairach space"; Ref. 60) and deformed to match the shape of the standard atlas brain (57). Images were averaged across subjects on a pixel-by-pixel basis to form statistical parametric maps (55, 61). A statistical threshold to identify significantly activated brain regions was determined by the use of a smoothed Gaussian field with a pooled variance (62).

Regional scan data were assessed in two ways. The analyses for both methods contrasted the subjects given isoproterenol with those given placebo. (No scans of brain structure were performed.) One method, involving a pixel-by-pixel analysis, provided assessment of potential differences between groups in regional brain activation without any preexisting assumptions about either the anatomically defined areas of the brain that were expected to be activated in this paradigm or the specific borders of those regions hypothesized to be involved. In this method, a pixel-by-pixel t-score analysis was performed across the whole brain with the analysis significance level of p <= .05, adjusted for multiple tests. The threshold parameters for statistical significance were defined based on peak height.

The other method was based on regions of interest (ROIs) predefined for each region by the standard brain atlas (60) and applied consistently to individual scans in the stereotactic coordinate system. This method makes specific assumptions of the boundaries of the anatomical regions being considered. Based on the brain areas hypothesized above to be activated by interoceptive stimulation, 14 ROIs were analyzed, including right and left sides for insular cortex, anterior cingulate gyrus, posterior cingulate gyrus, thalamus, frontal association cortex, primary sensory cortex, and amygdala. Specific ROIs were constructed by combining the appropriate small spherical regions into the 14 anatomically defined regions (60). Differences were assessed for individual brain regions with unpaired t tests. The ROI method provides one means of potential comparison across studies, that is, the same named regions can be assumed to have the same locales in the various studies being compared. Studies can also be compared on the basis of the axial coordinates of regions of activity change, applicable to the pixel-by-pixel method.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
For ratings of infusion-induced symptoms, there were statistically significant differences between groups for all symptoms (Table 1). Without adjustment for multiple tests, main effects of group and time, as well as interactions of group by time, were significant for all symptoms except the main effect of time for the symptom mental anxiety. With adjustment for multiple tests, mental anxiety was no longer significant, but all other symptoms remained so, except the main effect of time for the symptom fast breathing. Cardiac awareness was greater than respiratory. For example, for the 12 subjects who received isoproterenol (Table 1), results of repeated-measures t tests were as follows (all df = 11): for aware of heart beat vs. aware of breathing, t = 2.84, p < .02; for fast heart beat vs. fast breathing, t = 4.14, p < .002; and for hard heart beat vs. hard breathing, t = 4.02, p < .003. Four of the five most intense symptoms in response to isoproterenol related to cardiac function; the fifth of these five was the nonspecific symptom "aware of any symptom," and the next three were respiratory. The last three related to emotional reactions (distress and the two anxiety symptoms). Thus, isoproterenol produced very robust physical symptoms, especially cardiac, but a less intense emotional response.

For the pixel-by-pixel image analysis, including all 24 subjects, with adjustment for multiple tests (Table 2 and Fig. 1, top), two regions showed significant activation by isoproterenol. The first was the midline structure apparent most prominently at 41 mm above and, less intensely, at 50 mm above the anterior commissure-posterior commissure (ACPC) line. Based on the brain atlas (60), this structure is the medial region of the cingulate gyrus, straddling Brodmann areas 23 and 24 (and possibly involving other Brodmann areas as well, such as area 31), with the peak of activation in the anterior part of area 23. The other structure is in the posterior part of the left hemisphere at 50 mm above the ACPC line. In Talairach space, although being slightly posterior, it approximates the medial aspect of the left postcentral gyrus, that is, the left primary somatosensory region, with the peak of activation in that part associated with the trunk of the body. A small number of other small areas of subthreshold activation were also present. It is not clear, however, if they represent image noise or true activation that did not reach significance because of limits of statistical power. With all subjects included, no other brain regions at other levels showed any areas of activation that attained statistical significance, and no areas of significant deactivation were observed.


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  		TABLE 2. Locations of Significantly Activated Brain Regionsa
 


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  		Fig. 1. Top, Isoproterenol-induced regional brain glucose increases for all subjects. Two-sample t-statistic maps of normalized (to whole brain) increases in regional metabolic rate for glucose in response to intravenous isoproterenol (mean of subjects given isoproterenol at each pixel minus mean of subjects given saline placebo at each pixel). Scan slices are horizontal at indicated millimeters from ACPC line. Difference in each pixel is represented by color coding. Color coding bar indicating correspondence of color to t score is shown in the figure. The right hemisphere is displayed on the left side and vice versa. Map is overlaid on a generic magnetic resonance imaging template to provide anatomical orientation. All 24 subjects are included. Areas of statistically significant activation are in the medial cingulate gyrus and the left primary somatosensory cortex. Bottom, Isoproterenol-induced regional brain glucose increases for right-handed female subjects (N = 8 in each group). Data analysis and representation methods are the same as for the top figure. Area of statistically significant activation is in the right insular cortex.

 
All predetermined ROIs were assessed with unpaired two-tailed t tests. With all 24 subjects included, with or without adjustment for multiple tests, no region showed a statistically significant difference. Without adjustment, the right insular cortex showed a trend (t = 1.83, df = 22, p = .08). (Assuming the one-tailed hypothesis of activation in the isoproterenol group, without adjustment, this change would be significant, p = .04). The actual mean ratios (CMRglu: insula to whole brain) for the right insular cortex were as follows: placebo group = 1.036, isoproterenol group = 1.058.

Because of the possibility that gender and handedness might affect results (26, 27, 63), the right insular region was reanalyzed with both data analysis methods with the largest homogeneous subject group, right-handed females, included (N = 8 in each group). For this subgrouping the right insular cortex was now statistically significant (unadjusted two-tailed test, t = 3.03, df = 14, p < .01; Table 2 and Fig. 1, bottom). The actual mean ratios (to whole brain) now were 1.028 for the placebo group and 1.070 for the isoproterenol group. Further analyses of these right insular cortex predetermined regional data were consistent with the hypothesis that both handedness and gender influenced laterality. Excluding left-handed subjects only (leaving 10 in each group) or excluding males only (leaving 9 in each group) also produced significant p values (all right handed: t = 2.22, df = 18, p < .04; all females: t = 2.44, df = 16, p < .03). There were a few other sporadic areas of activation, including a smaller, weaker area of activation in the left insula (Fig. 1, bottom), but these areas did not approach statistical significance.

The question of potential relationships of activated ROIs with symptom ratings was investigated in two ways. First, for the 12 subjects who received isoproterenol, correlations were performed for the activated regions, both right and left side for primary somatosensory cortex, insula, anterior cingulate, and posterior cingulate, with each of the 11 symptom ratings for the infusion (post time in Table 2). Second, the same ROIs were also correlated with change scores (post time minus pre time). After adjustment for multiple tests, none of the correlations were significant at the p < .05 level, there was no discernible pattern of trends toward significance, and there was no consistent pattern of positive (or negative) correlations either for a specific symptom with several regions or a specific region with several symptoms.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
The study reported here is the first brain glucose metabolism study designed specifically to identify regions of the CNS associated with visceral activation and awareness in humans. Using isoproterenol, this study combined experimentally induced cardiorespiratory activation with measurement of both regional pattern of brain activation and assessment of magnitude and pattern of symptom induction produced by the experimental stimulus. It demonstrated, with the pixel-by-pixel analysis, that an increase in cardiovascular-respiratory function produced activation relative to whole brain for all subjects in the medial cingulate gyrus and the region of truncal representation of the left postcentral somatosensory region and in the right insular cortex in the subgroup of right-handed female subjects. (There was a suggestion of activation in the left insula as well; see Fig. 1, bottom).

Using the ROI analysis, the insula was significant with a one-tailed test and showed a trend with a two-tailed test when all subjects were included. It was significant with a two-tailed test in all right-handed or all female subjects. With this analysis the regions found to be significantly different in the pixel-by-pixel analysis, cingulate and left somatosensory cortex, were not different when predetermined ROIs were analyzed, most likely because the predefined regions did not precisely coincide with the regions observed in the pixel-by-pixel analysis. The areas significant in the pixel-by-pixel analysis were only "subregions" of the ROIs defined for this study; that is, only part of the whole somatosensory cortex and only part of the whole cingulate were activated. (In subsequent studies use of ROIs that coincide with the regions found to be significant with the pixel-by-pixel analysis would allow a priori tests of the hypotheses that these regions are activated by interoceptive processes.) Significance of the right insula with the ROI analysis is consistent with the fact that, for the insula, the ROIs closely coincided with the pattern of activation observed.

Activation of the insular cortex was more robust when only right-handed or only female subjects were included. This result is consistent with prior findings indicating that gender as well as handedness are related to cerebral hemispheric laterality effects (26, 27, 63), including results related to cardiac interoception (64–66). Prior studies indicated that the right hemisphere ("nondominant" for right-handed individuals) is mainly involved in cardiac control (67–72), although the left hemisphere is involved in some functions as well (70–73) (which would be consistent with possible activation of the left insula observed in this study, if further research indicates that left insular activation does occur in response to cardiovascular-respiratory stimulation). In this study hemispheric laterality effects were also seen in the primary somatosensory cortex. Activation was observed only in the hemisphere opposite to the side of insular activation (ie, "dominant" left hemisphere), typically associated with crossed sensory information originating from the right side of the body. Many of the prior studies referenced above also reported activations and/or deactivations of many regions occurring only unilaterally.

All three of the brain areas activated in this study have been associated in prior research with viscerosomatic sensation and emotion (including anxiety, and sadness or depression). A comparison of the brain regions activated in the present study to those regions activated in prior research, identified either by the coordinates in Talairach space (60) or by the brain regions defined by the Brodmann system (74), revealed the following. Respiratory stimulation (13, 14) produced activation in the insula and cingulate regions at approximately the same coordinate locations as seen in the present study. Insular activation (as well as posterior thalamus and medial prefrontal cortex) was also seen when cardiovascular-respiratory stimulation was produced by maximal inspiration, the Valsalva maneuver, and isometric handgrip (11). In contrast, pharmacologically induced anginal pain due to myocardial ischemia was associated with activation in a more anterior part of the cingulate, whereas decreases were reported in other cingulate areas, and neither insular cortex nor somatosensory cortex showed changes (15, 16). Thermal stimulation also activated the insula (12, 41), whereas production of the emotional reaction of disgust activated the insula in only one (48) of three (29, 47) comparison studies. One of these studies (47) also observed posterior cingulate activation, but in a different area than observed in the present study.

Various emotional states have been investigated. Anxiety activated insula (33, 34, 39); in one study it also activated posterior cingulate and left somatosensory cortex (33). One study of several self-generated emotions (18) reported activation in insula, posterior cingulate, and somatosensory cortex, and in a review (25) it was concluded that the posterior cingulate is often activated by emotion. Despite this most of the studies of fear, sadness and depression, or positive emotion referenced above, including those involving pharmacological provocation (15, 16, 49, 50), did not activate the same regions as those observed in the present study, with the exception of the yohimbine infusion study (7), which did activate insular cortex.

The occurrence of interoceptive processes does not require awareness of visceral organ function, but such awareness when present certainly makes an important contribution to the pattern of CNS activation observed. In the present study mental and especially cardiorespiratory symptoms were produced by the isoproterenol infusions, and most probably played a role in CNS activation. Despite this the precise role is unclear because correlations of symptoms with activated brain regions were not significant, undoubtedly in part because of the experimentally determined low level of variability in cardiovascular-respiratory activation as well as cardiac symptomatology (see Table 1). Because of this lack of correlation, it is not clear to what extent subjective symptom intensity contributed to the pattern or magnitude of CNS activation observed. With reference to the symptoms measuring emotional reactions to isoproterenol (anxiety and distress), they were the least intense and therefore probably least likely to influence the CNS activation pattern seen. Although it is highly likely that visceral sensory input to the brain contributes to the pattern of brain activation seen during some emotional states, the contribution occurring in the present study seems to be relatively small, making the results of this experiment mainly due to interoceptive processes per se.

To summarize briefly, those studies that produced states typically associated with viscerosomatic-autonomic activation (eg, cardiac, respiratory, or thermal stimulation), including studies of emotion that produced such activation (eg, anxiety), produced brain activation in regions similar to the results of the present study, whereas those that typically did not produce visceral activation with associated symptoms (sadness or depression, positive emotion) produced a different pattern. There were exceptions, including cardiac pain (15, 16), disgust (29, 47), and the various studies that produced fear. Overall, as noted above, the CNS activation pattern seen in this study seems to be indicative of interoceptive activation but distinct from emotional activation per se. In light of the findings of the present study along with prior research, the brain regions most consistently involved in cardiovascular-respiratory interoception seem to be the insula and medial or posterior cingulate.

There are benefits and limitations of the methods used and results obtained in this study. Use of isoproterenol to induce the cardiovascular-respiratory interoceptive stimulus has both advantages and disadvantages. The advantages are that it has a rapid onset and offset of physiological effect and a brief half-life in blood, allowing well-defined onset and offset of the experimental stimulus. Furthermore, moment-to-moment tracking of heart rate can provide a direct independent measurement of the physiological function of the heart, the presumptive primary source of the interoceptive cue. Determinations of blood pressure, other methods of baroreceptor functional assessment, and respiratory rate and excursion could also be performed in subsequent studies to further assess the physiological changes potentially associated with the interoceptive process.

A possible disadvantage of the use of isoproterenol is that a small amount does enter the brain (53); therefore, the pattern of brain activation observed in this study might be due in part to direct pharmacological effects rather than solely to interoceptive mechanisms. However, our study that used yohimbine, another substance that produces adrenergic activation but freely enters brain (7), found a different pattern of brain activation (including insula but otherwise different regions), indicating that direct adrenergic pharmacological effects on brain do not fully account for the pattern of regional brain activation observed in the present study.

In addition to the use of isoproterenol to produce the interoceptive stimulus, there are other advantages as well. Glucose metabolism is a better method of measurement of regional brain activation for this study than is cerebral blood flow. First, glucose metabolism might be more directly coupled to neuronal activity than is cerebral blood flow (75–77). If so, it would be generally a better measure of regional brain activation. Second, more directly related to the present study, we performed a study similar to the present study (unpublished) in which cerebral blood flow was measured after isoproterenol administration. Unlike the well-defined pattern of activation observed in the present study, the blood flow changes occurred in a patchy pattern of both increases and decreases that were not consistent with activation in hypothesized regions and did not clearly coincide with well-defined anatomical brain regions. There are several possible reasons for this. It could reflect regional effects of isoproterenol directly on the cerebral vasculature, which might or might not be due to hyperventilation. (Hyperventilation decreases whole-brain cerebral blood flow, but in humans, after adjustment for hyperventilation, whole-brain cerebral blood flow does not seem to be affected by isoproterenol (53). Prior research did not address potential regional changes.) Variability in the scan data leading to insufficient power to detect a consistent pattern is also possible, but this is less likely because distinctly significant changes were seen in some areas, and both the isoproterenol and placebo data were based on averaging of three scans in each condition from each of the six subjects studied. Third, unlike the findings in many functional imaging studies that areas of deactivation are observed along with areas of activation, no areas of significant deactivation were observed in the present study. The physiological meaning of deactivation in brain function is often hard to interpret.

Some aspects of the study could be considered both advantageous and disadvantageous. Using a between-subject design eliminates the need for subjects to have repeated studies on different days (unlike measurement of cerebral blood flow, repeated CMRglu studies on the same day are generally impractical), reducing potential subject data loss because a subject fails to return for the second study session. On the other hand, a within-subject design would reduce data variability (eg, variability due to imprecision in transforming individual brains to the shape of the standardized stereotactic coordinate system and thus imprecision in overlaying identical brain regions from different subjects). This would allow a smaller number of subjects to be studied with the same statistical power or the same number of subjects with augmented potential to identify interoceptive activation of other regions. Furthermore, a within-subject design would permit subject-by-subject calculation of ROI or pixel-by-pixel difference scores between conditions, which can be advantageous for interpretation of results such as correlational analyses. (In further studies robust correlational analyses will also need more subjects and, even more important, a range of heart rate increases.) Thus, the between-subject design has the advantage of reducing attrition problems, whereas the within-subject design provides several other methodological benefits.

Use of predetermined ROIs as the basis for analysis of regional brain activation can also be either advantageous or disadvantageous. As already noted, it permits other investigators using the same ROIs to make direct comparisons across studies. On the other hand, as seen in this study, if an area of activation does not clearly coincide with the predefined ROI, the area might be significantly activated, but it would not be apparent simply by the ROI analysis. For this reason both methods (ROI and pixel-by-pixel) were performed and reported in this study.

Several issues limit the interpretation or generalizability of these results. First, cardiovascular-respiratory interoception was produced by pharmacologically induced activation comparable to mild to moderate exercise. It is not certain how these results might relate to nonpharmacologically induced awareness, including awareness under basal conditions. Second, the placebo group was somewhat older than the isoproterenol group (mean difference approximately 6 years), but mean age for both groups was young adult. Results might or might not be applicable to other age groups. Third, the glucose metabolism scan data are not absolute; they are relative to whole brain. In other words these data do not literally demonstrate that the regions reported had increases in absolute metabolic rates. They had greater increases than whole brain, which could represent absolute increases or decreases, although increases (ie, increased neuronal activity) seem much more likely.

Finally, there are potential limitations related to mechanism that require comment. The regions that were activated might be directly involved in sensing physiological changes in the viscera, or they might be involved secondarily, reflecting not only sensation per se but also additional CNS processing of the bodily afferent impulses (such as is likely to occur in association with emotional reactions).

One important mechanistic question is the role that baroreceptor stimulation might have played in the observed results. Measurement of variables other than heart rate that might provide an estimate of potential baroreceptor involvement, such as blood pressure determinations, were avoided in the present study to keep any sensory input to the subjects to a minimum. Thus, the possible role of baroreceptor changes produced by isoproterenol on the pattern of regional brain activation observed in this study cannot be assessed directly. Prior research implicates involvement of the insular cortex in baroreceptor mechanisms (78–81). In contrast, it does not seem that either the somatosensory region or the cingulate region activated in this study are related in any direct way to baroreceptor function. Thus, baroreception might have contributed to the pattern seen, but it is unlikely to have been the sole source of the changes observed. This issue might be moot because a broad definition of interoception would include baroreception as a component of the larger phenomenon of interoceptive processes.

Some of the regions that might have been expected to show activation did not do so. The regions that were hypothesized to be activated in this study but were not–amygdala, frontal cortex, and thalamus–have been implicated in the neurobiology of emotion. It is possible, for example, that the amygdala was not activated because subjects rated the procedure as only mildly to moderately distressing and anxiogenic. It is likely that there is substantial overlap and convergence of regions involved in emotion with those involved in interoception, but it is unlikely that exactly the same regions are involved. It is most likely possible to separate or tease apart these regional differences. For example, the somatosensory cortex was activated in this study, whereas such activation has not been reported in imaging studies of cognitively induced emotion. The contribution of visceral sensory nerve impulses to the pattern of regional brain activation that is observed as part of an overall emotional reaction perhaps can be isolated from other neurobiological aspects of emotion.

In summary, isoproterenol infusion produced changes in heart rate, cardiorespiratory, and (to a lesser extent) mental anxiety symptoms, and increases in CMRglu in the medial region of the cingulate gyrus, the truncal region of the left somatosensory cortex, and the right insula. (Based on prior studies, increases in respiration and changes in blood pressure most likely also occurred, but these parameters were not measured in this study; Ref. 52.) Baroreceptor effects might contribute to the CNS activation pattern observed, but they are unlikely to account for it fully (eg, symptom awareness is not associated with baroreception per se). Increases in cardiac and respiratory function, associated with cardiorespiratory symptoms, are often observed during emotional states, especially negative emotions such as fear and anger. As such the pattern of CNS changes seen during somatic activation produced with isoproterenol is relevant to an overall understanding of the pattern of brain activation observed during emotion. But because cardiorespiratory interoceptive awareness does not require the presence of any increase in emotion, and given that the emotional experience reported in this study was not prominent, it is also unlikely that emotional reactions fully account for the results observed in this study. In other words interoceptive processes are probably linked to both baroreception and the bodily reaction to emotion but are not factually or logically synonymous with either. Beyond the importance of addressing the century-old question of their relevance to emotion, interoceptive processes are most likely intimately related to the pathophysiologies of a number of medical and psychiatric disorders and are themselves an understudied area of sensory physiology. Understanding the psychobiology of interoception will be fundamental to a full understanding of psychosomatic processes.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Donna Cross, BSE, and the technical staff of the University of Michigan Medical Center PET Center for their assistance in completing this study.

Received for publication December 21, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. LeDoux J. The emotional brain. New York: Simon & Schuster; 1996.
  2. Kandel ER, Squire LR. Neuroscience: breaking down scientific barriers to the study of brain and mind. Science 2000; 290: 1113–20.[Free Full Text]
  3. Toga AW, Mazziotta JC, editors. Brain mapping: the methods. New York: Academic Press; 1996.
  4. Bykov KM. The cerebral cortex and the internal organs. New York: Chemical Publishing Co; 1957.
  5. Reed SD, Harver A, Katkin ES. Interoception. In: Cacioppo JT, Tassinary LG, editors. Principles of psychophysiology: physical, social, and inferential elements. New York: Cambridge University Press; 1990.
  6. Adam G. Visceral perception: understanding internal cognition. New York: Plenum Press; 1998.
  7. Cameron OG, Zubieta JK, Grunhaus L, Minoshima S. Effects of yohimbine of cerebral blood flow, symptoms, and physiological functions in humans. Psychosom Med 2000; 62: 549–59.[Abstract/Free Full Text]
  8. Cameron OG. Interoception: the inside story—a model for psychosomatic processes. Psychosom Med 2001; 63: 697–710.[Abstract/Free Full Text]
  9. Cameron OG. Visceral sensory neuroscience: interoception. Oxford, England: Oxford University Press; 2002.
  10. James W. The principles of psychology. Vol 2. New York: Dover Publications; 1950.
  11. King AB, Menon RS, Hachinski V, Cechetto DF. Human forebrain activation by visceral stimuli. J Comp Neurol 1999; 413: 572–82.[CrossRef][Medline]
  12. Craig AD, Chen K, Bandy D, Reiman EM. Thermosensory activation of insular cortex. Nature Neurosci 2000; 3: 184–90.[CrossRef][Medline]
  13. Banzett RB, Mulnier HE, Murphy K, Rosen SD, Wise RJS, Adams L. Breathlessness in humans activates insular cortex. Neuroreport 2000; 11: 2117–20.[Medline]
  14. Liotti M, Brannan S, Egan G, Shade R, Madden L, Abplanalp B, Robillard R, Lancaster J, Zamarripa FE, Fox PT, Denton P. Brain responses associated with consciousness of breathlessness (air hunger). Proc Nat Acad Sci U S A 2001; 98: 2035–40.[Abstract/Free Full Text]
  15. Rosen SD, Paulesu E, Frith CD, Frackowiak RS, Davies GJ, Jones T, Camici PG. Central nervous pathways mediating angina pectoris. Lancet 1994; 344: 147–50.[CrossRef][Medline]
  16. Rosen S, Paulesu E, Nihoyannopoulos P, Tousoulis D, Frackowiak RSJ, Frith CD, Jones T, Camici P. Silent ischemia as a central problem: regional brain activation compared in silent and painful myocardial ischemia. Ann Intern Med 1996; 124: 939–49.[Abstract/Free Full Text]
  17. Paus T. Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nature Rev Neurosci 2001; 2: 417–24.[CrossRef][Medline]
  18. Damasio AR, Grabowski TJ, Bechara A, Damasio H, Ponto LLB, Parvizi J, Hichwa RD. Subcortical and cortical brain activity during the feeling of self-generated emotions. Nature Neurosci 2000; 3: 1049–56.[CrossRef][Medline]
  19. Jones GE. Perception of visceral sensations: a review of recent findings, methodologies, and future directions. In: JRJennings, PKAckles, MGHColes, editors. Advances in psychophysiology. Vol 5. London: Jessica Kingsley Publishers; 1994.
  20. Weitkunat R, Schandry R. Motivation and heartbeat evoked potentials. J Psychophysiol 1990; 4: 33–40.
  21. George MS, Ketter TA, Gill DS, Haxby JV, Ungerleider LG, Herscovitch P, Post RM. Brain regions involved in recognizing facial emotion or identity: an oxygen-15 PET study. J Neuropsychiatry Clin Neurosci 1993; 5: 384–94.[Abstract/Free Full Text]
  22. Cahill L, Haier RJ, Fallon J, Alkire MT, Tang C, Keator D, Wu J, McGaugh JL. Amygdala activity at encoding correlated with long-term, free recall of emotional information. Proc Nat Acad Sci U S A 1996; 93: 8016–21.[Abstract/Free Full Text]
  23. Dolan RJ, Fletcher P, Morris J, Kapur N, Deakin JFW, Frith CD. Neural activation during covert processing of positive emotional facial expressions. Neuroimage 1996; 4: 194–200.[CrossRef][Medline]
  24. Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, Yun L-S, Chen K. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997; 154: 918–25.[Abstract]
  25. Maddock RJ. The retrosplenial cortex and emotion: new insights from functional neuroimaging of the human brain. Trends Neurosci 1999; 22: 310–6.[CrossRef][Medline]
  26. George MS, Ketter TA, Parekh PI, Herscovitch P, Post RM. Gender differences in regional cerebral blood flow during transient self-induced sadness or happiness. Biol Psychiatry 1996; 40: 859–71.[CrossRef][Medline]
  27. Schneider F, Habel U, Kessler C, Salloum JB, Posse S. Gender differences in regional cerebral activity during sadness. Hum Brain Mapp 2000; 9: 226–38.[CrossRef][Medline]
  28. Gemar MC, Kapur S, Segal ZV, Brown GM, Houle S. Effects of self-generated sad mood on regional cerebral activity: a PET study in normal subjects. Depression 1996; 4: 81–8.[CrossRef][Medline]
  29. Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ. Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry 1997; 154: 926–33.[Abstract]
  30. Pardo JV, Pardo PJ, Raichle ME. Neural correlates of self-induced dysphoria. Am J Psychiatry 1993; 150: 713–9.[Abstract/Free Full Text]
  31. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerobek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999; 156: 675–82.[Abstract/Free Full Text]
  32. Baker SC, Frith CD, Dolan RJ. The interaction between mood and cognitive function studied with PET. Psychol Med 1997; 27: 565–78.[CrossRef][Medline]
  33. Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT. Differential limbic-cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 2000; 48: 30–42.[CrossRef][Medline]
  34. Osuch EA, Ketter TA, Kimbrell TA, George MS, Benson BE, Willis MW, Herscovitch P, Post RM. Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol Psychiatry 2000; 48: 1020–3.[CrossRef][Medline]
  35. Adolphs R. The human amygdala and emotion. Neuroscientist 1999; 5: 125–37.[Abstract/Free Full Text]
  36. Fendt M, Fanselow MS. The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 1999; 23: 743–60.[CrossRef][Medline]
  37. Calder AJ, Lawrence AD, Young AW. Neuropsychology of fear and loathing. Nature Rev Neurosci 2001; 2: 352–63.[CrossRef][Medline]
  38. Zubieta JK, Chinitz JA, Lombardo U, Fig LM, Cameron OG, Liberzon I. Medial frontal cortex involvement in PTSD symptoms: a SPECT study. J Psychiatr Res 1999; 33: 259–64.[CrossRef][Medline]
  39. Chua P, Krame M, Toni I, Passingham R, Dolan R. A functional anatomy of anticipatory anxiety. Neuroimage 1999; 9: 563–71.[CrossRef][Medline]
  40. Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA. The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation. Biol Psychiatry 1997; 42: 446–52.[CrossRef][Medline]
  41. Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Nat Acad Sci U S A 1999; 96: 7668–74.[Abstract/Free Full Text]
  42. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000; 288: 1769–72.[Abstract/Free Full Text]
  43. Kinomura S, Kawashima R, Yamada K, Ono S, Itoh M, Yoshioka S, Yamaguchi T, Matsui H, Miyazawa H, Itoh H, Goto R, Fujiwara T, Satoh K, Fukuda H. Functional anatomy of taste perception in the human brain studied with positron emission tomography. Brain Res 1994; 659: 263–6.[CrossRef][Medline]
  44. Rothstein RD, Stecker M, Reivich M, Alavi A, Ding XS, Jaggi J, Greenberg J, Ouyang A. Use of positron emission tomography and evoked potentials in the detection of cortical afferents from the gastrointestinal tract. Am J Gastroenterol 1996; 91: 2372–6.[Medline]
  45. Aziz Q, Anderson JLR, Valind S, Sundin A, Hamdy S, Jones AKP, Foster AK, Langstrom ER, Thompson DG. Identification of human brain loci processing esophageal sensation using positron emission tomography. Gastroenterology 1997; 113: 50–9.[CrossRef][Medline]
  46. Silverman DHS, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997; 112: 64–72.[CrossRef][Medline]
  47. Paradiso S, Robinson RG, Andreasen ND, Downhill JE, Davidson RJ, Kirchner PT, Watkins GL, Boles Ponto LL, Hichwa RD. Emotional activation of limbic circuitry in elderly normal subjects in a PET study. Am J Psychiatry 1997; 154: 384–9.[Abstract]
  48. Phillips ML, Young AW, Senior C, Brammer M, Andrews C, Calder AJ, Bullmore ET, Perrett DI, Rowland D, Williams SCR, Gray JA, David AS. A specific neural substrate for perceiving facial expressions of disgust. Nature 1997; 389: 495–8.[CrossRef][Medline]
  49. Ketter TA, Andreasen PJ, George MS, Lee C, Gill DS, Parekh PI, Willis MW, Herscovitch P, Post RM. Anterior paralimbic mediation of procaine-induced emotional and psychosensory experiences. Arch Gen Psychiatry 1996; 53: 59–69.[Abstract]
  50. Servan-Schreiber D, Perlstein WM, Cohen JD, Mintun M. Selective pharmacological activation of limbic structures in human volunteers: a positron emission tomography study. J Neuropsychiatr Clin Neurosci 1998; 10: 148–59.[Abstract/Free Full Text]
  51. Conolly ME, Davies DS, Dollery CT, Morgan CD, Paterson JW, Sandler M. Metabolism of isoprenaline in dog and man. Br J Pharmacol 1972; 46: 458–72.[Medline]
  52. Hoffman BB, Lefkowitz RJ. Catecholamines and sympathomimetic drugs. In: Gilman AG, Rall TW, Neis AS, Taylor P, editors. The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990.
  53. Olesen J, Hougard K, Hertz M. Isoproterenol and propranolol: ability to cross the blood-brain barrier and effects on cerebral circulation in man. Stroke 1978; 9: 344–9.[Abstract/Free Full Text]
  54. Fox PT, Mintun MA, Raichle ME, Herscovitch P. A noninvasive approach to quantitative functional brain mapping with H215O and positron emission tomography. J Cereb Blood Flow Metab 1984; 4: 329–33.[Medline]
  55. Minoshima S, Koeppe RA, Fessler JA, Mintun MA, Berger KL, Taylor SF, Kuhl DE. Integrated and automated data analysis method for neuronal activation studies using 15O-water PET. In: Uemura K, Lassen NA, Jones T, Kanno I, editors. Quantification of brain function, tracer kinetics, and image analysis in brain PET. Amsterdam: Elsevier; 1993.
  56. Minoshima S, Koeppe RA, Mintun MA, Berger KL, Taylor SF, Frey KA, Kuhl DE. Automated detection of the intercommissural line for stereotactic localization of functional brain images. J Nucl Med 1993; 34: 322–9.[Abstract/Free Full Text]
  57. Minoshima S, Koeppe RA, Frey KA, Kuhl DE. Anatomic standardization: linear scaling and nonlinear warping of functional brain images. J Nucl Med 1994; 35: 1528–37.[Abstract/Free Full Text]
  58. Minoshima S, Cross DJ, Koeppe RA, Casey KL. Brain activation studies using PET and SPECT: execution and analysis. In: Pain imaging. Vol 18. Casey KL, Bushnell MD, editors. Seattle: IASP Press; 2000.
  59. Hutchins GD, Holden JE, Koeppe RA, Halama JR, Gatley SJ, Nickles RJ. Alternative approach to single-scan estimation of cerebral glucose metabolic rate using glucose analogs, with particular application to ischemia. J Cereb Blood Flow Metab 1984; 4: 35–40.[Medline]
  60. Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. New York: Thieme Medical Publishers; 1988.
  61. Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ. Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab 1991; 11: 690–9.[Medline]
  62. Worsley KJ, Evans AC, Marrett S, Neelin P. A three-dimensional statistical analysis of rCBF activation studies in human brain. J Cereb Blood Flow Metab 1992; 12: 900–18.[Medline]
  63. McFarland RA, Kennison R. Handedness affects emotional valence asymmetry. Percept Motor Skills 1989; 68: 435–41.[Medline]
  64. Hantas MN, Katkin ES, Reed SD. Cerebral lateralization and heartbeat discrimination. Psychophysiology 1984; 21: 274–8.[Medline]
  65. Montgomery WA, Jones GE. Laterality, emotionality, and heartbeat perception. Psychophysiology 1984; 21: 459–65.[Medline]
  66. Weisz J, Balazs L, Adam G. The effect of monocular viewing on heartbeat discrimination. Psychophysiology 1994; 31: 370–4.[Medline]
  67. Walker BB, Sandman CA. Visual evoked potentials change as heart rate and carotid pressure change. Psychophysiology 1982; 19: 520–7.[Medline]
  68. Byung-Woo Y, Morillo CA, Cechetto DF, Hachinski V. Cerebral hemispheric lateralization in cardiac autonomic control. Arch Neurol 1997; 54: 741–4.[Abstract]
  69. Wittling W, Block A, Schweiger E, Genzel S. Hemisphere asymmetry in sympathetic control of the human myocardium. Brain Cogn 1998; 38: 17–35.[CrossRef][Medline]
  70. Natelson BH. Neurocardiology: an interdisciplinary area for the 80s. Arch Neurol 1985; 42: 178–84.[Abstract]
  71. Zamrini EY, Meador KJ, Loring DW, Nichols FT, Lee GP, Figueroa RE, Thompson WO. Unilateral cerebral inactivation produces differential left/right heart rate responses. Neurology 1990; 40: 1408–11.[Abstract/Free Full Text]
  72. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1990; 42: 1727–32.[Abstract/Free Full Text]
  73. Drake RA. Left cerebral hemisphere contributions to tachycardia: evidence and recommendations. Med Hypotheses 1986; 19: 261–6.[CrossRef][Medline]
  74. Toga AW, Thompson PM. Maps of the brain. Anat Rec 2001; 265: 37–53.[CrossRef][Medline]
  75. Sokoloff L. Local cerebral energy metabolism: its relationships to local functional activity and blood flow. In: Purves MJ, Elliott K, O’Connor M, editors. Cerebral vascular smooth muscle and its control. Ciba Foundation Symposium 56. Amsterdam: Elsevier; 1978.
  76. Roland PE, editor. Normal values and interrelationships between regional cerebral blood flow, regional blood volume, and regional cerebral metabolism. In: Brain activation. New York: Wiley-Liss; 1993. p. 469–504.
  77. Jueptner M, Weiller C. Does measurement of cerebral blood flow reflect synaptic activity? Implications for PET and fMRI. Neuroimage 1995; 2: 148–56.[CrossRef][Medline]
  78. Ruggiero DA, Mraovitch S, Granata AR, Anwar M, Reis DJ. A role of insular cortex in cardiovascular function. J Comp Neurol 1987; 257: 189–207.[CrossRef][Medline]
  79. Hanamori T, Kunitake T, Kato K, Kannan H. Responses of neurons in the insular cortex to gustatory, visceral, and nociceptive stimuli in rats. J Neurophysiol 1998; 79: 2535–45.[Abstract/Free Full Text]
  80. Zhang ZH, Rashba S, Oppenheimer SM. Insular cortex lesions alter baroreceptor sensitivity in the urethane-anesthetized rat. Brain Res 1998; 813: 73–81.[CrossRef][Medline]
  81. Zhang ZH, Dougherty PM, Oppenheimer SM. Characterization of baroreceptor-related neurons in the monkey insular cortex. Brain Res 1998; 796: 303–6.[CrossRef][Medline]
  82. Vogt BA, Nimchinsky EA, Vogt LJ, Hof PR. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol 1995; 359: 490–506.[CrossRef][Medline]
  83. Geyer S, Schleicher A, Zilles K. Areas 3a, 3b, and 1 of human primary somatosensory cortex. Neuroimage 1999; 10: 63–83.[CrossRef][Medline]
  84. Augustine JR. The insular lobe in primates including humans. Neurol Res 1985; 7: 2–10.[Medline]



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