Brain structures mediating cardiovascular arousal and interoceptive awareness

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s

Research Report

Brain structures mediating cardiovascular arousal and interoceptive awareness Olga Pollatos a,⁎, Rainer Schandry a , Dorothee P. Auer b,c , Christian Kaufmann b,d a

Biological Psychology, Department of Psychology, Ludwig-Maximilians-University, Munich, Germany Max Planck Institute of Psychiatry, Munich, Germany c Academic Radiology, Queen's Medical Centre, University of Nottingham, United Kingdom d Clinical Psychology, Department of Psychology, Humboldt-Universität zu Berlin, Germany b

A R T I C LE I N FO

AB S T R A C T

Article history:

Different emotions are accompanied by different bodily states and it is unclear which brain

Accepted 6 January 2007

structures are involved in both, the cerebral representation of the bodily change and the

Available online 12 January 2007

representation of its perception. Structures connecting bodily signals and interoceptive awareness could trigger, in a feedforward manner, behavioral responses appropriate to

Keywords:

maintain a desired state of the cardiovascular system. The present functional magnetic

Cardiovascular arousal

resonance imaging study aimed at identifying brain structures that are mutually activated

Interoceptive awareness

during interoceptive awareness of heartbeats and during cardiovascular arousal.

fMRI

Additionally, we searched for brain regions connecting interoception with feelings. During

Visceral sensation

the interoceptive task (directing attention towards heartbeats in relation to an exteroceptive

Insula

task) the thalamus, the insula, the medial frontal/dorsal cingulate and the inferior frontal

Cingulate gyrus

gyrus, as well as the somatomotor cortex were activated. The conjunction of the

Emotion

interoceptive awareness of heartbeats and cardiovascular arousal revealed structures presumably connecting both conditions, i.e. the right thalamus, insula, somatomotor cortex, and the dorsal cingulate as well as medial frontal gyrus. Furthermore, the degree of interoceptive awareness predicted the degree of activation of both the insula and the medial frontal/dorsal cingulate gyrus. Negative feelings correlated with the BOLD response of the interoceptive awareness condition in the dorsal cingulate gyrus extending into the dorsomedial prefrontal cortex. We provide evidence that the insula, the dorsal cingulate gyrus, and the dorsomedial prefrontal cortex are specifically involved in processing cardiac sensations. The dorsal cingulate gyrus and the dorsomedial prefrontal cortex presumably represent the neural substrates of experiencing negative emotions. © 2007 Elsevier B.V. All rights reserved.

1.

Introduction

The perception of signals arising from the body plays an important role in many theories of emotions (Damasio, 1999; James, 1884; Costa and McCrae, 1989; Schachter and Singer,

1962). William James (1884) was one of the first to present a psychological theory linking viscero-afferent feedback to emotional experience. James suggested that an emotional stimulus initiates particular visceral, vascular or somatic activities, like changes of blood pressure and heart rate, and

⁎ Corresponding author. Fax: +49 89 2180 5233. E-mail address: [email protected] (O. Pollatos). 0006-8993/$ − see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.01.026

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that perception of these bodily reactions may be the crucial component for mediating the emotional experience. This implies that different emotions are accompanied by different bodily states. The hypothesis was confirmed by studies using visual emotional stimuli (Critchley et al., 2005; Collet et al., 1997; Surakka and Hietanen, 1998; Levenson et al., 1990; Surakka and Hietanen, 1998). But interoceptive awareness, which is the ability to perceive bodily changes, differs substantially across individuals (Jones, 1994). Thus, according to James' theory emotional reactivity should vary between individuals depending on the level of interoceptive awareness. The latter trait is often quantified by measuring a person's ability to perceive one's heartbeats accurately (Critchley et al., 2004; Cameron, 2001; Pollatos et al., 2005; Schandry and Bestler, 1995; Jones, 1994). Brain structures which are activated during interoception induced by focussing attention to one's heartbeats are the insula, the cingulate cortex, the somatomotor and the prefrontal cortices, as has been shown in two recent studies: The accuracy of heartbeat perception did correlate with the BOLD response at the right insula (Critchley et al., 2004), and the dipole strength at the right insula and dorsal cingulate cortex (Pollatos et al., 2005). As it follows from James' theory, the perceived intensity of arousal, induced by an emotional stimulus, should influence the strength of an experienced emotion. It was recently demonstrated that heart rate increases when looking at pictures with emotional facial expressions, covaried with the level of brain activity in several interconnected brain regions including the amygdala, the insula, the cingulate cortex, and the brainstem (Critchley et al., 2005). Another line of research investigated brain structures activated by cardiovascular arousal, often by using nonemotional stimuli like physical or mental stress tasks (Critchley et al., 2001; King et al., 1999; Williamson et al., 2002). However, it is still unclear which brain structures are involved in both, the cerebral representation of the bodily change and the representation of its perception. Structures connecting bodily signals and interoceptive awareness could trigger, in a feedforward manner, behavioral responses appropriate to maintain a desired state of the cardiovascular system. Cardiovascular control mechanisms including afferent pathways participating in feedforward control are of a great complexity and variability (Mullen et al., 1997; Nollo et al., 2005; Ursino and Magosso, 2003). In a recent fMRI study by Critchley et al. (2003), it could be shown that – among others – the dorsal cingulate gyrus is related to sympathetic modulation of heart rate and the modulation of different bodily arousal states. Patients with focal damage involving this brain region showed abnormalities in autonomic cardiovascular responses to mental stress (Critchley et al., 2003). Other studies have shown a correlation between midbrain lesions and cardiovascular autonomic dysfunction (Macey et al., 2006; Saari et al., 2004). Moreover, enhancement of contingent negative variation (CNV)-related activity, which is regarded as a measure of anticipatory response activity, in anterior and midcingulate, somatomotor, supplementary motor area as well as insular cortices, was found to be associated with decreases in peripheral sympathetic arousal (Nagai et al., 2004). As a neuroanatomical construct of James' theory of emotional experience, one can conjecture that brain regions

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must exist with dual representation of both conscious awareness of visceral sensation and emotional perception. Former research suggests that the right insula and the cingulate gyrus are candidate regions for connecting interoceptive awareness with feelings. For the right insula a correlation has been shown between the intensity of negative emotions and the BOLD response during interoception (Critchley et al., 2004), and it was postulated that the right insula is crucial for conscious awareness of subjective feelings (Craig, 2004). Related research suggests that the insula might be responsible for visceral awareness, but proposes that the cingulate and prefrontal cortex are of key importance for the perception of feelings (Lane et al., 1998): The activity in the cingulate cortex has been shown to be relevant for the accurate detection of emotional signals which were perceived either interoceptively or exteroceptively. In another study it was demonstrated that conscious self-regulation of emotions involved the right cingulate cortex and the right superior frontal gyrus (Beauregard et al., 2001). Interestingly, tracing studies (An et al., 1998; Öngür et al., 1998) could demonstrate that there are strong connection between the insula and areas in the medial prefrontal brain including parts of the cingulate cortex of which posterior and ventral regions are of special importance for processing visceral signals (Devinsky et al., 1995; Vogt and Laureys, 2005; Vogt, 2005; Vogt et al., 1992). Confirming the proposed role of these structures in linking visceral sensation with emotions, a network for vascular responses to emotional stress was suggested comprising the infralimbic cortex, cingulate areas, the hypothalamus and the medulla (Saper, 2002). The insula as well as the prefrontal and cingulate cortex do also play an essential role in the somatic marker theory of Damasio (Bechara and Naqvi, 2004; Damasio, 1994, 1999). Here, it is stated that an emotional object, either derived from the environment or recalled from memory, causes activation in so-called emotion trigger sites (ventromedial prefrontal cortex, amygdala, brain stem nuclei, hypothalamus and basal forebrain) which induce changes towards the body and other brain regions. Both the organism with its ongoing visceral sensations and the object interacting with sensory and motor structures are mapped as neural patterns in so-called firstorder mapping structures (e.g. insula, somatosensory cortices). The right insula is therefore important for mapping visceral states and bringing interoceptive signals to conscious perception (Bechara and Naqvi, 2004). Concerning the described role of the insula, it is suggested that, especially within the right anterior insula, a meta-representation of the state of the body is re-represented which is associated with the subjective awareness of the ‘feeling self’ and the degree of emotional awareness (Craig, 2003, 2004, 2005). However, additional regions – so-called second-order regions such as the cingulate cortex and regions in the prefrontal cortex – are required for the integration of information about the body with information about the world (Damasio, 1999; Bechara and Naqvi, 2004); also it is yet unclear how these putative structures interact. The aim of the present study was twofold: Up to now brain structures being commonly involved in the processing of interoceptive signals and cardiovascular arousal have not been investigated. Such regions would be important interfaces

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Table 1 – BOLD activity related to intero- and exteroceptive attention

Table 2 – Covariation between the heartbeat perception score and activity during interoceptive attention

Anatomical region [Brodmann area]

Anatomical region [Brodmann area]

Hemisphere

Interoceptive > Exteroceptive task Insula [13]

Inferior/middle frontal gyrus [10/46] Medial frontal gyrus [6]/ cingulate gyrus (dorsal) [24] Thalamus (ventral) Inferior parietal lobule [40] Middle/inferior temporal gyrus [37] Exteroceptive > Interoceptive task Middle/superior temporal gyrus [21/22] Transverse temporal gyrus [42] Superior temporal gyrus [22/41]

MNI Z-value coordinates (x y z)

R L R R L R L

34 13 14 −38 8 4 38 2 2 44 52 2 −46 46 10 52 32 10 −2 0 52

4.49 3.98 3.48 4.09 4.07 3.74 4.07

R R

14 −8 16 56 −26 26

3.75 3.71

L

56 −58 − 1

3.66

R L R

58 −2 − 8 −46 − 30 2 61 −18 13

6.70 5.88 6.51

L

−51 − 16 6

5.39

for a feedforward system of cardiovascular control. We therefore measured BOLD activity both during a heartbeat perception task and during cardiovascular arousal due to enhanced physical load. In order to investigate whether brain regions mediating cardiovascular arousal and interoception are modulated by emotion also different personality traits were assessed.

2.

Results

2.1.

Functional imaging data

Interoceptive attention (heartbeat detection) compared to exteroceptive attention (tone detection) was associated with enhanced brain activation in bilateral regions of the insula and inferior/middle frontal gyrus, medial frontal/dorsal cingulate gyrus, right inferior parietal lobule, and thalamic nuclei

Insula [13] Inferior parietal lobule [40]/ insula [13] Medial frontal gyrus [6] Cingulate gyrus (dorsal) [24/32]/ medial frontal gyrus [32/6]

Hemisphere

MNI coordinates (x y z)

SVC voxels

Zvalue

R L

33 14 14 −48 − 30 22

524 524

3.29 3.23

R

6 3 55

524

3.15

R

10 7 46

524

3.12

(see Table 1 and Fig. 1). Increased activity during tone detection could be observed in bilateral acoustic cortices (see Table 1). Next, we tested for activity-mediating interoceptive awareness, correlating BOLD responses during interoceptive attention with performance on the heartbeat perception task. A group analysis that modelled the heartbeat perception score as a regressor of interest revealed a relationship between interoceptive accuracy and the BOLD activity at the insula, inferior parietal lobule, and the medial frontal gyrus extending into the cingulate gyrus (see Table 2). The strongest correlation (R = 0.56, p < 0.01) between interoceptive accuracy and BOLD activity was found in the right insula (MNI coordinates 33, 14, 14; Fig. 2).

2.2. Conjunction analysis between interoceptive awareness and physical stress The heart rate increased significantly during the physical stress condition (mean = 75.80, S.D. = 8.31) as compared to baseline (mean = 70.35, S.D. = 8.27; F(1,19) = 81.23, p < 0.001; Fig. 3). The activation pattern induced by physical stress is summarised in Table 3 and includes significant activation of the right insula and the cingulate gyrus. In the conjunction analysis we observed an overlapping activation pattern limited to the right hemisphere within the insula, the inferior parietal lobule and postcentral gyrus, the cingulate gyrus as well as the supplementary motor cortex, and the thalamus (SVC: small volume correction; Table 4 and Fig. 4), suggesting that this

Fig. 1 – Specific activity during interoceptive awareness (pFDR-corrected < 0.05; MedFG: medial frontal gyrus, CG: cingulate gyrus, PCG: precentral gyrus, MFG: middle frontal gyrus).

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Table 3 – Activation during physical exercise (corrected for whole volume, p < 0.05) Anatomical region [Brodmann area]

Hemisphere

Motor cortex (precentral gyrus) [4] Somatosensory cortex (postcentral gyrus) [3] Insula [13]

Fig. 2 – Correlation between heartbeat perception score and the BOLD response within the right insula (MNI coordinates 33, 14, 14).

network processes cardiovascular arousal (may be in- or output) and subserves interoceptive awareness in the heartbeat perception task.

2.3. Correlations between BOLD-contrast, heartbeat perception score and personality traits We observed positive correlations between BOLD activity (contrasting heartbeat perception with tone perception) within the cingulate/medial frontal gyrus (MNI coordinates 2, 0, 52) and STAI trait anxiety (R = 0.49, p < 0.05) and the neuroticism score, respectively (R = 0.53, p < 0.05). In addition, both variables correlated positively with the heartbeat perception score (trait anxiety: R = 0.58, neuroticism: R = 0.48; p < 0.05; see Fig. 5). No significant correlations were found for other personality domains such as extraversion and openness.

3.

Discussion

Regional brain activity was studied by means of functional magnetic resonance imaging during an interoceptive attention task and during enhanced physical load. Interoceptive attention activated several brain regions: the insula, the cingulate, medial and inferior frontal gyrus, the somatomotor cortex, and the thalamus. This network of activity is highly congruent with the anatomical structures identified by

Cerebellum (dentate/ cerebellar tonsil) Thalamus Medial frontal gyrus [6] Cingulate gyrus (dorsal) [24]

Z-value

R

40 −22 62

22.37

R R R R R L L R R R

38 −22 47 51 −25 42 40 2 11 54 −20 16 48 4 2 −16 − 54 − 31 −22 − 51 − 40 4 −17 16 4 −26 14 6 −13 50

20.44 4.60 8.74 7.12 6.74 16.38 14.38 8.74 8.69 7.37

R R

10 −3 48 4 2 39

5.37 5.17

Critchley et al. (2004). Since in the latter study a different heartbeat perception task was used as compared to our task, the overlapping results argue for the robustness of the obtained results. The heartbeat perception score correlated in both studies with the BOLD response at the right insula. The lateralization to the right hemisphere during interoceptive attention is in accordance with former EEG studies of the so-called heartbeat-evoked potential (HEP), showing greater amplitudes over right electrode positions for subjects with high interoceptive awareness (Pollatos and Schandry, 2004; Pollatos et al., 2005; Schandry and Bestler, 1995). Furthermore, empirical evidence suggests that the right hemisphere plays a pivotal role in cerebral regulation of cardiac functions (Leopold and Schandry, 2006; Naver et al., 1996; Meyer et al., 2004; Riordan et al., 1990): After strokes involving the right insular cortex the risk of cardio-autonomic dysfunctions is enhanced (Meyer et al., 2004). Additionally, a lateralization in autonomic activity was related to a reduced heart

Table 4 – Structures connecting interoceptive awareness and cardiovascular arousal Anatomical region [Brodmann area] Insula [13]

Fig. 3 – Heart rate enhancement due to experimental manipulation (p < 0.001).

MNI coordinates (x y z)

Thalamus (Pulvinar) Inferior parietal lobule [40]/ postcentral gyrus [40] Cingulate gyrus (dorsal) [24/32] Medial frontal gyrus [6]

Hemisphere

MNI SVC coordinates voxels (x y z)

Zvalue

R R R

40 4 4 44 4 4 10 − 24 4

2133 2133 515

2.98 2.95 2.91

R

48 − 40 56

5285

2.84

R R R

6 0 46 6 6 40 8 − 4 50

1170

2.81 2.17 2.36

1170

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Fig. 4 – Conjunction between heartbeat perception and physical exercise (pFDR < 0.05; IPL: inferior parietal lobule, CG: cingulate gyrus, IFG: inferior frontal gyrus).

rate variability after right-sided stroke (Naver et al., 1996). While we observed bilateral activation of the anterior insula during the interoceptive task confirming the role of this brain region for the processing of interoceptive signals, interoceptive accuracy did only correlate with the BOLD response at the right anterior insula which is in accordance to former data (Craig, 2003, 2004, 2005) suggesting that especially the right anterior insula is involved in re-representing the subjective awareness of the bodily state. In order to investigate brain structures being jointly involved in the processing of interoceptive signals and cardiovascular arousal, a physical stress task leading to heightened cardiac load was introduced. A conjunction analysis with the BOLD responses during interoceptive attention and enhanced cardiac

load demonstrated that, within the above mentioned interoceptive network, the insular cortex, the somatosensory cortex, the dorsal cingulate gyrus as well as the supplementary motor area, and the thalamus were activated by both tasks. It is known that areas of the orbital and medial prefrontal cortex are interconnected by an elaborate set of projections (Carmichael and Price, 1996) and especially structures of the medial prefrontal brain provide a cortical association system for higher control of autonomic functions (An et al., 1998; Carmichael and Price, 1996; Öngür et al., 1998) which is thought to be of critical importance for the control of behaviour (Öngür et al., 1998). In accordance to that assumption data exists showing that most of the prefrontal cortical projections of the hypothalamus arise from areas within the medial prefrontal cortex with some

Fig. 5 – Correlations between the personality variables trait anxiety and neuroticism, heartbeat perception score and BOLD response at the dorsal cingulate/medial frontal gyrus (Talairach coordinates 2, 0, 52).

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additional projections from neurons in the cingulate and the insular cortex (Öngür et al., 1998). We observed a strong lateralization to the right hemisphere which confirms the important role in the cerebral regulation of cardiac functions (Leopold and Schandry, 2006; Naver et al., 1996; Meyer et al., 2004; Riordan et al., 1990) and the proposed role of the right anterior insula in mapping subjective awareness of one's bodily state (Craig, 2003, 2004, 2005; Critchley et al., 2004). Concerning the conjunction analysis, conclusions from the observed lateralization are partly limited by the fact that subjects had to perform isometric exercise with their left hand. Nevertheless, there is strong evidence derived from the activation patterns during the interoceptive task as well as from other studies investigating interoceptive awareness (Critchley et al., 2004; Pollatos et al., 2005) suggesting a preponderance of the right hemisphere both for interoceptive awareness and for cardiovascular functioning. The observed activation in cardio-afferent processing areas like the insula and the dorsal cingulate gyrus during the interoceptive task due to focussing attention on one's heartbeats is similar to results from other modalities demonstrating that mere attention to a relevant stimulus enhances activity in modality-specific processing areas (Corbetta et al., 1991; Johansen-Berg et al., 2000; Jancke et al., 1999; King et al., 1999; Mima et al., 1998; Motter, 1993; Watanabe et al., 1998; Williamson et al., 2002). In order to anticipate changing cardiovascular requirements emerging from the environment, the observed brain regions could be target regions of afferent pathways participating in feedforward control. The observed activation in a dorsal region of the cingulate cortex extending into dorsomedial prefrontal cortex corroborates this interpretation since this region was found to be related to the sympathetic modulation of heart rate and to the modulation of bodily arousal states (Critchley et al., 2003). Damage of the dorsal cingulate cortex results in irregularities in autonomic cardiovascular responses (Critchley et al., 2003). The observed activity in the dorsal cingulate gyrus differs anatomically from rostral regions found to be associated with feelings and emotions (Lane et al., 1998). Thus, we suggest that this region is a specific cardiovascular target area probably involved in a feedforward system. We present further evidence that the insula and the dorsal cingulate gyrus also mediate the perception of cardiac signals, extending the results of former studies showing insula and cingulate cortex activation by cardiovascular arousal (Ahern et al., 2001; Critchley et al., 2000, 2001; Williamson et al., 1999, 2002; Yoon et al., 1997). We found that negative emotional experience as assessed by self-report (trait anxiety STAI score, neuroticism NEO–FFI score) correlated with the BOLD response of the interoceptive task in the dorsal cingulate and the inferior frontal gyrus, but not the right insula. This result is in contradiction to the finding of Critchley et al. (2004), who observed a relation between negative affect and BOLD response in the right insula. The importance of the cingulate and the inferior frontal gyrus for negative affect is underlined by several brain imaging studies demonstrating that the prefrontal and cingulate cortex are involved in trait anxiety (Kalisch et al., 2004; Bennett and Hacker, 2005; Pizzagalli et al., 2002; Pujol et al., 2002; Rusch et al., 2001; Sugiura et al., 2000; Tashiro et al., 2001; Zald et al., 2002). Both the cingulate and dorsal

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prefrontal cortices are also involved in the intentional modulation of bodily arousal (Phan et al., 2002). These structures have been implicated in the awareness and conscious self-regulation of subjective feelings (Damasio et al., 2000; Bennett and Hacker, 2005; Phan et al., 2002). In Damasio's proposed network of emotion processing (1999, 2000), the cingulate and dorsal prefrontal cortices represent the connection between an affective stimulus and related changes in the organism. Damasio (1994) asserts that the orbital and medial prefrontal cortex, driven by affective and motivational influences, modulates visceral states in order to evoke gut reactions which lead our decision making. Also previous research (Nauta, 1971) led to the proposal that the prefrontal cortex is required for visceral feelings that we experience in response to emotionally significant events and that a damage within these structures could lead to a loss of affective responsiveness and foresight (Öngür et al., 1998). Öngür et al. (1998) suggested that sensory information from several modalities related to motivational or emotional aspects of ongoing behaviour is processed in an orbital “viscerosensory” network with salient features of information being transferred to a medial “visceromotor” network which elicits an appropriate visceral reaction by modulating activity in the hypothalamus, the periaqueductal gray and related structures such as the amygdala. Supporting this assumption, it could be demonstrated that self-generated feelings require the involvement of regions responsible for the mapping and regulation of internal organism states like the cingulate and prefrontal cortices (Damasio et al., 2000). Our results further highlight the key role of these regions in emotional perception related to bodily states. We suggest a close link between negative subjective feelings, interoceptive awareness and the activity of both the dorsal cingulate gyrus and the dorsomedial prefrontal cortex. A possible limitation of our findings is that only male subjects were investigated. Numerous studies have shown genderspecific activation patterns during the processing of emotional stimuli (Azim et al., 2005; Butler et al., 2005; Cahill et al., 2004; Schienle et al., 2005; Wrase et al., 2003), and therefore replication of the observed results with a female subpopulation is necessary to allow a generalisation of the suggested interpretations. As we correlated the activity during interoceptive attention to heartbeat with indices of emotion processing measured by a questionnaire, there was a strong effect for regions involved in cardiovascular signal processing. This could be one reason why the observed activity in the cingulate gyrus differs from paracingulate regions associated with feelings and emotions (Lane et al., 1998). It remains to be studied whether identical or overlapping regions allow correlations between the extent of BOLD response during an emotional task and interoceptive awareness. The present study provides further evidence for a neural interface between cardiovascular arousal, interoception and the feeling of negative emotions assessed by the conjunction analysis between interoception and physical stress as well as the correlation analyses of BOLD responses during interoceptive attention with negative affect self-report. Experiencing bodily arousal and interoceptive awareness activate a concordant right-hemispheric neural network of which dorsal cingulate and the medial prefrontal cortex may be the key structure

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mediating negative affect. Subsequent studies should focus with their experimental design on the analysis of functional and effective connectivity patterns of the brain regions we found to act as an interface between arousal, interoception, and the experience of negative emotions, especially in order to establish more formally the influence medial frontal and dorsal cingulate regions exert onto other brain regions.

task, the intensity of the acoustic stimuli was varied for each subject separately and presented at a just noticeable threshold. The exteroceptive task required a reasonable amount of attentional load because the just noticeable tones were also presented concurrently with the background noise of the scanner. The total experiment lasted about 30 min.

4.4.

4.

Experimental procedures

4.1.

Subjects and questionnaires

20 right-handed male subjects (age mean = 26.8, S.D. = 3.7, ranging from 21 to 34 years) participated in the study. All subjects gave informed written consent. They completed two questionnaires indexing state and trait anxiety (State Trait Anxiety Inventory (Spielberger et al., 1983) as well as adult personality (NEO–Five Factor Inventory (Costa and McCrae, 1989). The mean scores were used for correlation analyses with heartbeat accuracy and regional brain activity. Heart rate was monitored using a digital amplifier system (Schwartzer), a sampling rate of 1000 Hz was used. Offline, beat-to-beat analyses were carried out with data averaged corresponding to the different experimental conditions.

4.2.

A heartbeat perception score reflecting accuracy of interoceptive awareness was calculated according to the following transformation (Schandry, 1981): 1=4

X ð1  ðj recorded heartbeats  counted heartbeatsj

=recorded heartbeatsÞÞ According to the used transformation, the heartbeat perception score can vary between 0 and 1 with high scores indicating only small differences between counted and recorded heartbeats. The calculated heartbeat perception scores varied between .58 and .98, with a mean score of .83 (S.D. = .13). In the exteroceptive task, a perception accuracy score was calculated in the same manner. The mean score was .90 (S.D. = .16). There was no significant difference concerning task difficulty between the interoceptive and the exteroceptive conditions (T(1,19) = −1.7, p = n.s.).

Scanning parameters 4.5.

Imaging was performed on a 1.5 T scanner (Signa Echospeed, GE, Medical Systems, MI, USA). During the MRI experiments, volumes with 23 slices of standard functional single-shot echo-planar images (time of repetition = 4000 ms, echo time = 60 ms, flip angle = 90°, matrix = 128 × 128, field of view = 28 × 28 cm, voxel dimensions 2.19 × 2.19 × 5 mm, no gap) were obtained using an axial slice orientation. The interoceptive and exteroceptive task lasted 4 min and 32 s each, corresponding to 68 volumes. The physical exercise condition lasted 10 min and 24 s, corresponding to 156 volumes.

4.3.

Interoceptive awareness

Experimental task

20 subjects were examined in two experimental sessions, i.e. a practice session outside the scanner and a scanning session. In both sessions, subjects had to perform one baseline condition and the following three experimental conditions: An interoceptive heartbeat perception task in which they were asked to count their heartbeats (four 32-s intervals for heartbeat perception, followed by four 16-s button-response intervals in which subjects reported their amount of counted heartbeats, and four 32-s intervals for baseline), an exteroceptive control task in which they had to count tones (tones at 1000 Hz and of 200 ms duration, presented in four 32-s intervals, followed by four 16-s button-response intervals, and four 32-s intervals for baseline followed by a button-response) and a physical stress task in which they squeezed a handgrip left-handed as hard as they could (four 60-s intervals, followed by four 96-s baseline intervals in which subjects should lightly hold and squeeze the handgrip). In order to achieve the same task difficulty for both the interoceptive and the exteroceptive

FMRI data analysis

FMRI time series data were analysed using SPM99 for image processing and SPM2 for statistical modeling (Friston et al., 1995) on a Matlab platform (Mathworks Inc.). For each subject, images were realigned to remove signal correlated with head motion. Images were transformed into standard ICBM space (Mazziotta et al., 1995) using an automated spatial normalization (12-parameter transformation followed by non-linear iterations using 7 × 8 × 7 basis functions) as integrated in SPM99. The normalized images were then smoothed with a Gaussian kernel (full-width at half-maximum of 8 mm) to create a local weighted average of the surrounding pixels. Effects were estimated in the context of the general linear model: For each subject, an analytic design matrix was constructed, modeling onset and duration of each trial as epochs convolved with a hemodynamic response function. Applying a multi-level approach we accounted for intrasubject variance in a fixed effects analysis, and for between-subject variance in a random effects analysis (subject × response interaction). Correlation analysis between the BOLD response, interoceptive accuracy score, and the emotion subscales were calculated using random effects analyses and small volume corrections (SVC) for regions of interest. Since the SPM brain template does not perfectly match Talairach space, we estimated the Talairach coordinates with a non-linear transformation of MNI (Montreal Neurologic Institute) to Talairach space (Brett et al., 2002) to localize results with the Talairach Daemon (Lancaster et al., 2004). All results are displayed as SPM maps, depicting the significant voxels. Threshold significance for functional imaging data was p < 0.05, using false discovery rate (FDR) corrections for multiple comparisons (Genovese

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et al., 2002). A mask image generated from the main effect of interoceptive attention (p < 0.05, corrected) was used for smallvolume region of interest correction of performance-related activity. Furthermore, anatomically informed mask images based on a brain in MNI space (Tzourio-Mazoyer et al., 2002) were used for small-volume region of interest correction of the conjunction analysis, which was carried out applying a conjunction inference with the minimum statistic (Nichols et al., 2005).

Acknowledgments We want to thank the Max Planck Institute of Psychiatry in Munich, Renate Wehrle who took care of the psychophysiological recording of the ECG, the technical staff, especially Rosa Hemauer of the MRI group who supported us in the data processing, Katrin Holler and Anna Nützel who took part in data processing and editing the manuscript and Dr. Martin Wiesmann for his helpful comments on the manuscript. REFERENCES

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