Edited by: Andrew Kemp, Universidade de São Paulo, Brazil
Reviewed by: Jason Moser, Michigan State University, USA; Hugo Critchley, University of Sussex, UK
*Correspondence: Agustin Ibanez, Laboratory of Experimental Psychology and Neuroscience, Institute of Cognitive Neurology and National Scientific and Technical Research Council, Pacheco de Melo 1860, Buenos Aires, Argentina
This article was submitted to Emotion Science, a section of the journal Frontiers in Psychology
†First Authors
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Interoception is the moment-to-moment sensing of the physiological condition of the body. The multimodal sources of interoception can be classified into two different streams of afferents: an internal pathway of signals arising from core structures (i.e., heart, blood vessels, and bronchi) and an external pathway of body-mapped sensations (i.e., chemosensation and pain) arising from peripersonal space. This study examines differential processing along these streams within the insular cortex (IC) and their subcortical tracts connecting frontotemporal networks. Two rare patients presenting focal lesions of the IC (insular lesion, IL) or its subcortical tracts (subcortical lesion, SL) were tested. Internally generated interoceptive streams were assessed through a heartbeat detection (HBD) task, while those externally triggered were tapped via taste, smell, and pain recognition tasks. A differential pattern was observed. The IC patient showed impaired internal signal processing while the SL patient exhibited external perception deficits. Such selective deficits remained even when comparing each patient with a group of healthy controls and a group of brain-damaged patients. These outcomes suggest the existence of distinguishable interoceptive streams. Results are discussed in relation with neuroanatomical substrates, involving a fronto-insulo-temporal network for interoceptive and cognitive contextual integration.
Interoception is the processing of the body's physiological condition (Craig,
The IC has been implicated in interoceptive processes, such as awareness of bodily sensations (Khalsa et al.,
Though generated in the external environment, pain and chemical signals involve a certain degree of body-mapping. This entails cross-modal processing of peripersonal space (Andre et al.,
The anterior insula supports more abstract encoding of internal–external information which interacts with other processes, such as emotion (Paulus et al.,
Hence, insular networks for body perception could presumably underlie sensing of (a) a core group of interoceptive sensations that are centered on internal viscera and blood composition; and (b) taste, smell, and pain sensations, which jointly trigger multimodal bodily sensations and interoceptive awareness. This study aims to test a model of multiple interoceptive signaling streams by disentangling the internal and external pathways of body awareness. We evaluated two patients, one with a focal lesion to the right insular cortex (IC), and another with a lesion to the right posterior putamen (including subcortical white matter connecting the posterior IC to the fronto-temporal nodes). The patients' performance in these perception domains was compared with that of healthy controls and other groups of brain-damaged patients.
Following Sherrington's pioneering definition (
In functional neuroanatomical terms, taste, smell, and pain sensations engage paralimbic (and mesocortical, including IC) areas and are transmitted through parallel pathways to cortical sites (Verhagen,
A reliable measure of internal drive is cardiac interoception, which relies on different pathways conveyed to the insular, secondary somatosensory (S2), and anterior cingulate cortices (ACC). The self-heartbeat detection (HBD) is a valid method to quantitatively measure cardiac interoception (Craig,
Given their similarities in functionality and gross neuroanatomical location within the IC, internal and external body perception can be functionally related. Here we aim to disentangle external (taste, smell, and pain) and internal (cardiac) body perception signals arriving to the IC by evaluating two rare patients with focal lesions of the (a) right IC and (b) right posterior IC connections to the fronto-temporal nodes. These patients—already evaluated by Couto et al. (
G.G. is a 51-year-old right-handed woman who suffered an ischemic IC stroke 18 months before the evaluation. Her initial symptoms were dysarthria, left hand hemiparesia, and left hemianesthesia. This symptomatology was transient and disappeared 3 days after the onset of the stroke, with no residual signs at neurological examination, despite complaints of a subjective change in taste perception and occasional mild pain in her left arm. Structural magnetic resonance imaging (MRI) of the brain, scanned between 6 and 12 months after the stroke, showed an ischemic focal lesion comprising the complete right anterior, mid, and posterior IC as well as the internal portion of the posterior part of the frontal opercula (fronto-opercular/insular) (Sridharan et al.,
Age | 51 | −1.21 | 0.14 | −1.291 | 59 | 0.02 | 0.49 | 0.02 | |||||||||
Formal education |
17 | 0.32 | 0.38 | 0.347 | 7 |
−3.45 | 0.01 |
−3.69 | |||||||||
Total score | 26/30 | 0.66 | 0.27 | 0.70 | 0.02 |
3.75 | 29/30 |
4.61 | <0.01 |
4.93 | 0.02 |
5.24 | |||||
Depression (BDI) | 3 | −0.99 | 0.18 | −1.06 | 24 | 2.74 | 0.02 |
2.93 | |||||||||
Anxiety state (STAI-S) | 21 | −2.07 | 0.04 |
−2.21 | 0.07 | −2.21 | 28 | −0.58 | 0.29 | −0.62 | 0.36 | −0.64 | |||||
Anxiety trait (STAI-T) | 28 | −1.12 | 0.15 | −1.19 | 0.34 | −0.55 | 55 | 1.43 | 0.10 | 1.52 | 0.13 | −2.27 |
Age | 51 | −0.16 | 0.44 | −0.17 | 59 | 0.16 | 0.44 | 0.17 | ||||||
Formal Education |
17 | 1.00 | 0.19 | 1.09 | 7 | −1.49 | 0.10 | −1.64 | ||||||
Total score | 26/30 | 0.96 | 0.20 | 1.05 | 0.13 | 2.06 | 29/30 | 1.76 | 0.08 | 1.93 | 0.17 | 1.59 | ||
Depression (BDI) | 3 | −1.16 | 0.16 | −1.27 | 24 | 1.00 | 0.19 | 1.10 | ||||||
Anxiety state (STAI-S) | 21 | −1.86 | 0.07 | −2.04 | 0.13 | −2.05 | 28 | −0.59 | 0.29 | −0.65 | 0.34 | −0.64 | ||
Anxiety trait (STAI-T) | 28 | −1.17 | 0.15 | −1.28 | 0.43 | −0.27 | 55 | 1.76 | 0.08 | 1.93 | 0.09 | 2.52 |
N.F. is a 59-year-old, right-handed woman who presented with a stroke that had occurred 12 months before the evaluation. Her initial symptoms consisted of left-sided hemiparesia and hemianesthesia, both of which remained for 4 months and then disappeared. At the time of evaluation, she presented with no neurological deficits and complained only about some pain in her left arm, leg, and foot. Brain MRIs, scanned between 6 and 12 months after the stroke, showed a right subcortical hemorrhage. Once normalized to an MNI (Montreal Neurology Institute) standardized brain atlas, the lesion demonstrated engagement of the right putamen and claustrum and the white matter belonging to the external capsule. An additional overlap with the JHU-Atlas of white matter showed damage to the external capsule (Couto et al.,
Seven right-handed women with no history of neurological or psychiatric conditions were evaluated as controls (Table
All the participants signed an informed consent before the evaluation. The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional ethics committee.
The neuropsychological and clinical evaluations of the patients and healthy controls (including assessment of executive functions, depression, and anxiety) have been described by Couto et al. (
To establish odor sensitivity thresholds, we used eight solutions at increasing concentrations of phenyl ethyl alcohol in a staircase procedure based on the design of the commercial Sniffin' Sticks (©2014 US Neurologicals, Poulsbo, Washington, USA; Hummel et al.,
Individual odor sensitivity was assessed by acquiring thresholds for phenyl ethyl alcohol with an ascending double-forced choice staircase procedure. We used an eight-step geometric series, starting from a 4% phenyl ethyl alcohol solution (dilution ratio 1:2 in deionized water). Each subject was presented for 3 s at a distance of 3 mm from each nostril with two bottles in a randomized order: one contained only the deionized water, and the other contained the odorant at a certain dilution. While blindfolded, the subjects were asked to identify the odor-containing bottle. The threshold was defined as the trial in which the participant correctly identified five consecutive stimuli (Hummel et al.,
Odor identification abilities were further evaluated through the B-SIT (B-SIT, Sensonics Inc.). This test consisted of 12 stimuli, each presented for 3 s at 3 mm from each nostril. Each participant selected which odor was perceived from a forced-choice list with four options. The smell identification score was measured as the number of correct choices, ranging from 0 to 12, with higher scores indicating better identification. The 12 odors commonly used in commercially available tests were smoke, chocolate, onion, strawberry, gasoline, turpentine, banana, pineapple, cinnamon, soap, lemon, and rose. The number of correct responses was later transformed into an identification percentage.
To evaluate taste intensity perception, each participant was given five sapid stimuli at four increasing concentrations: sucrose (0.03, 0.1, 0.3, 1.0 M), sodium chloride (NaCl; 0.03, 0.1, 0.3, 1.0 M), citric acid (0.001, 0.003, 0.01, 0.032 M), quinine hydrochloride (QHC1; 0.00003, 0.0001, 0.0003, 0.001 M), and monosodium glutamate (Glut; 0.006, 0.02, 0.06, 1.8 M). Each stimulus was dissolved in distilled water and presented at room temperature as part of an ascending concentration series (Bartoshuk et al.,
To measure the subjects' ability to identify five basic tastants, the maximum concentrated stimuli from the previous task (0.3 M sucrose, 0.3 M NaCl, 0.01 M citric acid, 0.0003 M QHC1, and 1.8 M Glut) or distilled water was applied to the tongue using the same procedure described above. Each side of the tongue was tested two times for the five tastants. Participants indicated the perceived flavor by pointing to a labeled card in a six-option forced choice: salty, sweet, sour, bitter, umami, or non-flavor. This test was conducted twice for each stimulus following procedures described elsewhere (Pritchard et al.,
Finally, taste intensity and identification measures were used to create a global score variable representing overall taste performance. Single
Using a Peltier-driven thermo test device (probe size 3 × 3 cm; TSA-II NeuroSensory Analyzer, Medoc Advanced Medical Systems, Rimat Yishai, Israel), we assessed the subjects' threshold for detecting innocuous warmth and innocuous cold, as well as pain thresholds for noxious heat and noxious cold. The Peltier probe was fixed with a rubber band over the skin of the thenar region of each palm and the dorsomedial region of each foot. Temperature stimuli were applied with a slope of 1°C/s, following the method of limits previously described (Yarnitsky and Sprecher,
Two different HBD tasks have been used in the literature: (i) mental tracking paradigms, currently questioned because the working memory load of the task might affect cardiac perception; (Richards and Lorraine,
The continuous EKG signal was scanned by an
The tapping–tracking design used in this study avoids the cognitive overload of complex processes (such as attentional and working memory demands) involved in mental tracking and discrimination paradigms. For instance, the former imposes this burden as subjects must internally count numbers to keep track of heartbeats (Schandry et al.,
Two expert vascular neurologists (LS and PR) evaluated the patients via a neurological examination. Two other experts in clinical neuroimaging (FM and BC) analyzed the patients' MRI lesion data. Subsequently, the subjects were compared with the both control groups (Tables
To compare the patients' performance with that of the control samples, we used a modified one-tailed
EKG data were analyzed using
Neither the IL nor the SL patients showed general cognitive impairments including the frontal lobe and executive functions (the SL patient even outperformed the healthy controls; see Tables
The IL patient did not differ significantly from controls (Figure
BDI | 3 | −0.99 | 0.18 | −1.06 | 24 | 2.74 | 2.93 | ||||||
Smell threshold | 41.6 | −0.61 | 0.28 | 0.40 | −0.65 | −0.34 | 50 | 0.00 | 0.50 | 0.30 | 0.00 | −0.96 | |
Smell identification | 75 | −1.00 | 0.18 | 0.20 | −1.07 | −1.15 | 33.3 | −5.37 | −5.75 | −5.54 | |||
Taste intensity | 29 | −0.36 | 0.37 | 0.43 | −0.39 | 0.25 | 52.7 | 1.25 | 0.13 | 0.40 | 1.35 | −0.49 | |
Taste identification | 70 | 0.42 | 0.35 | 0.09 | 0.45 | 2.39 | 30 | −1.60 | −1.73 | −7.75 | |||
Cool sensation | 28.2 | 0.50 | 0.32 | 0.30 | 0.54 | 0.71 | 5.92 | −6.70 | −7.16 | −7.72 | |||
Warm sensation | 36.7 | −0.42 | 0.34 | 0.36 | −0.45 | −0.47 | 45.5 | 3.55 | 3.79 | 3.86 | |||
Cold pain | 19.4 | 1.00 | 0.18 | 0.20 | 1.07 | 1.19 | 0 | −1.07 | 0.16 | 0.22 | −1.14 | −1.47 | |
Heat pain | 42.6 | −0.64 | 0.27 | 0.32 | −0.69 | −0.63 | 50 | 1.12 | 0.15 | 0.29 | 1.19 | 1.03 | |
0.05 | −0.30 | 0.39 | 0.26 | −0.33 | −1.01 | 0.03 | −0.70 | 0.26 | 0.38 | −0.77 | 0.65 | ||
Interoception | 0.5 | 5.63 | 6.17 | 5.71 | 0.09 | −0.61 | 0.29 | 0.43 | −0.67 | −0.34 |
When compared with frontal stroke patients, the IL patient showed no differences in either smell threshold or identification. Relative to the same group, the SL patient showed no difference in smell threshold. However, she did evidence impaired smell identification (
BDI | 3 | −1.16 | 0.16 | −1.27 | 24 | 1.00 | 0.19 | 1.10 | |||||
Smell threshold | 41.67 | −0.51 | 0.32 | 0.46 | −0.55 | −0.14 | 50 | −0.08 | 0.47 | 0.38 | −0.09 | −0.48 | |
Smell identification | 75 | 0.00 | 0.50 | 0.41 | 0.00 | 0.36 | 33.3 | −4.57 | −5.00 | −5.52 | |||
Taste intensity | 29 | −0.63 | 0.28 | 0.27 | −0.69 | −0.99 | 52.7 | 0.33 | 0.38 | 0.35 | 0.36 | 0.61 | |
Taste identification | 70 | 1.28 | 0.13 | 0.21 | 1.40 | 1.37 | 30 | −1.92 | 0.06 | 0.06 | −2.11 | −2.08 | |
Cool sensation | 28.25 | −0.32 | 0.38 | 0.33 | −0.36 | −0.73 | 5.92 | −15.10 | −16.5 | −16.8 | |||
Warm sensation | 36.72 | −0.17 | 0.44 | 0.35 | −0.18 | 0.61 | 45.5 | 3.08 | 3.38 | 3.31 | |||
Cold pain | 19.43 | −0.24 | 0.41 | 0.28 | −0.26 | −0.98 | 0 | −2.36 | 0.10 | −2.59 | −2.35 | ||
Heat pain | 42.68 | 0.22 | 0.42 | 0.18 | 0.24 | 1.55 | 50 | 1.489 | 0.11 | 0.23 | 1.63 | 1.20 | |
0.054 | −0.27 | 0.40 | 0.41 | −0.29 | 0.37 | 0.03 | −0.65 | 0.28 | 0.19 | −0.71 | −1.45 | ||
Interoception | 0.50 | 4.80 | 5.26 | 5.23 | 0.09 | −2.68 | −2.94 | −2.72 | |||||
Heart rate | 65 | −1.86 | −1.98 | 92 | 1.45 | 0.11 | 1.59 |
In sum, as hypothesized at the outset, the IL patient showed no smell impairments relative to frontal damage patients, but she exhibited lower smell performance than healthy controls (this difference, however, disappeared after covariation). Instead, the SL patient was outperformed in smell tasks by both groups. This was the case before and after covariation, a result that also supports our hypothesis.
Relative to healthy controls, the IL patient (Figure
Smell | 58.33 | −2.07 | 0.10 | −2.24 | −2.01 | 41.67 | −6.21 | −6.71 | −9.77 | ||||
Taste | 49.5 | 0.08 | 0.47 | 0.19 | 0.09 | 1.38 | 41.38 | −.37 | 0.37 | −0.40 | −4.08 | ||
Thermal sensation | 32.49 | 0.44 | 0.34 | 0.29 | 0.47 | 0.80 | 25.75 | −5.68 | −6.14 | −7.19 | |||
Pain | 31.05 | 1.01 | 0.18 | 0.19 | 1.09 | 1.31 | 25 | −1.02 | 0.18 | 0.21 | −1.11 | −1.64 | |
Thermal pain sensation | 31.77 | 0.89 | 0.21 | 0.20 | 0.97 | 1.23 | 25.38 | −2.38 | −2.57 | −3.25 | |||
Interoception | 0.5 | 5.63 | 6.17 | 6.59 | 0.09 | −.61 | 0.30 | 0.43 | −0.67 | 1.33 |
When compared with the brain damaged group (Figure
Smell | 58.33 | −0.48 | 0.33 | 0.48 | −0.53 | 0.08 | 41.67 | −2.08 | −2.28 | −3.27 | |||
Taste | 49.5 | 0.02 | 0.49 | 0.43 | 0.03 | −0.28 | 41.38 | −0.89 | 0.21 | 0.32 | −0.98 | −0.72 | |
Thermal sensation | 32.49 | −0.63 | 0.28 | 0.43 | −0.69 | 0.26 | 25.75 | −9.76 | −10.69 | −16.58 | |||
Pain | 31.05 | −0.18 | 0.43 | 0.44 | −0.20 | −0.24 | 25 | −2.77 | −3.03 | −3.00 | |||
Thermal pain sensation | 31.77 | −0.45 | 0.34 | 0.45 | −0.49 | −0.21 | 25.38 | −6.81 | −7.46 | −7.94 | |||
Interoception | 0.50 | 4.80 | 5.26 | 6.90 | 0.09 | −2.68 | −2.94 | −5.07 |
Therefore, our hypothesis is supported by the absence of impairment in the IL patient, although it does not account for spared performance in the SL patient. However, a qualitative analysis of this latter patient's responses indicated that she misidentified sweet as salty (3/4 times) or bitter (1/4 times), salty as sour (2/6 times), and bitter as salty (3/6 times) or sour (2/6 times), showing a disruption in her subjective taste experiences.
There were no differences between the IL patient and healthy controls (Figure
The IL patient and the frontal patients obtained similar scores for thermal cool sensation, warmth sensation, heat pain and cold pain (Table
Considering that cool/cold thresholds are higher as the temperature departs from baseline (diminishes from 32 to 0°C), these results represent a diminished sensitivity to all conditions in SL (cool and warmth sensations).
In sum, when compared with both control groups, the IL patient showed no impairments in taste or thermal-pain sensation, which confirms our hypothesis, but a lower smell performance than healthy controls, which did not survive covariation. Conversely, when compared with healthy controls, the SL patient exhibited impaired smell identification, and diminished sensitivity to cool and warm sensations as well as to global thermal-pain sensation. Such impairments remained in the comparison with the brain-damaged controls, also confirming the hypothesis.
Compared with healthy controls, the IL patient (Figure
The patients' differential patterns were replicated following comparison with the brain-damaged group. The IL patient exhibited impairments in the interoceptive (
Furthermore, we calculated for both IL and SL patients the heart-rate variability with three different methods and non-significant differences were found compared with healthy controls (see Table
In summary, before and after covariation for HBD performance, and when compared to both healthy controls and the brain-damaged group, the IL patient presented disrupted interoceptive performance, while the SL patient showed no such disruption. Both of these results are in line with the general hypothesis that the internal stream of interoception depends on the insula as its putative basis.
We presented two single cases with respective damage of the right insular cortex (IL) and of right putamen (affecting frontotemporal connections, SL). These patients showed a differential pattern of impairment regarding interoceptive-related behavior and body-mapped functions. The IL patient presented impaired internal (cardiac) interoception and preserved external perception (thermal pain, smell, and taste). A distinct pattern arose in SL, who displayed impaired processing via the external signals (smell identification and thermal-pain thresholds) with preserved cardiac interoception. Importantly, this partially opposite internal–external pattern was replicated when the patients' performance was compared to that of subjects with lesions in other regions. These results suggest that the deficits found in both patients relate to their specific focal lesions, as opposed to unspecific brain damage (Rorden and Karnath,
The existence of (external and internal) multimodal insular afferents and their differential requirements for processing (Cameron,
It has been suggested that the information carried by these external stream must first be integrated with stimulus saliency (Seeley et al.,
The IL patient exhibited cardiac interoceptive deficits with preserved processing of external signals. Cardiac interoception is a basic modality of visceral perception that relies on an internal drive. It has proven to influence both homeostasis (Oppenheimer et al.,
As proposed above, cardiovascular and respiratory reflexes (i.e., baroreflex and CO2 concentration) that are sensed and processed in a beat-to-beat manner in the brainstem (Barrett et al.,
As expected, the SL patient presented thermal-pain, taste and smell identification deficits. Other lesion studies (Pritchard et al.,
The possible existence of internal and external subdivisions of interoceptive afferents could reflect a distinction between high and low cognitive processing. The lower level may consist of internal organ signals or proper interoception, such as vegetative cardiac and respiratory rhythms serving vital processes (Oppenheimer et al.,
Conversely, external afferents would involve body-mapped sensory inputs (smell, pain, taste). These may indirectly modulate complex behaviors only after a contextual updating that occurs in the IC just before being projected to cognitive sites (Limongi et al.,
Here we show that the same SL patient who presented emotional awareness deficits (Couto et al.,
Interoceptive afferent information arriving to the insular cortex, through the lamina I spino-thalamocortical system (lamina 1–solitary tract nucleus–parabrachial nucleus–periaqueductal gray–VMPo thalamus-insula) constitutes the basic information for the elaboration of higher cognitive domains (Craig,
This work presents important limitations that should be tackled in future studies.
Interoceptive performance in the brain-damaged group was better than in the IL patient but worse than in the SL patient. These patients' extended damage of the frontal cortex and other regions (reaching adjacent cortical areas and white matter) would explain their intermediate cardiac interoceptive performance. Further studies could assess whether frontal patients present subtle interoceptive deficits and whether these are secondary to other cognitive deficits (e.g., executive dysfunction).
The SL patient showed unimpaired taste abilities, as attested by our methodological strategy. We first used a covariation method to report the variance of the patient's performance beyond the depression covariate. This is a meaningful result in light of the strong negative correlation (
The IL patient presented spared taste perception, which may seem to contradict the primary role of the IC in gustatory processing (Rolls et al.,
Although we made a covariation by depression scores, we cannot rule out their possible effect on interoception. In particular, smell sensitivity (but not smell identification) is reduced in Major Depressive Disorder (MDD) (Pause et al.,
The absence of impairments in pain, taste and smell identification in the IC patient could reflect the action of compensatory functions provided by an intact left insula. In fact, this structure has been implicated in pain, taste and smell recognition (Pritchard et al.,
Finally, the SL is not located in the primary gustatory cortex (dorsal anterior IC), which indicates that damage to the taste brain network beyond this critical hub does not compromise the function. In addition, this interpretation is reinforced by evidence that damage to the left insula causes a bilateral affectation in taste recognition (Pritchard et al.,
Since all perceptive tests require preserved language abilities, our deficits would not be explained by a lack of transmission between the right insular network and neural substrates of language. Indeed, there is evidence that absence of the more important bundle of inter-hemispheric communication does not affect the verbal report of chemosensation awareness (Aglioti et al.,
Most previous reports of the insular patients (Calder et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This research was partially supported by Grants CONICYT/FONDECYT Regular (1130920 and 1140114), FONCyT-PICT 2012-0412 and 2012-1309, CONICET, and the INECO Foundation.
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