Primary Interoceptive Cortex Research Articles

Neural processes linking joint hypermobility and anxiety: key roles for the amygdala and insular cortex.

Anxiety symptoms are elevated among people with joint hypermobility. The underlying neural mechanisms are attributed theoretically to effects of variant connective tissue on the precision of interoceptive representations contributing to emotions. To investigate the neural correlates of anxiety and hypermobility using functional neuroimaging. We used functional magnetic resonance neuroimaging to quantify regional brain responses to emotional stimuli (facial expressions) in people with generalised anxiety disorder (GAD) (N = 30) and a non-anxious comparison group (N = 33). All participants were assessed for joint laxity and were classified (using Brighton Criteria) for the presence and absence of hypermobility syndrome (HMS: now considered hypermobility spectrum disorder). Participants with HMS showed attenuated neural reactivity to emotional faces in specific frontal (inferior frontal gyrus, pre-supplementary motor area), midline (anterior mid and posterior cingulate cortices) and parietal (precuneus and supramarginal gyrus) regions. Notably, interaction between HMS and anxiety was expressed in reactivity of the left amygdala (a region implicated in threat processing) and mid insula (primary interoceptive cortex) where activity was amplified in people with HMS with GAD. Severity of hypermobility in anxious, compared with non-anxious, individuals correlated with activity within the anterior insula (implicated as the neural substrate linking anxious feelings to physiological state). Amygdala-precuneus functional connectivity was stronger in participants with HMS, compared with non-HMS participants. The predisposition to anxiety in people with variant connective tissue reflects dynamic interactions between neural centres processing threat (amygdala) and representing bodily state (insular and parietal cortices). Correspondingly, interventions to regulate amygdala reactivity while enhancing interoceptive precision may have therapeutic benefit for symptomatic hypermobile individuals.

The association between early regulatory problems and adult peer relationship quality is mediated by the brain's allostatic-interoceptive system.

Early regulatory problems (RPs), i.e., problems with crying, sleeping, and/or feeding during the first years, increase the risk for avoidant personality traits in adulthood, associated with social withdrawal and anxiety. Even more, RPs are linked with functional alterations in the adult default mode and salience networks, comprising the brain's allostatic-interoceptive system (AIS) and playing a role in social interactions. We investigated whether RPs assessed in infancy are associated with difficulties in adult peer relationships mediated by functional alterations of the AIS. As part of a large case-controlled prospective study, 42 adults with previous RPs and 70 matched controls (mean age = 28.48, SD = 2.65, 51% male) underwent fMRI during rest. The analysis focused on the intrinsic functional connectivity (iFC) of key nodes of the AIS. Peer relationship quality was assessed via a semi-structured Life Course Interview and the YASR scale. In these same individuals, RPs were assessed at ages 5, 20 and 56 months. RPs in infancy were associated with lower-quality peer relationships and enhanced functional connectivity of the AIS nodes in adulthood, with a stronger effect for multiple and persistent RPs compared with transient-multiple or single-persistent RPs. Importantly, iFC changes of the dorsal mid insula, a primary interoceptive cortex with frontal and temporal regions, mediated the relationship between early RPs and adult peer relationship quality. Results indicate long-lasting social and neural changes associated with early RPs. Our findings further implicate the AIS in both interoceptive and social processes, while indicating the need for early screening of early RPs.

Cytoarchitectonic and connection stripes in the dysgranular insular cortex in the macaque monkey.

The insula has been classically divided into broad granular, dysgranular, and agranular architectonic sectors. We previously proposed a novel partition, dividing each sector into four to seven sharply delimited architectonic areas, with the dysgranular areas being possibly further subdivided into subtle horizontal partitions or "stripes." In architectonics, discrete subparcellations are prone to subjective variability and need being supported with additional neuroanatomical methods. Here, using a secondary analysis of indirect connectional data in the rhesus macaque monkey, we examined the spatial relationship between the dysgranular architectonic stripes and tract-tracing labeling patterns produced in the insula with injections of neuronal tracers in other cortical regions. The injections consistently produced sharply delimited patches of anterograde and/or retrograde labeling, which formed stripes across consecutive coronal sections of the insula. While the overall pattern of labeling on individual coronal sections varied with the injection site, the boundaries of the patches consistently coincided with architectonic boundaries on an adjacent cyto- (Nissl) and/or myelo- (Gallyas) architectonic section. This overlap supports the existence of a fine dysgranular stripe-like partition of the primate insula, with possibly major implications for interoceptive processing in primates including humans. The modular organization of the insula could underlie a serial stream of integration from a dorsal primary interoceptive cortex toward progressively more ventral egocentric "self-agency" and allocentric "social" dysgranular processing units.

Interoceptive Awareness of the Breath Preserves Attention and Language Networks amidst Widespread Cortical Deactivation: A Within-Participant Neuroimaging Study.

Interoception, the representation of the body's internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoceptive attention are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions (N = 44) as part of a randomized control trial of Mindful Awareness in Body-oriented Therapy (MABT). Compared to Active Exteroception, Active Interoception deactivated somatomotor and prefrontal regions. Greater self-reported interoceptive sensibility (MAIA scale) predicted sparing from deactivation within the anterior cingulate cortex (ACC) and left-lateralized language regions. The right insula-typically described as a primary interoceptive cortex-was only specifically implicated by its deactivation during an exogenously paced respiration condition (Active Matching) relative to self-paced Active Interoception. Psychophysiological interaction (PPI) analysis characterized Active Interoception as promoting greater ACC connectivity with lateral prefrontal and parietal regions commonly referred to as the Dorsal Attention Network (DAN). In contrast to evidence relating accurate detection of liminal interoceptive signals such as the heartbeat to anterior insula activity, interoceptive attention towards salient signals such as the respiratory cycle may involve reduced cortical activity but greater ACC-DAN connectivity, with greater sensibility linked to reduced deactivation within the ACC and language-processing regions.Significance StatementInteroception, the representation of the body's internal state, is poorly understood compared to the external senses, with existing neuroimaging studies failing to match task difficulty between interoceptive and exteroceptive tasks. The present study used a novel fMRI task to compare interoceptive and exteroceptive attention and explore whether this distinction was moderated by self-reported interoceptive awareness. The results implicate three novel interoceptive mechanisms: interoceptive attention reduces widespread cortical activity while increasing prefrontal connectivity, wherein greater self-reported interoceptive awareness is linked to preserved activation of the anterior cingulate cortex and language regions. Rather than increasing activation of interoceptive cortex, interoceptive attention to the breath may involve attending to body representations typically ignored in favor of exteroceptive information and other forms of cognition.

Brain correlates of chemotherapy-induced peripheral neuropathy (CIPN) during somatosensory and interoceptive attention: A functional MRI (fMRI) study.

e24095 Background: Over half of patients receiving neurotoxic taxane, platinum, or bortezomib chemotherapy experience CIPN—a dose-limiting toxicity involving numbness and pain in the extremities. There are limited biomarkers and treatments for CIPN partly due to lack of knowledge of its pathophysiology. Here, we studied whether CIPN involves changes in the brain’s sensory processing circuitry to inform novel brain-based biomarkers and brain-based treatments for CIPN. Methods: Eleven patients scheduled to receive taxane, platinum, or bortezomib rated CIPN severity (CIPN-20) and completed an fMRI scan before starting neurotoxic chemotherapy and/or 12 weeks later. The 7-min fMRI task involved alternating 20-sec trials of distinct attentional focus: (1) their left fingertips (somatosensory attention), (2) their heart (interoceptive attention), and (3) a flashing word “target” (visual attention; the reference condition). We found an activation cluster in primary somatosensory cortex (S1) comparing somatosensory vs. visual attention and another cluster in primary interoceptive cortex (mid/posterior insula) comparing interoceptive vs. visual attention. We tested for associations between CIPN severity and task-based activations in S1 and the insula. Because this is a pilot study, we present effect sizes (ESs) using Cohen’s d and Pearson’s r, not p-values. Results: The 11 patients were 63±12 years old, 54% women, and 54% had breast cancer with high-quality fMRI data (16 scans; 8 pre-chemotherapy). As expected, somatosensory attention increased activation in S1 compared to visual attention (ES = 1.46), and interoceptive attention increased activation in the insula compared to visual attention (ES = 0.94). Patients with worse CIPN had smaller increases in S1 activation during somatosensory vs. visual attention (ES = 0.38), suggesting reduced S1 activation during somatosensory attention (i.e., failure to activate S1) and/or increased S1 activation during visual attention (i.e., S1 chronically activated). Similarly, patients with worse CIPN had smaller increases in insula activation during interoceptive vs. visual attention (ES = 0.57). Individual differences in S1 or insula activity were not significantly explained by age, anxiety, or problems remembering (all ESs < 0.12). Conclusions: CIPN severity was associated with changes in brain activity during a simple attentional task during fMRI scanning, implicating the brain’s somatosensory and interoceptive processing in CIPN. Future work should test for replication and develop biomarkers and treatments for CIPN that target somatosensory and interoceptive processing, perhaps using this attention task. NCT03021174. Funding: NIH R25CA102618, UG1CA189961, K07CA221931. Clinical trial information: NCT03021174.

Interoceptive insular cortex participates in sensory processing of gastrointestinal malaise and associated behaviors

The insular cortex plays a central role in the perception and regulation of bodily needs and emotions. Its modular arrangement, corresponding with different sensory modalities, denotes a complex organization, and reveals it to be a hub that is able to coordinate autonomic and behavioral responses to many types of stimuli. Yet, little is known about the dynamics of its electrical activity at the neuronal level. We recorded single neurons in behaving rats from the posterior insula cortex (pIC), a subdivision considered as a primary interoceptive cortex, during gastrointestinal (GI) malaise, a state akin to the emotion of disgust in humans. We found that a large proportion of pIC neurons were modulated during the rodent compensatory behaviors of lying on belly (LOB) and Pica. Furthermore, we demonstrated that LOB was correlated with low-frequency oscillations in the field potentials and spikes at the theta (8 Hz) band, and that low-frequency electrical microstimulation of pIC elicited LOB and Pica. These findings demonstrate that pIC neurons play a critical role in GI malaise perception, and that the pIC influences the expression of behaviors that alleviate GI malaise. Our model provides an accessible approach at the single cell level to study innate emotional behaviors, currently elusive in humans.

Interoceptive Insular Cortex Mediates Both Innate Fear and Contextual Threat Conditioning to Predator Odor.

The insular cortex (IC), among other brain regions, becomes active when humans experience fear or anxiety. However, few experimental studies in rats have implicated the IC in threat responses. We have recently reported that inactivation of the primary interoceptive cortex (pIC) during pre-training, or the intra-pIC blockade of protein synthesis immediately after training, impaired the consolidation of auditory fear conditioning. The present study was designed to investigate the role of the pIC in innate and learned defensive responses to predator odor. Freezing behavior was elicited by single or repetitive exposures to a collar that had been worn by a domestic cat. Sessions were video-recorded and later scored by video observation. We found that muscimol inactivation of the pIC reduced the expression of freezing reaction in response to a single or repeated exposure to cat odor. We also found that pIC inactivation with muscimol impaired conditioning of fear to the context in which rats were exposed to cat odor. Furthermore, neosaxitoxin inactivation of the pIC resulted in a prolonged and robust reduction in freezing response in subsequent re-exposures to cat odor. In addition, freezing behavior significantly correlated with the neural activity of the IC. The present results suggest that the IC is involved in the expression of both innate and learned fear responses to predator odor.

The Organization of the Primate Insular Cortex.

Long perceived as a primitive and poorly differentiated brain structure, the primate insular cortex recently emerged as a highly evolved, organized and richly connected cortical hub interfacing bodily states with sensorimotor, environmental, and limbic activities. This insular interface likely substantiates emotional embodiment and has the potential to have a key role in the interoceptive shaping of cognitive processes, including perceptual awareness. In this review, we present a novel working model of the insular cortex, based on an accumulation of neuroanatomical and functional evidence obtained essentially in the macaque monkey. This model proposes that interoceptive afferents that represent the ongoing physiological status of all the organs of the body are first being received in the granular dorsal fundus of the insula or “primary interoceptive cortex,” then processed through a series of dysgranular poly-modal “insular stripes,” and finally integrated in anterior agranular areas that serve as an additional sensory platform for visceral functions and as an output stage for efferent autonomic regulation. One of the agranular areas hosts the specialized von Economo and Fork neurons, which could provide a decisive evolutionary advantage for the role of the anterior insula in the autonomic and emotional binding inherent to subjective awareness.

Primary Interoceptive Cortex Activity during Simulated Experiences of the Body.

Studies of the classic exteroceptive sensory systems (e.g., vision, touch) consistently demonstrate that vividly imagining a sensory experience of the world-simulating it-is associated with increased activity in the corresponding primary sensory cortex. We hypothesized, analogously, that simulating internal bodily sensations would be associated with increased neural activity in primary interoceptive cortex. An immersive, language-based mental imagery paradigm was used to test this hypothesis (e.g., imagine your heart pounding during a roller coaster ride, your face drenched in sweat during a workout). During two neuroimaging experiments, participants listened to vividly described situations and imagined "being there" in each scenario. In Study 1, we observed significantly heightened activity in primary interoceptive cortex (of dorsal posterior insula) during imagined experiences involving vivid internal sensations. This effect was specific to interoceptive simulation: It was not observed during a separate affect focus condition in Study 1 nor during an independent Study 2 that did not involve detailed simulation of internal sensations (instead involving simulation of other sensory experiences). These findings underscore the large-scale predictive architecture of the brain and reveal that words can be powerful drivers of bodily experiences.

Topographic mapping of the primate primary interoceptive cortex

Topographic mapping of the primate primary interoceptive cortex

Neurobiology of visceral pain

Visceral pain is diffusely localized, referred into other tissues, frequently not correlated with visceral traumata, preferentially accompanied by autonomic and somatomotor reflexes, and associated with strong negative affective feelings. It belongs together with the somatic pain sensations and non-painful body sensations to the interoception of the body. (1) Visceral pain is correlated with the excitation of spinal (thoracolumbar, sacral) visceral afferents and (with a few exceptions) not with the excitation of vagal afferents. Spinal visceral afferents are polymodal and activated by adequate mechanical and chemical stimuli. All groups of spinal visceral afferents can be sensitized (e.g., by inflammation). Silent mechanoinsensitive spinal visceral afferents are recruited by inflammation. (2) Spinal visceral afferent neurons project into the laminae I, II (outer part IIo) and V of the spinal dorsal horn over several segments, medio-lateral over the whole width of the dorsal horn and contralateral. Their activity is synaptically transmitted in laminae I, IIo and deeper laminae to viscero-somatic convergent neurons that receive additionally afferent synaptic (mostly nociceptive) input from the skin and from deep somatic tissues of the corresponding dermatomes, myotomes and sclerotomes. (3) The second-order neurons consist of excitatory and inhibitory interneurons (about 90 % of all dorsal horn neurons) and tract neurons activated monosynaptically in lamina I by visceral afferent neurons and di- or polysynaptically in deeper laminae. (4) The sensitization of viscero-somatic convergent neurons (central sensitization) is dependent on the sensitization of spinal visceral afferent neurons, local spinal excitatory and inhibitory interneurons and supraspinal endogenous control systems. The mechanisms of this central sensitization have been little explored. (5) Viscero-somatic tract neurons project through the contralateral ventrolateral tract and presumably other tracts to the lower and upper brain stem, the hypothalamus and via the thalamus to various cortical areas. (6) Visceral pain is presumably (together with other visceral sensations and nociceptive as well as non-nociceptive somatic body sensations) primarily represented in the posterior dorsal insular cortex (primary interoceptive cortex). This cortex receives in primates its spinal synaptic inputs mainly from lamina I tract neurons via the ventromedial posterior nucleus of the thalamus. (7) The transmission of activity from visceral afferents to second-order neurons in spinal cord is modulated in an excitatory and inhibitory way by endogenous anti- and pronociceptive control systems in the lower and upper brain stem. These control systems are under cortical control. (8) Visceral pain is referred to deep somatic tissues, to the skin and to other visceral organs. This referred pain consists of spontaneous pain and mechanical hyperalgesia. The mechanisms underlying referred pain and the accompanying tissue changes have been little explored.

Mindfulness meditation training alters cortical representations of interoceptive attention

One component of mindfulness training (MT) is the development of interoceptive attention (IA) to visceral bodily sensations, facilitated through daily practices such as breath monitoring. Using functional magnetic resonance imaging (fMRI), we examined experience-dependent functional plasticity in accessing interoceptive representations by comparing graduates of a Mindfulness-Based Stress Reduction course to a waitlisted control group. IA to respiratory sensations was contrasted against two visual tasks, controlling for attentional requirements non-specific to IA such as maintaining sensation and suppressing distraction. In anatomically partitioned analyses of insula activity, MT predicted greater IA-related activity in anterior dysgranular insula regions, consistent with greater integration of interoceptive sensation with external context. MT also predicted decreased recruitment of the dorsomedial prefrontal cortex (DMPFC) during IA, and altered functional connectivity between the DMPFC and the posterior insula, putative primary interoceptive cortex. Furthermore, meditation practice compliance predicted greater posterior insula and reduced visual pathway recruitment during IA. These findings suggest that interoceptive training modulates task-specific cortical recruitment, analogous to training-related plasticity observed in the external senses. Further, DMPFC modulation of IA networks may be an important mechanism by which MT alters information processing in the brain, increasing the contribution of interoception to perceptual experience.

Attentional Modulation of Primary Interoceptive and Exteroceptive Cortices

How exteroceptive attention (EA) alters neural representations of the external world is well characterized, yet little is known about how interoceptive attention (IA) alters neural representations of the body's internal state. We contrasted visual EA against IA toward respiration. Visual EA modulated striate and extrastriate cortices and a lateral frontoparietal "executive" network. By contrast, respiratory IA modulated a posterior insula region sensitive to respiratory frequency, consistent with primary interoceptive cortex, and a posterior limbic and medial parietal network, including the hippocampus, precuneus, and midcingulate cortex. Further distinguishing between EA and IA networks, attention-dependent connectivity analyses revealed that EA enhanced visual cortex connectivity with the inferior parietal lobule and pulvinar of the thalamus, while IA enhanced insula connectivity with the posterior ventromedial thalamus, a relay of the laminar I spinothalamocortical pathway supporting interoceptive afference. Despite strong connectivity between the posterior and the anterior insula, anatomical parcellation of the insula revealed a gradient of IA to EA recruitment along its posterior-anterior axis. These results suggest that distinct networks may support EA and IA. Furthermore, the anterior insula is not an area of pure body awareness but may link representations of the outside world with the body's internal state--a potential basis for emotional experience.

Novel Mast Cell Stabilizers in the Treatment of Postoperative Ileus

SPM 8 was applied to test anatomical regions of interest in the pINS, aINS and the aMCC while maintaining a family-wise error rate at p<.05. We also tested the possible effects of gut distension on processing speed and cognitive performance, indexed by mean reaction time and accuracy.Results:Subliminal or supraliminal gut distention during performance of the high or low processing load task did not significantly increase activity in pINS or aINS. However, during the high cognitive load task,supraliminal distension resulted in a reduction of aMCC activity. As expected, reaction time was longer during the high processing load compared to the low processing load task. However,subliminal and supraliminal balloon inflation did not alter reaction time or accuracy rates on the task. Conclusions:In healthy participants: 1)When attention is focused away from the gut, subliminal andmildly supraliminal rectal distension is not associated with activation of the primary interoceptive cortex, while supraliminal distension is associated with a reduction of aMCC activity during a high processing load task. These findings are consistent with possible engagement of descending inhibitory systems during the attention task, reducing interoceptive inflow to the brain.2) Low intensity visceral stimulation does not interfere with cognitive performance.

Role of Altered Intestinal Function in the Protective Effects of Nematode Infection Against the Development of Type 1 Diabetes (T1d) in Non Obese Diabetic (NOD) Mice

SPM 8 was applied to test anatomical regions of interest in the pINS, aINS and the aMCC while maintaining a family-wise error rate at p<.05. We also tested the possible effects of gut distension on processing speed and cognitive performance, indexed by mean reaction time and accuracy.Results:Subliminal or supraliminal gut distention during performance of the high or low processing load task did not significantly increase activity in pINS or aINS. However, during the high cognitive load task,supraliminal distension resulted in a reduction of aMCC activity. As expected, reaction time was longer during the high processing load compared to the low processing load task. However,subliminal and supraliminal balloon inflation did not alter reaction time or accuracy rates on the task. Conclusions:In healthy participants: 1)When attention is focused away from the gut, subliminal andmildly supraliminal rectal distension is not associated with activation of the primary interoceptive cortex, while supraliminal distension is associated with a reduction of aMCC activity during a high processing load task. These findings are consistent with possible engagement of descending inhibitory systems during the attention task, reducing interoceptive inflow to the brain.2) Low intensity visceral stimulation does not interfere with cognitive performance.

Inactivation of the Interoceptive Insula Disrupts Drug Craving and Malaise Induced by Lithium

Addiction profoundly alters motivational circuits so that drugs become powerful reinforcers of behavior. The interoceptive system continuously updates homeostatic and emotional information that are important elements in motivational decisions. We tested the idea that interoceptive information is essential in drug craving and in the behavioral signs of malaise. We inactivated the primary interoceptive cortex in amphetamine-experienced rats, which prevented the urge to seek amphetamine in a place preference task. Interoceptive insula inactivation also blunted the signs of malaise induced by acute lithium administration. Drug-seeking and malaise both induced Fos expression, a marker of neuronal activation, in the insula. We conclude that the insular cortex is a key structure in the perception of bodily needs that provides direction to motivated behaviors.