Jason A. Avery

Keeping the body in mind: Insula functional organization and functional connectivity integrate interoceptive, exteroceptive, and emotional awareness

Relatively discrete experimental literatures have grown to support the insulas role in the domains of interoception, focal exteroceptive attention and cognitive control, and the experience of anxiety, even as theoretical accounts have asserted that the insula is a critical zone for integrating across these domains. Here we provide the first experimental demonstration that there exists a functional topography across the insula, with distinct regions in the same participants responding in a highly selective fashion for interoceptive, exteroceptive, and affective processing. Although each insular region is associated with areas of differential resting state functional connectivity relative to the other regions, overall their functional connectivity profiles are quite similar, thereby providing a map of how interoceptive, exteroceptive, and emotional awareness are integrated within the insular cortex. Hum Brain Mapp 34:2944–2958, 2013.

Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula.

BACKGROUND Somatic complaints and altered interoceptive awareness are common features in the clinical presentation of major depressive disorder (MDD). Recently, neurobiological evidence has accumulated demonstrating that the insula is one of the primary cortical structures underlying interoceptive awareness. Abnormal interoceptive representation within the insula may thus contribute to the pathophysiology and symptomatology of MDD. METHODS We compared functional magnetic resonance imaging blood oxygenation level-dependent responses between 20 unmedicated adults with MDD and 20 healthy control participants during a task requiring attention to visceral interoceptive sensations and also assessed the relationship of this blood oxygenation level-dependent response to depression severity, as rated using the Hamilton Depression Rating Scale. Additionally, we examined between-group differences in insula resting-state functional connectivity and its relationship to Hamilton Depression Rating Scale ratings of depression severity. RESULTS Relative to the healthy control subjects, unmedicated MDD subjects exhibited decreased activity bilaterally in the dorsal mid-insula cortex (dmIC) during interoception. Activity within the insula during the interoceptive attention task was negatively correlated with both depression severity and somatic symptom severity in depressed subjects. Major depressive disorder also was associated with greater resting-state functional connectivity between the dmIC and limbic brain regions implicated previously in MDD, including the amygdala, subgenual prefrontal cortex, and orbitofrontal cortex. Moreover, functional connectivity between these regions and the dmIC was positively correlated with depression severity. CONCLUSIONS Major depressive disorder and the somatic symptoms of depression are associated with abnormal interoceptive representation within the insula.

Category-specific integration of homeostatic signals in caudal but not rostral human insula.

Prevailing theories hold that the insula is functionally organized along its caudal-to-rostral axis, with posterior regions coding lower-level sensory information and anterior regions coding higher-level stimulus significance relative to the bodys homeostatic needs. Contrary to predictions of this model, the response of the taste-sensitive region of the caudal, but not rostral, insula to food images was directly related to the bodys homeostatic state as indexed by levels of peripheral glucose.

Altered Insula Activity during Visceral Interoception in Weight-Restored Patients with Anorexia Nervosa

Anorexia nervosa (AN) is a devastating psychiatric illness that is associated with significant morbidity and mortality. Aberrant visceral interoceptive processing within the insula has been hypothesized to be an important mechanism in AN’s pathophysiology due to the theoretical link between interoception and emotional experience. We therefore utilized functional magnetic resonance imaging (fMRI) to examine whether altered insula functioning underlies visceral interoception in AN. Fifteen females with restricting-type AN and 15 healthy control females underwent fMRI while performing an interoceptive attention task during which they focused on sensations in their heart, stomach, and bladder. Participants also performed an anxious rumination task while in the scanner. AN participants were weight-restored and free of psychotropic medications. Two distinct regions of the insula—anterior insula and dorsal mid-insula—exhibited a significant (p<0.05) interaction between group and interoceptive modality. The post hoc analyses revealed that in the dorsal mid-insula the interaction was driven by group differences during stomach interoception (p=0.002, Bonferroni corrected), whereas in the anterior insula the interaction was driven by group differences during heart interoception (p=0.03, Bonferroni corrected). In addition, individuals with AN displayed increased activation during anxious rumination in the dorsal mid-insula, and activation in this region during stomach interoception was correlated with measures of anxiety and psychopathology. This relationship between altered visceral interoception and clinical symptoms in AN suggests an important mechanism for the disorder. Additional research is needed to examine whether interventions targeting visceral interoception may increase the efficacy of treatments for AN.

A common gustatory and interoceptive representation in the human mid-insula.

The insula serves as the primary gustatory and viscerosensory region in the mammalian cortex. It receives visceral and gustatory afferent projections through dedicated brainstem and thalamic nuclei, which suggests a potential role as a site for homeostatic integration. For example, while human neuroimaging studies of gustation have implicated the dorsal mid‐insular cortex as one of the primary gustatory regions in the insula, other recent studies have implicated this same region of the insula in interoception. This apparent convergence of gustatory and interoceptive information could reflect a common neural representation in the insula shared by both interoception and gustation. This idea finds support in translational studies in rodents, and may constitute a medium for integrating homeostatic information with feeding behavior. To assess this possibility, healthy volunteers were asked to undergo fMRI while performing tasks involving interoceptive attention to visceral sensations as well as a gustatory mapping task. Analysis of the unsmoothed, high‐resolution fMRI data confirmed shared representations of gustatory and visceral interoception within the dorsal mid‐insula. Group conjunction analysis revealed overlapping patterns of activation for both tasks in the dorsal mid‐insula, and region‐of‐interest analyses confirmed that the dorsal mid‐insula regions responsive for visceral interoception also exhibit strong responses to tastants. Hum Brain Mapp 36:2996–3006, 2015.

The ventral pallidum and orbitofrontal cortex support food pleasantness inferences.

Food advertisements often promote choices that are driven by inferences about the hedonic pleasures of eating a particular food. Given the individual and public health consequences of obesity, it is critical to address unanswered questions about the specific neural systems underlying these hedonic inferences. For example, although regions such as the orbitofrontal cortex (OFC) are frequently observed to respond more to pleasant food images than less hedonically pleasing stimuli, one important hedonic brain region in particular has largely remained conspicuously absent among human studies of hedonic response to food images. Based on rodent research demonstrating that activity in the ventral pallidum underlies the hedonic pleasures experienced upon eating food rewards, one might expect that activity in this important ‘hedonic hotspot’ might also track inferred food pleasantness. To date, however, no human studies have assessed this question. We thus asked human subjects to undergo fMRI and make item-by-item ratings of how pleasant it would be to eat particular visually perceived foods. Activity in the ventral pallidum was strongly modulated with pleasantness inferences. Additionally, activity within a region of the orbitofrontal cortex that tracks the pleasantness of tastes was also modulated with inferred pleasantness. Importantly, the reliability of these findings is demonstrated by their replication when we repeated the experiment at a new site with new subjects. These two experiments demonstrate that the ventral pallidum, in addition to the OFC, plays a central role in the moment-to-moment hedonic inferences that influence food-related decision-making.

Trait impulsivity is related to ventral ACC and amygdala activity during primary reward anticipation

Trait impulsivity is characterized by behavioral disinhibition and rash decision-making that contribute to many maladaptive behaviors. Previous research demonstrates that trait impulsivity is related to the activity of brain regions underlying reward sensitivity and emotion regulation, but little is known about this relationship in the context of immediately available primary reward. This is unfortunate, as impulsivity in these contexts can lead to unhealthy behaviors, including poor food choices, dangerous drug use and risky sexual practices. In addition, little is known about the relationship between integration of reward and affective neurocircuitry, as measured by resting-state functional connectivity, and trait impulsivity in everyday life, as measured with a commonly used personality inventory. We therefore asked healthy adults to undergo a functional magnetic resonance imaging task in which they saw cues indicating the imminent oral administration of rewarding taste, as well as a resting-state scan. Trait impulsivity was associated with increased activation during anticipation of primary reward in the anterior cingulate cortex (ACC) and amygdala. Additionally, resting-state functional connectivity between the ACC and the right amygdala was negatively correlated with trait impulsivity. These findings demonstrate that trait impulsivity is related not only to ACC-amygdala activation but also to how tightly coupled these regions are to one another.

Convergent gustatory and viscerosensory processing in the human dorsal mid-insula.

The homeostatic regulation of feeding behavior requires an organism to be able to integrate information from its internal environment, including peripheral visceral signals about the bodys current energy needs, with information from its external environment, such as the palatability of energy‐rich food stimuli. The insula, which serves as the brains primary sensory cortex for representing both visceral signals from the body and taste signals from the mouth and tongue, is a likely candidate region in which this integration might occur. However, to date it has been unclear whether information from these two homeostatically critical faculties is merely co‐represented in the human insula, or actually integrated there. Recent functional neuroimaging evidence of a common substrate for visceral interoception and taste perception within the human dorsal mid‐insula suggests a model whereby a single population of neurons may integrate viscerosensory and gustatory signals. To test this model, we used fMRI‐Adaptation to identify whether insula regions that exhibit repetition suppression following repeated interoception trials would then also exhibit adapted responses to subsequent gustatory stimuli. Multiple mid and anterior regions of the insula exhibited adaptation to interoceptive trials specifically, but only the dorsal mid‐insula regions exhibited an adapted gustatory response following interoception. The discovery of this gustatory‐interoceptive convergence within the neurons of the human insula supports the existence of a heretofore‐undocumented neural pathway by which visceral signals from the periphery modulate the activity of brain regions involved in feeding behavior. Hum Brain Mapp 38:2150–2164, 2017.

How the Brain Wants What the Body Needs: The Neural Basis of Positive Alliesthesia

Discontinuing unhealthy behaviors, such as overeating or drug use, depends upon an individual’s ability to overcome the influence of environmental reward cues. The strength of that influence, however, varies greatly depending upon the internal state of the body. Characterizing the relationship between interoceptive signaling and shifting drug cue valuation provides an opportunity for understanding the neural bases of how changing internal states alter reward processing more generally. A total of 17 cigarette smokers rated the pleasantness of cigarette pictures when they were nicotine sated or nicotine abstinent. On both occasions, smokers also underwent functional magnetic resonance imaging (fMRI) scanning while performing a visceral interoceptive attention task and a resting-state functional connectivity scan. Hemodynamic, physiological, and behavioral parameters were compared between sated and abstinent scans. The relationships between changes in these parameters across scan sessions were also examined. Smokers rated cigarette pictures as significantly more pleasant while nicotine abstinent than while nicotine sated. Comparing abstinent with sated scans, smokers also exhibited significantly decreased mid-insula, amygdala, and orbitofrontal activity while attending to interoceptive signals from the body. Change in interoceptive activity within the left mid-insula predicted the increase in smoker’s pleasantness ratings of cigarette cues. This increase in pleasantness ratings was also correlated with an increase in resting-state functional connectivity between the mid-insula and the ventral striatum and ventral pallidum. These findings support a model wherein interoceptive processing in the mid-insula of withdrawal signals from the body potentiates the motivational salience of reward cues through the recruitment of hedonic ‘hot spots’ within the brain’s reward circuitry.

Obesity is associated with altered mid-insula functional connectivity to limbic regions underlying appetitive responses to foods:

Obesity is fundamentally a disorder of energy balance. In obese individuals, more energy is consumed than is expended, leading to excessive weight gain through the accumulation of adipose tissue. Complications arising from obesity, including cardiovascular disease, elevated peripheral inflammation, and the development of Type II diabetes, make obesity one of the leading preventable causes of morbidity and mortality. Thus, it is of paramount importance to both individual and public health that we understand the neural circuitry underlying the behavioral regulation of energy balance. To this end, we sought to examine obesity-related differences in the resting state functional connectivity of the dorsal mid-insula, a region of gustatory and interoceptive cortex associated with homeostatically sensitive responses to food stimuli. Within the present study, obese and healthy weight individuals completed resting fMRI scans during varying interoceptive states, both while fasting and after a standardized meal. We examined group differences in the pre- versus post-meal functional connectivity of the mid-insula, and how those differences were related to differences in self-reported hunger ratings and ratings of meal pleasantness. Obese and healthy weight individuals exhibited opposing patterns of eating-related functional connectivity between the dorsal mid-insula and multiple brain regions involved in reward, valuation, and satiety, including the medial orbitofrontal cortex, the dorsal striatum, and the ventral striatum. In particular, healthy weight participants exhibited a significant positive relationship between changes in hunger and changes in medial orbitofrontal functional connectivity, while obese participants exhibited a complementary negative relationship between hunger and ventral striatum connectivity to the mid-insula. These obesity-related alterations in dorsal mid-insula functional connectivity patterns may signify a fundamental difference in the experience of food motivation in obese individuals, wherein approach behavior toward food is guided more by reward-seeking than by homeostatically relevant interoceptive information from the body.