Better living through understanding the insula: Why subregions can make all the difference

doi:10.1016/j.neuropharm.2021.108765

Neuropharmacology

Volume 198, 15 October 2021, 108765

https://doi.org/10.1016/j.neuropharm.2021.108765 Get rights and content

Highlights

•
Insula is critical for many motivated behaviors, with subregions interesting but still poorly understood.
•
Insula regulates numerous functions, including, interoception, emotion, addiction, and other neuropsychiatric conditions.
•
Generally, posterior, mid, and anterior insula are linked to somatosensory, limbic/emotional, and cognitive integration.
•
We extensively review human and rodent findings, noting potential behavioral patterns for insular subregions.
•
This review is meant to guide formulation of future work to give critical mechanistic insights and dissociations.

Abstract

Insula function is considered critical for many motivated behaviors, with proposed functions ranging from attention, behavioral control, emotional regulation, goal-directed and aversion-resistant responding. Further, the insula is implicated in many neuropsychiatric conditions including substance abuse. More recently, multiple insula subregions have been distinguished based on anatomy, connectivity, and functional contributions. Generally, posterior insula is thought to encode more somatosensory inputs, which integrate with limbic/emotional information in middle insula, that in turn integrate with cognitive processes in anterior insula. Together, these regions provide rapid interoceptive information about the current or predicted situation, facilitating autonomic recruitment and quick, flexible action. Here, we seek to create a robust foundation from which to understand potential subregion differences, and provide direction for future studies. We address subregion differences across humans and rodents, so that the latter's mechanistic interventions can best mesh with clinical relevance of human conditions. We first consider the insula's suggested roles in humans, then compare subregional studies, and finally describe rodent work. One primary goal is to encourage precision in describing insula subregions, since imprecision (e.g. including both posterior and anterior studies when describing insula work) does a disservice to a larger understanding of insula contributions. Additionally, we note that specific task details can greatly impact recruitment of various subregions, requiring care and nuance in design and interpretation of studies. Nonetheless, the central ethological importance of the insula makes continued research to uncover mechanistic, mood, and behavioral contributions of paramount importance and interest.

This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Section snippets

Overview

The insular cortex is an expansive brain area spanning the anterior/posterior gradient of the brain in humans and animals. The insula has emerged as central in numerous subfields of neuroscience, where it seems to be an integral component of behavior in many disease and non-disease states. In recent years, clinical research of insula subregions has exploded, leading to identification of between 2 and 13 insula subregions based on anatomic and/or functional information used in the parcellation

The human insula

Unbiased clinical neuroimaging studies have long identified the insula as significantly involved in numerous behaviors, disorders, and related dysfunctions. However, many of these earlier human imaging studies failed to report specific subregions of the insula, complicating generalizable interpretations for the insula's many roles in human behavior. As will be discussed below, different subregions of the insula can have dramatically different-even seemingly diametrically opposed-roles in

Rodents and humans: promise and pitfalls of translation

Behavioral parallels between species (i.e. rodents and humans) are of particular translational value, and similarities in anatomical and functional connectivity also enhance the relevance of rodent findings to humans. However, connectivity needn't be identical between human and rodents since related regions could have similar anatomical compositions and neural circuitry that gives rise to similar behavioral functions. While rodent work holds3promise for understanding insula function, there are

Conclusion

This review was designed to comprehensively consider the functional roles of different insula subregions, comparing examples from the extensive human literature with the more limited work in rodents. Even with important species differences, there seems to be meaningful parallels between human and rodent insula contributions. Indeed, insula subregions likely play central roles for many emotion- and motivation-related behaviors, and may be particularly important for integrating sensory,

Acknowledgements

Supported by NIH-funded grants AA027774 (SWC), DA042987 (ACJ), AA027214 and AA07462 (BA), and AA024109 (FWH).

References (386)

J.M. Allman et al.
Intuition and autism: a possible role for Von Economo neurons
Trends Cognit. Sci.
(2005)
F.H. Alves et al.
Insular cortex alpha1-adrenoceptors modulate the parasympathetic component of the baroreflex in unanesthetized rats
Brain Res.
(2009)
J.R. Augustine
Circuitry and functional aspects of the insular lobe in primates including humans
Brain Res Brain Res Rev
(1996)
J.A. Avery et al.
Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula
Biol. Psychiatr.
(2014)
A.D. Barber et al.
Parasympathetic arousal-related cortical activity is associated with attention during cognitive task performance
Neuroimage
(2020)
V. Baur et al.
Resting-state functional and structural connectivity within an insula-amygdala route specifically index state and trait anxiety
Biol. Psychiatr.
(2013)
J.C. Britton et al.
Neural correlates of social and nonsocial emotions: an fMRI study
Neuroimage
(2006)
S.A. Bunge et al.
Immature frontal lobe contributions to cognitive control in children: evidence from fMRI
Neuron
(2002)
C. Butti et al.
Von Economo neurons: clinical and evolutionary perspectives
Cortex
(2013)
V.A. Cardenas et al.
Brain morphology at entry into treatment for alcohol dependence is related to relapse propensity
Biol. Psychiatr.
(2011)

F. Caruana et al.

Emotional and social behaviors elicited by electrical stimulation of the insula in the macaque monkey

Curr. Biol.

(2011)

J.P. Casanova et al.

A role for the interoceptive insular cortex in the consolidation of learned fear

Behav. Brain Res.

(2016)

X. Caseras et al.

Sex differences in neural responses to disgusting visual stimuli: implications for disgust-related psychiatric disorders

Biol. Psychiatr.

(2007)

F. Cauda et al.

Functional connectivity of the insula in the resting brain

Neuroimage

(2011)

F. Cauda et al.

Meta-analytic clustering of the insular cortex: characterizing the meta-analytic connectivity of the insula when involved in active tasks

Neuroimage

(2012)

C. Charroud et al.

Task- and rest-based functional brain connectivity in food-related reward processes among healthy adolescents

Neuroscience

(2021)

D.S. Chester et al.

How do negative emotions impair self-control? A neural model of negative urgency

Neuroimage

(2016)

M. Corbetta et al.

The reorienting system of the human brain: from environment to theory of mind

Neuron

(2008)

A.D. Craig

Forebrain emotional asymmetry: a neuroanatomical basis?

Trends Cognit. Sci.

(2005)

H.D. Critchley et al.

Neural activity in the human brain relating to uncertainty and arousal during anticipation

Neuron

(2001)

M. D'Esposito et al.

Functional MRI studies of spatial and nonspatial working memory

Brain Res. Cogn. Brain Res.

(1998)

J.W. Dalley et al.

Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates

Neurosci. Biobehav. Rev.

(2004)

D. Darevsky et al.

Behavioral indicators of succeeding and failing under higher-challenge compulsion-like alcohol drinking in rat

Behav. Brain Res.

(2020)

I.J. Deary et al.

The functional anatomy of inspection time: an event-related fMRI study

Neuroimage

(2004)

D.C. DeVille et al.

The neural bases of interoceptive encoding and recall in healthy adults and adults with depression

Biol Psychiatry Cogn Neurosci Neuroimaging

(2018)

K. Abe et al.

Cortico-amygdala interaction determines the insular cortical neurons involved in taste memory retrieval

Mol. Brain

(2020)

R. Abend et al.

Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy

J. Psychiatry Neurosci.

(2021)

M.A. Addicott et al.

Increased functional connectivity in an insula-based network is associated with improved smoking cessation outcomes

Neuropsychopharmacology

(2015)

M.A. Addicott et al.

Nicotine increases anterior insula activation to expected and unexpected outcomes among nonsmokers

Psychopharmacology (Berl)

(2017)

A. Adhikari

Distributed circuits underlying anxiety

Front. Behav. Neurosci.

(2014)

L.J. Agostinelli et al.

Input-output connections of LJA5 prodynorphin neurons

J. Comp. Neurol.

(2021)

S. Alcauter et al.

Consistent anterior-posterior segregation of the insula during the first 2 years of life

Cerebr. Cortex

(2015)

J.M. Allman et al.

The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans

Brain Struct. Funct.

(2010)

J.M. Allman et al.

The von Economo neurons in apes and humans

Am. J. Hum. Biol.

(2011)

D. Alnaes et al.

Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus

J Vis

(2014)

F.H. Alves et al.

Both alpha1- and alpha2-adrenoceptors in the insular cortex are involved in the cardiovascular responses to acute restraint stress in rats

PloS One

(2014)

L.R. Arcurio et al.

Neural mechanisms of high-risk decisions-to-drink in alcohol-dependent women

Addiction Biol.

(2015)

A.A. Arguello et al.

Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats

Psychopharmacology (Berl)

(2017)

A.R. Arulpragasam et al.

Corticoinsular circuits encode subjective value expectation and violation for effortful goal-directed behavior

Proc. Natl. Acad. Sci. U. S. A.

(2018)

B.K. Atwood et al.

Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum

Nat. Neurosci.

(2014)

J.A. Avery et al.

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

Hum. Brain Mapp.

(2015)

P. Ayton et al.

The hot hand fallacy and the gambler's fallacy: two faces of subjective randomness?

Mem. Cognit.

(2004)

Y. Bai et al.

Anterior insular cortex mediates hyperalgesia induced by chronic pancreatitis in rats

Mol. Brain

(2019)

B.A. Baldo et al.

GABA-mediated inactivation of medial prefrontal and agranular insular cortex in the rat: contrasting effects on hunger- and palatability-driven feeding

Neuropsychopharmacology

(2016)

M.B. Bales et al.

Extensive Gustatory Cortex Lesions Significantly Impair Taste Sensitivity to KCl and Quinine but Not to Sucrose in Rats

PLoS One

(2015)

B.W. Balleine et al.

The effect of lesions of the insular cortex on instrumental conditioning: evidence for a role in incentive memory

J. Neurosci.

(2000)

M. Barbier et al.

A basal ganglia-like cortical-amygdalar-hypothalamic network mediates feeding behavior

Proc. Natl. Acad. Sci. U. S. A.

(2020)

A. Bartels et al.

The neural basis of romantic love

Neuroreport

(2000)

A. Belin-Rauscent et al.

From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior

Mol. Psychiatr.

(2016)

A.M. Benison et al.

Caudal granular insular cortex is sufficient and necessary for the long-term maintenance of allodynic behavior in the rat attributable to mononeuropathy

J. Neurosci.

(2011)

Cited by (44)

Adolescent nicotine exposure promotes adulthood opioid consumption that persists despite adverse consequences and increases the density of insular perineuronal nets
2024, Addiction Neuroscience
Adolescence marks a sensitive period for neurodevelopment wherein exposure to drugs of abuse may disrupt maturation and induce persistent changes in neurophysiology which may exacerbate the risk for developing substance use disorders in adulthood. Adolescent nicotine exposure (ANE) enhances motivation to obtain drugs of abuse, particularly opioids, and increases vulnerability for the development of opioid use disorder (OUD). Here, we characterized ANE effects on learning about the adverse consequences of opioid consumption in adulthood in the absence of further nicotine administration. First, we show that ANE engenders punishment resistant fentanyl self-administration in a heterogenous seeking–taking chain schedule of reinforcement at least at the tested dose of fentanyl (0.75 µg/kg). We found that ANE rats consumed significantly more fentanyl and contingent foot shock punishment was less efficacious in limiting fentanyl seeking in ANE rats, relative to nicotine-naïve controls. Next, we demonstrated that ANE limits learning about the deleterious consequences of acute opioid intoxication in adulthood. In a combined conditioned taste avoidance and place preference paradigm we found that ANE resulted in significant reductions in the strength of morphine-induced CTA, and a simultaneous enhancement of CPP at a higher dose that was less capable of driving reinforcement in naïve controls. Finally, we examined the expression of perineuronal nets (PNNs) within insular cortex (IC) and found ANE rats to have increased density of PNNs across the anterior IC and significantly more parvalbumin-labeled IC cells relative to naïve controls. Together, these data lay the framework for a mechanistic explanation of the extreme comorbidity between nicotine use and development of OUDs.
The Predictive Potential of Heart Rate Variability for Depression
2024, Neuroscience
Heart rate variability (HRV), a measure of the fluctuations in the intervals between consecutive heartbeats, is an indicator of changes in the autonomic nervous system. A chronic reduction in HRV has been repeatedly linked to clinical depression. However, the chronological and mechanistic aspects of this relationship, between the neural, physiological, and psychopathological levels, remain unclear. In this review we present evidence by which changes in HRV might precede the onset of depression. We describe several pathways that can facilitate this relationship. First, we examine a theoretical model of the impact of autonomic imbalance on HRV and its role in contributing to mood dysregulation and depression. We then highlight brain regions that are regulating both HRV and emotion, suggesting these neural regions, and the Insula in particular, as potential mediators of this relationship. We also present additional possible mediating mechanisms involving the immune system and inflammation processes. Lastly, we support this model by showing evidence that modification of HRV with biofeedback leads to an improvement in some symptoms of depression. The possibility that changes in HRV precede the onset of depression is critical to put to the test, not only because it could provide insights into the mechanisms of the illness but also because it may offer a predictive and diagnostic physiological marker for depression. Importantly, it could also help to develop new effective clinical interventions for treating depression.
Emotional processing impairments in patients with insula lesions following stroke
2024, NeuroImage
Functional imaging has helped to understand the role of the human insula as a major processing network for integrating input with the current state of the body. However, these studies remain at a correlative level. Studies that have examined insula damage show lesion-specific performance deficits. Case reports have provided anecdotal evidence for deficits following insula damage, but group lesion studies offer a number of advances in providing evidence for functional representation of the insula. We conducted a systematic literature search to review group studies of patients with insula damage after stroke and identified 23 studies that tested emotional processing performance in these patients. Eight of these studies assessed emotional processing of visual (most commonly IAPS), auditory (e.g., prosody), somatosensory (emotional touch) and autonomic function (heart rate variability). Fifteen other studies looked at social processing, including emotional face recognition, gaming tasks and tests of empathy. Overall, there was a bias towards testing only patients with right-hemispheric lesions, making it difficult to consider hemisphere specificity. Although many studies included an overlay of lesion maps to characterise their patients, most did not differentiate lesion statistics between insula subunits and/or applied voxel-based associations between lesion location and impairment. This is probably due to small group sizes, which limit statistical comparisons. We conclude that multicentre analyses of lesion studies with comparable patients and performance tests are needed to definitively test the specific function of parts of the insula in emotional processing and social interaction.
The insula: Leveraging cellular and systems-level research to better understand its roles in health and schizophrenia
2024, Neuroscience and Biobehavioral Reviews
Schizophrenia is a highly heterogeneous disorder characterized by a multitude of complex and seemingly non-overlapping symptoms. The insular cortex has gained increasing attention in neuroscience and psychiatry due to its involvement in a diverse range of fundamental human experiences and behaviors. This review article provides an overview of the insula’s cellular and anatomical organization, functional and structural connectivity, and functional significance. Focusing on specific insula subregions and using knowledge gained from humans and preclinical studies of insular tracings in non-human primates, we review the literature and discuss the functional roles of each subregion, including in somatosensation, interoception, salience processing, emotional processing, and social cognition. Building from this foundation, we then extend these findings to discuss reported abnormalities of these functions in individuals with schizophrenia, implicating insular involvement in schizophrenia pathology. This review underscores the insula’s vast role in the human experience and how abnormal insula structure and function could result in the wide-ranging symptoms observed in schizophrenia.
Engagement for alcohol escalates in the 5-choice serial reaction time task after intermittent access
2024, Alcohol
Excessive intake plays a significant role in the development of alcohol use disorder and impacts 15 million Americans annually, with approximately 88 000 dying from alcohol related deaths. Several facets we contribute to alcohol use disorder include impulsivity, motivation, and attention. Previous studies have used the 5-Choice Serial Reaction Time Task (5-Choice) to analyze these types of behaviors using sugar, but recently we have published using 10% alcohol as the reward. This study analyzed 48 mice that were trained to respond for alcohol in the 5-Choice. All mice distributed and analyzed first by alcohol preference and then by consumption. Here, we became interested in a new classification called “engagement”. High-engaged and low-engaged mice were determined by the number of correct responses during final Late-Stage training sessions. Interestingly, during Early-Stage training, the mice began to separate themselves into two groups based on their interaction with the task. Throughout both training stages, high-engaged mice displayed a greater number of trials and correct responses, as well as a lower percentage of omissions compared to low-engaged mice. Following three weeks of intermittent access homecage drinking, low-engaged mice showed greater increase in perseverative responding relative to high-engaged. Additionally, low-engaged mice decreased their reward and correct latencies compared to high-engaged mice suggesting an increase in motivation for alcohol. Overall, engagement analysis presents two clearly different groups, with only one being motivated to work for alcohol. These two distinct phenotypes in the 5-Choice could be used to model alcohol motivated behavior, which could help us further understand alcohol use disorder.
Disorganized Functional Connectivity of Anterior Insular Subnetworks in Adults with Executive Dysfunction after Trauma Exposure
2024, Neuroscience
There is increasing evidence that major trauma can adversely affect the brain and cognition. In some cases, trauma may lead to deficits in executive function (EF). The anterior insula may be a causal outflow hub acting to coordinate EF-related brain networks. To clarify the neural underpinnings of EF deficits (EFD) after trauma, we performed a resting-state functional magnetic resonance imaging (rs-fMRI) study of anterior insular subnetworks in adults who have lost their only child. A total of 167 participants completed various psychological and cognitive assessments to assess EF-related deficits. Correlations were computed between abnormal connectivity and cognitive/post-traumatic stress symptoms. The results showed abnormal anterior insular subregion connectivity in the default mode network (DMN), prefrontal lobe, and cerebellum lobe in participants with EFD. No correlation was found between abnormal connectivity and cognitive/post-traumatic stress symptoms in participants with EFD. These results suggest that excessive connections between the insula and DMN could contribute to EFD after trauma. Overall, this study provides novel references into the neural mechanisms of EF status after trauma exposure.

View all citing articles on Scopus

¹: These authors contributed equally.

View full text

Invited ReviewBetter living through understanding the insula: Why subregions can make all the difference

Highlights

Abstract

Section snippets

Overview

The human insula

Rodents and humans: promise and pitfalls of translation

Conclusion

Acknowledgements

Trends Cognit. Sci.

Brain Res.

Brain Res Brain Res Rev

Biol. Psychiatr.

Neuroimage

Biol. Psychiatr.

Neuroimage

Neuron

Cortex

Biol. Psychiatr.

Curr. Biol.

Behav. Brain Res.

Biol. Psychiatr.

Neuroimage

Neuroimage

Neuroscience

Neuroimage

Neuron

Trends Cognit. Sci.

Neuron

Brain Res. Cogn. Brain Res.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Neuroimage

Biol Psychiatry Cogn Neurosci Neuroimaging

Cortico-amygdala interaction determines the insular cortical neurons involved in taste memory retrieval

Mol. Brain

Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy

J. Psychiatry Neurosci.

Increased functional connectivity in an insula-based network is associated with improved smoking cessation outcomes

Neuropsychopharmacology

Nicotine increases anterior insula activation to expected and unexpected outcomes among nonsmokers

Psychopharmacology (Berl)

Distributed circuits underlying anxiety

Front. Behav. Neurosci.

Input-output connections of LJA5 prodynorphin neurons

J. Comp. Neurol.

Consistent anterior-posterior segregation of the insula during the first 2 years of life

Cerebr. Cortex

The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans

Brain Struct. Funct.

The von Economo neurons in apes and humans

Am. J. Hum. Biol.

Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus

J Vis

Both alpha1- and alpha2-adrenoceptors in the insular cortex are involved in the cardiovascular responses to acute restraint stress in rats

PloS One

Neural mechanisms of high-risk decisions-to-drink in alcohol-dependent women

Addiction Biol.

Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats

Psychopharmacology (Berl)

Corticoinsular circuits encode subjective value expectation and violation for effortful goal-directed behavior

Proc. Natl. Acad. Sci. U. S. A.

Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum

Nat. Neurosci.

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

Hum. Brain Mapp.

The hot hand fallacy and the gambler's fallacy: two faces of subjective randomness?

Mem. Cognit.

Anterior insular cortex mediates hyperalgesia induced by chronic pancreatitis in rats

Mol. Brain

GABA-mediated inactivation of medial prefrontal and agranular insular cortex in the rat: contrasting effects on hunger- and palatability-driven feeding

Neuropsychopharmacology

Extensive Gustatory Cortex Lesions Significantly Impair Taste Sensitivity to KCl and Quinine but Not to Sucrose in Rats

PLoS One

The effect of lesions of the insular cortex on instrumental conditioning: evidence for a role in incentive memory

J. Neurosci.

A basal ganglia-like cortical-amygdalar-hypothalamic network mediates feeding behavior

Proc. Natl. Acad. Sci. U. S. A.

The neural basis of romantic love

Neuroreport

Invited Review
Better living through understanding the insula: Why subregions can make all the difference