Insula→Amygdala and Insula→Thalamus Pathways Are Involved in Comorbid Chronic Pain and Depression-Like Behavior in Mice.

The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated by mechanical, thermal, aversive, and stressful and appetitive stimulation in naive and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naive mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naive and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus (VM) of the thalamus mimicked PIC neurons in pain modulation in naive mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA, and VM neurons and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC→BLA and PIC→VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression.

fMRI, LFP, and anatomical evidence for hierarchical nociceptive routing pathway between somatosensory and insular cortices.

The directional organization of multiple nociceptive regions, particularly within obscure operculoinsular areas, underlying multidimensional pain processing remains elusive. This study aims to establish the fundamental organization between somatosensory and insular cortices in routing nociceptive information. By employing an integrated multimodal approach of high-field fMRI, intracranial electrophysiology, and transsynaptic viral tracing in rats, we observed a hierarchically organized connection of S1/S2 → posterior insula → anterior insula in routing nociceptive information. The directional nociceptive pathway determined by early fMRI responses was consistent with that examined by early evoked LFP, intrinsic effective connectivity, and anatomical projection, suggesting fMRI could provide a valuable facility to discern directional neural circuits in animals and humans non-invasively. Moreover, our knowledge of the nociceptive hierarchical organization of somatosensory and insular cortices and the interface role of the posterior insula may have implications for the development of targeted pain therapies.

Insular cortex stimulation alleviates neuropathic pain through changes in the expression of collapsin response mediator protein 2 involved in synaptic plasticity.

In recent studies, brain stimulation has shown promising potential to alleviate chronic pain. Although studies have shown that stimulation of pain-related brain regions can induce pain-relieving effects, few studies have elucidated the mechanisms of brain stimulation in the insular cortex (IC). The present study was conducted to explore the changes in characteristic molecules involved in pain modulation mechanisms and to identify the changes in synaptic plasticity after IC stimulation (ICS). Following ICS, pain-relieving behaviors and changes in proteomics were explored. Neuronal activity in the IC after ICS was observed by optical imaging. Western blotting was used to validate the proteomics data and identify the changes in the expression of glutamatergic receptors associated with synaptic plasticity. Experimental results showed that ICS effectively relieved mechanical allodynia, and proteomics identified specific changes in collapsin response mediator protein 2 (CRMP2). Neuronal activity in the neuropathic rats was significantly decreased after ICS. Neuropathic rats showed increased expression levels of phosphorylated CRMP2, alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR), and N-methyl-d-aspartate receptor (NMDAR) subunit 2B (NR2B), which were inhibited by ICS. These results indicate that ICS regulates the synaptic plasticity of ICS through pCRMP2, together with AMPAR and NR2B, to induce pain relief.

Response stopping under conflict: The integrative role of representational dynamics associated with the insular cortex.

Coping with distracting inputs during goal-directed behavior is a common challenge, especially when stopping ongoing responses. The neural basis for this remains debated. Our study explores this using a conflict-modulation Stop Signal task, integrating group independent component analysis (group-ICA), multivariate pattern analysis (MVPA), and EEG source localization analysis. Consistent with previous findings, we show that stopping performance is better in congruent (nonconflicting) trials than in incongruent (conflicting) trials. Conflict effects in incongruent trials compromise stopping more due to the need for the reconfiguration of stimulus-response (S-R) mappings. These cognitive dynamics are reflected by four independent neural activity patterns (ICA), each coding representational content (MVPA). It is shown that each component was equally important in predicting behavioral outcomes. The data support an emerging idea that perception-action integration in action-stopping involves multiple independent neural activity patterns. One pattern relates to the precuneus (BA 7) and is involved in attention and early S-R processes. Of note, three other independent neural activity patterns were associated with the insular cortex (BA13) in distinct time windows. These patterns reflect a role in early attentional selection but also show the reiterated processing of representational content relevant for stopping in different S-R mapping contexts. Moreover, the insular cortex's role in automatic versus complex response selection in relation to stopping processes is shown. Overall, the insular cortex is depicted as a brain hub, crucial for response selection and cancellation across both straightforward (automatic) and complex (conditional) S-R mappings, providing a neural basis for general cognitive accounts on action control.

The insular cortex is not insular in thyroid eye disease: neuroimaging revelations of central-peripheral system interaction.

BACKGROUND: Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. METHODS: This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. RESULTS: When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. CONCLUSIONS: This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central-peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central-peripheral system interaction mechanisms involved in autoimmune diseases.

Insights into interoceptive and emotional processing: Lessons from studies on insular HD-tDCS.

Interoception, the processing of internal bodily signals, is proposed as the fundamental mechanism underlying emotional experiences. Interoceptive and emotional processing appear distorted in psychiatric disorders. However, our understanding of the neural structures involved in both processes remains limited. To explore the feasibility of enhancing interoception and emotion, we conducted two studies using high-definition transcranial direct current stimulation (HD-tDCS) applied to the right anterior insula. In study one, we compared the effects of anodal HD-tDCS and sham tDCS on interoceptive abilities (sensibility, confidence, accuracy, emotional evaluation) in 52 healthy subjects. Study two additionally included physical activation through ergometer cycling at the beginning of HD-tDCS and examined changes in interoceptive and emotional processing in 39 healthy adults. In both studies, HD-tDCS was applied in a single-blind cross-over online design with two separate sessions. Study one yielded no significant effects of HD-tDCS on interoceptive dimensions. In study two, significant improvements in interoceptive sensibility and confidence were observed over time with physical preactivation, while no differential effects were found between sham and insula stimulation. The expected enhancement of interoceptive and emotional processing following insula stimulation was not observed. We conclude that HD-tDCS targeting the insula does not consistently increase interoceptive or emotional variables. The observed increase in interoceptive sensibility may be attributed to the activation of the interoceptive network through physical activity or training effects. Future research on HD-tDCS involving interoceptive network structures could benefit from protocols targeting larger regions within the network, rather than focusing solely on insula stimulation.

Impairment of the GABAergic system in the anterior insular cortex of heroin-addicted males.

Opioid addiction is a global problem, causing the greatest health burden among drug use disorders, with opioid overdose deaths topping the statistics of fatal overdoses. The multifunctional anterior insular cortex (AIC) is involved in inhibitory control, which is severely impaired in opioid addiction. GABAergic interneurons shape the output of the AIC, where abnormalities have been reported in individuals addicted to opioids. In these neurons, glutamate decarboxylase (GAD) with its isoforms GAD 65 and 67 is a key enzyme in the synthesis of GABA, and research data point to a dysregulation of GABAergic activity in the AIC in opioid addiction. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of the AIC in opioid addiction by densitometric evaluation of GAD 65/67-immunostained neuropil. The study showed bilaterally increased neuropil density in layers III and V in 13 male heroin-addicted males compared to 12 healthy controls, with significant U-test P values for layer V bilaterally. Analysis of confounding variables showed that age, brain volume and duration of formalin fixation did not confound the results. Our findings suggest a dysregulation of GABAergic activity in the AIC in opioid addiction, which is consistent with experimental data from animal models and human neuroimaging studies.

Increased ventral anterior insular connectivity to sports betting availability indexes problem gambling.

With the advent of digital technologies, online sports betting is spurring a fast-growing expansion. In this study, we examined how sports betting availability modulates the brain connectivity of frequent sports bettors with [problem bettors (PB)] or without [non-problem bettors (NPB)] problematic sports betting. We conducted functional connectivity analyses centred on the ventral anterior insular cortex (vAI), a brain region playing a key role in the dynamic interplay between reward-based processes. We re-analysed a dataset on sports betting availability undertaken in PB (n = 30) and NPB (n = 35). Across all participants, we observed that sports betting availability elicited positive vAI coupling with extended clusters of brain activation (encompassing the putamen, cerebellum, occipital, temporal, precentral and central operculum regions) and negative vAI coupling with the orbitofrontal cortex. Between-group analyses showed increased positive vAI coupling in the PB group, as compared with the NPB group, in the left lateral occipital cortex, extending to the left inferior frontal gyrus, the anterior cingulate gyrus and the right frontal pole. Taken together, these results are in line with the central assumptions of triadic models of addictions, which posit that the insular cortex plays a pivotal role in promoting the drive and motivation to get a reward by 'hijacking' goal-oriented processes toward addiction-related cues. Taken together, these findings showed that vAI functional connectivity is sensitive not only to gambling availability but also to the status of problematic sport betting.

Deciphering the functional role of insular cortex stratification in trigeminal neuropathic pain.

Trigeminal neuropathic pain (TNP) is a major concern in both dentistry and medicine. The progression from normal to chronic TNP through activation of the insular cortex (IC) is thought to involve several neuroplastic changes in multiple brain regions, resulting in distorted pain perception and associated comorbidities. While the functional changes in the insula are recognized contributors to TNP, the intricate mechanisms underlying the involvement of the insula in TNP processing remain subjects of ongoing investigation. Here, we have overviewed the most recent advancements regarding the functional role of IC in regulating TNP alongside insights into the IC's connectivity with other brain regions implicated in trigeminal pain pathways. In addition, the review examines diverse modulation strategies that target the different parts of the IC, thereby suggesting novel diagnostic and therapeutic management of chronic TNP in the future.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Sexual differences in neuronal and synaptic properties across subregions of the mouse insular cortex.

BACKGROUND: The insular cortex (IC) plays a pivotal role in processing interoceptive and emotional information, offering insights into sex differences in behavior and cognition. The IC comprises two distinct subregions: the anterior insular cortex (aIC), that processes emotional and social signals, and the posterior insular cortex (pIC), specialized in interoception and perception of pain. Pyramidal projection neurons within the IC integrate multimodal sensory inputs, influencing behavior and cognition. Despite previous research focusing on neuronal connectivity and transcriptomics, there has been a gap in understanding pyramidal neurons characteristics across subregions and between sexes. METHODS: Adult male and female C57Bl/6J mice were sacrificed and tissue containing the IC was collected for ex vivo slice electrophysiology recordings that examined baseline sex differences in synaptic plasticity and transmission within aIC and pIC subregions. RESULTS: Clear differences emerged between aIC and pIC neurons in both males and females: aIC neurons exhibited distinctive features such as larger size, increased hyperpolarization, and a higher rheobase compared to their pIC counterparts. Furthermore, we observed variations in neuronal excitability linked to sex, with male pIC neurons displaying a greater level of excitability than their female counterparts. We also identified region-specific differences in excitatory and inhibitory synaptic activity and the balance between excitation and inhibition in both male and female mice. Adult females demonstrated greater synaptic strength and maximum response in the aIC compared to the pIC. Lastly, synaptic long-term potentiation occurred in both subregions in males but was specific to the aIC in females. CONCLUSIONS: We conclude that there are sex differences in synaptic plasticity and excitatory transmission in IC subregions, and that distinct properties of IC pyramidal neurons between sexes could contribute to differences in behavior and cognition between males and females.

This study investigates differences in the insular cortex (IC), a region of the brain responsible for emotions and sensory perceptions, between male and female mice. The IC has two parts: the front (aIC) deals with emotions and social cues, while the back (pIC) is focused on sensing pain and bodily sensations. We examined specific brain cells called pyramidal neurons in both aIC and pIC and discovered noteworthy distinctions between these neurons in adult male and female mice. Firstly, aIC neurons were larger and had unique electrical properties in both male and female mice. Males had more excitable pIC neurons compared to females, indicating that their neurons were more likely to transmit signals. We also explored how these neurons communicate with each other through connections known as synapses. In adult females, the aIC had stronger connections than the pIC. Finally, we observed that specific types of basic synaptic learning occurred exclusively in males in the aIC. These findings underscore significant disparities in the IC between males and females, offering valuable insights into the potential reasons behind variations in behaviors and emotions between sexes.

Magnetoencephalographic detection of synchronized epileptic activity between the hippocampus and insular cortex.

Most magnetoencephalographic signals are derived from synchronized activity in the brain surface cortex. By contrast, the contribution of synchronized activity in the deep brain to magnetoencephalography (MEG) has remained unclear. We compared stereotactic electroencephalography (sEEG) with simultaneous MEG findings in a patient with temporal lobe epilepsy to determine the conditions under which MEG could also detect sEEG findings. The synchrony and similarity of the waves were evaluated using visual inspection and wavelet coherence. A 45-year-old woman with intractable temporal lobe epilepsy underwent sEEG and MEG simultaneously to determine the laterality and precise location of the epileptic focus. When spike-and-waves were seen in the right hippocampal head alone, no distinct spike-and-waves were observed visually in the right temporal MEG. The seizure then spread to the right insula on sEEG with a rhythmic theta frequency while synchronous activity was observed in the right temporal MEG channels. When polyspikes appeared in the right hippocampus, the right temporal MEG showed electrical activity with relatively high similarity to that of the right hippocampal head and insular cortex but less similarity to that of the right lateral temporal lobe cortex. MEG might detect epileptic activity synchronized between the hippocampus and insular cortex.

Functional roles of descending projections from the cerebral cortex to the trigeminal spinal subnucleus caudalis in orofacial nociceptive information processing.

BACKGROUND: The trigeminal spinal subnucleus caudalis (Sp5C), also known as the medullary dorsal horn, receives orofacial somatosensory inputs, particularly nociceptive inputs, from the trigeminal nerve. In the Sp5C, excitatory and inhibitory neurons, glutamatergic and GABAergic/glycinergic neurons, respectively, form the local circuits. The axons of the glutamatergic neurons in lamina I ascend toward the thalamic and parabrachial nuclei, and this projection is the main pathway of orofacial nociception. Additionally, the axons of the higher brain regions, including the locus coeruleus, dorsal raphe, and cerebral cortex, are sent to the Sp5C. HIGHLIGHT: Among these descending projections, this review focuses on the functional profiles of the corticotrigeminal projections to the Sp5C, along with their anatomical aspects. The primary and secondary somatosensory and insular cortices are of particular interest. CONCLUSION: Corticotrigeminal projections from the somatosensory cortex to the Sp5C play a suppressive role in nociceptive information processing, whereas recent studies have demonstrated a facilitative role of the insular cortex in nociceptive information processing at the Sp5C level.

The Insular Cortex: An Interface Between Sensation, Emotion and Cognition.

The insula is a complex brain region central to the orchestration of taste perception, interoception, emotion, and decision-making. Recent research has shed light on the intricate connections between the insula and other brain regions, revealing the crucial role of this area in integrating sensory, emotional, and cognitive information. The unique anatomical position and extensive connectivity allow the insula to serve as a critical hub in the functional network of the brain. We summarize its role in interoceptive and exteroceptive sensory processing, illustrating insular function as a bridge connecting internal and external experiences. Drawing on recent research, we delineate the insular involvement in emotional processes, highlighting its implications in psychiatric conditions, such as anxiety, depression, and addiction. We further discuss the insular contributions to cognition, focusing on its significant roles in time perception and decision-making. Collectively, the evidence underscores the insular function as a dynamic interface that synthesizes diverse inputs into coherent subjective experiences and decision-making processes. Through this review, we hope to highlight the importance of the insula as an interface between sensation, emotion, and cognition, and to inspire further research into this fascinating brain region.

Neurotrophin-3 into the insular cortex strengthens conditioned taste aversion memory.

Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2 M lithium chloride i.p.) or a weak-CTA (0.1 M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region.

Investigations on the Ability of the Insular Cortex to Process Peripheral Immunosuppression.

The brain and immune system communicate through complex bidirectional pathways, but the specificity by which the brain perceives or even remembers alterations in immune homeostasis is still poorly understood. Recent data revealed that immune-related information under peripheral inflammatory conditions, termed as "immunengram", were represented in specific neuronal ensembles in the insular cortex (IC). Chemogenetic reactivation of these neuronal ensembles was sufficient to retrieve the inflammatory stages, indicating that the brain can store and retrieve specific immune responses. Against this background, the current approach was designed to investigate the ability of the IC to process states of immunosuppression pharmacologically induced by the mechanistic target of rapamycin (mTOR) inhibitor rapamycin. We here show that the IC perceives the initial state of immunosuppression, reflected by increased deep-brain electroencephalography (EEG) activity during acute immunosuppressive drug treatment. Following an experienced period of immunosuppression, though, diminished splenic cytokine production as formerly induced by rapamycin could not be reinstated by nonspecific chemogenetic activation or inhibition of the IC. These findings suggest that the information of a past, or experienced status of pharmacologically induced immunosuppression is not represented in the IC. Together, the present work extends the view of immune-to-brain communication during the states of peripheral immunosuppression and foster the prominent role of the IC for interoception.

The Posterior Insular Cortex is Necessary for Feeding-Induced Jejunal Myoelectrical Activity in Male Rats.

The gastrointestinal tract exhibits coordinated muscle motility in response to food digestion, which is regulated by the central nervous system through autonomic control. The insular cortex is one of the brain regions that may regulate the muscle motility. In this study, we examined whether, and how, the insular cortex, especially the posterior part, regulates gastrointestinal motility by recording jejunal myoelectrical signals in response to feeding in freely moving male rats. Feeding was found to induce increases in jejunal myoelectrical signal amplitudes. This increase in the jejunal myoelectrical signals was abolished by vagotomy and pharmacological inhibition of the posterior insular cortex. Additionally, feeding induced a decrease and increase in sympathetic and parasympathetic nervous activities, respectively, both of which were eliminated by posterior insular cortical inhibition. These results suggest that the posterior insular cortex regulates jejunal motility in response to feeding by modulating autonomic tone.

Evaluation of brain activation related to resting pain using functional magnetic resonance imaging in cynomolgus macaques undergoing knee surgery.

Purpose: Functional magnetic resonance imaging (fMRI) visualizes hemodynamic responses associated with brain and spinal cord activation. Various types of pain have been objectively assessed using fMRI as considerable brain activations. This study aimed to develop a pain model in cynomolgus macaques undergoing knee surgery and confirm brain activation due to resting pain after knee surgery. Methods: An osteochondral graft surgery on the femoral condyle in the unilateral knee was performed on four cynomolgus macaques (Macaca fascicularis). Resting pain was evaluated as changes in brain fMRI findings with a 3.0-T MRI scanner preoperatively, postoperatively, and after postoperative administration of morphine. In the fMRI analysis, Z-values >1.96 were considered statistically significant. Results: Brain activation without stimulation after surgery in the cingulate cortex (3.09) and insular cortex (3.06) on the opposite side of the surgery was significantly greater than that before surgery (1.05 and 1.03, respectively) according to fMRI. After the administration of morphine, activation due to resting pain decreased in the cingulate cortex (1.38) and insular cortex (1.21). Conclusion: Osteochondral graft surgery on the femoral condyle can lead to postoperative resting pain. fMRI can reveal activation in pain-related brain areas and evaluate resting pain due to knee surgery.

Blunted perception of breathlessness in three cases of low grade insular-glioma.

Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5 mmHg above baseline (38.5 ± 5.7 mmHg), whilst ventilation was constrained (10.7 ± 2.3 L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8 ± 2 vs. 11 ± 4 %VAS/mmHg; p = 0.004), but similar threshold (40.5 ± 3.9 vs. 43.2 ± 5.1 mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.