Heterogeneous growth of the insula shapes the human brain.

The human cerebrum consists of a precise and stereotyped arrangement of lobes, primary gyri, and connectivity that underlies human cognition [P. Rakic, Nat. Rev. Neurosci. 10, 724-735 (2009)]. The development of this arrangement is less clear. Current models explain individual primary gyrification but largely do not account for the global configuration of the cerebral lobes [T. Tallinen, J. Y. Chung, J. S. Biggins, L. Mahadevan, Proc. Natl. Acad. Sci. U.S.A. 111, 12667-12672 (2014) and D. C. Van Essen, Nature 385, 313-318 (1997)]. The insula, buried in the depths of the Sylvian fissure, is unique in terms of gyral anatomy and size. Here, we quantitatively show that the insula has unique morphology and location in the cerebrum and that these key differences emerge during fetal development. Finally, we identify quantitative differences in developmental migration patterns to the insula that may underlie these differences. We calculated morphologic data in the insula and other lobes in adults (N = 107) and in an in utero fetal brain atlas (N = 81 healthy fetuses). In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Spherical projection analysis demonstrates that the lenticular nuclei obstruct 60 to 70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify radial glial fascicles that originate from the VZ and curve around the lenticular nuclei to form the insula. These results confirm existing models of radial migration to the cortex and illustrate findings that suggest differential insular and cerebral development, laying the groundwork to understand cerebral malformations and insular function and pathologies.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-ß-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

Individual differences of white matter characteristic along the anterior insula-based fiber tract circuit for pain empathy in healthy women and women with primary dysmenorrhea.

Pain empathy, defined as the ability of one person to understand another person's pain, shows large individual variations. The anterior insula is the core region of the pain empathy network. However, the relationship between white matter (WM) properties of the fiber tracts connecting the anterior insula with other cortical regions and an individual's ability to modulate pain empathy remains largely unclear. In this study, we outline an automatic seed-based fiber streamline (sFS) analysis method and multivariate pattern analysis (MVPA) to predict the levels of pain empathy in healthy women and women with primary dysmenorrhoea (PDM). Using the sFS method, the anterior insula-based fiber tract network was divided into five fiber cluster groups. In healthy women, interindividual differences in pain empathy were predicted only by the WM properties of the five fiber cluster groups, suggesting that interindividual differences in pain empathy may rely on the connectivity of the anterior insula-based fiber tract network. In women with PDM, pain empathy could be predicted by a single cluster group. The mean WM properties along the anterior insular-rostroventral area of the inferior parietal lobule further mediated the effect of pain on empathy in patients with PDM. Our results suggest that chronic periodic pain may lead to maladaptive plastic changes, which could further impair empathy by making women with PDM feel more pain when they see other people experiencing pain. Our study also addresses an important gap in the analysis of the microstructural characteristics of seed-based fiber tract network.

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.

Altered whole brain functional activity in patients with fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a chronic pain disorder that takes a severe physical and psychological toll on patients and severely reduces their quality of life. In recent years, an increasing number of studies have used functional magnetic resonance imaging (fMRI) to investigate its pathogenesis. However, a recent summary analysis of functional connectivity in patients with FM is lacking. METHODS: We searched bibliographic databases, including PubMed, Web of Science (from inception until September 1st, 2022). Two separate researchers assessed the bias and quality of the studies. In order to further explain the core mechanism for FM, the abnormal brain function of FM was investigated by Activation Likelihood Estimation (ALE) analysis. RESULTS: Twenty-six FM publications (1,056 subjects) were eligible to be included in an ALE analysis. We found that the anterior cingulate (ACC) and insula (Ins) were abnormally active in patients with FM. In particular, the peak coordinates of (8,46,4) and (-46, -4,10) correspond to brain regions that were less active than healthy individuals. Furthermore, the Z-values were 4.46 and 4.97, while the p-values were 4.06 and 3.38. Surprisingly, we found that the degree of pain was negatively correlated with the activation of Ins (SDM-Z = -2.714). CONCLUSIONS: This study demonstrates abnormal brain activation which could lead to increased sensitivity of pain in patients with FM. The study sheds light on the central mechanisms of FM and provides the basis for further research.

Loss, gain and choice difficulty in gambling patients: Neural and behavioural processes.

Impaired decision-making is often displayed by individuals suffering from gambling disorder (GD). Since there are a variety of different phenomena influencing decision-making, we focused in this study on the effects of GD on neural and behavioural processes related to loss aversion and choice difficulty. Behavioural responses as well as brain images of 23 patients with GD and 20 controls were recorded while they completed a mixed gambles task, where they had to decide to either accept or reject gambles with different amounts of potential gain and loss. We found no behavioural loss aversion in either group and no group differences regarding loss and gain-related choice behaviour, but there was a weaker relation between choice difficulty and decision time in patients with GD. Similarly, we observed no group differences in processing of losses or gains, but choice difficulty was weaker associated with brain activity in the right anterior insula and anterior cingulate cortex in patients with GD. Our results showed for the first time the effects of GD on neural processes related to choice difficulty. In addition, our findings on choice difficulty give new insights on the psychopathology of GD and on neural processes related to impaired decision-making in GD.

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.

Connectivity of the insular subdivisions differentiates posttraumatic headache-associated from nonheadache-associated mild traumatic brain injury: an arterial spin labelling study.

OBJECTIVE: The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed of functionally different subdivisions and each of which plays different role in PTH neuropathology. METHODS: Ninety-four mTBI patients were included in this study. Based on perfusion imaging data obtained from arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI), this study evaluated the insular subregion perfusion-based functional connectivity (FC) and its correlation with clinical characteristic parameters in patients with PTH after mTBI and non-headache mTBI patients. RESULTS: The insular subregions of mTBI + PTH (mTBI patients with PTH) and mTBI-PTH (mTBI patients without PTH) group had positive perfusion-based functional connections with other insular nuclei and adjacent discrete cortical regions. Compared with mTBI-PTH group, significantly increased resting-state perfusion-based FC between the anterior insula (AI) and middle cingulate cortex (MCC)/Rolandic operculum (ROL), between posterior insula (PI) and supplementary motor area (SMA), and decreased perfusion-based FC between PI and thalamus were found in mTBI + PTH group. Changes in the perfusion-based FC of the left posterior insula/dorsal anterior insula with the thalamus/MCC were significant correlated with headache characteristics. CONCLUSIONS: Our findings provide new ASL-based evidence for changes in the perfusion-based FC of the insular subregion in PTH patients attributed to mTBI and the association with headache features, revealing the possibility of potential neuroplasticity after PTH. These findings may contribute to early diagnosis of the disease and follow-up of disease progression.

Serotonergic modulation of effective connectivity in an associative relearning network during task and rest.

An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain-Meta-analytic evidence from neuroimaging studies.

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta-analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

Microbiota links to neural dynamics supporting threat processing.

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive-interoceptive appraisal of threat-related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling and computational modelling in healthy participants. Results showed interactions between high-level ecological indices with threat-related AIC-dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota-derived metabolites in the observed relationship with threat-related brain processes.

Actual and Imagined Movements Reveal a Dual Role of the Insular Cortex for Motor Control.

Movements rely on a mixture of feedforward and feedback mechanisms. With experience, the brain builds internal representations of actions in different contexts. Many factors are taken into account in this process among which is the immutable presence of gravity. Any displacement of a massive body in the gravitational field generates forces and torques that must be predicted and compensated by appropriate motor commands. The insular cortex is a key brain area for graviception. However, no attempt has been made to address whether the same internal representation of gravity is shared between feedforward and feedback mechanisms. Here, participants either mentally simulated (only feedforward) or performed (feedforward and feedback) vertical movements of the hand. We found that the posterior part of the insular cortex was engaged when feedback was processed. The anterior insula, however, was activated only in mental simulation of the action. A psychophysical experiment demonstrates participants' ability to integrate the effects of gravity. Our results point toward a dual internal representation of gravity within the insula. We discuss the conceptual link between these two dualities.

Structural Plastic Changes of Cortical Gray Matter Revealed by Voxel-Based Morphometry and Histological Analyses in a Monkey Model of Central Post-Stroke Pain.

Central post-stroke pain (CPSP) is a chronic pain caused by stroke lesions of somatosensory pathways. Several brain imaging studies among patients with CPSP demonstrate that the pathophysiological mechanism underlying this condition is the maladaptive plasticity of pain-related brain regions. However, the temporal profile of the regional plastic changes, as suggested by brain imaging of CPSP patients, as well as their cellular basis, is unknown. To investigate these issues, we performed voxel-based morphometry (VBM) using T1-weighted magnetic resonance imaging and immunohistochemical analysis with our established CPSP monkey model. From 8 weeks after a hemorrhagic lesion to the unilateral ventral posterolateral nucleus of the thalamus, the monkeys exhibited significant behavioral changes that were interpreted as reflecting allodynia. The present VBM results revealed a decrease in gray matter volume in the pain-related areas after several weeks following the lesion. Furthermore, immunohistochemical staining in the ipsilesional posterior insular cortex (ipsi-PIC) and secondary somatosensory cortex (ipsi-SII), where the significant reduction in gray matter volume was observed in the VBM result, displayed a significant reduction in both excitatory and inhibitory synaptic terminals compared to intact monkeys. Our results suggest that progressive changes in neuronal morphology, including synaptic loss in the ipsi-PIC/SII, are involved in theCPSP.

Insular Cortex Mediates Attentional Capture by Behaviorally Relevant Stimuli after Damage to the Right Temporoparietal Junction.

The right temporoparietal junction (rTPJ) and insula both play a key role for the processing of relevant stimuli. However, while both have been conceived as neural "switches" that detect salient events and redirect the focus of attention, it remains unclear how these brain regions interact to achieve this behavioral goal. Here, we tested human participants with focal left-hemispheric or right-hemispheric lesions in a spatial cuing task that requires participants to react to lateralized stimuli preceded by a distracter that shares or does not share a relevant feature with the target. Using machine learning to identify significant lesion-behavior relationships, we found that rTPJ damage produces distinctive, pathologically increased attentional capture, but only by relevant distracters. Functional connectivity analyses revealed that the degree of capture is positively associated with a functional connection between insula and rTPJ, together with functional isolation of the rTPJ from right dorsal prefrontal cortex (dPFC). These findings suggest a mechanistic model where the insula-rTPJ connection constitutes a crucial functional unit that breaks attentional focus upon detection of behaviorally relevant events, while the dPFC appears to attune this activity.

Decoding Music-Evoked Emotions in the Auditory and Motor Cortex.

Music can induce strong subjective experience of emotions, but it is debated whether these responses engage the same neural circuits as emotions elicited by biologically significant events. We examined the functional neural basis of music-induced emotions in a large sample (n = 102) of subjects who listened to emotionally engaging (happy, sad, fearful, and tender) pieces of instrumental music while their hemodynamic brain activity was measured with functional magnetic resonance imaging (fMRI). Ratings of the four categorical emotions and liking were used to predict hemodynamic responses in general linear model (GLM) analysis of the fMRI data. Multivariate pattern analysis (MVPA) was used to reveal discrete neural signatures of the four categories of music-induced emotions. To map neural circuits governing non-musical emotions, the subjects were scanned while viewing short emotionally evocative film clips. The GLM revealed that most emotions were associated with activity in the auditory, somatosensory, and motor cortices, cingulate gyrus, insula, and precuneus. Fear and liking also engaged the amygdala. In contrast, the film clips strongly activated limbic and cortical regions implicated in emotional processing. MVPA revealed that activity in the auditory cortex and primary motor cortices reliably discriminated the emotion categories. Our results indicate that different music-induced basic emotions have distinct representations in regions supporting auditory processing, motor control, and interoception but do not strongly rely on limbic and medial prefrontal regions critical for emotions with survival value.

Network properties and regional brain morphology of the insular cortex correlate with individual pain thresholds.

Pain thresholds vary considerably across individuals and are influenced by a number of behavioral, genetic and neurobiological factors. However, the neurobiological underpinnings that account for individual differences remain to be fully elucidated. In this study, we used voxel-based morphometry (VBM) and graph theory, specifically the local clustering coefficient (CC) based on resting-state connectivity, to identify brain regions, where regional gray matter volume and network properties predicted individual pain thresholds. As a main finding, we identified a cluster in the left posterior insular cortex (IC) reaching into the left parietal operculum, including the secondary somatosensory cortex, where both regional gray matter volume and the local CC correlated with individual pain thresholds. We also performed a resting-state functional connectivity analysis using the left posterior IC as seed region, demonstrating that connectivity to the pre- as well as postcentral gyrus bilaterally; that is, to the motor and primary sensory cortices were correlated with individual pain thresholds. To our knowledge, this is the first study that applied VBM in combination with voxel-based graph theory in the context of pain thresholds. The co-location of the VBM and the local CC cluster provide first evidence that both structure and function map to the same brain region while being correlated with the same behavioral measure; that is, pain thresholds. The study highlights the importance of the posterior IC, not only for pain perception in general, but also for the determination of individual pain thresholds.

Aberrant functional brain network dynamics in patients with functional constipation.

The aberrant static functional connectivity of brain network has been widely investigated in patients with functional constipation (FCon). However, the dynamics of brain functional connectivity in FCon patients remained unknown. This study aimed to detect the brain dynamics of functional connectivity states and network topological organizations of FCon patients and investigate the correlations of the aberrant brain dynamics with symptom severity. Eighty-three FCon patients and 80 healthy subjects (HS) were included in data analysis. The spatial group independent component analysis, sliding-window approach, k-means clustering, and graph-theoretic analysis were applied to investigate the dynamic temporal properties and coupling patterns of functional connectivity states, as well as the time-variation of network topological organizations in FCon patients. Four reoccurring functional connectivity states were identified in k-means clustering analysis. Compared to HS, FCon patients manifested the lower occurrence rate and mean dwell time in the state with a complex connection between default mode network and cognitive control network, as well as the aberrant anterior insula-cortical coupling patterns in this state, which were significantly correlated with the symptom severity. The graph-theoretic analysis demonstrated that FCon patients had higher sample entropy at the nodal efficiency of anterior insula than HS. The current findings provided dynamic perspectives for understanding the brain connectome of FCon and laid the foundation for the potential treatment of FCon based on brain connectomics.

Questioning the role of amygdala and insula in an attentional capture by emotional stimuli task.

Our senses are constantly monitoring the environment for emotionally salient stimuli that are potentially relevant for survival. Because of our limited cognitive resources, emotionally salient distractors prolong reaction times (RTs) as compared to neutral distractors. In addition, many studies have reported fMRI blood oxygen level-dependent (BOLD) activation of both the amygdala and the anterior insula for similar valence contrasts. However, a direct correlation of trail-by-trial BOLD activity with RTs has not been shown, yet, which would be a crucial piece of evidence to relate the two observations. To investigate the role of the above two regions in the context of emotional distractor effects, we study here the correlation between BOLD activity and RTs for a simple attentional capture by emotional stimuli (ACES) choice reaction time task using a general linear subject-level model with a parametric RT regressor. We found significant regression coefficients in the anterior insula, supplementary motor cortex, medial precentral regions, sensory-motor areas and others, but not in the amygdala, despite activation of both insula and amygdala in the traditional valence contrast across trials (i.e., negative vs. neutral pictures). In addition, we found that subjects that exhibit a stronger RT distractor effect across trials also show a stronger BOLD valence contrast in the right anterior insula but not in the amygdala. Our results indicate that the current neuroimaging-based evidence for the involvement of the amygdala in RT slowing is limited. We advocate that models of emotional capture should incorporate both the amygdala and the anterior insula as separate entities.

Dynamic functional connectivity profile of the salience network across the life span.

The insular cortex and anterior cingulate cortex together comprise the salience or midcingulo-insular network, involved in detecting salient events and initiating control signals to mediate brain network dynamics. The extent to which functional coupling between the salience network and the rest of the brain undergoes changes due to development and aging is at present largely unexplored. Here, we examine dynamic functional connectivity (dFC) of the salience network in a large life span sample (n = 601; 6-85 years old). A sliding-window analysis and k-means clustering revealed five states of dFC formed with the salience network, characterized by either widespread asynchrony or different patterns of synchrony between the salience network and other brain regions. We determined the frequency, dwell time, total transitions, and specific state-to-state transitions for each state and subject, regressing the metrics with subjects' age to identify life span trends. A dynamic state characterized by low connectivity between the salience network and the rest of the brain had a strong positive quadratic relationship between age and both frequency and dwell time. Additional frequency, dwell time, total transitions, and state-to-state transition trends were observed with other salience network states. Our results highlight the metastable dynamics of the salience network and its role in the maturation of brain regions critical for cognition.