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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., Competing Interests: Declarations. Conflict of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical approval: The study has been approved by the local ethics committee of the University of Magdeburg as performed in accordance with the ethical standards laid down in the Declaration of Helsinki of 1989. Consent to participate: Not applicable. Consent for publication: Not applicable., (© 2024. The Author(s).)

To test for sex differences in the impact of cannabis use on decision-making and brain correlates, we employed cortical thickness (CT) analysis of brain regions involved in intertemporal decision-making namely bilateral orbitofrontal cortex(OFC) and insula in young adult nondependent cannabis-users(CU) and non-users(NU) and their scores on delay discounting task. Neuroimaging analyzes of previously collected data were performed on 608CU and 503NU. CT analysis was performed on MRI images. OFC and insula thickness, scores on the delay discounting test were compared between groups and correlated. Controlling alcohol-use and intra-cranial-volume, CU exhibited sex differences in CT. The bilateral insula was significantly thinner in male CU. OFC was thinner in females relative to controls. Female CU had thinner Right-medial OFC, Left-lateral-OFC. While male CU scored significantly lower on items within delay discounting task, female CU delay-discounting scores were within normal range. Our results demonstrate that cannabis-use differentially affects decision-making across sexes. Cortical morphology mirrors this dimorphism. CU subjects did not show a correlation between CT of OFC or insula and delay discounting, implying that thinner cortices and lower DD scores in males may be independent alterations which may be premorbid to cannabis use and may lead to cognitive deficits in later years., Competing Interests: Declaration of competing interest The authors have no financial disclosures to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background: Theoretical and empirical contributions have identified insula as key in addiction. However, anatomical modifications of the insula in addictive states, and their variations across substance use disorders (SUDs), remain to be specifically explored. We therefore explored the specificities and commonalities of insula gray matter (GM) alterations in severe alcohol use disorder (sAUD) and severe cocaine use disorder (sCUD)., Methods: We explored insula GM volume through a refined parcellation in 12 subregions (six bilateral): anterior inferior cortex (AIC), anterior short gyrus, middle short gyrus, posterior short gyrus, anterior long gyrus (ALG), and posterior long gyrus (PLG). Using a linear mixed model analysis, we explored the insula volume profiles of 50 patients with sAUD, 61 patients with sCUD, and 36 healthy controls (HCs)., Results: In both sAUD and sCUD, we showed overall insular lower volume with a right-sided lateralization effect, and a major volume deficit in bilateral ALG. Moreover, differences emerged across groups, with higher left AIC and PLG volume deficits in sCUD compared to sAUD and HC., Conclusions: We offered the first joint exploration of GM insular volumes in two SUD through refined parcellation, thus unveiling the similarities and dissimilarities in volume deficit profiles. Our results bring evidence complementing prior ones suggesting the core role of the right and posterior insula in craving and interoception, two crucial processes in addiction. Left AIC and PLG group differences also show that, while insula is a region of interest in SUD, sCUD and sAUD generate distinct insular profiles, which might parallel clinical differences across SUD.

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 ., (© 2023. The Author(s).)

Abnormal resting-state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph-theoretical analyses, enabling improved resolution and fine-grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large-scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region-specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular-supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment., (© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Cigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person's sex influences these associations., Methods: The research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day., Results: Women reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P < .001). A 3-way interaction of sex, smoking condition, and right anterior circular insular sulcus thickness on craving (P = .033) reflected a negative association of cortical thickness with pre-smoking craving in women only (P = .012). No effects of cortical thickness in the left anterior circular insular sulcus were detected. Nicotine dependence was positively associated with craving (P < .001) across groups and sessions, with no sex differences in this association., Conclusions: A negative association of right anterior insula thickness with craving in women only suggests that this region may be a relevant therapeutic target for brain-based smoking cessation interventions in women., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Background and Purpose: Dysphagia is a common and severe symptom of acute stroke. Although intracerebral hemorrhages (ICHs) account for 10% to 15% of all strokes, the occurrence of dysphagia in this subtype of stroke has not been widely investigated. The aim of this study was to evaluate the overall frequency and associated lesion locations and clinical predictors of dysphagia in patients with acute ICH., Methods: Our analysis included 132 patients with acute ICH. Clinical swallowing assessment was performed within 48 hours after admission. All patients underwent computed tomography imaging. Voxel-based lesion-symptom mapping was performed to determine lesion sites associated with dysphagia., Results: Eighty-four patients (63.6%) were classified as dysphagic. Higher scores on the National Institutes of Health Stroke Scale, larger ICH volumes, and higher degree of disability were associated with dysphagia. Voxels showing a statistically significant association with dysphagia were mainly located in the right insular cortex, the right central operculum, as well as the basal ganglia, corona radiata, and the left thalamus and left internal capsule. In contrast to lobar regions, in subcortical deep brain areas also small lesion volumes (<10 mL) were associated with a substantial risk of dysphagia. Intraventricular ICH extension and midline shift as imaging findings indicating a space-occupying effect were not associated with dysphagia in multivariate analysis., Conclusions: Dysphagia is a frequent symptom in acute ICH. Distinct cortical and subcortical lesion sites are related to swallowing dysfunction and predictive for the development of dysphagia. Therefore, patients with ICH should be carefully evaluated for dysphagia independently from lesion size, in particular if deep brain regions are affected.

Associative learning allows animals to adapt their behavior in response to environmental cues. For example, sensory cues associated with food availability can trigger overconsumption even in sated animals. However, the neural mechanisms mediating cue-driven non-homeostatic feeding are poorly understood. To study this, we recently developed a behavioral task in which contextual cues increase feeding even in sated mice. Here, we show that an insular cortex to central amygdala circuit is necessary for conditioned overconsumption, but not for homeostatic feeding. This projection is marked by a population of glutamatergic nitric oxide synthase-1 (Nos1)-expressing neurons, which are specifically active during feeding bouts. Finally, we show that activation of insular cortex Nos1 neurons suppresses satiety signals in the central amygdala. The data, thus, indicate that the insular cortex provides top-down control of homeostatic circuits to promote overconsumption in response to learned cues., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mice cohabiting with a conspecific in chronic pain display anxiogenesis in the elevated plus-maze (EPM). Given that the anterior cingulate (ACC) and insular (InC) cortices play a role in the modulation of anxiety, pain, and emotional contagion, we investigated (a) the FosB activation in both brain areas and (b) the effects of intra-ACC or -InC injection of cobalt chloride (CoCl 2 , a synaptic blocker), on the anxiety of mice cohabiting with a cagemate suffering pain. Twenty-one days after birth, male Swiss mice were housed in pairs for 14 days to establish familiarity. On the 14th day, mice were divided into two groups: cagemate sciatic nerve constriction (CNC; i.e., one animal of each pair was subjected to sciatic nerve constriction), and cagemate sham (CS; i.e., a similar procedure but without suffering nerve constriction). After that, both groups were housed again with the same pairs for the other 14 days. On the 28th day, mice had their brains removed for the immunoassays analyses (Exp. 1). For experiments 2 and 3, on the 23rd day, the cagemates received guide cannula implantation bilaterally in the ACC or InC and, on the 28th day, they received local injections of saline or CoCl 2 , and then were exposed to the EPM. Results showed that cohabitation with a conspecific with chronic pain decreases and increases neuronal activation (FosB) within the ACC and InC, respectively. Intra-ACC or InC injection of CoCl 2 reversed the anxiogenic effect in those animals that cohabited with a conspecific in chronic pain. ACC and InC seem to modulate anxiety induced by emotional contagion in animals cohabitating with a conspecific suffering pain., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We present a 44-year-old male patient with new onset of right focal epilepsy and bilateral hand hypesthesia. Cerebral MRI showed bilateral T2w/DWI hyperintense subcortical lesions in the cingulate gyrus, insula, and amygdala, whereas spinal MRI revealed a cervical posterior column lesion, corresponding to subacute combined degeneration. Laboratory workup revealed a cobalamin deficiency due to type A gastritis, and no evidence of antibodies associated with limbic encephalitis. After sufficient cobalamin substitution, the cerebral and spinal lesions gradually regressed. Our case represents a unique cerebral subcortical MRI lesion pattern in a patient with epilepsy and cobalamin deficiency. Thus, the latter represents an important differential diagnosis for autoimmune encephalitis.

Conscious access to sensory information is likely gated at an intermediate site between primary sensory and transmodal association cortices, but the structure responsible remains unknown. We perform functional neuroimaging to determine the neural correlates of conscious access using a volitional mental imagery task, a report paradigm not confounded by motor behavior. Titrating propofol to loss of behavioral responsiveness in healthy volunteers creates dysfunction of the anterior insular cortex (AIC) in association with an impairment of dynamic transitions of default-mode and dorsal attention networks. Candidate subcortical regions mediating sensory gating or arousal (thalamus, basal forebrain) fail to show this association. The gating role of the AIC is consistent with findings in awake participants, whose conscious access is predicted by pre-stimulus AIC activity near perceptual threshold. These data support the hypothesis that AIC, situated at an intermediate position of the cortical hierarchy, regulates brain network transitions that gate conscious access., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Diagnostic criteria for prodromal dementia with Lewy bodies have recently been published. These include the use of imaging biomarkers to distinguish mild cognitive impairment with Lewy bodies (MCI-LB) from MCI due to other causes. Two potential biomarkers listed, though not formally included in the diagnostic criteria, due to insufficient evidence, are relatively preserved hippocampi, and atrophy of the insula cortex on structural brain imaging., Methods: In this report, we sought to investigate these imaging biomarkers in 105 research subjects, including well characterised groups of patients with MCI-LB (n = 38), MCI with no core features of Lewy body disease (MCI-AD; n = 36) and healthy controls (N = 31). Hippocampal and insula volumes were determined from T1 weighted structural MRI scans, using grey matter segmentation performed with SPM software., Results: Adjusting for age, sex and intracranial volume, there were no differences in hippocampal or insula volume between MCI-AD and MCI-LB, although in both conditions volumes were significantly reduced relative to controls., Conclusion: Our results do not support the use of either hippocampal or insula volume to identify prodromal dementia with Lewy bodies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Internet gaming disorder (IGD) is a concerning issue that requires further research. Here, we seek to examine its neural etiology with an emphasis on the role of the insula. To do so, we relied on the tripartite neurocognitive model of addictive behaviors as applied to IGD. We hypothesized that (a) video game cues will elicit stronger reward system activation and weaker prefrontal activation in gamers vs controls, (b) the IGD scores of gamers will be positively associated with activation of the reward system and negatively with activation of prefrontal regions, (c) deprivation from video gaming will result in increased activation of the insula, when gamers are exposed to video game cues vs to neutral cues, and (d) in deprivation conditions, there will be positive and negative coupling, respectively, between activation of the insula and the reward and prefrontal regions in gamers. We tested these hypotheses with a design with one between-subjects factor (gamers vs controls) and two within-subjects factors: stimuli (gaming vs neutral; for all participants) and session (deprivation vs satiety; only for gamers). Findings based on functional magnetic resonance imaging (fMRI; applied to all 52 subjects, 26 gamers, and 26 controls) and psychophysiological interaction (PPI; applied to the 26 gamers) engaged in a video reactivity task supported our assertions. The IGD score positively correlated with activity in the right ventral striatum and negatively with activity in the right dorsolateral prefrontal cortex (DLPFC). Left insular cortex activity was the highest when observing video gaming cues under deprivation. Lastly, there was an increased coupling between the left insula and left ventral striatum and a decreased coupling with left DLPFC when observing video gaming cues compared with when watching control videos in the deprivation condition., (© 2020 Society for the Study of Addiction.)