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BackgroundChronic pain diseases are characterised by an ongoing and fluctuating endogenous pain, yet it remains to be elucidated how this is reflected by the dynamics of ongoing functional cortical connections. The present study addresses this disparity by taking the individual perspective of pain patients into account, which is the varying intensity of endogenous pain.MethodsTo this end, we investigated the cortical encoding of 20 chronic back pain patients and 20 chronic migraineurs in four repeated fMRI sessions. During the recording, the patients were asked to continuously rate their pain intensity. A brain parcellation approach subdivided the whole brain into 408 regions. A 10 s sliding-window connectivity analysis computed the pair-wise and time-varying connectivity between all brain regions across the entire recording period. Linear mixed effects models were fitted for each pair of brain regions to explore the relationship between cortical connectivity and the observed trajectory of the patients’ fluctuating endogenous pain.ResultsTwo pain processing entities were taken into account: pain intensity (high, middle, low pain) and the direction of pain intensity changes (rising vs. falling pain). Overall, we found that periods of high and increasing pain were predominantly related to low cortical connectivity. For chronic back pain this applies to the pain intensity-related connectivity for limbic and cingulate areas, and for the precuneus. The change of pain intensity was subserved by connections in left parietal opercular regions, right insular regions, as well as large parts of the parietal, cingular and motor cortices. The change of pain intensity direction in chronic migraine was reflected by decreasing connectivity between the anterior insular cortex and orbitofrontal areas, as well as between the PCC and frontal and ACC regions.ConclusionsInterestingly, the group results were not mirrored by the individual patterns of pain-related connectivity, which is suggested to deny the idea of a common neuronal core problem for chronic pain diseases. In a similar vein, our findings are supported by the experience of clinicians, who encounter patients with a unique composition of characteristics: personality traits, various combinations of symptoms, and a wide range of individual responses to treatment. The diversity of the individual cortical signatures of chronic pain encoding results adds to the understanding of chronic pain as a complex and multifaceted disease. The present findings support recent developments for more personalised medicine.

BACKGROUND AND PURPOSE A sensitive and frequent clinical sign of a vestibular tone imbalance is the tilt of the perceived subjective visual vertical (SVV). There are no data yet focusing on lesion location at the cortical level as a factor for predicting compensation from the tilt of the SVV. METHODS With modern voxelwise lesion behavior mapping analysis, the present study determines whether lesion location in 23 right-hemispheric cortical stroke patients with an otolith dysfunction could predict the compensation of a vestibular tone imbalance in the chronic stage. RESULTS Our statistical anatomical lesion analysis revealed that lesions of the posterior insular cortex are involved in vestibular otolith compensation. CONCLUSION The insular cortex appears to be a critical anatomical region for predicting a tilt of the SVV as a chronic disorder in stroke patients.

Hypertension and increased blood pressure variability (BPV) are associated with the development of dementia. However, previous studies did not focus on the risk of dementia among participants with mild cognitive impairment (MCI) and controlled blood pressure level. To address this limitation, the authors performed a post‐hoc analysis of SPRINT MIND participants diagnosed with MCI (mean Montreal Cognitive Assessment score at diagnosis 16.1±3.1). The primary outcome was subsequent diagnosis of probable dementia. The exposure was mean blood pressure and BPV following MCI diagnosis until the end of follow‐up or a dementia event (mean follow‐up 2.6±1.2 years). The primary outcome occurred in 76/516 (14.7%) patients. The mean blood pressure was not significantly higher in participants who developed dementia. In the lowest quartile of BPV (systolic standard deviation), the rate of dementia was 8.5% (11/129), while in the highest quartile it was 21.7% (28/129). The highest quartile of systolic BPV had an adjusted hazard ratio for dementia of 2.73 (95% CI, 1.31–5.69) and for diastolic BPV it was 2.62 (95% CI, 1.26–5.47). In SPRINT MIND participants, the authors found that increased BPV after MCI diagnosis was associated with incident probable dementia during subsequent follow‐up.

The relevance of subcortical structures and interhemispheric subcortical-cortical interactions among positive/negative affect and approach/withdrawal tendencies during resting-state are not fully understood. Gaining this knowledge may foster the know-how on their role in subsequent task-engagement and also on the interlinkage among affective measures and approach/withdrawal dichotomy. Here we performed a study based on Region of Interest (ROI)-based analysis and graph-theory estimates for global and subnetworks on a limited sample of healthy 50 male volunteers who recorded resting functional magnetic resonance imaging (fMRI) and self-reported measures of Positive and Negative Affect Schedule (PANAS) and BAS-BIS (Behavioral Activation System-Behavioral Inhibition System) scores. Our study's initial results of region of interest-to-region of interest (ROI-to-ROI) connectivity revealed the connectivity of subcortical neural substrates of PANAS and BAS-BIS scores with bilateralized cortical regions. However, on probing the lateralization of strength of degree measures of the cortical-regions vital for subcortical-cortical interaction, we found, for positive affect, a left-hemispheric proclivity. Further, higher connectivity within the left hemisphere was also observed for the left-lateralized critical cortical regions of negative affect. Our study also revealed the association of emotion and memory-related subcortical-cortical interactions in positive and negative affect. Right amygdala-right thalamus-frontotemporal cortical areas emanated in positive affect, and right putamen-left hippocampus-frontotemporal cortical regions network stemmed for negative affect. Then, we show the involvement of basal-ganglia structures in approach-withdrawal dichotomy with tight coupling of right-caudate, left-accumbens with anterior cingulate, and insular regions for withdrawal/inhibition system. Further, distinct involvement of the insula (posterior) in affective states while insula (anterior) in approach/withdrawal systems builds up for the existence of a feedback loop between affective and approach/withdrawal systems. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cognitive control and working memory (WM) processes are essential for goal-directed behaviour. Cognitive control and WM are probably based on overlapping neurophysiological mechanisms. For example, theta-band activity (TBA) plays an important role in both functions. For cognitive control processes, it is known that different aspects of information about stimulus content, motor processes and stimulus-response relationships are encoded simultaneously in the TBA. All this information is probably processed during WM gating processes and must be controlled during them. However, direct data for this are lacking. This question is investigated in this study by combining methods of EEG temporal signal decomposition, time-frequency decomposition and beamforming. We show that portions of stimulus-related information, motor response-related information and information related to the interaction between the stimulus and motor responses in the TBA are influenced in parallel and to a similar extent by WM gate opening and gate closing processes. Nevertheless, it is stimulus-related information in the theta signal in particular that modulates behavioural performance in WM-gating. The data suggest that the identified processes are implemented in specific neuroanatomical structures. In particular, the medial frontal cortex, temporal cortical regions and insular cortex are involved in these dynamics. The study shows that principles of information coding relevant to cognitive control processes are also crucial for understanding WM gating.

PURPOSE OF REVIEW This review aims to summarize the current literature describing vestibular-autonomic interactions and to describe their putative role in various disorders' clinical presentations, including orthostatic dizziness and motion sensitivity. RECENT FINDINGS The vestibular-autonomic reflexes have long been described as they relate to cardiovascular and respiratory function. Although orthostatic dizziness may be in part related to impaired vestibulo-sympathetic reflex (orthostatic hypotension), there are various conditions that may present similarly. A recent clinical classification aims to improve identification of individuals with hemodynamic orthostatic dizziness so that appropriate recommendations and management can be efficiently addressed. Researchers continue to improve understanding of the underlying vestibular-autonomic reflexes with recent studies noting the insular cortex as a cortical site for vestibular sensation and autonomic integration and modulation. Work has further expanded our understanding of the clinical presentation of abnormal vestibular-autonomic interactions that may occur in various conditions, such as aging, peripheral vestibular hypofunction, traumatic brain injury, and motion sensitivity. SUMMARY The vestibular-autonomic reflexes affect various sympathetic and parasympathetic functions. Understanding these relationships will provide improved identification of underlying etiology and drive improved patient management.

Objective Epileptic seizures with insular genesis are often difficult to distinguish from those originating in the temporal lobe due to their complex and variable semiology. Here, we analyzed differentiating characteristics in the clinical spectrum of insulo-opercular seizures. Methods Ictal semiology in patients with a diagnosis of insulo-opercular epilepsy (IOE) based on imaging of epileptogenic lesions or electrophysiological evidence of an insulo-opercular seizure origin was retrospectively analyzed and compared to age-matched controls with mesial temporal lobe epilepsy (MTE). Results Forty-six IOE and 46 matched MTE patients were included. The most prominent ictal features in IOE were focal motor phenomena in 80.4% of these patients. Somatosensory sensations, version, tonic and clonic features, when present, were more frequent contralateral to the SOZ in MTE patients, while they occurred about equally often ipsilateral and contralateral to the SOZ in IOE patients. Ipsilateral manual automatisms were significantly more frequent in MTE patients than in IOE (p = 0.010). Multivariate analysis correctly identified IOE in 78.3% and MTE in 84.8% using five semiologic features (Chi-square = 53.79 with 5 degrees of freedom, p p = 0.010), while automatisms were significantly more frequent in MTE patients (p = 0.06). Significance Our study represents the first in-depth analysis of ictal semiology in IOE compared to MTE. Use of these differentiating characteristics can serve for a correct syndrome classification and to steer appropriate diagnostic and local therapeutic procedures.

The author previously worked extensively on the broad problem of the evolution of the vertebrate pallium. He proposed various Bauplan models covering at least gnathostomes, based in the definition of a set of pallial sectors with topologically invariant positional relationships and distinct molecular profiles. Out of one of these models, presented as the “updated tetrapartite pallium model,” a modified definition of the earlier lateral pallium sector (LPall) concept emerged, characterizing it in mammals as an unitary claustro-insular transitional (mesocortical) complex intercalated between the neocortex or dorsal pallium (DPall) above and olfactory cortex or ventral pallium (VPall) underneath. A distinctive molecular marker of the early-born deep claustral component of the LPall was found to be the transcription factor Nr4a2, which is not expressed significantly in the overlying insular cortex or in adjoining cortical territories. Given that earlier comparative studies had identified molecularly and topologically comparable VPall, LPall, and DPall sectors in the avian pallium, an avian Nr4a2 probe was applied, aiming to identify the reportedly absent avian claustro-insular complex. An early-born superficial subpopulation of the avian LPall that expresses this marker selectively through development was indeed found. This was proposed to be a claustrum homolog, whereas the remaining Nr4a2-negative avian LPall cells were assumed to represent a possible insular homolog. This last notion was subsequently supported by comparable selective expression of the mouse insular marker Cyp26b, also found restricted to the avian LPall. Some published data suggested that similar molecular properties and structure apply at the reptilian LPall. This analysis was reviewed in Puelles et al. [The pallium in reptiles and birds in the light of the updated tetrapartite pallium model. 2017]. Four years on, the present commentary discusses some international publications accrued in the interval that touch on the claustro-insular homology hypothesis. Some of them are opposed to the hypothesis whereas others corroborate or support it. This raises a number of secondary issues of general interest.

Reach&grasp requires highly coordinated activation of different brain areas. We investigated whether reach&grasp kinematics is associated to EEG-based networks changes. We enrolled 10 healthy subjects. We analyzed the reach&grasp kinematics of 15 reach&grasp movements performed with each upper limb. Simultaneously, we obtained a 64-channel EEG, synchronized with the reach&grasp movement time points. We elaborated EEG signals with EEGLAB 12 in order to obtain event related synchronization/desynchronization (ERS/ERD) and lagged linear coherence between Brodmann areas. Finally, we evaluated network topology via sLORETA software, measuring network local and global efficiency (clustering and path length) and the overall balance (small-worldness). We observed a widespread ERD in α and β bands during reach&grasp, especially in the centro-parietal regions of the hemisphere contralateral to the movement. Regarding functional connectivity, we observed an α lagged linear coherence reduction among Brodmann areas contralateral to the arm involved in the reach&grasp movement. Interestingly, left arm movement determined widespread changes of α lagged linear coherence, specifically among right occipital regions, insular cortex and somatosensory cortex, while the right arm movement exerted a restricted contralateral sensory-motor cortex modulation. Finally, no change between rest and movement was found for clustering, path length and small-worldness. Through a synchronized acquisition, we explored the cortical correlates of the reach&grasp movement. Despite EEG perturbations, suggesting that the non-dominant reach&grasp network has a complex architecture probably linked to the necessity of a higher visual control, the pivotal topological measures of network local and global efficiency remained unaffected.

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., This meta‐analysis shows that chronic pain patients present convergent neurofunctional maladaptations in a cluster located in the anterior insula cortex during the induction of acute pain processing.

Object Epilepsy surgery is an effective treatment for selected patients with focal intractable epilepsy. Complete removal of the epileptogenic zone significantly increases the chances for postoperative seizure-freedom. In complex surgical candidates, delineation of the epileptogenic zone requires a long-term invasive video/EEG from intracranial electrodes. It is especially challenging to achieve a complete resection in deep brain structures such as opercular-insular cortex. We report a novel approach utilizing intraoperative visual detection of stereotactically implanted depth electrodes to inform and guide the extent of surgical resection. Methods We retrospectively reviewed data of pediatric patients operated in Motol Epilepsy Center between October 2010 and June 2020 who underwent resections guided by intraoperative visual detection of depth electrodes following SEEG. The outcome in terms of seizure- and AED-freedom was assessed individually in each patient. Results Nineteen patients (age at surgery 2.9–18.6 years, median 13 years) were included in the study. The epileptogenic zone involved opercular-insular cortex in eighteen patients. The intraoperative detection of the electrodes was successful in seventeen patients and the surgery was regarded complete in sixteen. Thirteen patients were seizure-free at final follow-up including six drug-free cases. The successful intraoperative detection of the electrodes was associated with favorable outcome in terms of achieving complete resection and seizure-freedom in most cases. On the contrary, the patients in whom the procedure failed had poor postsurgical outcome. Conclusion The reported technique helps to achieve the complete resection in challenging patients with the epileptogenic zone in deep brain structures.

Previous studies have described the structure and function of the insular cortex in terms of spatially continuous gradients. Here we assess how spatial features of insular resting state functional organization correspond to individual pain sensitivity. From a previous multicenter study, we included 107 healthy participants, who underwent resting state functional MRI scans, T1-weighted scans and quantitative sensory testing on the left forearm. Thermal and mechanical pain thresholds were determined. Connectopic mapping, a technique using non-linear representations of functional organization was employed to describe functional connectivity gradients in both insulae. Partial coefficients of determination were calculated between trend surface model parameters summarizing spatial features of gradients, modal and modality-independent pain sensitivity. The dominant connectopy captured the previously reported posteroanterior shift in connectivity profiles. Spatial features of dominant connectopies in the right insula explained significant amounts of variance in thermal (R2 = 0.076; p 2 = 0.031; p 2 = 0.072; p

Anorexia nervosa (AN) typically emerges in adolescence. The cortico-striatal system (CSTS) and the default mode network (DMN) are brain circuits with a crucial development during this period. These circuits underlie cognitive functions that are impaired in AN, such as cognitive flexibility and inhibition, among others. Little is known about their involvement in adolescent AN and how weight and symptom improvement might modulate potential alterations in these circuits. Forty-seven adolescent females (30 AN, 17 healthy control) were clinically/neuropsychologically evaluated and scanned during a 3T-MRI resting-state session on two occasions, before and after a 6-month multidisciplinary treatment of the AN patients. Baseline and baseline-to-follow-up between-group differences in CSTS and DMN resting-state connectivity were evaluated, as well as their association with clinical/neuropsychological variables. Increased connectivity between the left dorsal putamen and the left precuneus was found in AN at baseline. At follow-up, body mass index and clinical symptoms had improved in the AN group. An interaction effect was found in the connectivity between the right dorsal caudate to right mid-anterior insular cortex, with lower baseline AN connectivity that improved at follow-up; this improvement was weakly associated with changes in neuropsychological (Stroop test) performance. These results support the presence of CSTS connectivity alterations in adolescents with AN, which improve with weight and symptom improvement. In addition, at the level of caudate-insula connectivity, they might be associated with inhibitory processing performance. Alterations in CSTS pathways might be involved in AN from the early stages of the disorder.

While the BDNF Val66Met polymorphism has been linked to various trauma and anxiety - related psychiatric disorders, limited focus has been on the neural structures that might modulate its relationship with objective measures of threat sensitivity. Therefore, we assessed whether there was an interaction of Val66Met polymorphism with brain area volumes previously associated with anxiety and PTSD, such as the ventromedial prefrontal cortex (vmPFC), insular cortex (IC), and dorsal and ventral anterior cingulate cortices (dACC and vACC), in predicting fear-potentiated psychophysiological response in a clinical sample of Veterans. 110 participants engaged in a fear-potentiated acoustic startle paradigm and provided genetic and imaging data. Fear conditions included no, ambiguous, and high threat conditions (shock). Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate (HR). PTSD status, trauma history, and demographics were also assessed. There was an interaction of Met allele carrier status with vmPFC, IC, dACC, and vACC volumes for predicting SCR (p&nbsp

Background The insular cortex is an eloquent island of mesocortex surrounded by vital structures making this region relatively challenging to neurosurgeons. Historically, lesions in this region were considered too high risk to approach given the strong chance of poor surgical outcome. Advances in recent decades have meant that surgeons can more safely access this eloquent region. Seizure outcome after excision of insular low-grade gliomas is well reported, but little is known about seizure outcomes after excision of insular high-grade gliomas. Methods A retrospective analysis was performed of all patients presenting with new-onset seizures during 2015–2019 who underwent excision of an insular high-grade glioma at 3 regional neurosurgical centers in the United Kingdom. Results We identified 38 patients with a mean (SD) age of 45.7 (15.3) years with median follow-up of 21 months. At long-term follow-up, of 38 patients, 23 were seizure-free (Engel class I), 2 had improved seizures (Engel class II), 6 had poor seizure control (Engel class III/IV), and 7 died. Conclusions Excision of insular high-grade gliomas is safe and results in excellent postoperative seizure control.

Objectives Feeding behavior is known to have potential to alleviate pain. We recently demonstrated that both 24 h fasting and 2 h refeeding (food intake after 24 h fasting) induce analgesia in inflammatory pain conditions via different brain mechanisms. However, brain structures that distinctly involved fasting- and refeeding-induced analgesia is still unknown. Hence, this study is aimed to reveal brain structures mediating fasting- and refeeding-induced analgesia. Methods Mice were given intraplantar (i.pl.) injection of formalin and complete Freund's adjuvant into the left hind paw to induce acute and chronic inflammatory pain, respectively. We examined changes in c-Fos expression with 24 h fasting and 2 h refeeding under acute and chronic inflammatory pain conditions in the contralateral brain. Results Under acute pain condition, c-Fos expression changed with fasting in the anterior cingulate cortex (ACC), central amygdala (CeA), lateral hypothalamus (LH) and nucleus accumbens core (NAcC). Refeeding changed c-Fos expression in the CeA, LH and lateral parabrachial nucleus (lPBN). On the other hand, under chronic inflammatory pain condition, c-Fos expression changed with fasting in the lPBN, medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcS) while refeeding changed c-Fos expression in the anterior insular cortex, lPBN, mPFC and NAcS. Conclusion The present results show that brain regions that participated in the fasting- and refeeding-induced analgesia were completely different in acute and chronic inflammatory pain conditions. Also, refeeding recruits more brain regions under chronic inflammatory pain conditions compared to the acute inflammatory pain condition. Collectively, our findings provide novel insights into brain regions involved in fasting- and refeeding-induced analgesia, which can be potential neural circuit-based targets for the development of novel therapeutics.

Experiments aimed to evaluate the tissue distribution of Mas-related G protein-coupled receptor D (MrgD) revealed the presence of immunoreactivity for the MrgD protein in the rostral insular cortex (rIC), an important area for autonomic and cardiovascular control. To investigate the relevance of this finding, we evaluated the cardiovascular effects produced by the endogenous ligand of MrgD, alamandine, in this brain region. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in urethane anesthetized rats. Unilateral microinjection of equimolar doses of alamandine (40 pmol/100 nL), angiotensin-(1–7), angiotensin II, angiotensin A, and Mas/MrgD antagonist d-Pro7-Ang-1-7 (50 pmol/100 nL), Mas antagonist A779 (100 pmol/100 nL), or vehicle (0.9% NaCl) were made in different rats ( n = 4–6/group) into rIC. To verify the specificity of the region, a microinjection of alamandine was also performed into intermediate insular cortex (iIC). Microinjection of alamandine in rIC produced an increase in MAP (Δ = 15 ± 2 mmHg), HR (Δ = 36 ± 4 beats/min), and RSNA (Δ = 31 ± 4%), but was without effects at iIC. Strikingly, an equimolar dose of angiotensin-(1–7) at rIC did not produce any change in MAP, HR, and RSNA. Angiotensin II and angiotensin A produced only minor effects. Alamandine effects were not altered by A-779, a Mas antagonist, but were completely blocked by the Mas/MrgD antagonist d-Pro7-Ang-(1–7). Therefore, we have identified a brain region in which alamandine/MrgD receptor but not angiotensin-(1–7)/Mas could be involved in the modulation of cardiovascular-related neuronal activity. This observation also suggests that alamandine might possess unique effects unrelated to angiotensin-(1–7) in the brain.

Purpose Structural magnetic resonance imaging is widely used to explore brain gray and white matter structure in trigeminal neuralgia (TN) but has yielded conflicting findings. This study investigated the relationship between disease duration as a clinical feature of TN and changes in brain structure. Methods We divided 49 TN patients into three groups (TN1–TN3) based on disease duration (TN1 = 1.1 ± 0.7 (0–2) years, TN2 = 4.8 ± 1.5 (3–7) years, TN3 = 15.1 ± 5.5 (10–30) years). We used voxel-based morphometry (VBM) to compare the gray matter volume (GMV) across groups and between TN patients and 18 matched healthy control subjects. Results The TN1 group showed reduced GMV of pain-related regions in the cerebellum; the TN2 group showed reduced GMV in the thalamus and the motor/sensory cortex; and the TN3 group showed reduced GMV in the emotional and reward circuits compared with healthy controls. Similar brain regions, including bilateral hippocampi, caudate, left insular cortex, and medial superior frontal cortex, were affected in TN2 and TN3 compared with TN1. Conclusion Disease duration can explain differences in structural alterations—especially in pain-related brain regions—in TN. These results highlight the advanced structural neuroimaging method that are valuable tools to assess the trigeminal system in TN and may further our current understanding of TN pathology.

The insular cortex is considered one of the most complex regions of the brain, defined as the "hub" of somatosensory areas. Here, we examine the case of a surgically treated haemorrhagic cavernoma involving the middle and posterior insular cortex, presenting both sensory, gustative and speech symptoms. By reviewing the recent findings in humans' and primates' basic research, we illustrated clinical and radiological correlations of the reported case, confirming insular role in sensitive and gustatory functions.

We report a 30-year-old right-handed man with a history of drug-resistant, non-lesional, childhood-onset focal epilepsy featuring (i) focal unaware seizures with left upper extremity automatisms and tonic posturing preceded by an aura of a ringing/beeping noise, and (ii) nocturnal hyperkinetic seizures. Non-invasive video-EEG, MEG, and PET were unable to delineate the epileptogenic zone (EZ) warranting an invasive investigation with bilateral depth electrodes (SEEG). SEEG data localized the EZ to the right superior temporal sulcus (STS) and right superior temporal gyrus (STG), wherein the auditory cortex lies, with subsequent ictal spread to anterior topography including the operculo-insular region. This hypothesis explained the patient's semiology consisting of focal aware seizures featuring auditory phenomena and nocturnal hyperkinetic seizures. Our multi-disciplinary team elected to proceed with a resection of the posterior right STG guided by electrocorticography (ECoG). Prior to resection, ECoG identified seizures arising from the peri-sylvian region, seemingly discordant to previous SEEG data. Following resection of the posterior right STG, ECoG continued to show seizures from contacts overlying the parietal operculum. It was not until the cortex was resected, at the depth of the right STS, that ECoG no longer showed epileptiform abnormalities. Pathology revealed focal cortical dysplasia type 1A.

Introduction The family of Amplatzer Vascular Plugs (AVPs) is characterized by their precise deployment and high resistance to migration. However, a risk of recanalization of the embolized vessels has been reported. To augment the effectiveness of embolization, the coil-in-plug (CIP) technique was developed, exclusively using AVP I or IV. However, these plugs cannot be used for large vessels like portovenous shunt because of the size limitation. AVP II has a larger-sized model up to 22 mm. This article reports two cases of embolizing high-flow and large-caliber portosystemic shunts where the CIP technique with multilayer AVP II was effectively employed. Materials and methods The CIP technique using AVP II was utilized for one case with a portocaval shunt and another with a splenorenal shunt. CIP was established with wire penetration through the multilayer meshes, followed by a microcatheter insertion. After the microcatheter was positioned in the central lobe, the internal space was embolized tightly using pushable or detachable coils. Results A use of guidewire with a high tip load enabled an establishment of CIP and complete occlusion of the target vessels immediately without migration of the embolic devices in both cases. The symptom of encephalopathy improved after the procedure in both the case of the portocaval and the splenorenal shunt. Conclusion The CIP technique with the AVP II was safe and effective to achieve complete occlusion of the large-caliber portosystemic shunts.

OBJECTIVE Ischemic stroke, as well as intracerebral hemorrhage (ICH), involving the insular cortex tends to be more severe. The impact of insular involvement on outcome of ICH remains enigmatic. METHODS We analyzed 159 patients with supratentorial ICH. Depending on insular involvement the patients were classified into two groups (ICHnon-insular vs. ICHinsular ). Volume and symptom severity of ICH were assessed. Electrocardiography, chest X-ray, and laboratory examinations including myocardial enzymes and inflammatory markers were made. In-hospital death and outcome at discharge from hospital were assessed on the modified Rankin scale (mRS). RESULTS The main finding was an association of insular involvement of ICH with worse short-term outcome as measured by mRS (common odds ratio: 4.08 (95% CI: 2.09-7.92); p

BACKGROUND Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood. METHODS We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87). RESULTS Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus. CONCLUSIONS These findings support single voxel placement targeting nociceptive processing areas in prior 1 H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia. SIGNIFICANCE This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.

Importance. Acupuncture is an effective treatment for stroke, especially in the aspect of motor deficit. Many brain imaging studies of acupuncture have found significant changes in brain function after acupuncture treatment in order to reveal its underlying mechanisms in regulating neural plasticity. However, no definite consensus has been reached. Objective. To analyze the pattern of intrinsic brain activity variability that is altered by acupuncture compared with conventional treatment in stroke patients with motor dysfunction, thus providing the mechanism of stroke treatment by acupuncture. Methods. Chinese and English articles published up to May 2020 were searched in the PubMed, Web of Science, EMBASE, and Cochrane Library databases, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Database. We only included randomized controlled trials (RCTs) using resting-state fMRI to observe the effect of acupuncture on stroke patients with motor dysfunction. R software was used to analyze the continuous variables, and Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) was used to perform an analysis of fMRI data. Findings. A total of 7 studies comprising 143 patients in the treatment group and 138 in the control group were included in the meta-analysis. The results suggest that acupuncture treatment helps the healing process of motor dysfunction in stroke patients and exhibits hyperactivation in the bilateral basal ganglia and insula and hypoactivation in motor-related areas (especially bilateral BA6 and left BA4). Conclusion. Acupuncture plays a role in promoting neuroplasticity in subcortical regions that are commonly affected by stroke and cortical motor areas that may compensate for motor deficits, which may provide a possible mechanism underlying the therapeutic effect of acupuncture.

Empathy for pain involves sensory and visceromotor brain regions relevant also in the first-person pain experience. Focusing on brain activations associated with vicarious experiences of pain triggered by artistic or non-artistic images, the present study aims to investigate common and distinct brain activation patterns associated with these two vicarious experiences of pain and to assess whether empathy for pain brain regions contributes to the formation of an aesthetic judgement (AJ) in non-art expert observers. Artistic and non-artistic facial expressions (painful and neutral) were shown to participants inside the scanner and then aesthetically rated in a subsequent behavioural session. Results showed that empathy for pain brain regions (i.e. bilateral insular cortex, posterior sector of the anterior cingulate cortex and the anterior portion of the middle cingulate cortex) and bilateral inferior frontal gyrus are commonly activated by artistic and non-artistic painful facial expressions. For the artistic representation of pain, the activity recorded in these regions directly correlated with participants’ AJ. Results also showed the distinct activation of a large cluster located in the posterior cingulate cortex/precuneus for non-artistic stimuli. This study suggests that non-beauty-specific mechanisms such as empathy for pain are crucial components of the aesthetic experience of artworks.

The experience of pain is generated by activations throughout a complex pain network with the insular cortex as a central processing area. The state of ongoing oscillatory activity can influence subsequent processing throughout this network. In particular the ongoing theta-band power can be relevant for later pain processing, however a direct functional relation to post-stimulus processing or behaviour is missing. Here, we used a non-invasive brain–computer interface to either increase or decrease ongoing theta-band power originating in the insular cortex. Our results show a differential modulation of oscillatory power and even more important a transfer to independently measured pain processing and sensation. Pain evoked neural power and subjective pain discrimination were differentially affected by the induced modulations of the oscillatory state. The results demonstrate a functional relevance of insular based theta-band oscillatory states for the processing and subjective discrimination of nociceptive stimuli and offer the perspective for clinical applications.

Neurobiological models of emotion focus traditionally on limbic/paralimbic regions as neural substrates of emotion generation, and insular cortex (in conjunction with isocortical anterior cingulate cortex, ACC) as the neural substrate of feelings. An emerging view, however, highlights the importance of isocortical regions beyond insula and ACC for the subjective feeling of emotions. We used music to evoke feelings of joy and fear, and multivariate pattern analysis (MVPA) to decode representations of feeling states in functional magnetic resonance (fMRI) data of n = 24 participants. Most of the brain regions providing information about feeling representations were neocortical regions. These included, in addition to granular insula and cingulate cortex, primary and secondary somatosensory cortex, premotor cortex, frontal operculum, and auditory cortex. The multivoxel activity patterns corresponding to feeling representations emerged within a few seconds, gained in strength with increasing stimulus duration, and replicated results of a hypothesis-generating decoding analysis from an independent experiment. Our results indicate that several neocortical regions (including insula, cingulate, somatosensory and premotor cortices) are important for the generation and modulation of feeling states. We propose that secondary somatosensory cortex, which covers the parietal operculum and encroaches on the posterior insula, is of particular importance for the encoding of emotion percepts, i.e., preverbal representations of subjective feeling.

Takotsubo syndrome (TTS) is a transient cardiomyopathy that is often associated with cerebrovascular diseases. Earlier studies have supported the concept that the cardiovascular system is regulated by a central autonomic network (CAN) consisting of the insular cortex (IC), anterior cingulate gyrus and amygdala. We report the case of a 79‐year‐old female diagnosed with a mid‐ventricular variant of TTS concomitant with right IC ischaemic stroke. After 12 h of hospitalization, she experienced a sudden collapse. Rapid cardiopulmonary resuscitation resulted in a return of spontaneous circulation. Subsequent left ventriculography revealed akinesis in the mid‐portion of the left ventricle with vigorous contraction of the basal and apex segment. Two weeks after admission, cardiac ultrasound showed improved left ventricular contraction. Right IC ischaemia in this patient might have been associated with a dysregulation of the CAN and subsequent increased sympathetic nervous system activity that triggered TTS.

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.

Emotion regulation to pleasant and unpleasant stimuli involves several brain areas, such as the prefrontal cortex, amygdala, and insular cortex. However, how a specific arousal level affects such brain dynamics is not fully understood. To this effect, we propose an electroencephalography (EEG)-based study, where 22 healthy subjects were emotionally elicited through affective pictures gathered from the International Affective Picture System. Based on the circumplex model of affect, we used four arousing levels, each with two valence levels (i.e., pleasant and unpleasant). Considering these levels, we investigated the EEG power spectra and functional connectivity among channels. We then used this information to build an automatic valence classifier. The experimental results showed that the functional connectivity at the highest frequency bands (i.e., > 30 Hz) was most sensitive to arousal modulation. Specifically, high connectivity over the right hemisphere occurred during pleasant elicitation, whereas that over the left hemisphere occurred during negative elicitation. In addition, short-range connections in the frontal regions became weaker with increased arousal level, whereas long-range connections were enhanced. Concerning the spectral analysis, the most significant valence-dependent changes were found at intermediate arousing elicitations over the prefrontal and occipital regions. The automatic valence classification showed a recognition accuracy of up to 86.37 percent.

The insular cortex is considered an important region for feeling emotions through interoception. Most studies that report the role of the insula in integrating interoception and emotion have used neuroimaging techniques such as functional magnetic resonance imaging (fMRI); however, there are limited neuropsychological studies. The effects of insular lesions on emotion and interoception have not been suitably investigated. In this study, we examined the role of the insular cortex in cardiac interoception and recognizing emotions from facial expressions by comparing them pre- and post-operatively in patients with glial tumors or brain metastases associated with the insular lobe. Although no significant difference in interoceptive accuracy was observed between the two phases, there were significant associations between the changes in interoceptive accuracy and sensitivity to expressions of anger and happiness. An increased error rate in the heartbeat counting task in the post-operation phase was associated with a decreased accuracy in recognizing anger and happiness. Since most patients had left insula lesions, generalizability of the findings to patients with right lesions is a future subject. To the best of our knowledge, this is the first study to examine the change in interoception and emotion after insular resection in humans. The study results indicate that removal of the insula affects the recognition of emotions such as anger and happiness through interoceptive processing.

Insular cortex is a critical brain region that participates in the interoceptive sensations. Here, we combined the iDISCO+ method and Fos immunostaining to confirm that the middle part of the right-side, but not the left-side, insular cortex in adult male mice is activated by intraperitoneal injection of lithium chloride. Lateralized activation of the insular cortex is also observed in adult female mice, but not in young or aged male mice. Furthermore, asymmetrical activation of the insular cortex was completely blocked when both sides of the vagal nerve are transected, whereas intravenous injection of lithium chloride has no effect on the insular activation. Combined together, these results indicate that the insular cortex unilaterally responds to aversive visceral stimuli in an age-dependent way and this process depends on the vagal afferent pathways.

Alcohol use disorder is complex and multi-faceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry.Significance StatementThe insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we utilize converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.

Our immune system and brain interact on multiple scales, but how the brain represents and remembers immune challenges remains unclear. In this issue of Cell, Koren et al. (2021) reveal that the brain's insular cortex stores information about inflammation in the body. Strikingly, these immunological "memory engrams" can restore the initial disease state when reactivated.

Sympathetic nervous system plays an important role in secondary injury of diseases. Accumulating evidence has observed association between ischemic stroke and renal dysfunction, but the mechanisms are incompletely clear. In this study, we investigated whether sympathetic hyperactivity can cause the development of renal dysfunction, apoptosis, and fibrogenesis after focal cerebral infarction. To determine the renal consequences of focal cerebral ischemia, we subjected a mice model of transient middle cerebral artery occlusion (tMCAO) and examined systolic blood pressure, heart rate, renal structure and function, serum catecholamine, and cortisol levels, and the expression of active caspase-3 bcl-2, bax, and phosphorylated p38 MAPK after 8 weeks. We also analyzed the relationship between insular cortex infarction and acute kidney injury (AKI) in 172 acute anterior circulation ischemic stroke (ACIS) patients. Transient right middle cerebral artery occlusion induced sympathetic hyperactivity, renal dysfunction, upregulation of apoptosis, and fibrogenesis in kidneys of mice. Metoprolol treatment relieves the development of renal injury. Study in stroke patients demonstrated that insular cortex infarction, especially the right insular cortex infarction, is an independent risk factor of AKI. Focal cerebral ischemia in mice leads to the development of renal injury driven by sympathetic hyperactivity. Right insular cortex infarction is an independent risk factor of AKI in older patients. Understanding the brain-kidney interaction after stroke would have clinical implications for the treatment and overall patient outcome.

Prior neuroimaging studies have supported the idea that the human insular cortex plays an important role in processing and representing internal bodily states, also termed "interoception." According to recent theoretical studies, interoception includes several aspects such as attention and accuracy. However, there is no consensus on the laterality and location of the insula to support each aspect of interoception. Thus, we aimed to identify the anatomical insular subdivisions involved in interoceptive attention and accuracy; we examined 28 healthy volunteers who completed the behavioral heartbeat counting task and interoceptive attention paradigm using functional magnetic resonance imaging. First, interoceptive attention induced significant activation in the bilateral frontal operculum, precentral gyrus, middle insula, middle cingulate cortex, and supplementary motor area. Then, we compared the activation in anatomically predefined insular subdivisions during interoceptive attention. The highest activation of the middle short gyrus was noted within the insular cortex, followed by the anterior short gyrus and posterior short gyrus, while no significant hemispheric differences were observed. Finally, the interoceptive accuracy index, measured using the heartbeat counting task, strongly correlated with the activity of the right dorsal anterior insula/frontal operculum. These findings suggest that interoceptive attention is associated with the bilateral dorsal mid-anterior insula, which supports the processing and representation of bodily signals. In contrast, the more dorsal anterior portion of the right insula plays a key role in obtaining accurate interoception.

Nociception is the neuronal process of encoding noxious stimuli and could be modulated at peripheral, spinal, brainstem, and cortical levels. At cortical levels, several areas including the anterior cingulate cortex (ACC), prefrontal cortex (PFC), ventrolateral orbital cortex (VLO), insular cortex (IC), motor cortex (MC), and somatosensory cortices are involved in nociception modulation through two main mechanisms: (i) a descending modulatory effect at spinal level by direct corticospinal projections or mostly by activation of brainstem structures (i.e. periaqueductal grey matter (PAG), locus coeruleus (LC), the nucleus of raphe (RM) and rostroventral medulla (RVM)); and by (ii) cortico-cortical or cortico-subcortical interactions. This review summarizes evidence related to the participation of the aforementioned cortical areas in nociception modulation and different neurotransmitters or neuromodulators that have been studied in each area. Besides, we point out the importance of considering intracortical neuronal populations and receptors expression, as well as, nociception-induced cortical changes, both functional and connectional, to better understand this modulatory effect. Finally, we discuss the possible mechanisms that could potentiate the use of cortical stimulation as a promising procedure in pain alleviation.

Substance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry is selectively necessary for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate the necessity of brain regions in drug- versus natural reward-associated behaviors.