Search Results (90)

Brain lateralization is a biological asymmetry in which a bilaterally organized nervous system develops direction-specific functional organization. This hypothesis distinguishes gravity-driven physical symmetry reduction from informational symmetry breaking. Gravity provides a stable vertical reference, yet matched leftward and rightward tilts become biologically relevant only when noisy vestibular population responses carry decodable tilt-sign information. At fixed unsigned tilt magnitude, the criterion is nonzero conditional mutual information between binary tilt sign and vestibular population response; for equal sign priors, this is equivalent to Jensen–Shannon divergence between sign-conditioned response distributions. Shannon entropy describes within-condition response spread, Fisher information describes local continuous-angle precision, and noise-aware representational distance describes PIVC-centered state separation. The otolith-to-perceptual pathway is formulated as a constrained effective state-space transformation from vestibular population responses through an intermediate brainstem–cerebellar state to distributed parieto-insular vestibular cortex (PIVC)-centered cortical states and perceived self-orientation. The framework predicts sign-specific vestibular and PIVC information for matched tilts, reduced or reorganized sign information in bilateral vestibulopathy, and covariance among cortical geometry, orientation-estimation reliability, and orientation-dependent behavior. Auditory and visual spatial transformations provide computational precedents rather than anatomical homology. The model offers a testable sensorimotor scaffold without determining a fixed hemispheric sign. Full article

Background/Objectives: Regular physical exercise conditioning attenuates nociceptive responses. However, it remains unclear whether physical exercise performed before local inflammation exerts prolonged preventive effects. This study determined whether treadmill run (TR) preconditioning produces sustained preventive effects on craniofacial nociception and associated brain responses following persistent craniofacial inflammation. Methods: Male C57BL/6J mice were assigned to sedentary or TR groups. Daily TR conditioning was performed for 10 days before masseter muscle injection of complete Freund’s adjuvant (CFA) on Day 0. Craniofacial-pain- and related anxiety-like behaviors were determined by the orofacial formalin, elevated plus maze, and open-field tests before and 3 (CFA3) or 7 (CFA7) days after CFA injection. Brain responses in the amygdala, insular cortex, hippocampal CA1, and primary motor cortex were assessed using multiple epigenetic- and neural-activity-related markers. Results: Under sedentary conditions, both CFA3 and CFA7 groups showed increased pain- and anxiety-like behaviors and elevated expression of epigenetic- and neural-activity-related markers in most brain regions. TR preconditioning attenuated these behavioral responses even three and seven days after TR cessation and altered the expression of epigenetic markers in several brain regions, although the direction of change varied by region and time point. TR preconditioning consistently reduced the expression of neural activity markers in most brain areas in both the CFA3 and CFA7 groups, with a few exceptions. Conclusions: TR preconditioning exerted prolonged preventive effects on craniofacial-pain-like behaviors and associated brain responses following craniofacial inflammation. Full article

Background/Objectives: Chronic pain in osteoarthritis alters large-scale brain networks, including the insular cortex and default mode network. While total hip arthroplasty (THA) provides substantial relief, the early postoperative reorganization of functional connectivity (FC) remains unclear. This longitudinal fMRI study exploratively investigated how early improvements in pain intensity and catastrophizing are associated with insular FC alterations following THA. Methods: In this exploratory, longitudinal observational study, 10 female patients with hip osteoarthritis underwent resting-state fMRI and clinical assessments—Pain Visual Analogue Scale (VAS), Pain Catastrophizing Scale (PCS), and Japanese Orthopaedic Association (JOA) hip score—preoperatively and two weeks post-THA Whole-brain seed-to-voxel FC analyses were conducted using the bilateral anterior insular cortex as the seed. Changes in FC (ΔFC) were correlated with preoperative scores and postoperative clinical changes (ΔVAS, ΔPCS). Results: Following THA, VAS and PCS scores decreased significantly, while JOA scores improved. rs-fMRI analysis revealed that FC between the left anterior insula and major DMN regions as well as the right anterior cingulate cortex (ACC) increased significantly overall. Correlation analysis showed that greater reductions in pain intensity (ΔVAS) were significantly associated with increased ΔFC across these regions. Conversely, greater reductions in pain catastrophizing (ΔPCS) were associated with a suppression of these FC increases. Conclusions: Given the preliminary nature of this study, these findings suggest that the alleviation of pain catastrophizing following THA may be associated with the initial reorganization of the aIC network, rather than establishing a definitive causal relationship. Further large-scale longitudinal studies are required to confirm these potential neural signatures. Full article

Objectives: Autism spectrum disorder (ASD) is increasingly conceptualized as a neurodevelopmental condition with prenatal origins. Advances in fetal magnetic resonance imaging (MRI), including high-resolution structural imaging and resting-state functional connectivity analysis, now enable in vivo characterization of the developing human brain before birth. This review examines whether fetal MRI biomarkers are associated with later ASD diagnosis or autistic traits. Methods: We conducted a PRISMA-informed narrative review of human studies identified through MEDLINE, EMBASE, SCOPUS, and Web of Science. Eligible studies included original human investigations using fetal MRI to assess brain structure and/or function, with postnatal ASD diagnosis or standardized autistic-trait outcomes. Results: Eight eligible studies provide converging evidence that neurodevelopmental divergence associated with ASD may be detectable in utero. Structural analyses consistently report prenatal volumetric alterations, particularly enlargement of the insular cortex between the second and third trimesters. Additional findings of regional overgrowth and hemispheric asymmetries suggest distributed deviations in cortical maturation. Functional fetal MRI studies further demonstrate atypical large-scale network organization prior to birth. Altered connectivity within cingulate, prefrontal, temporal, and cerebellar circuits has been prospectively associated with later autistic traits, indicating that network-level integration may diverge before behavioral symptoms emerge. Evidence from high-risk conditions, including isolated ventriculomegaly and tuberous sclerosis complex, reinforces the association between prenatal structural abnormalities and increased ASD risk. Conclusions: Current evidence suggests that structural and functional brain alterations identifiable by fetal MRI may precede the clinical manifestation of ASD. These findings support a model of ASD as a condition potentially rooted in prenatal neurodevelopmental divergence. However, larger, standardized, multicenter studies are required before fetal MRI biomarkers can be translated into predictive or clinical applications. Full article

Background: Observational fear, a form of empathic response to others’ distress, exhibits marked sex differences. Oxytocin (OT) is a key modulator of social and emotional behaviors, but its role in observational fear—and how this varies by sex and administration route—remains controversial. Methods: We studied behavioral responses in male and female mice during observational fear. We first blocked systemic oxytocin (OT) signaling with a peripheral antagonist. We then tested different routes of OT administration (intranasal, intraperitoneal). Further, we microinjected OT directly into the anterior insular cortex (AIC). Finally, we used a chemogenetics strategy to selectively activate or inhibit OT neurons. Results: Male mice exhibited sustained freezing behavior and elevated corticosterone levels in response to observational fear. In contrast, females more quickly resumed baseline activity levels and showed an increased number of interactions. Systemic blockade of oxytocin (OT) signaling selectively reduced fear expression in males. Strikingly, intranasal OT administration elicited heightened fear-related responses in both sexes, whereas intraperitoneal OT administration induced anxiolytic-like effects. Direct OT microinjection into the anterior insular cortex (AIC) produced sex-divergent reductions in fear responses: decreasing freezing duration in males and reducing avoidance behaviors in females. Chemogenetic activation of OTergic neurons replicated these anxiolytic effects, while inhibition had no effect. Conclusions: OT bidirectionally regulates observational fear in a sex-, route-, and site-specific manner, challenging the simplistic view of OT as universally prosocial. The AIC is a critical node in empathetic fear circuits. These findings underscore the necessity for precision in targeting the OT system for treating stress-related psychiatric disorders. Full article

Sympathetic remodeling following myocardial infarction (MI) is a critical mechanism underlying the development of malignant arrhythmias and sudden cardiac death (SCD). The cardiac sympathetic nervous system functions as a multi-level regulatory network, integrating centers from the cerebral cortex (e.g., the insular lobe and anterior cingulate gyrus), subcortical structures (e.g., the paraventricular nucleus of the hypothalamus), and brainstem nuclei (e.g., the rostral ventrolateral medulla and nucleus of the solitary tract), down to the peripheral ganglia. Post-MI, this entire neural axis undergoes significant remodeling, which manifests as neuroinflammation in the central nervous system, alongside peripheral sympathetic nerve sprouting and heterogeneous hyperinnervation. This article provides a systematic review of the anatomical architecture of the cardiac sympathetic nerve and the regulatory mechanisms of sympathetic remodeling at various levels of the central nervous system after MI. It particularly focuses on key signaling pathways—including the TLR4/MyD88/NF-κB and P2X7R/NLRP3 inflammasome pathways, as well as GABAergic inhibition within the paraventricular nucleus—in addition to the peripheral remodeling mechanisms within the stellate ganglia. By synthesizing insights from these studies, this review offers a novel perspective for understanding the neuroimmune mechanisms of post-MI malignant arrhythmias and provides a theoretical foundation for elucidating the mechanisms of SCD in clinical practice. Full article

Major depressive disorder is a mental health condition characterized by ongoing feelings of sadness, trouble focusing or making decisions, and a frequent sense of fatigue or hopelessness that lasts for a prolonged period. If left undiagnosed, it can have serious consequences, including suicide. This study proposes a 3D convolutional neural network model to detect major depressive disorder using 3D grey matter images from magnetic resonance imaging. The proposed 3D convolutional architecture comprises multiple hierarchical convolutional and pooling layers, designed to automatically learn spatial patterns from magnetic resonance imaging data. The model was optimized via Bayesian hyperparameter tuning, achieving an accuracy of 72.26%, an area under the receiver operating characteristic curve of 0.80, and an area under the precision–recall curve of 0.81 on a large multisite dataset comprising 1276 patients and 1104 healthy controls. Gradient-weighted class activation mapping is utilized to find brain regions associated with major depressive disorder. From this study, six regions were identified, namely, the frontal lobe, parietal lobe, temporal lobe, thalamus, insular cortex and corpus callosum which may be affected by major depressive disorder. Full article

Background/Objectives: There is increasing interest within cognitive neuro-surgery in preserving domains not traditionally assessed during awake surgery. The study aims at proposing a specific protocol to assist surgical resection in right temporal areas. Patients were not evaluated during direct cortical stimulation; instead, assessments occurred during the resection itself. The real-time neuropsychological testing (RTNT) protocol employed tasks evaluating visuospatial and social cognition, administered repeatedly throughout the resection using varied items. Methods: A consecutive series of 24 patients (median age 44) performed RTNT. The aim of RTNT is to maintain high accuracy through resection. Lesions in the right temporal cortex and the subcortical white matter beneath can cause deficits; accordingly, not all of our patients had pre-surgery performance within the normal range. In this case, the aim of RTNT is to maintain the not perfect pre-surgery level. Results: We found a statistically significant between-tasks difference in the patients’ median values (across RTNT runs), in their minimum score reached during resection, and in the delta between performance at the last vs. the first RTNT run. The tasks that varied belonged to visual–spatial attention (landmark task), face processing (recognition of famous faces), and social cognition (theory of mind). The outcome was measured by pre- vs. post-surgery neuropsychological score comparison. The number of patients scoring below the normal range did not significantly differ between post- vs. pre-intervention. Conclusions: Results demonstrated the feasibility of implementing a continuous monitoring protocol during the resection phase, and the potential of the selected tasks to assess visuospatial and social functions associated with the non-dominant (right) hemisphere. Full article

The insular cortex has emerged as a key region implicated in a wide array of cognitive, emotional, and sensory processes. The anterior part of the insula (AIC) is central to emotional awareness, decision-making, and interoception, while the posterior insula (PIC) is more associated with somatosensory processing. The insula acts as a functional hub within the salience network and integrates homeostatic, affective, and cognitive information; thus, its role in different mental disorders seems to be prominent. Altered structure and connectivity of the insular cortex are evident in several psychiatric conditions. In schizophrenia, reductions in insular volume—especially on the left—correlate with hallucinations, emotional dysregulation, and cognitive deficits. Bipolar and major depressive disorders exhibit AIC volume loss and aberrant connectivity patterns linked to impaired affect regulation and interoceptive awareness. Anxiety disorders show functional hyperactivity of the insula, especially in response to fear-inducing stimuli, though findings on structural changes are mixed. Overall, growing evidence underscores the insular cortex’s central role in psychiatric pathophysiology and highlights its potential as a target for future diagnostic and therapeutic strategies. Full article

Background/Objectives: The insula is a deep, functionally heterogeneous region involved in various pathological conditions. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising therapeutic avenue for neuromodulation, yet very few studies have directly investigated its effects on insular activity. Moreover, empirical evidence of target engagement of this region remains scarce. This study aimed to stimulate the insula with rTMS and assess blood oxygen level-dependent (BOLD) signal modulation using concurrent functional magnetic resonance imaging (fMRI). Methods: Ten participants were recruited, six of whom underwent a single session of 5 Hz high-frequency rTMS over the right insular cortex inside the MRI scanner. Stimulation was delivered using a compatible MRI-B91 TMS coil. Stimulation consisted of 10 trains of 10 s each, with a 50 s interval between trains. Frameless stereotactic neuronavigation ensured precise targeting. Paired t-tests were used to compare the mean BOLD signal obtained between stimulation trains with resting-state fMRI acquired before the rTMS stimulation session. A significant cluster threshold of q < 0.01 (False Discovery Rate; FDR) with a minimum cluster size of 10 voxels was applied. Results: Concurrent rTMS-fMRI revealed the significant modulation of BOLD activity within insular subregions. Increased activity was observed in the anterior, middle, and middle-inferior insula, while decreased activity was identified in the ventral anterior and posterior insula. Additionally, two participants reported transient dysgeusia following stimulation, which provides further evidence of insular modulation. Conclusions: These findings provide preliminary evidence that rTMS can modulate distinct subregions of the insular cortex. The combination of region-specific BOLD responses and stimulation-induced dysgeusia supports the feasibility of using rTMS to modulate insular activity. Full article

Background/Objectives: Major Depression (MD) is a common disorder that has significant social and economic impacts. Approximately 30% of all MD patients are refractory to common treatments, representing a major obstacle to managing the impacts of depression. One potential explanation for the incomplete treatment efficacy in MD is a substantial divergence in the mechanisms and brain networks involved in different subtypes of the disorder. The aim of this study was to identify novel brain regional targets for MD clinical screening using a gene-informed approach. Methods: A new analysis pipeline, called “Analysis Tool for Local Association of Neuronal Transcript Expression” (ATLANTE), was generated and validated. The pipeline identifies brain regions based on the shared high expression of user-generated gene lists; in this study, the pipeline was applied to discover brain regions that may be significant to MD. Results: Nine discrete brain regions of interest to MD were identified, including the temporal pole, anterior transverse temporal gyrus (Heschl’s gyrus), olfactory tubercle, ventral tegmental area, postcentral gyrus, CA1 of the hippocampus, olfactory area, perirhinal gyrus, and posterior insular cortex. The application of network and clustering analyses identified genes of special importance, including, most notably, PRKN. Conclusions: This study provides two major insights. The first is that several brain regions have unique MD-associated genetic architectures, indicating a potential explanation for subtype-specific dysfunction. The second insight is that the PRKN gene, which is strongly associated with Parkinson’s disease, is a key player amongst the MD-associated genes. These findings reveal novel targets for the clinical screening of depression and reinforce a mechanistic connection between MD and Parkinson’s disease. Full article

Background/Objective: The Trail Making Test (TMT) is a widely used neuropsychological tool to assess processing speed (Part A) and executive function (Part B). However, the neuroanatomical substrates underlying its Black & White variant (TMT-B&W) and the influence of demographic factors remain poorly understood. This study aimed to identify gray matter (GM) correlates of TMT-B&W performance across unadjusted and covariate-adjusted models in cognitively healthy adults. Methods: In this cross-sectional study, 87 participants (40–80 years) underwent structural magnetic resonance imaging (MRI) and completed TMT-B&W. Whole-brain voxel-based morphometry (VBM) was conducted using FreeSurfer for preprocessing and Computational Anatomy Toolbox (CAT12)/Statistical Parametric Mapping (SPM12) for analysis. Two voxel-wise regression models (unadjusted and adjusted for age, education, gender, and total intracranial volume (TICV)) assessed GM associations with TMT-B&W-A-B performance. Statistical thresholds were voxel-level p < 0.001 (uncorrected) and cluster-level Family-Wise Error (FWE) correction (p < 0.001). Results: In unadjusted models, TMT-B&W-A performance correlated with GM reductions in the right orbitofrontal cortex (T = 42.64, equivk = 515.60, representing peak voxel level T-statistic and cluster size in voxels), while TMT-B&W-B linked to the right insular cortex (T = 50.65, equivk = 515.50). After adjustment, both tasks converged on the left thalamus (TMT-A: T = 8.05, equivk = 594; TMT-B: T = 8.11, equivk = 621), with TMT-B&W-B showing a denser thalamic cluster. Demographic covariates attenuated cortical associations, revealing thalamic integration as a shared mechanism. Conclusions: The thalamus emerges as a critical hub for TMT-B&W performance when accounting for demographic variation, while distinct cortical regions mediate task-specific demands in unadjusted models. These findings support the TMT-B&W as a practical, low-cost neurobehavioral marker of brain integrity in older populations. Full article

Background/Objectives: Fibromyalgia (FM) is a chronic pain condition that includes symptoms of hyperalgesia and has an unknown etiology. This study aimed to further investigate the underlying neural signaling mechanisms and their relation to observed blood oxygenation-level dependent (BOLD) signal increases at the onset of functional magnetic resonance imaging (fMRI) runs. Methods: The possible neural mechanisms were first explored by reviewing the current literature. The second component of this study involved a voxel-by-voxel analysis of BOLD responses in all regions of the brain. The fMRI data were obtained from a previous study of participants with and without fibromyalgia during fMRI runs involving either a noxious heat pain stimulus or no stimulus. Results: The literature review indicates that no single factor can explain the initial BOLD signal rise observed in FM but that there are likely multiple interacting influences. These include physiological dysregulation via mechanisms, such as oxidative stress, mitochondrial dysfunction, and cytokine activity, and may involve the sympathetic nervous system. The analysis of BOLD responses demonstrated that the initial BOLD rises occur specifically in gray matter regions and are largest in regions involved with pain processing, including the right insular cortex and periaqueductal gray region. Moreover, the BOLD rise is significantly larger in people with FM prior to the application of a noxious stimulus. Conclusions: The initial rise in BOLD response demonstrates heightened metabolic demand that is exaggerated in people with FM. It appears to be influenced by cognitive factors such as anticipation and may reflect neural dysregulation, possibly involving autonomic signaling. Full article

Background/Objectives: The human insula is a key structure implicated in integrating internal states and external food cues, yet its precise role remains unclear, in part due to the temporal limitations of neuroimaging techniques like fMRI. To address this gap, we conducted an exploratory study using an intracranial EEG (iEEG) to investigate how the insula encodes both the subjective and objective properties of food-related stimuli, and how this encoding is modulated by hunger and satiety. Methods: Eight patients with drug-resistant epilepsy undergoing a pre-surgical evaluation between 2017 and 2023 participated in this study. Depth electrodes implanted in the insular cortex recorded event-related potentials (ERPs) in response to visual food cues. The sessions were conducted in two prandial states (hungry and satiated). The subjective ratings (appetite and palatability) and objective nutritional values (e.g., calories, carbohydrates) were collected and analyzed using paired t-tests, MANOVAs, and partial correlations. Results: Hunger increased the ERP amplitudes within the 350–450 ms interval, consistent with the EPIC model and positive alliesthesia, while satiety unexpectedly enhanced the early responses (150–250 ms). Importantly, the neural activity related to nutritional values was largely uncorrelated with the subjective ratings, suggestive of distinct processing streams. The mid- and posterior insula showed greater sensitivity to both subjective and nutritional information than the anterior insula. Conclusions: These findings offer novel electrophysiological insights into how the insula differentiates between implicit and explicit food-related signals, depending on the homeostatic state. This work supports a dual-route model of food cue processing, and may inform interventions targeting insular activity in disordered eating. Full article

Background/Objectives: Intracranial macroelectrode implantation is a pivotal clinical tool in the evaluation of drug-resistant epilepsy, allowing further insights into the localization of the epileptogenic zone and the delineation of eloquent cortical regions through cortical stimulation. Additionally, it provides an avenue to study brain functions by analyzing cerebral responses during neuropsychological paradigms. By combining macroelectrodes with microelectrodes, which allow recording the activity of individual neurons or smaller neural clusters, recordings could provide deeper insights into neuronal microcircuits and the brain’s transitions in epilepsy and contribute to a better understanding of neuropsychological functions. In this study, one or two hybrid macro-micro electrodes were implanted in the anterior-inferior insular region in patients with refractory epilepsy. We report our experience and share some preliminary results; we also provide some recommendations regarding the implantation procedure for hybrid electrodes in the insular cortex. Methods: Stereoelectroencephalography was performed in 13 patients, with one or two hybrid macro-microelectrodes positioned in the insular region in each patient. Research neuropsychological paradigms could not be implemented in two patients for clinical reasons. In total, 23 hybrid macro-microelectrodes with eight microcontacts each were implanted, of which 20 were recorded. Spiking activity was detected and assessed using WaveClus3. Results: No spiking neural activity was detected in the microcontacts of the first seven patients. After iterative refinement during this process, successful recordings were obtained from 13 microcontacts in the anterior-inferior insula in the last four patients (13/64, 20.3%). Hybrid electrode implantation was uneventful with no complications. Obstacles included the absence of spiking activity signals, unsuccessful microwire dispersion, and the interference of environmental electrical noise in recordings. Conclusions: Human microelectrode recording presents a complex array of challenges; however, it holds the potential to facilitate a more comprehensive understanding of individual neuronal attributes and their specific stimulus responses. Full article