Human Orbitofrontal Cortex Research Articles

Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease

Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The risk for neurodegenerative disorders is also increased in individuals with psychiatric disorders. Here, we characterized age-related transcriptomic changes in the brain by profiling ~800,000 nuclei from the orbitofrontal cortex from 87 individuals with and without psychiatric diagnoses and replicated findings in an independent cohort with 32 individuals. Aging affects all cell types, with LAMP5+LHX6+ interneurons, a cell-type abundant in primates, by far the most affected. Disrupted synaptic transmission emerged as a convergently affected pathway in aged tissue. Age-related transcriptomic changes overlapped with changes observed in Alzheimer’s disease across multiple cell types. We find evidence for accelerated transcriptomic aging in individuals with psychiatric disorders and demonstrate a converging signature of aging and psychopathology across multiple cell types. Our findings shed light on cell-type-specific effects and biological pathways underlying age-related changes and their convergence with effects driven by psychiatric diagnosis.

Temporal interference electrical neurostimulation at 20 Hz beat frequency leads to increased fMRI BOLD activation in orbitofrontal cortex in humans

Temporal interference electrical neurostimulation (TI) is a relatively new method of non-invasive neurostimulation that may be able to stimulate deep brain regions without stimulating the overlying superficial regions. Although some recent studies have demonstrated the success of TI in modulating task-induced BOLD activity in humans, there is limited information on intended and off-target effects of TI during resting-state. We simultaneously performed TI stimulation with the set-up optimized for maximum focality in the left caudate and collected resting-state fMRI data to investigate the effects of TI on human BOLD signals. We found increased BOLD activation in a part of the mid-orbitofrontal cortex (OFC) and parahippocampal gyrus. Results indicate that TI can induce increased BOLD activation in the region that receives the highest magnitude of TI amplitude modulation in humans, with good safety and tolerability profiles. We also show the limits of spatial precision and explore the nature and causes of additional off-target effects. TI may be a promising approach for addressing questions about the causal role of deep brain structures in human cognition and may also afford new clinical treatments.

Neuronal-specific methylome and hydroxymethylome analysis reveal significant loci associated with alcohol use disorder.

Background: Alcohol use disorder (AUD) is a complex condition associated with adverse health consequences that affect millions of individuals worldwide. Epigenetic modifications, including DNA methylation (5mC), have been associated with AUD and other alcohol-related traits. Epigenome-wide association studies (EWAS) have identified differentially methylated genes associated with AUD in human peripheral and brain tissue. More recently, epigenetic studies of AUD have also evaluated DNA hydroxymethylation (5hmC) in the human brain. However, most of the epigenetic work in postmortem brain tissue has examined bulk tissue. In this study, we investigated neuronal-specific 5mC and 5hmC alterations at CpG sites associated with AUD in the human orbitofrontal cortex (OFC). Methods: Neuronal nuclei from the OFC were evaluated in 34 human postmortem brain samples (10 AUD, 24 non-AUD). Reduced representation oxidative bisulfite sequencing was used to assess 5mC and 5hmC at the genome-wide level. Differential 5mC and 5hmC were evaluated using the methylKit R package and significance was set at false discovery rate < 0.05 and differential methylation > 2. Functional enrichment analyses were performed, and gene-level convergence was evaluated in an independent dataset that assessed 5mC and 5hmC of AUD in bulk cortical tissue. Results: We identified 417 5mC and 3635hmC significant differential CpG sites associated with AUD, with 59% in gene promoters. Some of the identified genes have been previously implicated in alcohol consumption, including SYK, DNMT3A for 5mC, GAD1, DLX1, DLX2, for 5hmC and GATA4 in both. Convergence with a previous AUD 5mC and 5hmC study was observed for 28 genes. We also identified 5 and 35 differential regions for 5mC and 5hmC, respectively. Lastly, GWAS enrichment analysis showed an association with AUD for differential 5mC genes. Discussion: This study reveals neuronal-specific methylome and hydroxymethylome dysregulation associated with AUD, identifying both previously reported and potentially novel gene associations with AUD. Our findings provide new insights into the epigenomic dysregulation of AUD in the human brain.

A Neural Mechanism in the Human Orbitofrontal Cortex for Preferring High-Fat Foods Based on Oral Texture.

Although overconsumption of high-fat foods is a major driver of weight gain, the neural mechanisms that link the oral sensory properties of dietary fat to reward valuation and eating behavior remain unclear. Here we combine novel food-engineering approaches with functional neuroimaging to show that the human orbitofrontal cortex (OFC) translates oral sensations evoked by high-fat foods into subjective economic valuations that guide eating behavior. Male and female volunteers sampled and evaluated nutrient-controlled liquid foods that varied in fat and sugar ("milkshakes"). During oral food processing, OFC activity encoded a specific oral-sensory parameter that mediated the influence of the foods' fat content on reward value: the coefficient of sliding friction. Specifically, OFC responses to foods in the mouth reflected the smooth, oily texture (i.e., mouthfeel) produced by fatty liquids on oral surfaces. Distinct activity patterns in OFC encoded the economic values associated with particular foods, which reflected the subjective integration of sliding friction with other food properties (sugar, fat, viscosity). Critically, neural sensitivity of OFC to oral texture predicted individuals' fat preferences in a naturalistic eating test: individuals whose OFC was more sensitive to fat-related oral texture consumed more fat during ad libitum eating. Our findings suggest that reward systems of the human brain sense dietary fat from oral sliding friction, a mechanical food parameter that likely governs our daily eating experiences by mediating interactions between foods and oral surfaces. These findings identify a specific role for the human OFC in evaluating oral food textures to mediate preference for high-fat foods.SIGNIFICANCE STATEMENT Fat and sugar enhance the reward value of food by imparting a sweet taste and rich mouthfeel but also contribute to overeating and obesity. Here we used a novel food-engineering approach to realistically quantify the physical-mechanical properties of high-fat liquid foods on oral surfaces and used functional neuroimaging while volunteers sampled these foods and placed monetary bids to consume them. We found that a specific area of the brain's reward system, the orbitofrontal cortex, detects the smooth texture of fatty foods in the mouth and links these sensory inputs to economic valuations that guide eating behavior. These findings can inform the design of low-calorie fat-replacement foods that mimic the impact of dietary fat on oral surfaces and neural reward systems.

Adaptor protein complex 2 in the orbitofrontal cortex predicts alcohol use disorder.

Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences. The inability of individuals with AUD to regulate drinking may involve functional deficits in cortical areas that normally balance actions that have aspects of both reward and risk. Among these, the orbitofrontal cortex (OFC) is critically involved in goal-directed behavior and is thought to maintain a representation of reward value that guides decision making. In the present study, we analyzed post-mortem OFC brain samples collected from age- and sex-matched control subjects and those with AUD using proteomics, bioinformatics, machine learning, and reverse genetics approaches. Of the 4,500+ total unique proteins identified in the proteomics screen, there were 47 proteins that differed significantly by sex that were enriched in processes regulating extracellular matrix and axonal structure. Gene ontology enrichment analysis revealed that proteins differentially expressed in AUD cases were involved in synaptic and mitochondrial function, as well as transmembrane transporter activity. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and social interactions. Machine learning analysis of the post-mortem OFC proteome revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Using a reverse genetics approach to validate a target protein, we found that prefrontal Ap2a1 expression significantly correlated with voluntary alcohol drinking in male and female genetically diverse mouse strains. Moreover, recombinant inbred strains that inherited the C57BL/6J allele at the Ap2a1 interval consumed higher amounts of alcohol than those that inherited the DBA/2J allele. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms and proteins that control drinking in individuals with AUD.

Electrophysiological signatures of inequity-dependent reward encoding in the human OFC

Social decision making requires the integration of reward valuation and social cognition systems, both dependent on the orbitofrontal cortex (OFC). How these two OFC functions interact is largely unknown. We recorded intracranial activity from the OFC of ten patients making choices in a social context where reward inequity with a social counterpart varied and could be either advantageous or disadvantageous. We find that OFC high-frequency activity (HFA; 70-150Hz) encodes self-reward, consistent with previous reports. We also observe encoding of the social counterpart's reward, as well as the type of inequity being experienced. Additionally, we find evidence of inequity-dependent reward encoding: depending on the type of inequity, electrodes rapidly and reversibly switch between different reward-encoding profiles. These results provide direct evidence for encoding of self- and other rewards in the human OFC and highlight the dynamic nature of encoding in the OFC as a function of social context.

Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this is mostly limited to DNA methylation (5mC). DNA hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD in a male cohort, integrating neuronal-specific 5mC and 5hmC as well as gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD = 26). Single locus methylomic analysis and co-methylation analysis showed a higher number of OUD-associated genes and gene networks for 5hmC compared to 5mC; these were enriched for GPCR, Wnt, neurogenesis, and opioid signaling. 5hmC marks also showed a higher correlation with gene expression patterns and enriched for GWAS of psychiatric traits. Drug interaction analysis revealed interactions with opioid-related drugs, some used as OUD treatments. Our multi-omics findings suggest an important role of 5hmC and reveal loci epigenetically dysregulated in OFC neurons of individuals with OUD.

Epigenetic silencing of OR and TAS2R genes expression in human orbitofrontal cortex at early stages of sporadic Alzheimer’s disease

Modulation of brain olfactory (OR) and taste receptor (TASR) expression was recently reported in neurological diseases. However, there is still limited evidence of these genes’ expression in the human brain and the transcriptional regulation mechanisms involved remain elusive. We explored the possible expression and regulation of selected OR and TASR in the human orbitofrontal cortex (OFC) of sporadic Alzheimer’s disease (AD) and non-demented control specimens using quantitative real-time RT-PCR and ELISA. Global H3K9me3 amounts were measured on OFC total histone extracts, and H3K9me3 binding at each chemoreceptor locus was examined through native chromatin immunoprecipitation. To investigate the potential interactome of the repressive histone mark H3K9me3 in OFC specimens, native nuclear complex co-immunoprecipitation (Co-IP) was combined with reverse phase-liquid chromatography coupled to mass spectrometry analysis. Interaction between H3K9me3 and MeCP2 was validated by reciprocal Co-IP, and global MeCP2 levels were quantitated. We found that OR and TAS2R genes are expressed and markedly downregulated in OFC at early stages of sporadic AD, preceding the progressive reduction in their protein levels and the appearance of AD-associated neuropathology. The expression pattern did not follow disease progression suggesting transcriptional regulation through epigenetic mechanisms. We discovered an increase of OFC global H3K9me3 levels and a substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages of AD, ultimately lost at advanced stages. We revealed the interaction between H3K9me3 and MeCP2 at early stages and found that MeCP2 protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R transcriptional regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.Graphical abstract

Human orbitofrontal cortex signals decision outcomes to sensory cortex during behavioral adaptations

The ability to respond flexibly to an ever-changing environment relies on the orbitofrontal cortex (OFC). However, how the OFC associates sensory information with predicted outcomes to enable flexible sensory learning in humans remains elusive. Here, we combine a probabilistic tactile reversal learning task with functional magnetic resonance imaging (fMRI) to investigate how lateral OFC (lOFC) interacts with the primary somatosensory cortex (S1) to guide flexible tactile learning in humans. fMRI results reveal that lOFC and S1 exhibit distinct task-dependent engagement: while the lOFC responds transiently to unexpected outcomes immediately following reversals, S1 is persistently engaged during re-learning. Unlike the contralateral stimulus-selective S1, activity in ipsilateral S1 mirrors the outcomes of behavior during re-learning, closely related to top-down signals from lOFC. These findings suggest that lOFC contributes to teaching signals to dynamically update representations in sensory areas, which implement computations critical for adaptive behavior.

NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder.

Many disorders of the central nervous system (CNS), including alcohol use disorder (AUD), are associated with induction of proinflammatory neuroimmune signalling and neurodegeneration. In previous studies, we found increased expression of Toll-like receptors (TLRs), activated NF-κB p65 (RELA), and other proinflammatory signalling molecules. Proinflammatory NADPH oxidases generate reactive oxygen species, which are linked to neurodegeneration. We tested the hypothesis that AUD increased RELA activation increases NADPH oxidase-oxidative stress and endoplasmic reticulum (ER) stress cell death cascades in association with neuronal cell death in the human orbitofrontal cortex (OFC). In the AUD OFC, we report mRNA induction of several NADPH oxidases, the dual oxidase DUOX2, and the oxidative stress lipid peroxidation marker 4-HNE and the DNA oxidation marker 8-OHdG that correlate with RELA, a marker of proinflammatory NF-κB activation. This was accompanied by increased expression of the ER stress-associated regulator protein glucose-regulated protein 78 (GRP78), transmembrane sensors activating transcription factor 6 (ATF6), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and inositol-requiring kinase/endonuclease 1 (pIRE1), and the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Expression of NADPH oxidase-oxidative stress markers correlate with ER stress-associated molecules. Induction of oxidative stress and ER stress signalling pathways correlate with expression of cell death-associated caspases and neuronal cell loss. These data support the hypothesis that proinflammatory RELA-mediated induction of NADPH oxidase-oxidative stress and ER stress-associated signalling cascades is associated with neuronal cell death in the post-mortem human OFC of individuals with AUD.

The hippocampus, ventromedial prefrontal cortex, and episodic and semantic memory

The human ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex is implicated in reward and emotion, but also in memory. It is shown how the human orbitofrontal cortex connecting with the vmPFC and anterior cingulate cortex provide a route to the hippocampus for reward and emotional value to be incorporated into episodic memory, enabling memory of where a reward was seen. It is proposed that this value component results in primarily episodic memories with some value component to be repeatedly recalled from the hippocampus so that they are more likely to become incorporated into neocortical semantic and autobiographical memories. The same orbitofrontal and anterior cingulate regions also connect in humans to the septal and basal forebrain cholinergic nuclei, thereby helping to consolidate memory, and helping to account for why damage to the vMPFC impairs memory. The human hippocampus and vmPFC thus contribute in complementary ways to forming episodic and semantic memories.

The orbitofrontal cortex represents advantageous choice in the Iowa gambling task.

A good‐based model, the central neurobiological model of economic decision‐making, proposes that the orbitofrontal cortex (OFC) represents binary choice outcome, that is, the chosen good. A good is defined by a group of determinants characterizing the conditions in which the commodity is offered, including commodity type, cost, risk, time delay, and ambiguity. Previous studies have found that the OFC represents the binary choice outcome in decision‐making tasks involving commodity type, cost, risk, and delay. Real‐life decisions are often complex and involve uncertainty, rewards, and penalties; however, whether the OFC represents binary choice outcomes in a complex decision‐making situation, for example, Iowa gambling task (IGT), remains unclear. Here, we propose that the OFC represents binary choice outcome, that is, advantageous choice versus disadvantageous choice, in the IGT. We propose two hypotheses: first, the activity pattern in the human OFC represents an advantageous choice; and second, choice induces an OFC‐related functional network. Using functional magnetic resonance imaging and advanced machine‐learning tools, we found that the OFC represented an advantageous choice in the IGT. The OFC representation of advantageous choice was related to decision‐making performance. Choice modulated the functional connectivity between the OFC and the superior medial gyrus. In conclusion, the OFC represents an advantageous choice during the IGT. In the framework of a good‐based model, the results extend the role of the OFC to complex decision‐making situation when making a binary choice.

The orbitofrontal cortex of the sheep. Topography, organization, neurochemistry, digital tensor imaging and comparison with the chimpanzee and human

Areas dedicated to higher brain functions such as the orbitofrontal cortex (OFC) are thought to be unique to hominidae. The OFC is involved in social behavior, reward and punishment encoding and emotional control. Here, we focused on the putative corresponding area in the sheep to assess its homology to the OFC in humans. We used classical histology in five sheep (Ovis aries) and four chimpanzees (Pan troglodytes) as a six-layered-cortex primate, and Diffusion Tensor Imaging (DTI) in three sheep and five human brains. Nissl’s staining exhibited a certain alteration in cortical lamination since no layer IV was found in the sheep. A reduction of the total cortical thickness was also evident together with a reduction of the prevalence of layer one and an increased layer two on the total thickness. Tractography of the sheep OFC, on the other hand, revealed similarities both with human tracts and those described in the literature, as well as a higher number of cortico-cortical fibers connecting the OFC with the visual areas in the right hemisphere. Our results evidenced the presence of the basic components necessary for complex abstract thought in the sheep and a pronounced laterality, often associated with greater efficiency of a certain function, suggested an evolutionary adaptation of this prey species.

The human orbitofrontal cortex, vmPFC, and anterior cingulate cortex effective connectome: emotion, memory, and action.

The human orbitofrontal cortex, ventromedial prefrontal cortex (vmPFC), and anterior cingulate cortex are involved in reward processing and thereby in emotion but are also implicated in episodic memory. To understand these regions better, the effective connectivity between 360 cortical regions and 24 subcortical regions was measured in 172 humans from the Human Connectome Project and complemented with functional connectivity and diffusion tractography. The orbitofrontal cortex has effective connectivity from gustatory, olfactory, and temporal visual, auditory, and pole cortical areas. The orbitofrontal cortex has connectivity to the pregenual anterior and posterior cingulate cortex and hippocampal system and provides for rewards to be used in memory and navigation to goals. The orbitofrontal and pregenual anterior cortex have connectivity to the supracallosal anterior cingulate cortex, which projects to midcingulate and other premotor cortical areas and provides for action-outcome learning including limb withdrawal or flight or fight to aversive and nonreward stimuli. The lateral orbitofrontal cortex has outputs to language systems in the inferior frontal gyrus. The medial orbitofrontal cortex connects to the nucleus basalis of Meynert and the pregenual cingulate to the septum, and damage to these cortical regions may contribute to memory impairments by disrupting cholinergic influences on the neocortex and hippocampus.

Coexistence of sensory qualities and value representations in human orbitofrontal cortex

Despite the multiple regions and neural networks associated with value-based decision-making, the orbitofrontal cortex (OFC) is possible a particularly important one. Although the role of the OFC in reinforcer devaluation tasks, which assess the ability to represent identity, sensory qualities, and subjective values of the expected outcomes, has been established, the specific aspect represented in this area remains unclear. In this study, using functional magnetic resonance imaging, wherein participants rated the palatability of 128 food items using photographs, we investigated whether the human OFC represents object identity, sensory qualities, or value. Employing many items helped us dissociate object identity from sensory qualities and values; the inferred sensory qualities of identical items were manipulated by a change in metabolic state. Moreover, value differences between items were analytically controlled by employing a technique similar to age adjustment. The palatability ratings for food items significantly decreased after a meal. Using representational similarity analysis, we confirmed that the OFC represents value. Moreover, identical items were represented similarly in the lateral OFC in a given metabolic state; however, these representations were altered post-feeding. Importantly, this change was not explained by subjective value, suggesting that the OFC represents sensory quality and value, but not object identity.

Theta low-gamma phase amplitude coupling in the human orbitofrontal cortex increases during a conflict-processing task

Objective. The human orbitofrontal cortex (OFC) is involved in automatic response inhibition and conflict processing, but the mechanism of frequency-specific power changes that control these functions is unknown. Theta and gamma activity have been independently observed in the OFC during conflict processing, while theta–gamma interactions in other brain areas have been noted primarily in studies of memory. Within the OFC, it is possible that theta–gamma phase amplitude coupling (PAC) drives conflict processing. This study aims to characterize the coupled relationship between theta and gamma frequency bands in the OFC during conflict processing using a modified Stroop task. Approach. Eight epilepsy patients implanted with OFC stereotactic electroencephalography electrodes participated in a color-word modified Stroop task. PAC between theta phase and gamma amplitude was assessed to determine the timing and magnitude of neural oscillatory changes. Group analysis was conducted using a non-parametric cluster-permutation t-test on coherence values. Main results. Theta-low gamma (LG) PAC significantly increased in five out of eight patients during successful trials of the incongruent condition compared with the congruent condition. Significant increases in theta-LG PAC were most prominent during cue processing 200–800 ms after cue presentation. On group analysis, trial-averaged mean theta-LG PAC was statistically significantly greater in the incongruent condition compared to the congruent condition (p < 0.001, Cohen’s d = 0.51). Significance. For the first time, we report that OFC theta phase and LG amplitude coupling increases during conflict resolution. Given the delayed onset after cue presentation, OFC theta-LG PAC may contribute to conflict processing after conflict detection and before motor response. This explanation follows the hypothesis that global theta waves modulate local gamma signals. Understanding this relationship within the OFC will help further elucidate the neural mechanisms of human conflict resolution.

Neural Representations of Food-Related Attributes in the Human Orbitofrontal Cortex during Choice Deliberation in Anorexia Nervosa.

Decisions about what to eat recruit the orbitofrontal cortex (OFC) and involve the evaluation of food-related attributes such as taste and health. These attributes are used differently by healthy individuals and patients with disordered eating behavior, but it is unclear whether these attributes are decodable from activity in the OFC in both groups and whether neural representations of these attributes are differentially related to decisions about food. We used fMRI combined with behavioral tasks to investigate the representation of taste and health attributes in the human OFC and the role of these representations in food choices in healthy women and women with anorexia nervosa (AN). We found that subjective ratings of tastiness and healthiness could be decoded from patterns of activity in the OFC in both groups. However, health-related patterns of activity in the OFC were more related to the magnitude of choice preferences among patients with AN than healthy individuals. These findings suggest that maladaptive decision-making in AN is associated with more consideration of health information represented by the OFC during deliberation about what to eat.SIGNIFICANCE STATEMENT An open question about the OFC is whether it supports the evaluation of food-related attributes during deliberation about what to eat. We found that healthiness and tastiness information was decodable from patterns of neural activity in the OFC in both patients with AN and healthy controls. Critically, neural representations of health were more strongly related to choices in patients with AN, suggesting that maladaptive overconsideration of healthiness during deliberation about what to eat is related to activity in the OFC. More broadly, these results show that activity in the human OFC is associated with the evaluation of relevant attributes during value-based decision-making. These findings may also guide future research into the development of treatments for AN.

The hippocampus and orbitofrontal cortex jointly represent task structure during memory-guided decision making.

SUMMARYThe hippocampus, well known for its role in episodic memory, might also be an important brain region for extracting structure from our experiences in order to guide future decisions. Recent evidence in rodents suggests that the hippocampus supports decision making by representing task structure in cooperation with the orbitofrontal cortex (OFC). Here, we examine how the human hippocampus and OFC represent task structure during an associative learning task that required learning of both context-determined and context-invariant probabilistic associations. We find that after learning, hippocampal and lateral OFC representations differentiated between context-determined and context-invariant task structures. The degree of this differentiation within the hippocampus and lateral OFC is highly correlated. These results advance our understanding of the hippocampus and suggest that the hippocampus and OFC support goal-directed behavior by representing information that guides the selection of appropriate decision strategies.

Cortical and Subcortical Anatomy of the Orbitofrontal Cortex: A White Matter Microfiberdissection Study and Case Series

The literature on white matter anatomy underlying the human orbitofrontal cortex (OFC) is scarce in spite of its relevance for glioma surgery. To describe the anatomy of the OFC and of the underlying white matter fiber anatomy, with a particular focus on the surgical structures relevant for a safe and efficient orbitofrontal glioma resection. Based on anatomical and radiological data, the secondary objective was to describe the growth pattern of OFC gliomas. The study was performed on 10 brain specimens prepared according to Klingler's protocol and dissected using the fiber microdissection technique modified according to U.T., under the microscope at high magnification. A detailed stratigraphy of the OFC was performed, from the cortex up to the frontal horn of the lateral ventricle. The interposed neural structures are described together with relevant neighboring topographic areas and nuclei. Combining anatomical and radiological data, it appears that the anatomical boundaries delimiting and guiding the macroscopical growth of OFC gliomas are as follows: the corpus callosum superiorly, the external capsule laterally, the basal forebrain and lentiform nucleus posteriorly, and the gyrus rectus medially. Thus, OFC gliomas seem to grow ventriculopetally, avoiding the laterally located neocortex. The findings in our study supplement available anatomical knowledge of the OFC, providing reliable landmarks for a precise topographical diagnosis of OFC lesions and for perioperative orientation. The relationships between deep anatomic structures and glioma formations described in this study are relevant for surgery in this highly interconnected area.

Increased Toll-like Receptor-MyD88-NFκB-Proinflammatory neuroimmune signaling in the orbitofrontal cortex of humans with alcohol use disorder.

BackgroundMany brain disorders, including alcohol use disorder (AUD), are associated with induction of multiple proinflammatory genes. One aspect of proinflammatory signaling is progressive increases in expression across cells and induction of other innate immune genes. High‐mobility group box 1 (HMGB1) heteromers contribute to amplification by potentiating multiple proinflammatory responses, including Toll‐like receptors (TLRs). TLR signaling recruits coupling proteins linked to nuclear transcription factors that induce proinflammatory cytokines and chemokines and their respective receptors. We tested the hypothesis that AUD induction of TLR expression increases levels of proinflammatory genes and cellular signaling cascades in association with neurodegeneration in the orbitofrontal cortex (OFC).MethodsPostmortem human OFC tissue samples (n = 10) from males diagnosed with AUD were compared to age‐matched moderate drinking controls (CON). Neuroimmune signaling molecules were assessed using immunohistochemistry for protein and reverse transcription polymerase chain reaction for messenger RNA (mRNA).ResultsIn the AUD OFC, we report induction of the endogenous TLR agonist HMGB1 as well as all TLRs assessed (i.e., TLR2‐TLR9) except TLR1. This was accompanied by increased expression of the TLR adaptor protein myeloid differentiation primary response 88 (MyD88), activation of the proinflammatory nuclear transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), and downstream induction of proinflammatory cytokines, chemokines, and their corresponding receptors. Several of these proinflammatory signaling markers are expressed in glia and neurons. The induction of HMGB1‐TLR‐MyD88‐NFκB proinflammatory signaling pathways correlates with neurodegeneration (i.e., Fluoro‐Jade B), lifetime alcohol consumption, and age of drinking onset.ConclusionThese data implicate the induction of HMGB1‐TLR‐MyD88‐NFκB cascades through coordinated glial and neuronal signaling as contributors to the neurodegeneration seen in the postmortem human OFC of individuals with AUD.