Medial Orbitofrontal Cortex Research Articles

BDNF rs6265 single-nucleotide polymorphism is involved in levodopa-induced dyskinesia in Parkinson's disease via its regulation of the cortical thickness of the left postcentral gyrus.

Brain-derived neurotrophic factor (BDNF) gene rs6265 single-nucleotide polymorphism (SNP) is thought to be involved in neuroplasticity and influence the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). This study aimed to determine how the BDNF rs6265 SNP regulates cortical thickness and to investigate the association between BDNF and the pathological mechanisms of LID in PD. This cross-sectional study recruited 75 patients with PD, including 37 patients with LID and 38 patients without LID, and 33 healthy controls. All the participants underwent T1-weighted magnetic resonance imaging (MRI) scans, clinical evaluations, and BDNF rs6265 genotyping. Two-way factorial analysis of covariance (ANCOVA) was used to explore the primary effects of disease status, rs6265 genotype, and their interactions on cortical thickness. Associations between cortical thickness in the regions of the brain affected by disease status-genotype interactions and clinical symptoms were detected using Spearman's rank-order correlation. Receiver operating characteristic (ROC) curve analysis was used to test cortical thickness measurements as an indicator of LID. The main effects of disease status were observed in the right pars orbitalis (F=4.229, P=0.017), medial orbitofrontal cortex (F=3.639, P=0.030), and left banks superior temporal sulcus (F=3.172, P=0.046). The left pars orbitalis (F=4.541, P=0.036) and lingual gyrus (F=4.307, P=0.041) were thicker in carriers of the CC genotype than in carriers of the TC/TT genotype. Interaction between disease status and genotype showed that in the LID group, carriers of the CC genotype had a thicker left postcentral gyrus (mean difference =0.103, 95% confidence interval, 0.036 to 0.107, Bonferroni-corrected P<0.005) than did carriers of the TC/TT genotype, whereas no difference was found in the non-LID and healthy control (HC) groups. In carriers of the CC genotype, the cortical thickness of the left postcentral gyrus could identify whether patients with PD had LID, with an area under the receiver operating curve (AUC) of 0.757 (P=0.033, optimal cut-off =2.102). The cortical thickness of the left postcentral gyrus was also positively correlated with the Unified Dyskinesia Rating Scale (UDysRS) score in the LID-CC subgroup (r=0.825, P=0.001). The BDNF rs6265 SNP might be associated with dyskinesia symptoms in patients with PD and LID through its regulation of cortical thickness in the left postcentral gyrus.

No Consistent Evidence for Brain Volumetric Correlates of Resilience in Two Independent Cohort Studies

IntroductionChildhood adversities have been associated with long-lasting brain morphological differences and poor psychological outcomes over the lifespan. Evidence with regard to protective factors counteracting the detrimental effect of childhood adversity on neurobiology is scarce.ObjectivesTherefore, we examined the interplay of childhood adversity with multiple protective factors in relation to brain morphology in a child and an adult cohort.MethodsWe analyzed data from two epidemiological longitudinal birth cohorts, the Generation R Study (N=3,008) and the Mannheim Study of Children at Risk (MARS) (N=179). Cumulative exposure to 12 adverse events (such as physical and sexual abuse), and the presence of protective factors, including child temperament, cognition, self-esteem, friendship quality and maternal sensitivity were assessed at different time points during childhood. Anatomical scans were acquired at the ages of 9-11 years in Generation R and at 25 years in MARS.ResultsChildhood adversity was related to smaller global brain volumes in Generation R, with similar effect sizes observed for the cerebellar volume in MARS. While small interaction effects between adversity and protective factors were found on the medial orbitofrontal cortex, the cerebellum and the amygdala in either cohort study, no interactions were consistent across cohorts or survived correction for multiple comparisons.ConclusionsWe found no consistent or strong evidence for interaction effects between multiple protective factors and childhood adversities on brain structure in a child and an adult cohort study. Instead, small interaction effects were found in either children or adults warranting further investigation and more fine-grained analyses.DisclosureTB:consultancy for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Novartis, Shire; conference support by Lilly, Medice, Novartis, Shire; clinical trials by Shire and Viforpharma; royalties by Hogrefe, Kohlhammer, CIP Medien, Oxford University Press

Gender Differences in Hippocampal/Parahippocampal Functional Connectivity Network in Patients Diagnosed with Chronic Insomnia Disorder.

BackgroundGender differences in hippocampal and parahippocampal gyrus (HIP/PHG) volumes have been reported in sleep disorders. Therefore, this study investigated the moderating effect of gender on the relationship between chronic insomnia disorder (CID) and the HIP/PHG functional connectivity (FC) network.MethodsFor this study, 110 patients diagnosed with CID (43 men and 67 women) and 60 matched good sleep control (GSC) (22 men and 38 women) were recruited. These participants underwent resting-state functional magnetic resonance imaging scans, after which a 2 × 2 (diagnosis × gender) analysis of variance was used to detect the main and interactive effect of insomnia and gender on their HIP/PHG FC networks.ResultsAlthough the main effect of insomnia on the HIP FC network was observed in the bilateral cerebellar tonsil, superior frontal gyrus, and the medial orbitofrontal cortex, effects on the PHG FC network were observed in the bilateral HIP and amygdala. In contrast, the main effect of gender on the HIP FC network was observed in the right cerebellum posterior lobe, the dorsolateral prefrontal cortex (DLPFC), and the supplemental motor area. Of note, the interactive effect of both insomnia and gender was observed in FCs between the right HIP and the dorsal anterior cingulate cortex, and then between the right PHG and DLPFC. Moreover, the FC between the right PHG and left DLPFC was positively associated with anxiety scores in the female patients with CID.ConclusionOur study identified that gender differences in brain connectivity existed between the HIP/PHG and executive control network in patients diagnosed with CID, these results will eventually extend our understanding of the important role that gender plays in the pathophysiology of CID.

The medial orbitofrontal cortex governs reward-related circuits in an age-dependent manner.

Nucleus accumbens (NAc) neurons integrate excitatory inputs from cortical and limbic structures, contributing to critical cognitive functions, including decision-making. As these afferents mature from adolescence through adulthood, incoming signals to the NAc may summate differently between age groups. Decision-making evaluates both reward and risk before action selection, suggesting an interplay between reward- and risk-related circuits. Medial orbitofrontal cortex (MO)-NAc circuits permit risk assessment behaviors and likely underlie risk information incorporation. As adolescents make reward-centric choices regardless of risk, we hypothesized the impact of MO activity alters reward-related NAc circuits in an age-dependent manner. To test this hypothesis, we used single-unit electrophysiology to measure MO train stimulation's effect on reward-related pathways, specifically the basolateral amygdala (BLA)-NAc circuit, in adult and adolescent rats. MO train stimulation altered the strength but not the timing of BLA-NAc interactions in a frequency-dependent manner. In adults, MO train stimulation produced a frequency-dependent, bidirectional effect on BLA-evoked NAc AP probability. Contrastingly, MO train stimulation uniformly attenuated BLA-NAc interactions in adolescents. While the mature MO can govern reward-related circuits in an activity-dependent manner, perhaps to adapt to positive or negative decision-making outcomes, the adolescent MO may be less able to bidirectionally impact reward-related pathways resulting in biased decision-making.

Fluorodeoxyglucose positron emission tomography scans in patients with alcohol use disorder.

Diminished uptake of fluorodeoxyglucose (FDG) has been observed in patients with alcohol use disorder (AUD) but little statistical contrast of the regional brain deficits has been undertaken. This study examined prefrontal cortex inter-regional Brodmann area differences to delineate patterns associated with behavioral, neurotransmitter, and general toxicity hypotheses of cerebral involvement in AUD. We obtained data from FDG positron emission tomography (PET) and anatomical magnetic resonance imaging (MRI) for 87 patients with AUD and 41 age- and sex-matched healthy volunteers. Patients were alcohol dependent and had negative breathalyzer tests at the time of imaging. They were assessed with the Beck Depression Inventory, Alcohol Urge Questionnaire, Obsessive Compulsive Drinking Scale, Spielberger State/Trait Anxiety Scale, Buss-Durkee Hostility Inventory, and the Drinker Inventory of Consequences (DrInC). PET images were co-registered to MRI and both voxel×voxel statistical mapping and stereotaxic regions of interest were obtained. Compared with healthy volunteers, patients with AUD had lower relative metabolic rates in the frontal, temporal, and parietal lobes, localizable most prominently to the dorsolateral and nearly all orbital prefrontal cortex, superior temporal gyrus, and inferior parietal lobule. In contrast, metabolic rates in the medial orbitofrontal and anterior cingulate cortex, and the subcortical structures (thalamus, cerebellum, ventral striatum, and the dorsal raphe nucleus) in patients were significantly greater. The severity of alcohol-related consequences as assessed by the DrInC scale was most highly associated with lower metabolism in the caudate, dorsolateral prefrontal, frontopolar, and anteroposterior cingulate cortex. Despite widespread metabolic abnormalities, decreases in AUD were most marked in frontal executive areas, consistent with diminished impulse control, and increases were most prominent in the striatum and cingulate areas, consistent with a suppressed reward system.

Associations between aerobic exercise and dopamine-related reward-processing: Informing a model of human exercise engagement

Endurance or aerobic exercise has many physical and mental health benefits, but less is known about the specific impact that cardiovascular activity may have on dopamine-associated brain circuits involved in reward processing and mood regulation in humans. Understanding such effects will help to explain individual differences in both exercise uptake and maintenance. This study evaluated neural response to a classical taste-conditioning reward prediction error task with the use of functional magnetic resonance imaging, along with data on self-reported aerobic exercise among healthy young adult females (N = 111). Results indicated positive associations between reported aerobic exercise and regional brain response that remained significant after multiple comparison correction for the right medial orbital frontal cortex response to unexpected sucrose receipt (r = 0.315, p = .0008). The medial orbitofrontal cortex is implicated in reward and outcome value computation and the results suggest that aerobic exercise may strengthen this circuitry, or reciprocally, higher orbitofrontal cortical activity may reinforce exercise behavior. The findings aid in developing a model of how exercise engagement can modify reward-circuit function and could be used therapeutically in conditions associated with altered brain salience response.

Stimulation of medial amygdala GABA neurons with kinetically different channelrhodopsins yields opposite behavioral outcomes.

The medial amygdala (MeA) receives pheromone information about conspecifics and has crucial functions in social behaviors. A previous study showed that activation of GABA neurons in the postero-dorsal MeA (MeApd) with channelrhodopsin-2H134R (ChR2) stimulates inter-male aggression. When performing these experiments using the faster channelrhodopsinH134R,E123T (ChETA), we find the opposite behavioral outcome. A systematic comparison between the two channelrhodopsin variants reveals that optogenetic activation of MeApd GABA neurons with ChETA suppresses aggression, whereas activation under ChR2 increases aggression. Although the mechanism for this paradoxical difference is not understood, we observe that activation of MeApd GABA neurons with ChR2 causes larger plateau depolarizations, smaller action potentials, and larger local inhibition than with ChETA. Thus, the channelrhodopsin variant used for invivo optogenetic experiments can radically influence the behavioral outcome. Future work should continue to study the role of specific sub-populations of MeApd GABA neurons in aggression control.

Sex-Dependent Alterations of Regional Homogeneity in Cigarette Smokers.

Biological sex may play a large role in cigarette use and cessation outcomes and neuroimaging studies have demonstrated that cigarette smoking is associated with sex-related differences in brain structure and function. However, less is known about sex-specific alterations in spontaneous brain activity in cigarette smokers. In this study, we investigated the sex-related effects of cigarette smoking on local spontaneous brain activity using regional homogeneity (ReHo) based on resting-state fMRI. Fifty-six smokers (24 females) and sixty-three (25 females) healthy non-smoking controls were recruited. Whole-brain voxelwise 2-way analysis of covariance of ReHo was performed to detect brain regions with sex-dependent alterations on the spontaneous brain activity. Compared to non-smokers, smokers exhibited significant ReHo differences in several brain regions, including the right medial orbitofrontal cortex extended to the ventral striatum/amygdala/parahippocampus, left precuneus, and bilateral cerebellum crus. Smoking and sex interaction analysis revealed that male smokers showed significantly lower ReHo in the right ventral striatum, left cerebellum crus1, and left fusiform gyrus compared to male non-smokers, whereas there are no significant differences between female smokers and non-smokers. Furthermore, the ReHo within the left cerebellum crus1 was negatively correlated with craving scores in male smokers but not in female smokers. Such sex-dependent differences in spontaneous brain activity lays a foundation for further understanding the neural pathophysiology of sex-specific effects of nicotine addiction and promoting more effective health management of quitting smoking.

Brain functional connectivities that mediate the association between childhood traumatic events, and adult mental health and cognition.

SummaryBackgroundChildhood traumatic events are risk factors for psychopathology, but large-scale studies of how childhood traumatic events relate to mental health and cognition in adulthood, and how the brain is involved, are needed.MethodsThe associations between childhood traumatic events (such as abuse and neglect, and defined by the ‘Childhood Trauma’ questions in the UK Biobank database) and brain functional connectivity, mental health problems, and cognitive performance were investigated by a univariate correlation analysis with 19,535 participants aged 45–79 from the UK Biobank dataset. The results were replicated with 17,747 independent participants in the second release from the same dataset.FindingsChildhood traumatic events were significantly associated with mental health problems in adulthood including anxiety (r=0.19, p<1.0 × 10−323), depression (r=0.21, p<1.0 × 10−323), and self-harm (r=0.24, p<1.0 × 10−323), and with adult cognitive performance including fluid intelligence (r=−0.05, p=2.8 × 10−10) and prospective memory (r=−0.04, p=6.8 × 10−8). Functional connectivities of the medial and lateral temporal cortex, the precuneus, the medial orbitofrontal cortex; and the superior, middle and inferior prefrontal cortex extending back to precentral regions were negatively correlated with the childhood traumatic events (FDR corrected, p<0.01). These lower functional connectivities significantly mediated the associations between childhood traumatic events and addiction, anxiety, depression and well-being (all p<1.0 × 10−3), and cognitive performance. The association between childhood traumatic events and behavioural measures and functional connectivity were confirmed in a replication with different participants in the second release of the UK Biobank dataset.InterpretationChildhood traumatic events are strongly associated with adult mental health problems mediated by brain functional connectivities in brain areas involved in executive function, emotion, face processing, and memory. This understanding may help with prevention and treatment.FundingFunding was provided by the National Key R&D Program of China (No. 2018YFC1312900 and No. 2019YFA0709502).

Correlation between cognitive performance and structural neuroanatomy in patients with type I bipolar affective disorder treated with and without lithium

IntroductionLithium treatment of bipolar disorder (BD) has been associated with less cognitive impairment and fewer changes in structural brain anatomy compared to other treatments. However, the studies are heterogeneous and few assess whether these effects are related. The objective of this study was to evaluate and relate cognitive performance and structural neuroanatomy in patients treated with and without lithium. MethodsCross-sectional study that included 48 subjects with BD-I, of which 22 were treated with lithium and 26 without lithium. Performance was assessed on Wechsler III (WAIS III), TMT A and B (Trial Making Test) neuropsychological tests, California verbal learning test (CVLT), Rey complex figure test and Wisconsin card sorting test. Brain structures obtained by magnetic resonance imaging (MRI) were evaluated. The standardised mean difference (SMD) between both groups was calculated, adjusted for confounding variables using a propensity score, and the Spearman correlation coefficient (ρ) was used to assess the relationship between cognitive performance and neuroanatomical regions. ResultsCompared to the group without lithium, the group with lithium had fewer perseverative errors in the Wisconsin test (SMD = –0.69) and greater left and right cortical areas (SMD = 0.85; SMD = 0.92); greater surface area in the left anterior cingulate (SMD = 1.32), right medial orbitofrontal cortex (SMD = 1.17), right superior frontal gyrus (SMD = 0.82), and right and left precentral gyrus (SMD = 1.33; SMD = 0.98); greater volume of the right amygdala (SMD = 0.57), right hippocampus (SMD = 0.66), right putamen (SMD = 0.87) and right thalamus (SMD = .67). In the lithium group, a correlation was found with these errors and the thickness of the left precentral gyrus (ρ = –0.78), the volume of the right thalamus (ρ = –0.44), and the right amygdala (ρ = 0.6). ConclusionsThe lithium group had better cognitive flexibility and greater dimension in some frontal and subcortical cortical regions. Furthermore, there was a moderate to high correlation between performance in this executive function and the thickness of the right precentral gyrus, and the volumes of the thalamus and the right amygdala. These findings could suggest a neuroprotective effect of lithium.

Impact of Adolescent Intermittent Ethanol Exposure on Social Investigation, Social Preference, and Neuronal Activation in cFos-LacZ Male and Female Rats.

Adolescence is a sensitive developmental period during which alcohol use is often initiated and consumed in high quantities, often at binge or even high-intensity drinking levels. Our lab has repeatedly found that adolescent intermittent ethanol (AIE) exposure in rats results in long-lasting social impairments, specifically in males, however our knowledge of the neuronal underpinnings to this sex-specific effect of AIE is limited. The present study was designed to test whether social anxiety-like alterations in AIE-exposed males would be accompanied by alterations of neuronal activation across brain regions associated with social behavior, with AIE females demonstrating no social impairments and alterations in neuronal activation. Adolescent male and female cFos-LacZ transgenic rats on a Sprague-Dawley background were exposed to ethanol (4 g/kg, 25% v/v) or water via intragastric gavage every other day during postnatal days (P) 25–45 for a total of 11 exposures (n = 13 per group). Social behavior of adult rats was assessed on P70 using a modified social interaction test, and neuronal activation in brain regions implicated in social responding was assessed via β-galactosidase (β-gal) expression. We found that AIE exposure in males resulted in a significantly lower social preference coefficient relative to water-exposed controls, with no effect evident in females. Exposure-specific relationships between social behavior and neuronal activation were identified, with AIE eliminating correlations found in water controls related to social interaction, and eliciting negative correlations mainly in limbic regions in a sex-specific manner. AIE exposure in the absence of social testing was also found to differentially affect neural activity in the orbitofrontal cortex and central amygdala in males and females. These data suggest that AIE produces sex-specific social impairments that are potentially driven by differential neuronal activation states in regions important for social behavior, including the medial prefrontal and orbitofrontal cortices, nucleus accumbens, lateral septum, and central amygdala. Future studies should be focused on identification of specific neuronal phenotypes activated by interaction with a social partner in AIE-exposed subjects and their control counterparts.

Midsagittal corpus callosal thickness and cognitive impairment in Parkinson's disease

People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment; and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants (n = 35), PD participants with mild cognitive impairment (n = 22), PD participants with dementia (n = 17) and healthy controls (n = 27). We found thinning of the callosum in PD‐related dementia compared with PD‐related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD‐related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD‐related dementia, which occur in line with changes to the cortex in this advanced disease stage.

Differential and long-lasting changes in neurotransmission in the amygdala of male Wistar rats during extended amphetamine abstinence

Amphetamine addiction is associated with maladaptive actions that promotes continued use despite negative consequences, and a high risk of relapse even after protracted abstinence. Considering the role of the amygdala in regulating incentive motivation and reward-based behavior, the aim of this study was to assess neuroadaptations in subregions of the amygdala elicited by a brief period of discontinuous amphetamine exposure (2.0 mg/kg/day, 5 days) followed by abstinence (2 weeks, 1 month, 3 months) in male Wistar rats. Electrophysiological field potential recordings demonstrated that repeated amphetamine exposure significantly depressed evoked populations spikes in the basolateral amygdala (BLA). Evoked populations spikes were normalized after three months abstinence, but one challenge dose of amphetamine (0.5 mg/kg) was sufficient to reinstate synaptic depression in animals previously receiving amphetamine. In the central nucleus of the amygdala (CeA), amphetamine produced a long-lasting hyperexcitability that sustained even after three months abstinence. In the CeA, there were no significant differences between treatment groups following bath perfusion of the GABAA receptor antagonist bicuculline, indicating that amphetamine acts by reducing the inhibitory tone. Recordings performed in brain subregions interlinked with the amygdala, including medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens shell (nAc), revealed no significant neuroadaptations after two weeks abstinence. However, synaptic output was significantly depressed in the nAc after one- and three-month abstinence. In conclusion, the data presented here shows that five days of discontinuous exposure to amphetamine is sufficient to produce long-lasting neuroadaptations, which may contribute to compulsive drug taking and increase the risk for relapse.

A Social Gradient of Cortical Thickness in Adolescence: Relationships With Neighborhood Socioeconomic Disadvantage, Family Socioeconomic Status, and Depressive Symptoms

BackgroundMental and physical health are affected by family and neighborhood socioeconomic status (SES). Accelerated maturation in the context of lower SES is one mechanism that might contribute to underlying health disparities; few studies, however, have considered neighborhood SES in relation to putative markers of brain maturation in adolescents. MethodsIn 120 adolescents 13 to 18 years of age, we examined family and neighborhood SES in relation to cortical thickness adjusted for age. We also examined whether cortical thickness was related to depressive symptoms and explored regions of interest. ResultsControlling for age, neighborhood socioeconomic disadvantage was associated with a thinner cortex in the left hemisphere (standardized β = −0.20), which was related to more severe depressive symptoms (standardized β = −0.33). Family SES was not significantly associated with age-adjusted mean cortical thickness in either hemisphere after controlling for relevant covariates. In exploratory, covariate-adjusted analyses of cortical thickness at the regional level, neighborhood socioeconomic disadvantage was associated with reduced cortical thickness in the left superior frontal gyrus (standardized β = −0.27), fusiform gyrus (standardized β = −0.20), and insula (standardized β = −0.21), whereas family SES was positively associated with cortical thickness in the right lateral and right medial orbitofrontal cortex (standardized β = 0.21 and standardized β = 0.19, respectively) and left transverse temporal gyrus (standardized β = 0.22). ConclusionsOur findings provide evidence for a social gradient of cortical thickness during adolescence. Adolescents living in less advantaged community or family contexts appear to have a thinner cortex according to global and regional measures. Reduced cortical thickness in the left hemisphere may indicate increased risk for depression in adolescence.

Sex moderates effects of alcohol and cannabis co-use on alcohol and stress reactivity.

Simultaneous or concurrent use (co-use) of alcohol and cannabis is associated with greater use of both substances over time, academic difficulties, more severe substance use consequences, and adverse impacts on cognitive functioning than the use of a single substance or no substance use. This study examined potential neural mechanisms underlying co-use behaviors in comparison to single substance use. Specifically, we compared alcohol cue reactivity and stress-cue reactivity among individuals who reported frequent same-day co-use of alcohol and cannabis and individuals who reported only alcohol use. The sample included 88 individuals (41 women) who reported only alcohol use and 24 individuals (8 women) who reported co-use of alcohol and cannabis on at least 50% of drinking occasions. All participants completed fMRI stress and alcohol cue reactivity tasks. Because of known sex effects on stress reactivity and alcohol cue reactivity, we tested sex by co-use interactions. During alcohol cue presentation, co-users had less activation in the thalamus and dorsomedial prefrontal cortex than alcohol-only users, effects that were driven by differences in responses to neutral cues. Examination of stress cue reactivity revealed sex by co-use interactions in the lingual gyrus, with women co-users showing a greater difference between negative and neutral cue reactivity than all other groups. In addition, women co-users had greater connectivity between the nucleus accumbens and both the medial orbitofrontal cortex and the rostral anterior cingulate cortex during negative cue presentation than the other groups. These results provide preliminary evidence of enhanced stress cue reactivity in individuals reporting co-use of alcohol and cannabis, particularly women co-users.

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.

Bipolar spectrum disorders are associated with increased gray matter volume in the medial orbitofrontal cortex and nucleus accumbens.

Elevated sensitivity to rewards prospectively predicts Bipolar Spectrum Disorder (BSD) onset; however, it is unclear whether volumetric abnormalities also reflect BSD risk. BSDs emerge when critical neurodevelopment in frontal and striatal regions occurs in sex-specific ways. The current paper examined the volume of frontal and striatal brain regions in both individuals with and at risk for a BSD with exploratory analyses examining sex-specificity. One hundred fourteen medication-free individuals ages 18-27 at low-risk for BSD (moderate-reward sensitivity; N = 37), at high-risk without a BSD (high-reward sensitivity; N = 47), or with a BSD (N = 30) completed a structural MRI scan of the brain. We examined group differences in gray matter volume in a priori medial orbitofrontal cortex (mOFC) and nucleus accumbens (NAcc) regions-of-interest. The BSD group had enlarged frontostriatal volumes (mOFC, NAcc) compared to low individuals (d = 1.01). The mOFC volume in BSD was larger than low-risk (d = 1.01) and the high-risk groups (d = 0.74). This effect was driven by males with a BSD, who showed an enlarged mOFC compared to low (d = 1.01) and high-risk males (d = 0.74). Males with a BSD also showed a greater NAcc volume compared to males at low-risk (d = 0.49), but not high-risk males. An enlarged frontostriatal volume (averaged mOFC, NAcc) is associated with the presence of a BSD, while subvolumes (mOFC vs. NAcc) showed unique patterning in relation to risk. We report preliminary evidence that sex moderates frontostriatal volume in BSD, highlighting the need for larger longitudinal risk studies examining the role of sex-specific neurodevelopmental trajectories in emerging BSDs.

Epigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans

Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder prevalent in military veterans. Epigenetic mechanisms have been implicated in the etiology of PTSD, with DNA methylation being the most studied to identify novel molecular biomarkers associated with this disorder. We performed one of the largest single-sample epigenome-wide association studies (EWAS) of PTSD to date. Our sample included 1135 male European–American U.S. veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). DNA was collected from saliva samples and the Illumina HumanMethylation EPIC BeadChip was used for the methylation analysis. PTSD was assessed using the PTSD Checklist. An EWAS was conducted using linear regression adjusted for age, cell-type proportions, first 10 principal components, and smoking status. After Bonferroni correction, we identified six genome-wide significant (GWS) CpG sites associated with past-month PTSD and three CpGs with lifetime PTSD (prange = 10−10–10−8). These CpG sites map to genes involved in immune function, transcription regulation, axonal guidance, cell signaling, and protein binding. Among these, SENP7, which is involved in transcription regulation and has been linked to risk-taking behavior and alcohol consumption in genome-wide association studies, replicated in an independent veteran cohort and was downregulated in medial orbitofrontal cortex of PTSD postmortem brain tissue. These findings suggest potential epigenetic biomarkers of PTSD that may help inform the pathophysiology of this disorder in veterans and other trauma-affected populations.

Unifying Evidence on Delay Discounting: Open Task, Analysis Tutorial, and Normative Data from an Italian Sample.

Despite the widespread use of the delay discounting task in clinical and non-clinical contexts, several task versions are available in the literature, making it hard to compare results across studies. Moreover, normative data are not available to evaluate individual performances. The present study aims to propose a unified version of the delay discounting task based on monetary rewards and it provides normative values built on an Italian sample of 357 healthy participants. The most used parameters in the literature to assess the delay discount rate were compared to find the most valid index to discriminate between normative data and a clinical population who typically present impulsivity issues, i.e., patients with a lesion to the medial orbitofrontal cortex (mOFC). In line with our hypothesis, mOFC patients showed higher delay discounting scores than the normative sample and the normative group. Based on this evidence, we propose that the task and indexes here provided can be used to identify extremely high (above the 90th percentile for hyperbolic k or below the 10th percentile for AUC) or low (below the 10th percentile for hyperbolic k or above the 90th percentile for AUC) delay discounting performances. The complete dataset, the R code used to perform all analyses, a free and modifiable version of the delay discounting task, as well as the R code that can be used to extract all indexes from such tasks and compare subjective performances with the normative data here presented are available as online materials.

Distinct Medial Orbitofrontal-Striatal Circuits Support Dissociable Component Processes of Risk/Reward Decision-Making.

The medial orbitofrontal cortex (mOFC) regulates a variety of cognitive functions, including refining action selection involving reward uncertainty. This region sends projections to numerous subcortical targets, including the ventral and dorsal striatum, yet how these corticostriatal circuits differentially regulate risk/reward decision-making is unknown. The present study examined the contribution of mOFC circuits linking the nucleus accumbens (NAc) and dorsomedial striatum (DMS) to risk/reward decision-making using pharmacological disconnections. Male rats were well trained on a probabilistic discounting task involving choice between small/certain or large/risky rewards, with the probability of obtaining the larger reward decreasing or increasing over a session. Disconnection of mOFC-striatal pathways was achieved using infusions of GABA agonists inactivating the mOFC in one hemisphere, combined with NAc or DMS inactivation in the contralateral or ipsilateral hemisphere. Perturbing mOFC → NAc circuits induced suboptimal, near-random patterns of choice that manifested as a flattening of the discounting curve. Animals were equally likely to stay or shift following rewarded/nonrewarded choices, suggesting this pathway mediates use of information about reward history to stabilize decision biases. In contrast, mOFC → DMS disconnection impaired adjustments in decision biases, causing opposing changes in risky choice depending on how probabilities varied over time. This was driven by alterations in lose-shift behavior, suggesting mOFC → DMS circuits track volatility in nonrewarded actions to adjust choice in accordance with changes in profitability. Thus, separate mOFC-striatal projection pathways regulate dissociable processes underlying decision-making, with mOFC → NAc circuits aiding in establishing and stabilizing tasks states and mOFC → DMS circuits facilitating transitions across states to promote flexible reward seeking.SIGNIFICANCE STATEMENT The medial orbitofrontal cortex regulates a variety of goal-directed behaviors, yet the functional circuits through which it mediates higher order decision-making functions are unclear. The present study revealed that different mOFC projection pathways facilitate diverse aspects of decision-making involving risks and rewards by engaging separate networks of neurons that interface with distinct ventral and dorsal striatal targets. These findings clarify some of the normal functions of these corticostriatal pathways and may have implications for understanding how dysfunction in these circuits relate to certain psychiatric disorders.