Medial Orbitofrontal Cortex Research Articles

Unraveling the causal relationships between depression and brain structural imaging phenotypes: A bidirectional Mendelian Randomization study

BackgroundPrevious studies have revealed structural brain abnormalities in individuals with depression, but the causal relationship between depression and brain structure remains unclear. MethodsA genetic correlation analysis was conducted using summary statistics from the largest genome-wide association studies for depression (N = 674,452) and 1,265 brain structural imaging-derived phenotypes (IDPs, N = 33,224). Subsequently, a bidirectional two-sample Mendelian Randomization (MR) approach was employed to explore the causal relationships between depression and the IDPs that showed genetic correlations with depression. The main MR results were obtained using the inverse variance weighted (IVW) method, and other MR methods were further employed to ensure the reliability of the findings. ResultsNinety structural IDPs were identified as being genetically correlated with depression and were included in the MR analyses. The IVW MR results indicated that reductions in the volume of several brain regions, including the bilateral subcallosal cortex, right medial orbitofrontal cortex, and right middle-posterior part of the cingulate cortex, were causally linked to an increased risk of depression. Additionally, decreases in surface area of the right middle temporal visual area, right middle temporal cortex, right inferior temporal cortex, and right middle-posterior part of the cingulate cortex were causally associated with a heightened risk of depression. Validation and sensitivity analyses supported the robustness of these findings. However, no evidence was found for a causal effect of depression on structural IDPs. ConclusionsOur findings reveal the causal influence of specific brain structures on depression, providing evidence to consider brain structural changes in the etiology and treatment of depression.

Appetitive conditioning with pornographic stimuli elicits stronger activation in reward regions than monetary and gaming-related stimuli.

Appetitive conditioning plays an important role in the development and maintenance of pornography-use and gaming disorders. It is assumed that primary and secondary reinforcers are involved in these processes. Despite the common use of pornography and gaming in the general population appetitive conditioning processes in this context are still not well studied. This study aims to compare appetitive conditioning processes using primary (pornographic) and secondary (monetary and gaming-related) rewards as unconditioned stimuli (UCS) in the general population. Additionally, it investigates the conditioning processes with gaming-related stimuli as this type of UCS was not used in previous studies. Thirty-one subjects participated in a differential conditioning procedure in which four geometric symbols were paired with either pornographic, monetary, or gaming-related rewards or with nothing to become conditioned stimuli (CS + porn, CS + game, CS + money, and CS-) in an functional magnetic resonance imaging study. We observed elevated arousal and valence ratings as well as skin conductance responses for each CS+ condition compared to the CS-. On the neural level, we found activations during the presentation of the CS + porn in the bilateral nucleus accumbens, right medial orbitofrontal cortex, and the right ventral anterior cingulate cortex compared to the CS-, but no significant activations during CS + money and CS + game compared to the CS-. These results indicate that different processes emerge depending on whether primary and secondary rewards are presented separately or together in the same experimental paradigm. Additionally, monetary and gaming-related stimuli seem to have a lower appetitive value than pornographic rewards.

Functional specialization of medial and lateral orbitofrontal cortex in inferential decision-making

Inferring prospective outcomes and updating behavior are prerequisites for making flexible decisions in the changing world. These abilities are highly associated with the functions of the orbitofrontal cortex (OFC) in humans and animals. The functional specialization of OFC subregions in decision-making has been established in animals. However, the understanding of how human OFC contributes to decision-making remains limited. Therefore, we studied this issue by examining the information representation and functional interactions of human OFC subregions during inference-based decision-making. We found that the medial OFC (mOFC) and lateral OFC (lOFC) collectively represented the inferred outcomes which, however, were context-general coding in the mOFC and context-specific in the lOFC. Furthermore, the mOFC-motor and lOFC-frontoparietal functional connectivity may indicate the motor execution of mOFC and the cognitive control of lOFC during behavioral updating. In conclusion, our findings support the dissociable functional roles of OFC subregions in decision-making.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Sensory over-responsivity and orbitofrontal cortex connectivity in obsessive-compulsive disorder

BackgroundSensory over-responsivity (SOR) in obsessive-compulsive disorder (OCD) is associated with illness severity and functional impairment. However, the neural substrates of SOR in OCD have not yet been directly probed. MethodsWe examined resting-state global functional connectivity markers of SOR in 119 adults with OCD utilizing the CONN-fMRI Functional Connectivity Toolbox for SPM (v21a). We quantified SOR with the sensory sensitivity and sensory avoiding subscales of the Adult and Adolescent Sensory Profile (AASP). We also measured: OCD severity, with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Obsessive-Compulsive Inventory-Revised (OCI-R); sensory phenomena with the Sensory Phenomena Scale (SPS); general anxiety, with the Beck Anxiety Inventory (BAI); and depressive symptomatology, with Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR). ResultsThere was a significant positive relationship of SOR with global connectivity in anterior and medial OFC (Brodmann's area 11, k = 154, x = 14, y = 62, z = −18, whole-brain corrected at FWE p < 0.05). LimitationsFuture investigations should explore neural responses to sensory stimulation tasks in OCD and compare findings with those obtained in other conditions also characterized by high SOR, such as autism spectrum disorder. ConclusionsThis study implicates OFC functional connectivity as a neurobiological mechanism of SOR in OCD and suggests that the substrates of SOR in OCD may be dissociable from both that of other symptoms in OCD, and SOR in other disorders. With replication and extension, the finding may be leveraged to develop and refine treatments for OCD and investigate the pathophysiology of SOR in other conditions.

Neurophysiological analysis of disadvantageous social inequity: Exploring emotional behavior changes and c-Fos expression in a male rat model

Humans and other animals exhibit aversive behavioral and emotional responses to unequal reward distributions compared with their conspecifics. Despite the significance of this phenomenon, experimental animal models designed to investigate social inequity aversion and delve into the underlying neurophysiological mechanisms are limited. In this study, we developed a rat model to determine the effects of socially equal or unequal reward and stress on emotional changes in male rats. During the training session, the rats were trained to escape when a sound cue was presented, and they were assigned to one of the following groups: all escaping rats [advantageous equity (AE)], freely moving rats alongside a restrained rat [advantageous inequity (AI)], all restrained rats [disadvantageous equity (DE)], and a rat restrained in the presence of freely moving companions [disadvantageous inequity (DI)]. During the test session, rats in the advantageous group (AE and AI) escaped after the cue sound (expected reward acquisition), whereas rats in the disadvantageous group (DE and DI) could not escape despite the cue being presented (expected reward deprivation). Emotional alteration induced by exposure to restraint stress under various social interaction circumstances was examined using an open field test. Notably, the DI group displayed reduced exploration of the center zone during the open field tests compared with the other groups, indicating heightened anxiety-like behaviors in response to reward inequity. Immunohistochemical analysis revealed increased c-Fos expression in the medial prefrontal and orbitofrontal cortices, coupled with reduced c-Fos expression in the striatum and nucleus accumbens under DI conditions, in contrast to the other experimental conditions. These findings provide compelling evidence that rats are particularly sensitive to reward inequity, shedding light on the neurophysiological basis for distinct cognitive processes that manifest when individuals are exposed to social equity and inequity situations.

Hereditary and cortical morphological biomarker of sensitivity to reward in short-term withdrawal methamphetamine abusers.

Higher sensitivity to reward (SR) and weaker sensitivity to punishment (SP) construct the fundamental craving characteristics of methamphetamine abuse. However, few studies have appraised relationships between SR/SP (SR or SP) and cortical morphological alterations in methamphetamine abusers and whether hereditary factors take effects on SR/SP is unclear. Based on surface-based morphometric analysis, cortical discrepancy was investigated between 38 methamphetamine abusers and 37 healthy controls. Within methamphetamine abusers, correlation profiling was performed to discover associations among aberrant neuroimaging substrates, SR, SP, and craving. According to nine single nucleotide polymorphism sites of dopamine-related genes, we conducted univariate general linear model to find different effects of genotypes on cortical alterations and SR/SP/craving (SR, SP, or craving). Ultimately, mediation analyses were conducted among single nucleotide polymorphism sites, SR/SP/craving, and cortical morphological alterations to discover their association pathways. Compared to healthy controls, thinner cortices in inferior temporal gyrus, lateral orbitofrontal cortex, medial orbitofrontal cortex, inferior parietal lobule, and lateral occipital cortex in the left hemisphere were found in methamphetamine abusers (P < 0.05, family-wise error corrected). Cortical thickness in the inferior temporal gyrus was negatively correlated with SR scores. We found that rs1800497 A-containing genotypes had lower cortical thickness in the left inferior parietal lobule than the GG genotype. The rs5751876 had effects on SR scores. This study would provide convincing biomarkers for SR in methamphetamine abusers and offer potential genetic targets for personalizing relapse prevention.

Altered brain morphology and functional connectivity in postmenopausal women: automatic segmentation of whole-brain and thalamic subnuclei and resting-state fMRI.

The transition to menopause is associated with various physiological changes, including alterations in brain structure and function. However, menopause-related structural and functional changes are poorly understood. The purpose of this study was not only to compare the brain volume changes between premenopausal and postmenopausal women, but also to evaluate the functional connectivity between the targeted brain regions associated with structural atrophy in postmenopausal women. Each 21 premenopausal and postmenopausal women underwent magnetic resonance imaging (MRI). T1-weighted MRI and resting-state functional MRI data were used to compare the brain volume and seed-based functional connectivity, respectively. In statistical analysis, multivariate analysis of variance, with age and whole brain volume as covariates, was used to evaluate surface areas and subcortical volumes between the two groups. Postmenopausal women showed significantly smaller cortical surface, especially in the left medial orbitofrontal cortex (mOFC), right superior temporal cortex, and right lateral orbitofrontal cortex, compared to premenopausal women (p < 0.05, Bonferroni-corrected) as well as significantly decreased functional connectivity between the left mOFC and the right thalamus was observed (p < 0.005, Monte-Carlo corrected). Although postmenopausal women did not show volume atrophy in the right thalamus, the volume of the right pulvinar anterior, which is one of the distinguished thalamic subnuclei, was significantly decreased (p < 0.05, Bonferroni-corrected). Taken together, our findings suggest that diminished brain volume and functional connectivity may be linked to menopause-related symptoms caused by the lower sex hormone levels.

Association of in utero HIV exposure with child brain structure and language development: a South African birth cohort study

BackgroundThere is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not understood and neuroimaging studies are lacking. We aimed to investigate the cortical brain structure of children who are HIV-exposed and uninfected (HEU) compared to HIV-unexposed (HU) children and to examine the relationship with neurodevelopment.MethodsThe Drakenstein Child Health birth cohort study enrolled pregnant women from a high HIV prevalence area in South Africa with longitudinal follow-up of mother–child pairs. High-resolution magnetic resonance imaging scans from 162 children (70 HEU; 92 HU) were acquired at 2–3 years of age. All HEU children were born to mothers taking antiretroviral therapy. Measures of brain structure (cortical thickness and surface area) in the prefrontal cortex regions were extracted from T1-weighted images and compared between groups using multivariate analysis of variance and linear regression. Child development, assessed using the Bayley Scales of Infant and Toddler Development-III, was correlated with cortical structure, and mediation analyses were performed.ResultsAnalyses demonstrated an association between HIV exposure and cortical thickness across the prefrontal cortex (p = 0.035). Children who were HEU had thicker cortices in prefrontal regions, with significantly greater cortical thickness in the medial orbitofrontal cortex (mOFC) bilaterally compared to HU children (3.21 mm versus 3.14 mm, p = 0.009, adjusted effect size 0.44 [95% CI 0.12 to 0.75]). Estimates held across multiple sensitivity analyses. There were no group differences in cortical surface area. Language scores, which were lower in HEU versus HU children (81.82 versus 86.25, p = 0.011, effect size − 0.44 [95% CI − 0.78 to − 0.09]), negatively correlated with prefrontal cortical thickness in both groups. Cortical thickness in the mOFC mediated the relationship between HIV exposure and poor language outcomes (Sobel test p = 0.032).ConclusionsIn this cohort study, exposure to HIV during pregnancy was associated with altered cortical structure in early life. Our findings indicate that differences in cortical thickness development in the prefrontal region in children who are HEU may be a pathway leading to language impairment. Longitudinal studies are needed to determine the lasting impact.

Opposite changes in morphometric similarity of medial reward and lateral non-reward orbitofrontal cortex circuits in obesity

Obesity has a profound impact on metabolic health thereby adversely affecting brain structure and function. However, the majority of previous studies used a single structural index to investigate the link between brain structure and body mass index (BMI), which hinders our understanding of structural covariance between regions in obesity. This study aimed to examine the relationship between macroscale cortical organization and BMI using novel morphometric similarity networks (MSNs). The individual MSNs were first constructed from individual eight multimodal cortical morphometric features between brain regions. Then the relationship between BMI and MSNs within the discovery sample of 434 participants was assessed. The key findings were further validated in an independent sample of 192 participants. We observed that the lateral non-reward orbitofrontal cortex (lOFC) exhibited decoupling (i.e., reduction in integration) in obesity, which was mainly manifested by its decoupling with the cognitive systems (i.e., DMN and FPN) while the medial reward orbitofrontal cortex (mOFC) showed de-differentiation (i.e., decrease in distinctiveness) in obesity, which was mainly represented by its de-differentiation with the cognitive and attention systems (i.e., DMN and VAN). Additionally, the lOFC showed de-differentiation with the visual system in obesity, while the mOFC showed decoupling with the visual system and hyper-coupling with the sensory-motor system in obesity. As an important first step in revealing the role of underlying structural covariance in body mass variability, the present study presents a novel mechanism that underlies the reward-control interaction imbalance in obesity, thus can inform future weight-management approaches.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Subcortical-cortical white matter connectivity in adults with autism spectrum disorder and schizophrenia patients

Autism spectrum disorder (ASD) and schizophrenia (SZ) are neuropsychiatric disorders that overlap in symptoms associated with social-cognitive impairment. Alterations of the cingulate cortex, subcortical, medial-temporal, and orbitofrontal structures are frequently reported in both disorders. In this study, we examined white-matter connectivity between these structures in adults with ASD and SZ patients compared with their respective neurotypical controls and indirectly with each other, using probabilistic and local DTI tractography. This exploratory study utilized publicly available neuroimaging databases, of adults with ASD (ABIDE II; n = 28) and SZ (COBRE; n = 38), age-gender matched neurotypicals (NT) and associated phenotypic data. Tractography was performed using Freesurfer and MRtrix software, and diffusion metrics of white-matter tracts between cingulate-, orbitofrontal- cortices, subcortical structures, parahippocampal, entorhinal cortex were assessed. In ASD, atypical diffusivity parameters were found in the isthmus cingulate and parahippocampal connectivity to subcortical and rostral-anterior cingulate, which were also associated with IQ and social skills (SRS). In contrast, atypical diffusivity parameters were observed between the medial-orbitofrontal cortex and subcortical structures in SZ, and were associated with executive function (i.e., IQ, processing speed) and emotional regulation. Overall, the results suggest that defects in the isthmus cingulate, medial-orbitofrontal, and striato-limbic white matter connectivity may help unravel the neural underpinnings of executive and social-emotional dysfunction at the core of neuropsychiatric disorders.

Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia.

Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied NLRP1 expression and content in the postmortem brain tissue of 10 schizophrenia and 10 control subjects. In the medial orbitofrontal cortex (Brodmann's area 11/12) and dorsolateral prefrontal cortex (area 46) from both hemispheres of six schizophrenia subjects, the NLRP1 mRNA expression was significantly higher than in six control brains (p < 0.05). As the expression difference was highest for the medial orbitofrontal cortex in the right hemisphere, we assessed NLRP1-immunoreactive pyramidal neurons in layers III, V, and VI in the medial orbitofrontal cortex in the right hemisphere of seven schizophrenia and five control brains. Compared to controls, we quantified a significantly higher number of NLRP1-positive pyramidal neurons in the schizophrenia brains (p < 0.01), suggesting NLRP1 inflammasome activation in schizophrenia subjects. Layer III pyramidal neuron dysfunction aligns with working memory deficits, while impairments of pyramidal neurons in layers V and VI likely disrupt predictive processing. We propose NLRP1 inflammasome as a potential biomarker and therapeutic target in schizophrenia.

Disrupted small-world white matter networks in patients with major depression and recent suicide plans or attempts.

Suicide is a major concern for health, and depression is an established proximal risk factor for suicide. This study aimed to investigate white matter features associated with suicide. We constructed white matter structural networks by deterministic tractography via diffusion tensor imaging in 51 healthy controls, 47 depressed patients without suicide plans or attempts and 56 depressed patients with suicide plans or attempts. Then, graph theory analysis was used to measure global and nodal network properties. We found that local efficiency was decreased and path length was increased in suicidal depressed patients compared to healthy controls and non-suicidal depressed patients; moreover, the clustering coefficient was decreased in depressed patients compared to healthy controls; and the global efficiency and normalized characteristic path length was increased in suicidal depressed patients compared to healthy controls. Similarly, compared with those in non-suicidal depressed patients, nodal efficiency in the thalamus, caudate, medial orbitofrontal cortex, hippocampus, olfactory cortex, supplementary motor area and Rolandic operculum was decreased. In summary, compared with those of non-suicidal depressed patients, the structural connectome of suicidal depressed patients exhibited weakened integration and segregation and decreased nodal efficiency in the fronto-limbic-basal ganglia-thalamic circuitry. These alterations in the structural networks of depressed suicidal brains provide insights into the underlying neurobiology of brain features associated with suicide.

Clinical and neuroimaging predictors of benzodiazepine response in catatonia: A machine learning approach

Catatonia is a well characterized psychomotor syndrome combining motor, behavioural and neurovegetative signs. Benzodiazepines are the first-choice treatment, effective in 70 % of cases. Currently, the factors associated with benzodiazepine resistance remain unknown. We aimed to develop machine learning models using clinical and neuroimaging data to predict benzodiazepine response in catatonic patients. This study examined a cohort of catatonic patients who underwent standardized clinical evaluation, 3 T brain MRI, and benzodiazepine trial. Based on clinical response, patients were classified as benzodiazepine responders or non-responders. Cortical thickness and regional brain volumes were measured. Two machine learning models (linear model and gradient boosting tree model) were developed to identify predictors of treatment response using clinical, demographic, and neuroimaging data. The cohort included 65 catatonic patients, comprising 30 benzodiazepine responders and 35 non-responders. Using clinical data alone, the linear model achieved 63% precision, 51% recall, a specificity of 61%, and 58% AUC, while the gradient boosting tree (GBT) model attained 46% precision, 60% recall, a specificity of 62% and 64% AUC. Incorporating neuroimaging data improved model performance, with the linear model achieving 66% precision, 57% recall, a specificity of 67%, and 70% AUC, and the GBT model attaining 50% precision, 50% recall, a specificity of 62% and 70% AUC. The integration of imaging data with demographic and clinical information significantly enhanced the predictive performance of the models. The duration of the catatonic syndrome, along with the presence of mitgehen (passive obedience) and immobility/stupor, and the volume of the right medial orbito-frontal cortex emerged as important factors in predicting non-response to benzodiazepines.

Prefrontal cortex structural and developmental associations with callous-unemotional traits and aggression.

Youths with high levels of callous-unemotional (CU) traits and aggression are at an increased risk for developing antisocial behaviours into adulthood. In this population, neurostructural grey matter abnormalities have been observed in the prefrontal cortex. However, the directionality of these associations is inconsistent, prompting some to suggest they may vary across development. Although similar neurodevelopmental patterns have been observed for other disorders featuring emotional and behavioural dysregulation, few studies have tested this hypothesis for CU traits, and particularly not for aggression subtypes. The current study sought to examine grey matter correlates of CU traits and aggression (including its subtypes), and then determine whether these associations varied by age. Fifty-four youths (10-19years old) who were characterized for CU traits and aggression underwent MRI. Grey matter volume and surface area within the anterior cingulate cortex was positively associated with CU traits. The correlation between CU traits and medial orbitofrontal cortex (mOFC) volume varied significantly as a function of age, as did the correlation between reactive aggression and mOFC surface area. These associations became more positive with age. There were no significant findings for proactive/total aggression. Results are interpreted considering the potential for delayed cortical maturation in youths with high CU traits/aggression.

Sex and pubertal variation in reward-related behavior and neural activation in early adolescents

This study aimed to characterize the role of sex and pubertal markers in reward motivation behavior and neural processing in early adolescence. We used baseline and two-year follow-up data from the Adolescent Brain and Cognitive DevelopmentSM study (15844 observations; 52% from boys; age 9–13). Pubertal development was measured with parent-reported Pubertal Development Scale, and DHEA, testosterone, and estradiol levels. Reward motivation behavior and neural processing at anticipation and feedback stages were assessed with the Monetary Incentive Delay task. Boys had higher reward motivation than girls, demonstrating greater accuracy difference between reward and neutral trials and higher task earnings. Girls had lower neural activation during reward feedback than boys in the nucleus accumbens, caudate, rostral anterior cingulate, medial orbitofrontal cortex, superior frontal gyrus and posterior cingulate. Pubertal stage and testosterone levels were positively associated with reward motivation behavior, although these associations changed when controlling for age. There were no significant associations between pubertal development and neural activation during reward anticipation and feedback. Sex differences in reward-related processing exist in early adolescence, signaling the need to understand their impact on typical and atypical functioning as it unfolds into adulthood.

Long-Term Impact of Early-Life Stress on Serotonin Connectivity

BackgroundChronic childhood stress is a prominent risk factor for developing affective disorders, yet mechanisms underlying this association remain unclear. Maintenance of optimal serotonin (5-HT) levels during early postnatal development is critical for the maturation of brain circuits. Understanding the long-lasting effects of early-life stress (ELS) on serotonin-modulated brain connectivity is crucial to develop treatments for affective disorders arising from childhood stress. MethodsUsing a mouse model of chronic developmental stress, we determined the long-lasting consequences of ELS on 5-HT circuits and behavior in females and males. Using FosTRAP mice, we cross-correlated regional c-Fos density to determine brain-wide functional connectivity of the raphe nucleus. We next performed in vivo fiber photometry to establish ELS-induced deficits in 5-HT dynamics and optogenetics to stimulate 5-HT release to improve behavior. ResultsAdult female and male mice exposed to ELS showed heightened anxiety-like behavior. ELS further enhanced susceptibility to acute stress by disrupting the brain-wide functional connectivity of the raphe nucleus and the activity of 5-HT neuron population, in conjunction with increased orbitofrontal cortex (OFC) activity and disrupted 5-HT release in medial OFC. Optogenetic stimulation of 5-HT terminals in the medial OFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner. ConclusionsThese findings suggest a significant disruption in 5-HT–modulated brain connectivity in response to ELS, with implications for sex-dependent vulnerability. The anxiolytic effect of the raphe–medial OFC circuit stimulation has potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.

Longitudinal Brain Perfusion and Symptom Presentation Following Pediatric Concussion: A Pediatric Concussion Assessment of Rest and Exertion+MRI (PedCARE+MRI) Substudy.

Emerging evidence suggests that advanced neuroimaging modalities such as arterial spin labelling (ASL) might have prognostic utility for pediatric concussion. This study aimed to: 1) examine group differences in global and regional brain perfusion in youth with concussion or orthopedic injury (OI) at 72 h and 4 weeks post-injury; 2) examine patterns of abnormal brain perfusion within both groups and their recovery; 3) investigate the association between perfusion and symptom burden within concussed and OI youths at both time-points; and 4) explore perfusion between symptomatic and asymptomatic concussed and OI youths. Youths ages 10.00-17.99 years presenting to the emergency department with an acute concussion or OI were enrolled. ASL-magnetic resonance imaging scans were conducted at 72 h and 4 weeks post-injury to measure brain perfusion, along with completion of the Health Behavior Inventory (HBI) to measure symptoms. Abnormal perfusion clusters were identified using voxel-based z-score analysis at each visit. First, mixed analyses of covariance (ANCOVAs) investigated the Group*Time interaction on global and regional perfusion. Post hoc region of interest (ROI) analyses were performed on significant regions. Second, within-group generalized estimating equations investigated the recovery of abnormal perfusion at an individual level. Third, multiple regressions at each time-point examined the association between HBI and regional perfusion, and between HBI and abnormal perfusion volumes within the concussion group. Fourth, whole-brain one-way ANCOVAs explored differences in regional and abnormal perfusion based on symptomatic status (symptomatic vs. asymptomatic) and OIs at each time-point. A total of 70 youths with a concussion [median age (interquartile range; IQR) = 12.70 (11.67-14.35), 47.1% female] and 29 with an OI [median age (IQR) = 12.05 (11.18-13.89), 41.4% female] were included. Although no Group effect was found in global perfusion, the concussion group showed greater adjusted perfusion within the anterior cingulate cortex/middle frontal gyrus (MFG) and right MFG compared with the OI group across time-points (ps ≤ 0.004). The concussion group showed lower perfusion within the right superior temporal gyrus at both time-points and bilateral occipital gyrus at 4 weeks, (ps ≤ 0.006). The number of hypoperfused clusters was increased at 72 h compared with 4 weeks in the concussion youths (p < 0.001), but not in the OIs. Moreover, Group moderated the HBI-perfusion association within the left precuneus and superior frontal gyrus at both time-points, (ps ≤ 0.001). No association was found between HBI and abnormal perfusion volume within the concussion group at any visits. At 4 weeks, the symptomatic sub-group (n = 10) showed lower adjusted perfusion within the right cerebellum and lingual gyrus, while the asymptomatic sub-group (n = 59) showed lower adjusted perfusion within the left calcarine, but greater perfusion within the left medial orbitofrontal cortex, right middle frontal gyrus, and bilateral caudate compared with OIs. Yet, no group differences were observed in the number of abnormal perfusion clusters or volumes at any visit. The present study suggests that symptoms may be associated with changes in regional perfusion, but not abnormal perfusion levels.

Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment.

We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.