During adolescence, considerable social and biological changes occur that interact with functional brain maturation, some of which are sex-specific. The amygdala is one brain area that has displayed sexual dimorphism, specifically in socio-affective (superficial amygdala [SFA]), stress (centromedial amygdala [CMA]), and learning and memory (basolateral amygdala [BLA]) processing. The amygdala has also been implicated in mood and anxiety disorders which also display sex-specific features, most prominently observed during adolescence. Using functional magnetic resonance imaging (fMRI), the present study examined the interaction of age and sex on resting state functional connectivity (RSFC) of amygdala sub-regions, BLA and SFA, in a sample of healthy adolescents between the ages 10-16 years (n=122, 71 boys). Whole-brain, voxel-wise partial correlation analyses were conducted to determine RSFC of bilateral BLA and SFA seed regions, created using the Eickhoff-Zilles maximum probability maps based on cytoarchitectonic mapping and FMRIB's Integrated Registration and Segmentation Tool (FIRST). Monte Carlo simulation was implemented to correct for multiple comparisons (threshold of 53 contiguous voxels with a z-value ≥ 2.25). Results indicated that with increasing age, there was a corresponding decrease in RSFC between both amygdala sub-regions and parieto-occipital cortices, with a concurrent increase in RSFC with medial prefrontal cortex (mPFC). Specifically, boys and girls demonstrated increased coupling of mPFC and left and right SFA with age, respectively; however, neither sex showed increased connectivity between mPFC and BLA, which could indicate relative immaturity of fronto-limbic networks that is similar across sex. A dissociation in connectivity between BLA- and SFA- parieto-occipital RSFC emerged, in which girls had weaker negative RSFC between SFA and parieto-occipital regions and boys had weaker negative RSFC of BLA and parieto-occipital regions with increased age, both standing in contrast to adult patterns of amygdala sub-regional RSFC. The present findings suggest relative immaturity of amygdala sub-regional RSFC with parieto-occipital cortices during adolescence, with unique patterns in both sexes that may support memory and socio-affective processing in boys and girls, respectively. Understanding the underlying normative functional architecture of brain networks associated with the amygdala during adolescence may better inform future research of the neural features associated with increased risk for internalizing psychopathology.

Objective To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol. Method PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol. Results In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms. Conclusions Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results.

Transcription factors are major determinants of cell-specific gene expression in all cell types. Studies in rodent liver have shown that alterations in transcription factor expression determine lineage specification during fetal liver development and signify transdifferentiation of cells of the biliary compartment into 'oval' cells and eventually hepatocytes in adult liver. We examined the cellular localization of hepatocyte-or BEC-associated transcription factors in human fetal and adult liver and in diseases in which transdifferentiation between hepatocytes and biliary cells may play a role. In the normal adult human liver, hepatocyte nuclear factor (HNF)4a and HNF6 appeared exclusively in hepatocytes; HNF1b, HNF3a, and HNF3b were observed only in BEC. During fetal development both BEC and hepatocytes expressed HNF3a, HNF3b, and HNF6. HNF1a was expressed only in fetal hepatocytes. We further examined expression of transcription factors in massive hepatic necrosis and in specific types of chronic liver disease. Hepatocyte-associated transcription factors HNF4a and HNF6 also appeared in BEC in massive hepatic necrosis and chronic hepatitis C virus infection. Similarly, HNF3b that is expressed only in BEC in normal adult liver was also observed in hepatocytes in primary biliary cirrhosis and chronic biliary obstruction. These data mimic previous findings in rodents in which hepatocyte-associated transcription factors appear in biliary cells prior to emergence of oval cells, which function as progenitor cells for hepatocytes when the regenerative capacity of the latter is compromised.

Objectives Elevated body mass index (BMI) is associated with deficits in working memory, reduced gray matter volume in frontal and parietal lobes, as well as changes in white matter (WM) microstructure. The current study examined whether BMI was related to working memory performance and blood oxygen level dependent (BOLD) activity, as well as WM microstructure during adolescence. Methods Linear regressions with BMI and (1) verbal working memory BOLD signal, (2) spatial working memory BOLD signal, and (3) fractional anisotropy (FA), a measure of WM microstructure, were conducted in a sample of 152 healthy adolescents ranging in BMI. Results BMI was inversely related to IQ and verbal and spatial working memory accuracy; however, there was no significant relationship between BMI and BOLD response for either verbal or spatial working memory. Furthermore, BMI was negatively correlated with FA in the left superior longitudinal fasciculus (SLF) and left inferior longitudinal fasciculus (ILF). ILF FA and IQ significantly mediated the relationship between BMI and verbal working memory performance, whereas SLF FA, but not IQ, significantly mediated the relationship between BMI and accuracy of both verbal and spatial working memory. Conclusions These findings indicate that higher BMI is associated with decreased FA in WM fibers connecting brain regions that support working memory, and that WM microstructural deficits may underlie inferior working memory performance in youth with higher BMI. Of interest, BMI did not show the same relationship with working memory BOLD activity, which may indicate that changes in brain structure precede changes in function.

Our study shows a positive pro-inflammatory status of HFD-induced MONW characterized by raised COX-2 expression, increase of the CRP levels, reduction of NO release and oxidative stress-controlled conditions in an early stage of metabolic alterations characteristic of metabolic syndrome. Endothelial dysfunction and increased vascular reactivity in MONW individuals may be biomarkers of early vascular injury. Therefore, the metabolic changes induced by HFD even in normal weight individuals may be associated to functional alterations of blood vessels.

Risky decision making is prominent during adolescence, perhaps contributed to by heightened sensation seeking and ongoing maturation of reward and dopamine systems in the brain, which are, in part, modulated by sex hormones. In this study, we examined sex differences in the neural substrates of reward sensitivity during a risky decision-making task and hypothesized that compared with girls, boys would show heightened brain activation in reward-relevant regions, particularly the nucleus accumbens, during reward receipt. Further, we hypothesized that testosterone and estradiol levels would mediate this sex difference. Moreover, we predicted boys would make more risky choices on the task. While boys showed increased nucleus accumbens blood oxygen level-dependent (BOLD) response relative to girls, sex hormones did not mediate this effect. As predicted, boys made a higher percentage of risky decisions during the task. Interestingly, boys also self-reported more motivation to perform well and earn money on the task, while girls self-reported higher state anxiety prior to the scan session. Motivation to earn money partially mediated the effect of sex on nucleus accumbens activity during reward. Previous research shows that increased motivation and salience of reinforcers is linked with more robust striatal BOLD response, therefore psychosocial factors, in addition to sex, may play an important role in reward sensitivity. Elucidating neurobiological mechanisms that support adolescent sex differences in risky decision making has important implications for understanding individual differences that lead to advantageous and adverse behaviors that affect health outcomes.

Objective-Suicide is the second leading cause of death among adolescents; however, objective biomarkers of suicide risk are lacking. Aberrant self-face amygdala activity is associated with suicide ideation, and its connectivity with neural regions that enable self-processing (eg medial prefrontal cortex) may be a suicide risk factor.Method-Adolescents (aged 11-17 years; N = 120) were sorted into four groups: healthy controls (HC), depressed individuals with low suicide ideation (LS), depressed individuals with high suicide ideation (HS), and depressed suicide attempters (SA). Youth completed an emotional (Happy, Sad, Neutral) self-face recognition task in the scanner. Bilateral amygdala task-dependent functional connectivity was determined with psychophysiological interaction analysis. Connectivity was compared across groups and within Self versus Other faces across emotions and hemispheres. Voxelwise results were thresholded (p < .005, uncorrected) and corrected for multiple comparisons (p < .05, familywise error).Results-Both HS and SA displayed greater amygdala connectivity with the dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and precuneus, compared to LS, who, in turn, showed greater connectivity than HC. Greater left amygdala-rostral anterior cingulate cortex (rACC) connectivity was observed in SA compared to all other groups, whereas right amygdala-rACC connectivity was greater in HS versus LS and HC.

Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level-dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence.