Sex differences in pubertal associations with fronto-accumbal white matter morphometry: Implications for understanding sensitivity to reward and punishment.
ABSTRACT: Researchers have reported sex-differentiated maturation of white matter (WM) during puberty. It is not clear, however, whether such distinctions contribute to documented sex differences in sensitivity to reward and punishment during adolescence. Given the role of the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in reward and punishment-related behaviors, we tested in a cross-sectional study whether males and females (N = 156, 89 females; ages 9-14 years) differ in the association between pubertal stage and fixel-based morphometry of WM fibers connecting the OFC and NAcc (i.e., the fronto-accumbal tract). Further, we examined whether males and females differ in associations between fronto-accumbal WM measures and self-reported sensitivity to reward and punishment. Pubertal stage was positively associated with fronto-accumbal fiber density and cross-section (FDC) in males, but not in females. Consistent with previous reports, males reported higher reward sensitivity than did females, although fronto-accumbal combined FDC was not related to reward sensitivity in either sex. Meanwhile, only males showed a negative association between fronto-accumbal tract FDC and sensitivity to punishment. Follow-up analyses revealed that fiber cross-section, but not density, was related to pubertal stage and punishment sensitivity in males, as well as to reward sensitivity in all participants. Our findings suggest there are sex differences in puberty-related maturation of the fronto-accumbal tract, and this tract is related to lower punishment sensitivity in adolescent males compared to females.
Project description:Aggression is widely observed in children with attention deficit/hyperactivity disorder (ADHD) and has been frequently linked to frustration or the unsatisfied anticipation of reward. Although animal studies and human functional neuroimaging implicate altered reward processing in aggressive behaviors, no previous studies have documented the relationship between fronto-accumbal circuitry-a critical cortical pathway to subcortical limbic regions-and aggression in medication-naive children with ADHD. To address this, we collected behavioral measures and parental reports of aggression and impulsivity, as well as structural and diffusion MRI, from 30 children with ADHD and 31 healthy controls (HC) (mean age, 10±2.1?SD). Using grey matter morphometry and probabilistic tractography combined with multivariate statistical modeling (partial least squares regression and support vector regression), we identified anomalies within the fronto-accumbal circuit in childhood ADHD, which were associated with increased aggression. More specifically, children with ADHD showed reduced right accumbal volumes and frontal-accumbal white matter connectivity compared with HC. The magnitude of the accumbal volume reductions within the ADHD group was significantly correlated with increased aggression, an effect mediated by the relationship between the accumbal volume and impulsivity. Furthermore, aggression, but not impulsivity, was significantly explained by multivariate measures of fronto-accumbal white matter connectivity and cortical thickness within the orbitofrontal cortex. Our multi-modal imaging, combined with multivariate statistical modeling, indicates that the fronto-accumbal circuit is an important substrate of aggression in children with ADHD. These findings suggest that strategies aimed at probing the fronto-accumbal circuit may be beneficial for the treatment of aggressive behaviors in childhood ADHD.
Project description:Animal approach-avoidance conflict paradigms have been used extensively to characterize effects of anxiolytic agents and probe neural circuitry related to anxiety. However, there are few behavioral approaches to measure conflict in human populations, limiting the translation of findings from animal conflict tasks to human clinical research. We developed a novel approach-avoidance conflict (AAC) paradigm involving situations in which the same decision is associated with "reward" (points) and "punishment" (negative affective stimuli). The AAC task was completed by 95 young adults (56 female) with varying levels of self-reported trait anxiety. As expected, conflict-related approach behavior correlated with self-reported motivation to approach reward and avoid punishment and greater reward level increased approach behavior. Additionally, females exhibited less approach behavior than males. Anxiety Sensitivity Index (Physical subscale) scores related negatively to approach behavior for males, while Behavioral Activation Scale (BAS, Fun Seeking subscale) scores related positively to approach behavior for females. Results support the utility of the AAC task as a behavioral test that has strong reverse translational features. Findings indicate that approach drives and anxiety sensitivity may be important in determining conflict behavior for females and males respectively. The approach-avoidance conflict task offers a novel, translational measure to probe neural systems underlying conflict behavior, motivational processes, and anxiety disorders.
Project description:Atypical white matter (WM) microstructure is commonly implicated in the neuropathophysiology of autism spectrum disorder (ASD). Fixel based analysis (FBA), at the cutting-edge of diffusion-weighted imaging, can account for crossing WM fibers and can provide indices of both WM micro- and macrostructure. We applied FBA to investigate WM structure between 25 (12 males, 13 females) adults with ASD and 24 (12 males, 12 females) matched controls. As the role of biological sex on the neuropathophysiology of ASD is of increasing interest, this was also explored. There were no significant differences in WM micro- or macrostructure between adults with ASD and matched healthy controls. When data were stratified by sex, females with ASD had reduced fiber density and cross-section (FDC), a combined metric comprised of micro- and macrostructural measures, in the corpus callosum, a finding not detected between the male sub-groups. We conclude that micro- and macrostructural WM aberrations are present in ASD, and may be influenced by biological sex.
Project description:Females demonstrate greater risk aversion than males on a variety of tasks, but the underlying neurobiological basis is still unclear. We studied how theta (4-7 Hz) oscillations at rest related to three different measures of risk taking. Thirty-five participants (15 females) completed the Bomb Risk Elicitation Task (BRET), which allowed us to measure risk taking during an economic game. The Domain-Specific Risk-Taking Scale (DOSPERT) was used to measure self-assessed risk attitudes as well as reward and punishment sensitivities. In addition, the Barratt Impulsiveness Scale (BIS11) was included to quantify impulsiveness. To obtain measures of frontal theta asymmetry and frontal theta power, we used magnetoencephalography (MEG) acquired prior to task completion, while participants were at rest. Frontal theta asymmetry correlated with average risk taking during the game but only in the female sample. By contrast, frontal theta power correlated with risk taking as well as with measures of reward and punishment sensitivity in the joint sample. Importantly, we showed that reward sensitivity mediated a correlation between risk taking and the power of theta oscillations localized to the anterior cingulate cortex. In addition, we observed significant sex differences in source- and sensor-space theta power, risk taking during the game, and reward sensitivity. Our findings suggest that sensitivity to rewards, associated with resting-state theta oscillations in the anterior cingulate cortex, is a trait that potentially contributes to sex differences in risk taking.
Project description:Background: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward-related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated (FTO) gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers. Methods: We have tested WM integrity in 21 male participants genotyped on the FTO risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: "risk tracts", "obesity-associated tracts", and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the "risk-tracts" (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire. Results: An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the "risk tracts". Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks. Conclusions: A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the FTO AA risk-allele, and possibly act as a predisposing factor to the development of obesity.
Project description:Adolescence is characterized by rapid brain development in white matter (WM) that is attributed in part to surges in gonadal hormones. To date, however, there have been few longitudinal investigations relating changes in gonadal hormones and WM development in adolescents. We acquired diffusion-weighted MRI to estimate mean fractional anisotropy (FA) from 10 WM tracts and salivary testosterone from 51 females and 29 males (ages 9-14 years) who were matched on pubertal stage and followed, on average, for 2 years. We tested whether interactions between sex and changes in testosterone levels significantly explained changes in FA. We found positive associations between changes in testosterone and changes in FA within the corpus callosum, cingulum cingulate, and corticospinal tract in females (all ps<0.05, corrected) and non-significant associations in males. We also collected salivary estradiol from females and found that increases in estradiol were associated with increases in FA in the left uncinate fasciculus (p?=?0.04, uncorrected); however, this effect was no longer significant after accounting for changes in testosterone. Our findings indicate there are sex differences in how changes in testosterone relate to changes in WM microstructure of tracts that support impulse control and emotion regulation across the pubertal transition.
Project description:Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
Project description:This study examined whether adolescents with anorexia nervosa (AN) are more sensitive to punishment and less sensitive to reward than a non-eating disorder comparison group. Both self-report and performance measures were used to index reward and punishment sensitivity. Participants were adolescents with AN (n = 69) and an individually matched comparison group with healthy weight (n = 69). They completed the Behavioral Inhibition Scale/Behavioral Activation Scale and the Sensitivity to Punishment and Sensitivity to Reward Questionnaire to index self-reported reward and punishment sensitivity, and performed the Spatial Orientation Task to index attention to cues signaling reward and punishment. There was extremely strong evidence (BF10 > 100), that adolescents with AN reported higher sensitivity to punishment than adolescents without an eating disorder. However, adolescents with AN did not differ from the comparison group on self-reported reward sensitivity, and attention to cues signaling reward or punishment. Adolescents with AN clearly show heightened punishment sensitivity, yet this was not paralleled by a heightened proneness to detect signals of punishment. An important next step would be to examine whether punishment sensitivity is a reliable risk factor for the development or maintenance of AN.
Project description:Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.