Diurnal Fluctuations in Steroid Hormones Tied to Variation in Intrinsic Functional Connectivity in a Densely Sampled Male.

Most of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into how the endocrine system dynamically regulates aspects of the human brain. Recently, we established estrogen's ability to drive widespread patterns of connectivity and enhance the global efficiency of large-scale brain networks in a woman sampled every 24 h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6 and 7 A.M. and nadir between 7 and 8 P.M. To capture the brain's response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12-24 h across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, 17ß-estradiol-the primary form of estrogen-and cortisol. Standardized regression analyses revealed widespread associations between testosterone, estradiol, and cortisol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in the Dorsal Attention Network was coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and a naturally cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence in both sexes and to a heightened degree in the male. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are associated with patterns of whole-brain functional connectivity.

Striatal and Behavioral Responses to Reward Vary by Socioeconomic Status in Adolescents.

Disparities in socioeconomic status (SES) lead to unequal access to financial and social support. These disparities are believed to influence reward sensitivity, which in turn are hypothesized to shape how individuals respond to and pursue rewarding experiences. However, surprisingly little is known about how SES shapes reward sensitivity in adolescence. Here, we investigated how SES influenced adolescent responses to reward, both in behavior and the striatum-a brain region that is highly sensitive to reward. We examined responses to both immediate reward (tracked by phasic dopamine) and average reward rate fluctuations (tracked by tonic dopamine) as these distinct signals independently shape learning and motivation. Adolescents (n = 114; 12-14 years; 58 female) performed a gambling task during functional magnetic resonance imaging. We manipulated trial-by-trial reward and loss outcomes, leading to fluctuations between periods of reward scarcity and abundance. We found that a higher reward rate hastened behavioral responses, and increased guess switching, consistent with the idea that reward abundance increases response vigor and exploration. Moreover, immediate reward reinforced previously rewarding decisions (win-stay, lose-switch) and slowed responses (postreward pausing), particularly when rewards were scarce. Notably, lower-SES adolescents slowed down less after rare rewards than higher-SES adolescents. In the brain, striatal activations covaried with the average reward rate across time and showed greater activations during rewarding blocks. However, these striatal effects were diminished in lower-SES adolescents. These findings show that the striatum tracks reward rate fluctuations, which shape decisions and motivation. Moreover, lower SES appears to attenuate reward-driven behavioral and brain responses.

Diminished Repetition Suppression Reveals Selective and Systems-Level Face Processing Differences in ASD.

Repeated exposure to a stimulus results in reduced neural response, or repetition suppression, in brain regions responsible for processing that stimulus. This rapid accommodation to repetition is thought to underlie learning, stimulus selectivity, and strengthening of perceptual expectations. Importantly, reduced sensitivity to repetition has been identified in several neurodevelopmental, learning, and psychiatric disorders, including autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by challenges in social communication and repetitive behaviors and restricted interests. Reduced ability to exploit or learn from repetition in ASD is hypothesized to contribute to sensory hypersensitivities, and parallels several theoretical frameworks claiming that ASD individuals show difficulty using regularities in the environment to facilitate behavior. Using fMRI in autistic and neurotypical human adults (females and males), we assessed the status of repetition suppression across two modalities (vision, audition) and with four stimulus categories (faces, objects, printed words, and spoken words). ASD individuals showed domain-specific reductions in repetition suppression for face stimuli only, but not for objects, printed words, or spoken words. Reduced repetition suppression for faces was associated with greater challenges in social communication in ASD. We also found altered functional connectivity between atypically adapting cortical regions and higher-order face recognition regions, and microstructural differences in related white matter tracts in ASD. These results suggest that fundamental neural mechanisms and system-wide circuits are selectively altered for face processing in ASD and enhance our understanding of how disruptions in the formation of stable face representations may relate to higher-order social communication processes.SIGNIFICANCE STATEMENT A common finding in neuroscience is that repetition results in plasticity in stimulus-specific processing regions, reflecting selectivity and adaptation (repetition suppression [RS]). RS is reduced in several neurodevelopmental and psychiatric conditions including autism spectrum disorder (ASD). Theoretical frameworks of ASD posit that reduced adaptation may contribute to associated challenges in social communication and sensory processing. However, the scope of RS differences in ASD is unknown. We examined RS for multiple categories across visual and auditory domains (faces, objects, printed words, spoken words) in autistic and neurotypical individuals. We found reduced RS in ASD for face stimuli only and altered functional connectivity and white matter microstructure between cortical face-recognition areas. RS magnitude correlated with social communication challenges among autistic individuals.

Reward-Sensitive Basal Ganglia Stabilize the Maintenance of Goal-Relevant Neural Patterns in Adolescents.

Maturation of basal ganglia (BG) and frontoparietal circuitry parallels developmental gains in working memory (WM). Neurobiological models posit that adult WM performance is enhanced by communication between reward-sensitive BG and frontoparietal regions, via increased stability in the maintenance of goal-relevant neural patterns. It is not known whether this reward-driven pattern stability mechanism may have a role in WM development. In 34 young adolescents (12.16-14.72 years old) undergoing fMRI, reward-sensitive BG regions were localized using an incentive processing task. WM-sensitive regions were localized using a delayed-response WM task. Functional connectivity analyses were used to examine the stability of goal-relevant functional connectivity patterns during WM delay periods between and within reward-sensitive BG and WM-sensitive frontoparietal regions. Analyses revealed that more stable goal-relevant connectivity patterns between reward-sensitive BG and WM-sensitive frontoparietal regions were associated with both greater adolescent age and WM ability. Computational lesion models also revealed that functional connections to WM-sensitive frontoparietal regions from reward-sensitive BG uniquely increased the stability of goal-relevant functional connectivity patterns within frontoparietal regions. Findings suggested (1) the extent to which goal-relevant communication patterns within reward-frontoparietal circuitry are maintained increases with adolescent development and WM ability and (2) communication from reward-sensitive BG to frontoparietal regions enhances the maintenance of goal-relevant neural patterns in adolescents' WM. The maturation of reward-driven stability of goal-relevant neural patterns may provide a putative mechanism for understanding the developmental enhancement of WM.

Circadian rhythms tied to changes in brain morphology in a densely-sampled male.

Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.

Exploring sex-specific neuroendocrine influences on the sensorimotor-association axis in single individuals.

Human neuroimaging studies consistently show multimodal patterns of variability along a key principle of macroscale cortical organization - the sensorimotor-association (S-A) axis. However, little is known about day-to-day fluctuations in functional activity along this axis within an individual, including sex-specific neuroendocrine factors contributing to such transient changes. We leveraged data from two densely sampled healthy young adults, one female and one male, to investigate intra-individual daily variability along the S-A axis, which we computed as our measure of functional cortical organization by reducing the dimensionality of functional connectivity matrices. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, and was more strongly pronounced in the male subject. Next, we probed local- and system-level effects of steroid hormones and self-reported perceived stress on functional organization. Our findings revealed modest effects that differed between participants, hinting at subtle -potentially sex-specific- associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis. In sum, our study points to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization, highlighting the need for further research in larger samples.

Neuroanatomical changes observed over the course of a human pregnancy.

Pregnancy is a period of profound hormonal and physiological change experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation have not been studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through two years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, which stand in contrast to increases in white matter microstructural integrity, ventricle volume, and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as the first comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to stimulate further exploration and discovery.

Diurnal fluctuations in steroid hormones tied to variation in intrinsic functional connectivity in a densely sampled male.

Most of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into the means through which our endocrine system regulates dynamic properties of the human brain. Recently, we established estrogen's ability to drive widespread patterns of connectivity and enhance the functional efficiency of large-scale brain networks in a woman sampled every 24h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6-7am and nadir between 7-8pm. To capture the brain's response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12-24 hours across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, cortisol, and estradiol. Standardized regression analyses revealed predominantly positive associations between testosterone, cortisol, and estradiol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in Dorsal Attention and Salience/Ventral Attention Networks were coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and naturally-cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence to a comparable degree in both sexes. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are tied to patterns of whole-brain functional connectivity.

Phenazine content in the cystic fibrosis respiratory tract negatively correlates with lung function and microbial complexity.

Although much is known about how virulence factors affect pathogens and host tissues in vitro, far less is understood about their dynamics in vivo. As a step toward characterizing the chemistry of infected environments, we measured phenazine abundance in the lungs of patients with cystic fibrosis (CF). Phenazines are redox-active small molecules produced by Pseudomonas aeruginosa that damage host epithelia, curb the growth of competing organisms, and play physiologically important roles in the cells that produce them. Here, we quantify phenazines within expectorated sputum, characterize the P. aeruginosa populations responsible for phenazine production, and assess their relationship to CF lung microflora. Chemical analyses of expectorated sputum showed that the concentrations of two phenazines, namely, pyocyanin (PYO) and phenazine-1-carboxylic acid (PCA), were negatively correlated (ρ = -0.68 and -0.57, respectively) with lung function. Furthermore, the highest phenazine concentrations were found in patients whose pulmonary function showed the greatest rates of decline. The constituent P. aeruginosa populations within each patient showed diverse capacities for phenazine production. Early during infection, individual isolates produced more PYO than later during infection. However, total PYO concentrations in sputum at any given stage correlated well with the average production by the total P. aeruginosa population. Finally, bacterial community complexity was negatively correlated with phenazine concentrations and declines in lung function, suggesting a link to the refinement of the overall microbial population. Together, these data demonstrate that phenazines negatively correlate with CF disease states in ways that were previously unknown, and underscore the importance of defining in vivo environmental parameters to better predict clinical outcomes of infections.

Neuroplasticity associated with changes in conversational turn-taking following a family-based intervention.

Children's early language environments are associated with linguistic, cognitive, and academic development, as well as concurrent brain structure and function. This study investigated neurodevelopmental mechanisms linking language input to development by measuring neuroplasticity associated with an intervention designed to enhance language environments of families primarily from lower socioeconomic backgrounds. Families of 52 4-to-6 year-old children were randomly assigned to a 9-week, interactive, family-based intervention or no-contact control group. Children completed pre- and post-assessments of verbal and nonverbal cognition (n = 52), structural magnetic resonance imaging (n = 45), and home auditory recordings of language exposure (n = 39). Families who completed the intervention exhibited greater increases in adult-child conversational turns, and changes in turn-taking mediated intervention effects on language and executive functioning measures. Collapsing across groups, turn-taking changes were also positively correlated with cortical thickening in left inferior frontal and supramarginal gyri, the latter of which mediated relationships between changes in turn-taking and children's language development. This is the first study of longitudinal neuroplasticity in response to changes in children's language environments, and findings suggest that conversational turns support language development through cortical growth in language and social processing regions. This has implications for early interventions to enhance children's language environments to support neurocognitive development.

Fixed and flexible: Dynamic prefrontal activations and working memory capacity relationships vary with memory demand.

Prefrontal cortex (PFC) activation during encoding of memoranda (proactive responses) is associated with better working memory (WM) compared to reactive/retrieval-based activation. This suggests that dynamic PFC activation patterns may be fixed, based upon one's WM ability, with individuals who have greater WM ability relying more on proactive processes and individuals with lesser WM ability relying more on reactive processes. We newly tested whether this heuristic applied when challenging an individual's WM capacity. Twenty-two participants (N = 22) underwent functional near-infrared spectroscopy (fNIRS) during a modified Sternberg WM paradigm. We tested whether the relationship between dynamic PFC activation patterns and WM capacity changed, as a function of WM demands (N = 14 after quality control). Here, higher-WM capacity was associated with more proactive PFC patterns, but only when WM capacity was overloaded. Lower-WM capacity was associated with these same patterns, but only when WM demand was low. Findings are inconsistent with a purely fixed view of dynamic PFC activation patterns and suggest higher- and lower-WM-capacity individuals flexibly engage PFC processes in a fundamentally different manner, dependent upon current WM demands.

Associations between cortical thickness and reasoning differ by socioeconomic status in development.

Although lower socioeconomic status (SES) is generally negatively associated with performance on cognitive assessments, some children from lower-SES backgrounds perform as well as their peers from higher-SES backgrounds. Yet little research has examined whether the neural correlates of individual differences in cognition vary by SES. The current study explored whether relationships between cortical structure and fluid reasoning differ by SES in development. Fluid reasoning, a non-verbal component of IQ, is supported by a distributed frontoparietal network, with evidence for a specific role of rostrolateral prefrontal cortex (RLPFC). In a sample of 115 4-7-year old children, bilateral thickness of RLPFC differentially related to reasoning by SES: thicker bilateral RLPFC positively correlated with reasoning ability in children from lower-SES backgrounds, but not in children from higher-SES backgrounds. Similar results were found in an independent sample of 59 12-16-year old adolescents. Furthermore, young children from lower-SES backgrounds with strong reasoning skills were the only group to show a positive relationship between RLPFC thickness and age. In sum, we found that relationships between cortical thickness and cognition differ by SES during development.