Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis.

OBJECTIVE: Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. DESIGN: Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. RESULTS: After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. CONCLUSIONS: The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. TRIAL REGISTRATION NUMBER: NCT04777812.

A novel method to efficiently differentiate human osteoclasts from blood-derived monocytes.

BACKGROUND: Osteoclasts are the tissue-specific macrophage population of the bone and unique in their bone-resorbing activity. Hence, they are fundamental for bone physiology in health and disease. However, efficient protocols for the isolation and study of primary human osteoclasts are scarce. In this study, we aimed to establish a protocol, which enables the efficient differentiation of functional human osteoclasts from monocytes. RESULTS: Human monocytes were isolated through a double-density gradient from donor blood. Compared to standard differentiation schemes in polystyrene cell culture dishes, the yield of multinuclear osteoclasts was significantly increased upon initial differentiation of monocytes to macrophages in fluorinated ethylene propylene (FEP) Teflon bags. This initial differentiation phase was then followed by the development of terminal osteoclasts by addition of Receptor Activator of NF-κB Ligand (RANKL). High concentrations of RANKL and Macrophage colony-stimulating factor (M-CSF) as well as an intermediate cell density further supported efficient cell differentiation. The generated cells were highly positive for CD45, CD14 as well as the osteoclast markers CD51/ITGAV and Cathepsin K/CTSK, thus identifying them as osteoclasts. The bone resorption of the osteoclasts was significantly increased when the cells were differentiated from macrophages derived from Teflon bags compared to macrophages derived from conventional cell culture plates. CONCLUSION: Our study has established a novel protocol for the isolation of primary human osteoclasts that improves osteoclastogenesis in comparison to the conventionally used cultivation approach.

Cardiac Vagal Regulation Is Impeded in Children With Cyclic Vomiting Syndrome.

INTRODUCTION: The pathophysiology underlying cyclic vomiting syndrome (CVS) remains undefined. Scant data and distinct clinical features point to altered autonomic nervous system function. Autonomic signaling can be noninvasively assessed through cardiac indices of parasympathetic vagal regulation, which is reduced in children with disorders of gut-brain interaction. We aimed to examine dynamic cardiac vagal regulation in children with CVS compared with that in healthy controls (HC). METHODS: A total of 31 children with CVS evaluated in a tertiary care CVS center and 66 HC (ages 8-18 years) underwent cardiac autonomic function assessment. Electrocardiogram recordings were conducted during 3-minute sit/stand/sit posture challenges. The electrocardiogram-derived variables heart period, respiratory sinus arrhythmia (RSA), and vagal efficiency (VE) were analyzed using linear regression and mixed-effects modeling. RESULTS: After exclusion of medication confounders, 23 patients with CVS were included in analyses. Both groups were comparable in age, gender, and body mass index. Compared with HC, children with CVS had shorter heart period (standardized mean difference range: 1.15-1.22, all P values < 0.05) and lower RSA (SMD range: 0.66-0.88, all P values < 0.05). Patients with CVS had significantly lower VE during the entire course of posture shifts, compared with HC ( B = -19.87, SE = 6.95, t = -2.86, P = 0.005, SMD = 0.76). DISCUSSION: Children with CVS have suboptimal parasympathetic autonomic regulation compared with HC, indexed by reduced RSA and VE, even during their interepisodic well phase. Abnormal vagal modulation may underlie CVS pathophysiology, comorbidities, and triggers. Assessing VE during posture stressors could inform therapeutic interventions.

GENA: A knowledge graph for nutrition and mental health.

While a large number of knowledge graphs have previously been developed by automatically extracting and structuring knowledge from literature, there is currently no such knowledge graph that encodes relationships between food, biochemicals and mental illnesses, even though a large amount of knowledge about these relationships is available in the form of unstructured text in biomedical literature articles. To address this limitation, this article describes the development of GENA - (Graph of mEntal-health and Nutrition Association), a knowledge graph that represents relations between nutrition and mental health, extracted from biomedical abstracts. GENA is constructed from PubMed abstracts that contain keywords relating to chemicals, food, and health. A hybrid named entity recognition (NER) model is firstly applied to these abstracts to identify various entities of interest. Subsequently, a deep syntax-based relation extraction model is used to detect binary relations between the identified entities. Finally, the resulting relations are used to populate the GENA knowledge graph, whose relationships can be accessed in an intuitive and interpretable manner using the Neo4J Database Management System. To evaluate the reliability of GENA, two annotators manually assessed a subset of the extracted relations. The evaluation results show that our methods obtain high precision for the NER task and acceptable precision and relative recall for the relation extraction task. GENA consists of 43,367 relationships that encode information about nutrition and health, of which 94.04% are new relations that are not present in existing ontologies of food and diseases. GENA is constructed based on scientific principles, and has the potential to be used within further applications to contribute towards scientific research within the domain. It is a pioneering knowledge graph in nutrition and mental health, containing a diverse range of relationship types. All of our source code and results are publicly available at https://github.com/ddlinh/gena-db.

Factors Associated With High Rates of Depressive Symptomatology in Older People in Vietnam.

OBJECTIVES: This study aimed to identify the prevalence and correlates of depressive symptomatology among Vietnamese older people. METHOD: We used baseline survey data collected in 2018 from the Longitudinal Study of Ageing and Health in Vietnam (LSAHV) conducted across seven regions and comprising 6,050 people aged 60 years and over of whom 4962 completed the brief 11-item Center for Epidemiological Studies-Depression (CES-D) scale. Clinically significant depressive symptomatology was a CES-D score of 8.8 or higher. The association between demographic, physical, and mental factors with depressive symptomatology was examined using univariate and multivariable logistic regression. RESULTS: The prevalence of depressive symptomatology was 31.3% (95% CI 29.8% - 32.9%). Depressive symptomatology was highest among people living in the Central Coast region (46.8%, 95% CI 44.5% - 49.2%). Factors associated with depressive symptomatology from the multivariable model included female sex (OR 1.3, 95% CI: 1.1-1.6), rural residence (OR 1.4, 95%CI: 1.1-1.7), not having a partner (OR 1.6, 95% CI: 1.3-1.9), low income (OR 1.8, 95% CI: 1.5-2.1), and health-limitations on activities (OR 1.3, 95% CI: 1.1-1.6). Poorer self-rated mental health (OR 2.1, 95% CI:1.8-2.5) or general health status (OR 1.5, 95% CI: 1.3-1.9) was associated with a higher prevalence of depressive symptomatology, as was poorer function with respect to different activities of daily living, and dissatisfaction with current life (OR 6.1, 95% CI: 4.4-8.4). CONCLUSIONS: Depressive symptomatology was frequent among older Vietnamese. Efforts to improve mental health in older persons in Vietnam, including prevention, early intervention and better medical care, appear warranted.

Self-Relation Attention and Temporal Awareness for Emotion Recognition via Vocal Burst.

Speech emotion recognition (SER) is one of the most exciting topics many researchers have recently been involved in. Although much research has been conducted recently on this topic, emotion recognition via non-verbal speech (known as the vocal burst) is still sparse. The vocal burst is concise and has meaningless content, which is harder to deal with than verbal speech. Therefore, in this paper, we proposed a self-relation attention and temporal awareness (SRA-TA) module to tackle this problem with vocal bursts, which could capture the dependency in a long-term period and focus on the salient parts of the audio signal as well. Our proposed method contains three main stages. Firstly, the latent features are extracted using a self-supervised learning model from the raw audio signal and its Mel-spectrogram. After the SRA-TA module is utilized to capture the valuable information from latent features, all features are concatenated and fed into ten individual fully-connected layers to predict the scores of 10 emotions. Our proposed method achieves a mean concordance correlation coefficient (CCC) of 0.7295 on the test set, which achieves the first ranking of the high-dimensional emotion task in the 2022 ACII Affective Vocal Burst Workshop & Challenge.

Effectiveness of an Automated Error Checking and Feedback System to Improve Text Message Reporting for Disease Surveillance in Viet Nam.

Purpose: Viet Nam currently relies on a manual paper-based system to track and monitor 28 major infectious diseases. This inefficient system takes 2 or more months to complete. Method: We designed and pilot tested the use of text messaging to report certain infectious disease symptoms in rural areas of northern Viet Nam. The project was divided into three 6-month phases carried out in two provinces. The current analysis focuses on the implementation of a two-way feedback system between Phases II and III, which aims at (1) evaluating whether this system improves efficiency by determining the number of correctly (vs. incorrectly) formatted text messages; (2) assessing this system's influence on accuracy by comparing text messages with their respective official paper-based documented forms; and (3) determining whether the amount of information required to report through text messages influences the efficiency and accuracy of the text messages. Results: Between Phases II and III, results revealed a significant improvement in correctly formatted texts in comparison to incorrectly formatted texts. As the number of fields required to report increased, the number of correctly formatted texts (efficiency) as well as the number of matched text messages (accuracy) decreased. Conclusion: Our research demonstrates that an automated error bidirectional feedback system can significantly improve both the efficiency and accuracy of a Short Message Service-based method for disease surveillance. Also, our data may suggest that two-way communication has better engaged health care staff to follow reporting protocols as well as to maintain accuracy from their clinic's own data.

Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior.

Differential regional decline in dopamine receptor availability across adulthood: Linear and nonlinear effects of age.

Theories of adult brain development, based on neuropsychological test results and structural neuroimaging, suggest differential rates of age-related change in function across cortical and subcortical sub-regions. However, it remains unclear if these trends also extend to the aging dopamine system. Here we examined cross-sectional adult age differences in estimates of D2-like receptor binding potential across several cortical and subcortical brain regions using PET imaging and the radiotracer [18 F]Fallypride in two samples of healthy human adults (combined N = 132). After accounting for regional differences in overall radioligand binding, estimated percent difference in receptor binding potential by decade (linear effects) were highest in most temporal and frontal cortical regions (~6-16% per decade), moderate in parahippocampal gyrus, pregenual frontal cortex, fusiform gyrus, caudate, putamen, thalamus, and amygdala (~3-5%), and weakest in subcallosal frontal cortex, ventral striatum, pallidum, and hippocampus (~0-2%). Some regions showed linear effects of age while many showed curvilinear effects such that binding potential declined from young adulthood to middle age and then was relatively stable until old age. Overall, these data indicate that the rate and pattern of decline in D2 receptor availability is regionally heterogeneous. However, the differences across regions were challenging to organize within existing theories of brain development and did not show the same pattern of regional change that has been observed in gray matter volume, white matter integrity, or cognitive performance. This variation suggests that existing theories of adult brain development may need to be modified to better account for the spatial dynamics of dopaminergic system aging.

Individual differences in dopamine D2 receptor availability correlate with reward valuation.

Reward valuation, which underlies all value-based decision-making, has been associated with dopamine function in many studies of nonhuman animals, but there is relatively less direct evidence for an association in humans. Here, we measured dopamine D2 receptor (DRD2) availability in vivo in humans to examine relations between individual differences in dopamine receptor availability and neural activity associated with a measure of reward valuation, expected value (i.e., the product of reward magnitude and the probability of obtaining the reward). Fourteen healthy adult subjects underwent PET with [18F]fallypride, a radiotracer with strong affinity for DRD2, and fMRI (on a separate day) while performing a reward valuation task. [18F]fallypride binding potential, reflecting DRD2 availability, in the midbrain correlated positively with neural activity associated with expected value, specifically in the left ventral striatum/caudate. The present results provide in vivo evidence from humans showing midbrain dopamine characteristics are associated with reward valuation.

Reduced effects of age on dopamine D2 receptor levels in physically active adults.

Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.

Associations between dopamine D2 receptor availability and BMI depend on age.

OBJECTIVE: The dopamine D2/3 receptor subtypes (DRD2/3) are the most widely studied neurotransmitter biomarker in research on obesity, but results to date have been inconsistent, have typically involved small samples, and have rarely accounted for subjects' ages despite the large impact of age on DRD2/3 levels. We aimed to clarify the relation between DRD2/3 availability and BMI by examining this association in a large sample of subjects with BMI spanning the continuum from underweight to extremely obese. SUBJECTS: 130 healthy subjects between 18 and 81years old underwent PET with [18F]fallypride, a high affinity DRD2/3 ligand. RESULTS: As expected, DRD2/3 availability declined with age. Critically, age significantly interacted with DRD2/3 availability in predicting BMI in the midbrain and striatal regions (caudate, putamen, and ventral striatum). Among subjects under 30years old, BMI was not associated with DRD2/3 availability. By contrast, among subjects over 30years old, BMI was positively associated with DRD2/3 availability in the midbrain, putamen, and ventral striatum. CONCLUSION: The present results are incompatible with the prominent dopaminergic hypofunction hypothesis that proposes that a reduction in DRD2/3 availability is associated with increased BMI, and highlights the importance of age in assessing correlates of DRD2/3 function.

Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults.

Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24-34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.

Pigment epithelium-derived factor mediates impaired lung vascular development in neonatal hyperoxia.

Bronchopulmonary dysplasia is a chronic lung disease of preterm infants characterized by arrested microvascularization and alveolarization. Studies show the importance of proangiogenic factors for alveolarization, but the importance of antiangiogenic factors is unknown. We proposed that hyperoxia increases the potent angiostatin, pigment epithelium-derived factor (PEDF), in neonatal lungs, inhibiting alveolarization and microvascularization. Wild-type (WT) and PEDF(-/-) mice were exposed to room air (RA) or 0.9 fraction of inspired oxygen from Postnatal Day 5 to 13. PEDF protein was increased in hyperoxic lungs compared with RA-exposed lungs (P < 0.05). In situ hybridization and immunofluorescence identified PEDF production primarily in alveolar epithelium. Hyperoxia reduced alveolarization in WT mice (P < 0.05) but not in PEDF(-/-) mice. WT hyperoxic mice had fewer platelet endothelial cell adhesion molecule (PECAM)-positive cells per alveolus (1.4 ± 0.4) than RA-exposed mice (4.3 ± 0.3; P < 0.05); this reduction was absent in hyperoxic PEDF(-/-) mice. The interactive regulation of lung microvascularization by vascular endothelial growth factor and PEDF was studied in vitro using MFLM-91U cells, a fetal mouse lung endothelial cell line. Vascular endothelial growth factor stimulation of proliferation, migration, and capillary tube formation was inhibited by PEDF. MFLM-91U cells exposed to conditioned medium (CM) from E17 fetal mouse lung type II (T2) cells cultured in 0.9 fraction of inspired oxygen formed fewer capillary tubes than CM from T2 cells cultured in RA (hyperoxia CM, 51 ± 10% of RA CM, P < 0.05), an effect abolished by PEDF antibody. We conclude that PEDF mediates reduced vasculogenesis and alveolarization in neonatal hyperoxia. Bronchopulmonary dysplasia likely results from an altered balance between pro- and antiangiogenic factors.

Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of "unhealthy" foods.

The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual's COMT genotype status (n = 61) and investigated food desirability based on self-rated "healthy" and "unhealthy" food perceptions. Here we found val/val individuals (n = 19) have greater desirability for self-rated "unhealthy" food items, but not self-rated "healthy" food items, as compared to val/met (n = 24) and met/met (n = 18) individuals (p < 0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined "unhealthy" food items, as compared to met/met individuals (p < 0.01). This work further substantiates the role of dopamine in food-related behaviors and more specifically in relationship to food desirability for "unhealthy" food items.

Dopamine and the cognitive downside of a promised bonus.

It is often assumed that the promise of a monetary bonus improves cognitive control. We show that in fact appetitive motivation can also impair cognitive control, depending on baseline levels of dopamine-synthesis capacity in the striatum. These data not only demonstrate that appetitive motivation can have paradoxical detrimental effects for cognitive control but also provide a mechanistic account of these effects.

A new paradigm for disease surveillance in Vietnam.

Medical surveillance data from all government health clinics in Vietnam are currently collected through a slow, paper-driven process. Short message service (SMS) technology delivered through mobile phones offers a simple solution to improving the speed through which disease surveillance information can be collected. Identifying health concerns earlier with this mobile-based disease surveillance system has the potential to improve the care for patients seen at community health clinics as well as predict more quickly that a medical emergency, such as a pandemic, will occur. Thus, we piloted the feasibility of an SMS-based disease surveillance system designed for healthcare workers in Vietnam to directly report disease information on diarrhea and influenza-like illness to a central data repository using their mobile phones and an intuitive, user-friendly platform. This article reports data from 1,579 patient data entries in 20 Vietnamese health clinics during a 6-month period.

Coordinated Care Experiences Among Middle-Aged and Older Adults With Multiple Chronic Conditions: Characteristics, Correlates, and Consequences for Health and Healthcare Utilization.

BACKGROUND AND OBJECTIVES: Although coordinated care (CC) seeks to improve patient experiences and ultimately health outcomes, evidence from empirical research on the impacts of CC is mixed. This study examined the relationship between CC and healthcare outcomes over a 4-year period among older adults with multiple chronic conditions. RESEARCH DESIGN AND METHODS: This observational cohort study is based on data from the 2016-2020 Health and Retirement Study. Analysis is limited to respondents with 2+ chronic conditions who completed an experimental module on CC in 2016 (n = 906). Three domains of CC were assessed: perceptions, informal (family/friends) and formal (healthcare staff) tangible support, and technical support (using a "patient portal"). The longitudinal relationship between CC and health (e.g., pain, functioning, and self-rated health [SRH]) and healthcare (e.g., doctor visits, hospitalization, and care satisfaction) outcomes was investigated using mixed-effects models. RESULTS: Better perceptions of CC were associated with lower odds of ADL limitations (Odds ratio [OR] = 0.91; 95% CI = 0.84-0.99) and greater satisfaction with care (B = 0.04, 95% CI = 0.02-0.06). Receipt of more informal tangible support was associated with 1.34 higher odds of ADL limitations (95% CI = 1.19-1.51) and 1.74 higher odds of hospitalization (95% CI = 1.07-1.21). Use of technical support was associated with better SRH and greater satisfaction with care. DISCUSSION AND IMPLICATIONS: The longitudinal relationship between CC and health is multifaceted. Although positive perceptions and more technical support have beneficial effects on health outcomes, higher utilization of tangible support may reflect a higher demand among older adults with more complex healthcare needs.

Dopamine supports coupling of attention-related networks.

Attentional processing has been associated with the dorsal attention, default mode, and frontoparietal control networks. The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The frontoparietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network, depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We used PET with 6-[(18)F]fluoro-L-m-tyrosine to quantify dopamine synthesis capacity in vivo and fMRI to acquire stimulus-independent brain activity in cognitively healthy human subjects. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the frontoparietal control network and the default mode network while reducing the coupling between the frontoparietal control network and the dorsal attention network. These results add a neurochemical perspective to the role of network interaction in modulating attention.

Genetic effects on behavior are mediated by neurotransmitters and large-scale neural networks.

Claims of gene-behavior associations are complex and sometimes difficult to replicate because these relationships involve many downstream endogenous and environmental processes that mediate genetic effects. Knowing these mediating processes is critical to understanding the links between genes and behavior and how these factors differ between people. We identified and characterized the effects of a gene on neurochemistry and neural networks to elucidate the mechanism, at the systems level, whereby genes influence cognition. Catechol-O-methyltransferase (COMT) degrades dopamine in the prefrontal cortex (PFC) and is polymorphic with alleles differing in enzymatic activity. We found that COMT genotype determined dopamine synthesis, such that individuals with greater COMT activity synthesized more dopamine. Dopamine synthesis in the midbrain and ventral striatum affected functional connectivity in the default mode network, likely through the mesocorticolimbic pathway, in an inverted-U pattern with greater functional connectivity in medial PFC associated with intermediate levels of COMT activity and dopamine. Greater functional connectivity correlated with greater deactivation during performance of a set-shifting task that engaged the PFC. Greater deactivation was in turn associated with better performance. The integration of these results yields a model whereby COMT affects prefrontal function by a mechanism involving dopaminergic modulation of the default mode network. The model features the well-known inverted-U function between dopamine and performance and supports the hypothesis that dopamine and the default mode network shift attentional resources to influence prefrontal cognition.