Faculty Bibliography

PURPOSE/OBJECTIVE:Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS:Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS:The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION/CONCLUSIONS:Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.

Nonrapid eye movement (NREM) sleep is associated with fading consciousness in humans. Recent neuroimaging studies have demonstrated the spatiotemporal alterations of the brain functional connectivity (FC) in NREM sleep, suggesting the changes of information integration in the sleeping brain. However, the common stationarity assumption in FC does not satisfactorily explain the dynamic process of information integration during sleep. The dynamic FC (dFC) across brain networks is speculated to better reflect the time-varying information propagation during sleep. Accordingly, we conducted simultaneous EEG-fMRI recordings involving 12 healthy men during sleep and observed dFC across sleep stages using the sliding-window approach. We divided dFC into two aspects: mean dFC (dFC_mean ) and variance dFC (dFC_var ). A high dFC_mean indicates stable brain network integrity, whereas a high dFC_var indicates instability of information transfer within and between functional networks. For the network-based dFC, the dFC_var were negatively correlated with the dFC_mean across the waking and three NREM sleep stages. As sleep deepened, the dFC_mean decreased (N0~N1 > N2 > N3), whereas the dFC_var peaked during the N2 stage (N0~N1 < N3 < N2). The highest dFC_var during the N2 stage indicated the unstable synchronizations across the entire brain. In the N3 stage, the overall disrupted network integration was observed through the lowest dFC_mean and elevated dFC_var, compared with N0 and N1. Conclusively, when the network specificity (dFC_mean ) breaks down, the consciousness dissipates with increasing variability of information exchange (dFC_var ).

Bilingual infants from 6- to 24-months of age are more likely to generalize, flexibly reproducing actions on novel objects significantly more often than age-matched monolingual infants are. In the current study, we examine whether the addition of novel verbal labels enhances memory generalization in a perceptually complex imitation task. We hypothesized that labels would provide an additional retrieval cue and aid memory generalization for bilingual infants. Specifically, we hypothesized that bilinguals might be more likely than monolinguals to map multiple perceptual features onto a novel label and therefore show enhanced generalization. Eighty-seven 18-month-old monolingual and bilingual infants were randomly assigned to one of two experimental conditions or a baseline control condition. In the experimental conditions, either no label or a novel label was added during demonstration and again at the beginning of the test session. After a 24-hr delay, infants were tested with the same stimulus set to test cued recall and with a perceptually different but functionally equivalent stimulus set to test memory generalization. Bilinguals performed significantly above baseline on both cued recall and memory generalization in both experimental conditions, whereas monolinguals performed significantly above baseline only on cued recall in both experimental conditions. These findings show a difference between monolinguals and bilinguals in memory generalization and suggest that generalization differences between groups may arise from visual perceptual processing rather than linguistic processing. A video abstract of this article can be viewed at https://youtu.be/yXB4pM3fF2k.

While our understanding of appetitive motivation has benefited immensely from the use of selective outcome devaluation tools, the same cannot be said about aversive motivation. Findings from appetitive conditioning studies have shown that basal amygdala is required for behaviors that are sensitive to updates in outcome value, but similar results in aversive motivation are difficult to interpret due to a lack of outcome specificity. The studies reported here sought to develop procedures to isolate sensory-specific processes in aversive learning and behavior and to assess the possible contribution of the basal amygdala. Post-training changes to outcome value produced commensurate changes to subsequently tested conditioned responding in male rodents. Specifically, increases in shock intensity (i.e., inflation) augmented, while repeated exposure to (i.e., habituation of) an aversive sound (klaxon-horn) reduced freezing to conditioned stimuli previously paired with these outcomes. This was extended to a discriminative procedure, in which following revaluation of one event, but not the other, responding was found to be dependent on outcome value signaled by each cue. Chemogenetic inactivation of basal amygdala impaired this discrimination between stimuli signaling differently valued outcomes, but did not affect the revaluation process itself. These findings demonstrate a contribution of the basal amygdala to aversive outcome-dependent motivational processes.SIGNIFICANCE STATEMENT The specific content of pavlovian associative learning has been well studied in appetitive motivation, where the value of different foods can be easily manipulated. This has facilitated our understanding of the neural circuits that generate different forms of motivation (i.e., sensory specific vs general). Studies of aversive learning have not produced the same degree of understanding with regard to sensory specificity due to a lack of tools for evaluating sensory-specific processes. Here we use a variant of outcome devaluation procedures with aversive stimuli to study the role of basal amygdala in discriminating between aversive stimuli conveying different degrees of threat. These findings have implications for how we study generalized threat to identify dysregulation that can contribute to generalized anxiety.

Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (non-syndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies.

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.

Large-scale functional connectome formation and re-organization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated prior to birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.SIGNIFICANCE STATEMENTThe fetal to neonatal period is well known as a critical stage in brain development. Rapid neurodevelopmental processes establish key functional neural circuits of the human brain. Prenatal risk factors may interfere with early trajectories of connectome formation and thereby shape future health outcomes. Recent advances in MRI have made it possible to examine fetal brain functional connectivity. In this study, we evaluate the network topography of normative functional network development during connectome genesis in utero Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction.

Goal-directed actions involve problem solving-how to coordinate perception and action to get the job done. Whereas previous work focused on the ages at which children succeed in problem solving, we focused on how children solve motor problems in real time. We used object fitting as a model system to understand how perception and action unfold from moment to moment. Preschoolers (N = 25) and adults (N = 24) inserted three-dimensional objects into their corresponding openings in a "shape-sorting" box. We applied a new combination of real-time methods to the problem of object fitting-head-mounted eye tracking to record looking behaviors, video microcoding to record adjustments in object orientation between reach and insertion, and real-time analysis techniques (recurrent quantification analysis and Granger causality) to test the timing relations between visual and manual actions. Children, like adults, solved the problem successfully. However, adults outperformed children in terms of their speed of fitting, and speed depended on when adjustments of object orientation occurred. Adults adjusted object orientation during transport, whereas children adjusted object orientation after arriving at the box. Children's delays in adjustment resulted from delays in looking at the target shape and its corresponding aperture. Findings show that planning is a real-time cascade of perception and action, and looking provides the basis for planning actions prospectively. We suggest that developmental improvements in problem solving are driven by real-time changes in the instigation of the planning cascade and the timing of its components.

Importance/UNASSIGNED:An increasing prevalence of adult attention-deficit/hyperactivity disorder (ADHD) diagnosis and treatment has been reported in clinical settings and administrative data in the United States. However, there are limited data on recent trends of adult ADHD diagnosis among racial/ethnic subgroups. Objective/UNASSIGNED:To examine trends, including associated demographic characteristics, psychiatric diagnoses, and negative outcomes, in the prevalence and incidence of adult ADHD diagnosis among 7 racial/ethnic groups during a 10-year period. Design, Setting, and Participants/UNASSIGNED:This cohort study investigated trends in the diagnosis of ADHD in adults who identified as African American or black, Native American, Pacific Islander, Latino or Hispanic, non-Hispanic white, Asian American, or other using the Kaiser Permanente Northern California health plan medical records. A total of 5 282 877 adult patients and 867 453 children aged 5 to 11 years who received care at Kaiser Permanente Northern California from January 1, 2007, to December 31, 2016, were included. Data analysis was performed from January 2017 through September 2019. Exposures/UNASSIGNED:Period of ADHD diagnosis. Main Outcomes and Measures/UNASSIGNED:Prevalence and incidence of licensed mental health clinician-diagnosed ADHD in adults and prevalence of licensed mental health clinician-diagnosed ADHD in children aged 5 to 11 years. Results/UNASSIGNED:Of 5 282 877 adult patients (1 155 790 [21.9%] aged 25-34 years; 2 667 562 [50.5%] women; 2 204 493 [41.7%] white individuals), 59 371 (1.12%) received diagnoses of ADHD. Prevalence increased from 0.43% in 2007 to 0.96% in 2016. Among 867 453 children aged 5 to 11 years (424 449 [48.9%] girls; 260 236 [30.0%] white individuals), prevalence increased from 2.96% in 2007 to 3.74% in 2016. During the study period, annual adult ADHD prevalence increased for every race/ethnicity, but white individuals consistently had the highest prevalence rates (white individuals: 0.67%-1.42%; black individuals: 0.22%-0.69%; Native American individuals: 0.56%-1.14%; Pacific Islander individuals: 0.11%-0.39%; Hispanic or Latino individuals: 0.25%-0.65%; Asian American individuals: 0.11%-0.35%; individuals from other races/ethnicities: 0.29%-0.71%). Incidence of ADHD diagnosis per 10 000 person-years increased from 9.43 in 2007 to 13.49 in 2016. Younger age (eg, >65 years vs 18-24 years: odds ratio [OR], 0.094; 95% CI, 0.088-0.101; P < .001), male sex (women: OR, 0.943; 95% CI, 0.928-0.959; P < .001), white race (eg, Asian patients vs white patients: OR, 0.248; 95% CI, 0.240-0.257; P < .001), being divorced (OR, 1.131; 95% CI, 1.093-1.171; P < .001), being employed (eg, retired vs employed persons: OR, 0.278; 95% CI, 0.267-0.290; P < .001), and having a higher median education level (OR, 2.156; 95% CI, 2.062-2.256; P < .001) were positively associated with odds of ADHD diagnosis. Having an eating disorder (OR, 5.192; 95% CI, 4.926-5.473; P < .001), depressive disorder (OR, 4.118; 95% CI, 4.030-4.207; P < .001), bipolar disorder (OR, 4.722; 95% CI, 4.556-4.894; P < .001), or anxiety disorder (OR, 2.438; 95% CI, 2.385-2.491; P < .001) was associated with higher odds of receiving an ADHD diagnosis. Adults with ADHD had significantly higher odds of frequent health care utilization (OR, 1.303; 95% CI, 1.272-1.334; P < .001) and sexually transmitted infections (OR, 1.289; 95% CI 1.251-1.329; P < .001) compared with adults with no ADHD diagnosis. Conclusions and Relevance/UNASSIGNED:This study confirmed the reported increases in rates of ADHD diagnosis among adults, showing substantially lower rates of detection among minority racial/ethnic subgroups in the United States. Higher odds of negative outcomes reflect the economic and personal consequences that substantiate the need to improve assessment and treatment of ADHD in adults.