Faculty Bibliography

[This corrects the article on p. 409 in vol. 20, PMID: 30881565.].

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes' lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.

Fixation is essential for preserving cellular morphology in biomedical research. However, it may also affect spectra captured in multispectral fluorescence microscopy, impacting molecular interpretations. To investigate fixation effects on tissue, multispectral fluorescence microscopy images of pairs of samples with and without fixation are captured. Each pixel might exhibit overlapping spectra, creating a blind source separation problem approachable with linear unmixing. With multiple excitation wavelengths, unmixing is intuitively extended to tensor factorizations. Yet these approaches are limited by nonlinear effects like attenuation. Further, light exposure during image acquisition introduces subtle Brownian motion between image channels of non-fixed tissue. Finally, hypothesis testing for spectral differences due to fixation is nontrivial as retrieved spectra are paired sequential samples. To these ends, we present three contributions, (1) a novel robust non-negative tensor factorization using the β-divergence and L _2,1-norm, which decomposes the data into a low-rank multilinear and group-sparse non-multilinear tensor without making any explicit nonlinear modeling choices or assumptions on noise statistics; (2) a diffeomorphic atlas-based strategy for motion correction; (3) a non-parametric hypothesis testing framework for paired sequential data using functional principal component analysis.

BACKGROUND:A single-dose (150 mg/kg) of valproic acid (VPA) has been shown to decrease brain lesion size and improve neurologic recovery in preclinical models of traumatic brain injury (TBI). However, the longer-term (30 days) impact of single-dose VPA treatment after TBI has not been well evaluated. STUDY DESIGN:Yorkshire swine were subjected to TBI (cortical impact), hemorrhagic shock, and polytrauma. Animals remained in hypovolemic shock for 2 hours before resuscitation with normal saline (NS; volume = 3× hemorrhaged volume) or NS + VPA (150 mg/kg) (n = 5/cohort). Brain samples were harvested 30 days after injuries. The cerebral cortex adjacent to the site of cortical impact was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot analysis. Neural apoptosis, inflammation, degeneration, plasticity, and signaling pathways were evaluated. RESULTS:For apoptosis, VPA treatment significantly decreased (p < 0.05) the number of TUNEL (+) cells and expression of cleaved-caspase 3. For inflammation and degeneration, expression of ionized calcium binding adaptor molecule-1, glial fibrillary acid protein, amyloid-β, and phosphorylated-Tau protein were significantly attenuated (p < 0.05) in the VPA-treated animals compared with the NS group. For, plasticity, VPA treatment also increased expression of brain-derived neurotrophic factor significantly (p < 0.05) compared with the NS group. For signaling pathways, nuclear factor-κB was decreased significantly (p < 0.05) and cytosolic IκBα expression was increased significantly (p < 0.05) in the VPA-treated animals compared with the NS group. CONCLUSIONS:Administration of a single dose of VPA (150 mg/kg) can decrease neural apoptosis, inflammation, and degenerative changes, and promote neural plasticity at 30 days after TBI. In addition, VPA acts, in part, via regulation of nuclear factor-κB and IκBα pathways.

Although parenting behavior and friendship quality predict adolescent externalizing behaviors (EBs), individual differences in temperament may differentially affect susceptibility to these factors over time. In a multi-method and multi-informant study of 141 children followed prospectively from toddlerhood to adolescence, we tested the independent and interactive associations of age 3 reactive temperament (e.g., negative emotionality) and age 13 observed parenting (i.e., positive and negative behavior) and friendship (i.e., conflict and warmth), with multi-informant ratings of age 15 aggression and rule-breaking behavior. Negative parenting predicted growth in parent-rated EB, but only for adolescents with early reactive temperament. Temperament did not affect sensitivity to positive parenting or friendship. Results are discussed in the context of differential susceptibility theory and intervention implications for adolescents.

Social skills are traditionally viewed as acquired through social environments including parenting. However, biopsychosocial models highlight the importance of genetic influences and gene-environment interactions (G×Es) in child development. Extant G×E investigations often fail to account for developmental changes in the phenotype or rigorously assess the social environment using observational measures. The present study prospectively assessed 110 children (44.5% female) and their parents to explore biologically plausible independent and interactive associations of the serotonin transporter-linked polymorphic region (5-HTTLPR) and observed positive and negative parenting in prediction of (a) initial levels of social skills at school entry (age 6 years) and (b) developmental changes in social skills across the early school years (ages 6-9 years). Overall, the SS (vs. SL/LL) 5-HTTLPR genotype inversely predicted social skills across all domains, although parenting behavior moderated these associations wherein putative G×E effects differed by developmental timing and social skills domain. Positive parenting positively predicted concurrent (age 6) overall social skills for children with SL/LL genotypes, but not the SS genotype. However, for the SS group only, age 6 positive parenting positively predicted prospective growth in social responsibility, although negative parenting positively predicted growth in social cooperation. Findings suggest that 5-HTTLPR may signal differential sensitivities to parenting styles and patterns of social development, which may help to inform targeted intervention approaches to enhance person-environment fit. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

OBJECTIVE:We tested mediation of birth weight and ADHD symptoms by multiple biologically plausible neurocognitive functions and evaluated familiality of observed indirect effects. METHOD/METHODS:647 youth from 284 multiplex families with ADHD completed the Arithmetic, Digit Span, Vocabulary, and Block Design subtests of the Wechsler Intelligence Scale for Children (WISC). Multiple mediation tested WISC subtests as mediators of birth weight and multi-informant ADHD symptoms. Familiality of indirect effects was estimated via moderated mediation comparing conditional indirect effects across siblings concordant and discordant for ADHD. RESULTS:Controlling for IQ and demographic factors, Arithmetic uniquely mediated birth weight and ADHD symptoms. Conditional indirect effects through Arithmetic did not differ across ADHD concordant and discordant siblings. CONCLUSION/CONCLUSIONS:These cross-sectional findings support previous prospective longitudinal research implicating Arithmetic (i.e., fluid reasoning) as a preliminary causal mediator of birth weight and ADHD symptoms, and suggest that this pathway is independent of genetic influences on ADHD.

BACKGROUND:The retention of youth living with HIV (YLHIV) in adult care after transfer from pediatric care in the United States is a challenge. A targeted comprehensive retention strategy (CRS) may improve retention among YLHIV. METHODS:A retrospective cohort study of YLHIV after transfer from pediatric to adult care for patients with at least 1 adult visit at 2 urban HIV care programs in the United States employing CRSs with internal medicine/pediatrics-trained providers, peer navigators, social workers and mental health resources. Primary outcomes were successful retention in care after transfer (≥2 provider visits in the adult clinic ≥90 days apart within 1 year of transfer) and successful transition (successful retention plus a stable HIV viral load (VL) defined as VL 1 year after transfer that was less than or equal to the VL obtained at or immediately before transfer). Logistic regression assessed factors associated with successful transition. A subgroup analysis was performed to examine rates of successful transfer and linkage from pediatric to adult clinics (attending at least 1 adult visit after transition). RESULTS:Of the 89 patients included in the study, 79 (89%) patients had successful retention and 53 (60%) had successful transition to the adult program. Factors associated with successful transition included non-African American race [adjusted odds ratio (aOR) = 11.26, 95% confidence interval (CI): 1.32-95.51], perinatal HIV (aOR = 8.00, 95% CI: 1.39-46.02) and CD4 count > 500 cells/mm (aOR = 5.22, 95% CI: 1.54-17.70). Of those who were retained, 53/79 (67%) had stable or improved virologic control at 1 year after transition. In a subgroup analysis, 54/56 (96%) patients who were targeted to transition successfully linked to adult care. CONCLUSIONS:Overall, YLHIV in the United States engaged in a CRS program appear to have high retention rates but suboptimal virologic control after transfer from pediatric HIV care.

Delayed memory deficits are common for patients with mild traumatic brain injury (mTBI), according to a recent systematic review of meta-analyses (Karr et al., 2014). However, there has been little work to identify different cognitive processes that may be underpinning these delayed memory deficits for mTBI. Frontal cortex is important for delayed memory, and is implicated in the pathophysiology of mTBI; moreover, frontal lobes are typically considered the locus of executive abilities. To further explore these relationships, we sought to partly explain delayed memory deficits after mTBI by examining behavioral indicators of executive function. Results showed that sub-acute as well as chronic mTBI patients performed worse than controls on the delayed memory trial of the Hopkins Verbal Learning Test-Revised (Brandt & Benedict, 2001), recalling approximately 18% and 15% fewer words, respectively. Furthermore, worse delayed memory performance was associated with less use of the cognitive strategy of semantic clustering, and with lower scores for the executive function composite from a standardized neuropsychological battery (NIH EXAMINER; Kramer et al., 2014). In contrast, serial clustering, a memory organizational strategy thought to be less dependent on executive function, did not show strong relationships to clinical status or delayed memory performance. This exploratory work suggests novel hypotheses to be tested in future, confirmatory studies, including that general executive functions and/or semantic clustering will mediate delayed memory deficits following mTBI.

Mild traumatic brain injury (mTBI) can affect high-level executive functioning long after somatic symptoms resolve. We tested if simple EEG responses within an oddball paradigm could capture variance relevant to this clinical problem. The P3a and P3b components reflect bottom-up and top-down processes driving engagement with exogenous stimuli. Since these features are related to primitive decision abilities, abnormal amplitudes following mTBI may account for problems in the ability to exert executive control. Sub-acute (<2 weeks) mTBI participants (N = 38) and healthy controls (N = 24) were assessed at an initial session as well as a two-month follow-up (sessions 1 and 2). We contrasted the initial assessment to a comparison group of participants with chronic symptomatology following brain injury (N = 23). There were no group differences in P3a or P3b amplitudes. Yet in the sub-acute mTBI group, higher symptomatology on the Frontal Systems Behavior scale (FrSBe), a questionnaire validated as measuring symptomatic distress related to frontal lobe injury, correlated with lower P3a in session 1. This relationship was replicated in session 2. These findings were distinct from chronic TBI participants, who instead expressed a relationship between increased FrSBe symptoms and a lower P3b component. In the sub-acute group, P3b amplitudes in the first session correlated with the degree of symptom change between sessions 1 and 2, above and beyond demographic predictors. Controls did not show any relationship between FrSBe symptoms and P3a or P3b. These findings identify symptom-specific alterations in neural systems that vary along the time course of post-concussive symptomatology.