Zu Wei Zhai

Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately

Persistent dendritic spine enlargement is associated with stable long-term potentiation (LTP), and the latter is thought to underlie long-lasting memories. Extracellular proteolytic remodeling of the synaptic microenvironment could be important for such plasticity, but whether or how proteolytic remodeling contributes to persistent modifications in synapse structure and function is unknown. Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is activated perisynaptically after LTP induction and required for LTP maintenance. Here, by monitoring spine size and excitatory postsynaptic potentials (EPSPs) simultaneously with combined 2-photon time-lapse imaging and whole-cell recordings from hippocampal neurons, we find that MMP-9 is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both structural and functional MMP-driven forms of plasticity are mediated through β1-containing integrin receptors, are associated with integrin-dependent cofilin inactivation within spines, and require actin polymerization. In contrast, postsynaptic exocytosis and protein synthesis are both required for MMP-9-induced potentiation, but not for initial MMP-9-induced spine expansion. However, spine expansion becomes unstable when postsynaptic exocytosis or protein synthesis is blocked, indicating that the 2 forms of plasticity are expressed independently but require interactions between them for persistence. When MMP activity is eliminated during theta-stimulation-induced LTP, both spine enlargement and synaptic potentiation are transient. Thus, MMP-mediated extracellular remodeling during LTP has an instructive role in establishing persistent modifications in both synapse structure and function of the kind critical for learning and memory.

Age of Alcohol and Cannabis Use Onset Mediates the Association of Transmissible Risk in Childhood and Development of Alcohol and Cannabis Disorders: Evidence for Common Liability

Age at the time of first alcohol and cannabis use was investigated in relation to a measure of transmissible (intergenerational) risk for addiction in childhood and development of alcohol use disorder (AUD) and cannabis use disorder (CUD). It was hypothesized that age at the time of first experience with either substance mediates the association between transmissible risk and subsequent diagnosis of both disorders. The Transmissible Liability Index (TLI; (Vanyukov et al., 2009) was administered to 339 10- to 12-year-old boys (n = 254) and girls (n = 85). Age at the time of first alcohol and cannabis use, and diagnosis of AUD and CUD, were prospectively tracked to age 22. Each standard deviation unit increase in TLI severity corresponded to a reduction in age of alcohol and cannabis use onset by 3.2 months and 4.6 months, respectively. Age at the time of first alcohol use mediated the association of TLI with both AUD and CUD. Parallel results were obtained for cannabis. Whereas transmissible risk is congenerous to both AUD and CUD, its magnitude was 7 times greater in youths who initiated substance use with cannabis. TLI predicts age of first use of alcohol and cannabis that is common to developing both AUD and CUD. The ramifications of these findings for prevention are discussed.

Neuroimaging Methods for Adolescent Substance Use Disorder Prevention Science

Magnetic resonance imaging (MRI) methods safely provide in vivo indicators of cerebral macrostructure, microstructure, and activation that can be examined in relation to substance use disorder (SUD) risks and effects. This article will provide an overview of MRI approaches, including volumetric measures, diffusion tensor imaging, and functional MRI, that have been applied to studies of adolescent neuromaturation in relationship to risk phenotypes and adolescent SUD. To illustrate these applications, examples of research findings will be presented. MRI indicators have demonstrated that neurobiological maturation continues throughout adolescence. MRI research has suggested that variations in neurobiological maturation may contribute to SUD risk, and that substance use adversely influences adolescent brain development. Directly measured neurobiological variables may be viable preventive intervention targets and outcome indicators. Further research is needed to provide definitive findings on neurodevelopmental immaturity as an SUD risk and to determine the directions such observations suggest for advancing prevention science.

Psychological dysregulation during adolescence mediates the association of parent-child attachment in childhood and substance use disorder in adulthood

Abstract Objective: This prospective study tested the hypothesis that psychological dysregulation in mid-adolescence (age 16) mediates the association between parent-child attachment in late childhood (age 10–12) and development of substance use disorder (SUD) in adulthood (age 22). Method: The Youth Attachment to Parents Scale (YAPS) was developed in 10–12-year-old boys and girls (N = 694) at baseline residing in western Pennsylvania. Psychological dysregulation was measured by the neurobehavior disinhibition trait. Substance use was assessed at ages 10–12, 12–14, 16 and 19. SUD was diagnosed at age 22 using the Structured Clinical Interview for DSM Disorders. The mediation of parent-child attachment and SUD by neurobehavior disinhibition was tested separately for mothers and fathers while controlling for baseline substance use. Results: Psychological dysregulation mediates the association between attachment to mothers and SUD, and partially mediates the association between attachment to fathers and SUD. Significant mediation effects remains after controlling for baseline substance use. Conclusion: Optimal prevention of SUD should include ameliorating both psychological dysregulation predisposing to SUD and quality of the parent-child relationship.

The relationship between second-to-fourth digit (2D:4D) ratios and problematic and pathological Internet use among Turkish university students

Background and aims The ratio of the second and fourth fingers (2D:4D ratio) is a sexually dimorphic trait, with men tending to have lower values than women. This ratio has been related to prenatal testosterone concentrations and addictive behaviors including problematic video-gaming. We aimed to investigate the possible association between 2D:4D ratios and Internet addiction and whether such a relationship would be independent of impulsivity. Methods A total of 652 university students (369 women, 283 men), aged 17–27 years, were enrolled in the study. Problematic and pathological Internet use (PPIU) was assessed using the Internet Addiction Test (IAT). The participants also completed the Barratt Impulsiveness Scale (version 11; BIS-11) and had their 2D:4D ratios measured. Results 2D:4D ratios were not significantly different in women with PPIU and in those with adaptive Internet use (AIU). Men with PPIU exhibited lower 2D:4D ratios on both hands when compared with those with AIU. Correlation analysis revealed that 2D:4D ratios on both hands were negatively correlated with IAT scores among men, but not among women. The multiple linear regression analysis revealed that age, duration of weekly Internet use, impulsiveness, and 2D:4D ratios on the right hand were independently associated with IAT scores among men, and impulsivity did not mediate the relationship between 2D:4D ratios and PPIU. Conclusions For men, 2D:4D ratios on the right hand were inversely correlated with Internet addiction severity even after controlling for individual differences in impulsivity. These findings suggest that high prenatal testosterone levels may contribute to the occurrence of PPIU among men.

High and low neurobehavior disinhibition clusters within locales: implications for community efforts to prevent substance use disorder.

Background: Knowledge of where substance use and other such behavioral problems frequently occur has aided policing, public health, and urban planning strategies to reduce such behaviors. Identifying locales characterized by high childhood neurobehavioral disinhibition (ND), a strong predictor of substance use and consequent disorder (SUD), may likewise improve prevention efforts. Objectives: The distribution of ND in 10–12-year olds was mapped to metropolitan Pittsburgh, PA, and tested for clustering within locales. Methods: The 738 participating families represented the population in terms of economic status, race, and population distribution. ND was measured using indicators of executive cognitive function, emotion regulation, and behavior control. Innovative geospatial analyzes statistically tested clustering of ND within locales while accounting for geographic barriers (large rivers, major highways), parental SUD severity, and neighborhood quality. Results: Clustering of youth with high and low ND occurred in specific locales. Accounting for geographic barriers better delineated where high ND is concentrated, areas which also tended to be characterized by greater parental SUD severity and poorer neighborhood quality. Conclusions and Significance: Offering programs that have been demonstrated to improve inhibitory control in locales where youth have high ND on average may reduce youth risk for SUD and other problem behaviors. As demonstrated by the present results, geospatial analysis of youth risk factors, frequently used in community coalition strategies, may be improved with greater statistical and measurement rigor.

Relationships Between Perceived Family Gambling and Peer Gambling and Adolescent Problem Gambling and Binge-Drinking

The study systematically examined the relative relationships between perceived family and peer gambling and adolescent at-risk/problem gambling and binge-drinking. It also determined the likelihood of at-risk/problem gambling and binge-drinking as a function of the number of different social groups with perceived gambling. A multi-site high-school survey assessed gambling, alcohol use, presence of perceived excessive peer gambling (peer excess—PE), and family gambling prompting concern (family concern—FC) in 2750 high-school students. Adolescents were separately stratified into: (1) low-risk, at-risk, and problem/pathological gambling groups; and, (2) non-binge-drinking, low-frequency-binge-drinking, and high-frequency-binge-drinking groups. Multinomial logistic regression showed that relative to each other, FC and PE were associated with greater likelihoods of at-risk and problem/pathological gambling. However, only FC was associated with binge-drinking. Logistic regression revealed that adolescents who endorsed either FC or PE alone, compared to no endorsement, were more likely to have at-risk and problem/pathological gambling, relative to low-risk gambling. Adolescents who endorsed both FC and PE, compared to PE alone, were more likely to have problem/pathological gambling relative to low-risk and at-risk gambling. Relative to non-binge-drinking adolescents, those who endorsed both FC and PE were more likely to have low- and high-frequency-binge-drinking compared to FC alone or PE alone, respectively. Family and peer gambling individually contribute to adolescent at-risk/problem gambling and binge-drinking. Strategies that target adolescents as well as their closely affiliated family and peer members may be an important step towards prevention of harm-associated levels of gambling and alcohol use in youths.

White-matter crossing-fiber microstructure in adolescents prenatally exposed to cocaine

BACKGROUND Prenatal cocaine exposure (PCE) is associated with risk-taking behaviors, including increased initiation of substance use in adolescence. The neurobiological underpinnings of these behaviors in adolescents with PCE are not well understood. The goal of this study was to compare diffusion-weighted imaging data between adolescents with and without PCE using crossing-fiber models, which may provide more comprehensive estimates of white-matter microstructure within regions of multiple (e.g., primary and secondary) fiber orientations. METHODS Thirty-nine PCE individuals and 17 comparably aged prenatally non-drug-exposed (NDE) youths were recruited from a longitudinal cohort followed since birth. White matter was examined using tensor-derived and crossing-fiber models. Whole-brain investigations were performed, as were analyses on seven white-matter regions, which included the splenium, body and genu of the corpus callosum, bilateral cingulum, and the right and left superior longitudinal fasciculus (SLF). RESULTS Whole-brain analyses revealed no group differences. However, ROI analyses for anisotropy estimates derived from the crossing-fiber model revealed significant group differences for secondary fibers, with reduced anisotropy among PCE adolescents compared to prenatally non-exposed youth in the right cingulum and the left SLF, and increased anisotropy in the genu. CONCLUSIONS Our findings suggest that white-matter differences in PCE adolescents are subtle and localized primarily within secondary fiber orientations, perhaps arising from altered white-matter development.

Detecting initiation or risk for initiation of substance use before high school during pediatric well-child check-ups

BACKGROUND Youth substance use (SU) is prevalent and costly, affecting mental and physical health. American Academy of Pediatrics and Affordable Care Act call for SU screening and prevention. The Youth Risk Index(©) (YRI) was tested as a screening tool for having initiated and propensity to initiate SU before high school (which forecasts SU disorder). YRI was hypothesized to have good to excellent psychometrics, feasibility and stakeholder acceptability for use during well-child check-ups. DESIGN A high-risk longitudinal design with two cross-sectional replication samples, ages 9-13 was used. Analyses included receiver operating characteristics and regression analyses. PARTICIPANTS A one-year longitudinal sample (N=640) was used for YRI derivation. Replication samples were a cross-sectional sample (N=345) and well-child check-up patients (N=105) for testing feasibility, validity and acceptability as a screening tool. RESULTS YRI has excellent test-retest reliability and good sensitivity and specificity for concurrent and one-year-later SU (odds ratios=7.44, CI=4.3-13.0) and conduct problems (odds ratios=7.33, CI=3.9-13.7). Results were replicated in both cross-sectional samples. Well-child patients, parents and pediatric staff rated YRI screening as important, acceptable, and a needed service. CONCLUSIONS Identifying at-risk youth prior to age 13 could reap years of opportunity to intervene before onset of SU disorder. Most results pertained to YRIs association with concurrent or recent past risky behaviors; further replication ought to specify its predictive validity, especially adolescent-onset risky behaviors. YRI well identifies youth at risk for SU and conduct problems prior to high school, is feasible and valid for screening during well-child check-ups, and is acceptable to stakeholders.

Childhood trauma moderates inhibitory control and anterior cingulate cortex activation during stress

Objective: The anterior cingulate cortex (ACC) is critical for both stress and inhibitory control processes and has been implicated in childhood trauma. This prospective study tested the hypothesis that early trauma moderates the association between inhibitory control during late childhood and ACC stress reactivity during adolescence. Method: Sixty‐four adolescents were stratified into higher‐ or lower‐childhood‐trauma groups. Inhibitory control was indicated by fewer errors on a Stroop Color‐Word task. Personalized stress cues during functional magnetic resonance imaging assessed neural correlates of stress in adolescents. Results: Using a priori‐defined anterior (rCZa) and posterior rostral cingulate zones of the ACC, associated with Stroop Color‐Word task performance in prior meta‐analyses, Stroop errors correlated inversely with activation in the rCZa during stress‐cue exposure (r = −.23, p = .04). Childhood trauma moderated the association between Stroop errors and rCZa stress reactivity (interaction = −1.26, p = .02, 95%CI = −2.33,‐0.20), where Stroop errors were inversely associated with brain activation among those with higher childhood trauma (simple slopes = −.83, p = .007, 95%CI = −1.40,‐0.25). Low stress‐related rCZa activation inversely (R2 = 0.19, b = −0.43, p = .001, 95%CI = −4.11,‐1.06) and Stroop errors directly (R2 = 0.09, b = 0.27, p = .048, 95%CI = 0.02, 5.8) associated with baseline subjective anxiety while controlling for childhood trauma. Conclusions: This is the first study to demonstrate a moderating role of childhood trauma on the relationship between inhibitory control and stress‐related ACC activation. Childhood trauma may portend neurodevelopmental changes that impede recruitment of control‐associated ACC‐functioning during distress, which may relate to dysregulation of stress‐induced affective responses. Further work is needed to elucidate relationships between childhood trauma and addictive behaviors precipitated by stress. HighlightsA novel method found trauma moderated an inhibition‐ACC stress‐reactivity pathway.Higher‐trauma youth with poor inhibition developed lower ACC stress reactivity.Lower ACC stress reactivity portended greater subjective anxiety.Using a meta‐analysis‐defined ROI approach improves generalizability of findings.Childhood trauma burdens ACC‐related stress regulation.