Jillian E. Hardee

Patterns of neural connectivity during an attention bias task moderate associations between early childhood temperament and internalizing symptoms in young adulthood.

BACKGROUND Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. METHODS Children were assessed for BI at multiple age points from infancy through age seven. On the basis of a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (n = 44). Participants completed an event-related functional magnetic resonance imaging attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews. RESULTS The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms. CONCLUSIONS Behavioral inhibition during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology.

Left middle frontal gyrus response to inhibitory errors in children prospectively predicts early problem substance use

BACKGROUND A core vulnerability trait for substance use disorder (SUD) is behavioral disinhibition. Error processing is a central aspect of inhibitory control that determines adaptive adjustment of performance; yet it is a largely overlooked aspect of disinhibition as it relates to risk for SUD. We investigated whether differences in brain activation during both successful and failed inhibition predicts early problem substance use. METHOD Forty-five 9-12 year olds underwent a functional MRI scan during a go/no-go task. They were then followed over approximately 4 years, completing assessments of substance use. Externalizing behavior was measured at ages 3-8, 9-12 and 11-13. Participants with drug use or problem alcohol use by ages 13-16 (n=13; problem-user group) were individually matched by gender, age, and family history of alcoholism with non-substance-using children (n=13; non-user group). The remaining 19 participants provided an independent sample from which to generate unbiased regions-of-interest for hypothesis testing in the problem-user and non-user groups. RESULTS No differences were observed between groups in activation during correct inhibition compared with baseline. A significant difference arose in left middle frontal gyrus (LMFG) activation during failed inhibition compared with correct inhibition, with the problem-user group demonstrating blunted activation. The problem-user group also had more externalizing problems at ages 11-13. Logistic regression found that activation of LMFG significantly predicted group membership over and above externalizing problems. CONCLUSIONS Blunted LMFG activation during performance errors may underlie problems adapting behavior appropriately, leading to undercontrolled behavior, early problem substance use and increased risk for SUD.

Development of Impulse Control Circuitry in Children of Alcoholics

BACKGROUND Difficulty with impulse control is heightened in children with a family history of alcohol use disorders and is a risk factor for later substance problems. Cross-sectional functional magnetic resonance imaging studies have shown altered impulse control processing in adolescents with a positive family history, yet developmental trajectories have yet to be examined. METHODS Longitudinal functional magnetic resonance imaging was conducted in children of alcoholic families (family history positive [FH+]; n = 43) and children of control families (family history negative [FH-]; n = 30) starting at ages 7-12 years. Participants performed a go/no-go task during functional magnetic resonance imaging at intervals of 1-2 years, with two to four scans performed per subject. We implemented a repeated-measures linear model fit across all subjects to conduct a whole-brain search for developmental differences between groups. RESULTS Performance improved with age in both groups, and there were no performance differences between groups. Significant between-group differences in linear age-related activation changes were found in the right caudate, middle cingulate, and middle frontal gyrus. Post hoc analyses revealed significant activation decreases with age in the caudate and middle frontal gyrus for FH- subjects and a significant increase with age in middle cingulate activation for FH+ subjects. Group differences were evident at age 7-12 years, even in alcohol- and drug-naïve participants, with FH+ subjects showing significantly blunted activation at baseline compared with FH- subjects. CONCLUSIONS Differences in response inhibition circuitry are visible in FH+ individuals during childhood; these differences continue into adolescence, displaying trajectories that are inconsistent with development of normal response inhibition. These patterns precede problem drinking and may be a contributing factor for subsequent substance use problems.

Neuroimaging Risk Markers for Substance Abuse: Recent Findings on Inhibitory Control and Reward System Functioning

Rates of alcohol and other drug use rise sharply throughout adolescence and peak in the early 20s. Likewise, prevalence of first-time substance use disorder (SUD) and past-year SUD both peak between ages 18–23. SUD is associated with a host of negative outcomes and is a serious health concern. Understanding the mechanisms that precede the onset and escalation of substance use is crucial in order to develop more effective prevention and intervention strategies for children and adolescents at risk for SUD. In this review, we discuss recent findings from functional neuroimaging studies in children, adolescents, and emerging adults that focus on uncovering the neural underpinnings of SUD risk. The focus is on inhibitory control and reward circuitry due to their involvement in risk-taking behaviors, which are heightened in adolescence and may facilitate substance use. We discuss convergences in the literature and highlight findings suggesting that the association between SUD risk and neurofunctioning may be moderated by age, gender, and history of substance use. Recommendations for future directions are also discussed.

Association of Marijuana Use With Blunted Nucleus Accumbens Response to Reward Anticipation

IMPORTANCE Marijuana use may alter ventral striatal response to reward, which might heighten susceptibility to substance use disorder. Longitudinal research is needed to determine the effects of marijuana use on neural function involved in reward response. OBJECTIVE To determine whether marijuana use among young adults prospectively affects nucleus accumbens (NAcc) activation during reward anticipation. DESIGN, SETTING, AND PARTICIPANTS One hundred eight young adults were recruited from the Michigan Longitudinal Study, an ongoing study of youth at high risk for substance use disorder and a contrast sample of control families. Participants underwent 3 consecutive functional magnetic resonance imaging scans at approximate ages of 20 (time 1), 22 (time 2), and 24 (time 3) years. Self-report data on marijuana and other drug use occasions were collected annually since age 11 years. MAIN OUTCOMES AND MEASURES Cross-lagged models were used to test the association of marijuana use with neural response in the NAcc to reward anticipation during a monetary incentive delay task controlling for sex, age, other substance use, and family history of substance use disorder. RESULTS Of 108 participants, 39 (36.1%) were female and mean (SD) age at baseline was 20.1 (1.4) years. Greater marijuana use was associated with later blunted activation in the NAcc during reward anticipation (time 1 to time 2: β = -0.26, P = .04; time 2 to time 3: β = -0.25, P = .01). When the cross-lagged model was tested with the inclusion of previous and concurrent cigarette use, the effect of marijuana use from time 2 to time 3 remained significant (β = -0.29; P = .005) and the effect of cigarette use was nonsignificant. CONCLUSIONS AND RELEVANCE The findings of this study indicate that marijuana use is associated with decreased neural response in the NAcc during the anticipation of nondrug rewards. Over time, marijuana use may alter anticipatory reward processing in the NAcc, which may increase the risk for continued drug use and later addiction.

Multiple faces elicit augmented neural activity

How do our brains respond when we are being watched by a group of people?Despite the large volume of literature devoted to face processing, this question has received very little attention. Here we measured the effects on the face-sensitive N170 and other ERPs to viewing displays of one, two and three faces in two experiments. In Experiment 1, overall image brightness and contrast were adjusted to be constant, whereas in Experiment 2 local contrast and brightness of individual faces were not manipulated. A robust positive-negative-positive (P100-N170-P250) ERP complex and an additional late positive ERP, the P400, were elicited to all stimulus types. As the number of faces in the display increased, N170 amplitude increased for both stimulus sets, and latency increased in Experiment 2. P100 latency and P250 amplitude were affected by changes in overall brightness and contrast, but not by the number of faces in the display per se. In Experiment 1 when overall brightness and contrast were adjusted to be constant, later ERP (P250 and P400) latencies showed differences as a function of hemisphere. Hence, our data indicate that N170 increases its magnitude when multiple faces are seen, apparently impervious to basic low-level stimulus features including stimulus size. Outstanding questions remain regarding category-sensitive neural activity that is elicited to viewing multiple items of stimulus categories other than faces.

Sex differences in the development of emotion circuitry in adolescents at risk for substance abuse: a longitudinal fMRI study

Abstract There is substantial evidence for behavioral sex differences in risk trajectories for alcohol and substance use, with internalizing factors such as negative affectivity contributing more to female risk. Because the neural development of emotion circuitry varies between males and females across adolescence, it represents a potential mechanism by which underlying neurobiology contributes to risk for substance use. Longitudinal functional magnetic resonance imaging was conducted in males and females (n = 18 each) with a family history of alcohol use disorders starting at ages 8–13 years. Participants performed an affective word task during functional magnetic resonance imaging at 1- to 2-year intervals, covering the age range of 8.5–17.6 years (3–4 scans per participant). Significant age-related sex differences were found in the right amygdala and right precentral gyrus for the negative vs neutral word condition. Males showed a significant decrease in both amygdala and precentral gyrus activation with age, whereas the response in females persisted. The subjective experience of internalizing symptomatology significantly increased with age for females but not for males. Taken together, these results reveal sex differences in negative affect processing in at-risk adolescents, and offer longitudinal neural evidence for female substance use risk through internalizing pathways.

Sex differences in the developmental neuroscience of adolescent substance use risk

Adolescence is a period associated with the initiation and escalation of substance use and is also a time during which substantial changes take place in neural development, personality and behavior. Although rates of substance use between adolescent girls and boys do not differ substantially, there is evidence for sex differences in underlying vulnerability pathways associated with the development of substance use disorder. Here we review sex differences in adolescent brain development and how these differences may contribute to different risk pathways between females and males that emerge during this developmental period. We also discuss methodological considerations in the study of sex differences in brain and behavior and their implications for interpretation. We close by highlighting promising areas for future work.

Effects of the serotonin transporter gene, sensitivity of response to alcohol, and parental monitoring on risk for problem alcohol use

The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) has been previously associated with alcohol-related risk. Most findings point to short (S) allele carriers being at increased risk for negative alcohol outcomes relative to long allele homozygotes, although some work indicates a more complex relationship. The current prospective study aimed to clarify how and under what circumstances variations in 5-HTTLPR transmit risk for various alcohol-related outcomes. Participants were 218 adolescents and young adults (29% female) enrolled in the Michigan Longitudinal Study. We tested a moderated mediation model with 5-HTTLPR as the predictor, Self-Rating of the Effects of Alcohol (SRE) score as the mediator, alcohol-related outcomes as the dependent variables, parental monitoring as the moderator of the SRE to alcohol outcomes path, and prior drinks, sex, age, and body mass index as covariates. Four alcohol-related outcomes were tested. The S allele was associated with higher SRE scores (i.e., lower response to alcohol). Parental monitoring was a significant moderator: At low levels of parental monitoring, higher SRE scores predicted more drinks consumed and binge drinking episodes. At high levels of monitoring, higher SRE scores were significantly related to fewer alcohol-related problems. Findings suggest that one mechanism by which 5-HTTLPR variation transmits alcohol-related risk is through level of response to alcohol. Furthermore, the strength and direction of this effect varied by level of parental monitoring, indicating that even in the presence of genetic and physiological vulnerability, parents can influence the likelihood of offspring developing problematic alcohol-related behaviors.

Reduced brain activation during inhibitory control in children with COMT Val/Val genotype

Behavioral undercontrol is a well‐established risk factor for substance use disorder, identifiable at an early age well before the onset of substance use. However, the biological mechanistic structure underlying the behavioral undercontrol/substance use relationship is not well understood. The enzyme catechol O‐methyltransferase (COMT) catabolizes dopamine and norepinephrine in the prefrontal cortex and striatum, brain regions involved in behavioral control. The goal of this work was to investigate the association between genetic variation in COMT functioning and fronto‐striatal brain functioning during successful inhibitory control, a critical aspect of behavioral control.