Juliane H. Fröhner

Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control

The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N = 1586, behavioral total N = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence p = 1.33 * 10−5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals cognitive control abilities. SIGNIFICANCE STATEMENT The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes and is dysregulated in several neuropsychiatric disorders. Despite this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show the impact of a common polymorphism of the high-affinity nicotinic receptor α4β2 that is consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance and higher behavioral alertness performance than both homozygous groups. This gene–brain–behavior relationship informs about the biological basis of interindividual differences in cognitive control.

Epigenetic variance in dopamine D2 receptor: a marker of IQ malleability?

Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the “missing heritability” between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.

Examination of the Neural Basis of Psychoticlike Experiences in Adolescence During Reward Processing

Importance Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses. Objective To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task. Design, Setting, and Participants A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017. Main Outcomes and Measures Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori–defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined. Results Of the 1434 adolescents, 2 groups (nu2009=u2009149 each) (high PLEs, nu2009=u2009149, 50 [33.6%] male; low PLEs, nu2009=u2009149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation (F1, 93u2009=u20095.559; Pu2009=u2009.02; F1, 93u2009=u20095.009; Pu2009=u2009.03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant timeu2009×u2009group interaction (F1, 93u2009=u20097.448; Pu2009=u2009.01). Conclusion and Relevance The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them.

Mapping adolescent reward anticipation, receipt, and prediction error during the monetary incentive delay task

The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental periods association with altered reward sensitivity. Here, a large sample (nu2009=u20091,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward‐related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.

Individual differences in stop-related activity are inflated by the adaptive algorithm in the stop signal task

Research using the Stop Signal Task employing an adaptive algorithm to accommodate individual differences often report inferior performance on the task in individuals with ADHD, OCD, and substance use disorders compared to non‐clinical controls. Furthermore, individuals with deficits in inhibitory control tend to show reduced neural activity in key inhibitory regions during successful stopping. However, the adaptive algorithm systematically introduces performance‐related differences in objective task difficulty that may influence the estimation of individual differences in stop‐related neural activity. This report examines the effect that these algorithm‐related differences have on the measurement of neural activity during the stop signal task. We compared two groups of subjects (nu2009=u2009210) who differed in inhibitory ability using both a standard fMRI analysis and an analysis that resampled trials to remove the objective task difficulty confound. The results show that objective task difficulty influences the magnitude of between‐group differences and that controlling for difficulty attenuates stop‐related activity differences between superior and poor inhibitors. Specifically, group differences in the right inferior frontal gyrus, right middle occipital gyrus, and left inferior frontal gyrus are diminished when differences in objective task difficulty are controlled for. Also, when objective task difficulty effects are exaggerated, group differences in stop related activity emerge in other regions of the stopping network. The implications of these effects for how we interpret individual differences in activity levels are discussed.

COMT Val158Met Polymorphism and Social Impairment Interactively Affect Attention-Deficit Hyperactivity Symptoms in Healthy Adolescents

The dopaminergic system has been shown to have substantial effects on the etiology of attention-deficit hyperactivity disorder (ADHD). However, while some studies found a significant direct effect, others did not. In this context, social behavior might play an important role as a factor that is related both to the dopaminergic system and ADHD. In a large epidemiological sample of adolescents (N = 462; 16–17 years), we assessed the level of ADHD symptoms using the Strengths and Difficulties Questionnaire, social behavior using the Social Responsiveness Scale, and the allelic distribution of the dopaminergic catechol-O-methyltransferase (COMT) Val158Met polymorphism. We found a significant association between COMT and social impairment, insofar as Met-allele carriers showed increased levels of social impairment. Moreover, social impairment significantly determined an association between COMT and ADHD (explained variance: 19.09%). This effect did not significantly differ between males and females. COMT and social impairment might interactively affect ADHD symptomatology, and could thus represent significant gene-phenotypic risk factors for ADHD symptomatology. This might have interesting implications for prevention and intervention strategies with a focus on social behavior in genetically at-risk individuals.

Extending the Construct Network of Trait Disinhibition to the Neuroimaging Domain: Validation of a Bridging Scale for Use in the European IMAGEN Project:

Trait disinhibition, a clinical-liability construct, has well-established correlates in the diagnostic, self-rating, task-behavioral, and brain potential response domains. Recently, studies have begun to test for neuroimaging correlates of this liability factor, but more work of this type using larger data sets is needed to clarify its brain bases. The current study details the development and validation of a scale measure of trait disinhibition composed of questionnaire items available in the IMAGEN project, a large-scale longitudinal study of factors contributing to substance abuse that includes clinical interview, self-report personality, task-behavioral, neuroimaging, and genomic measures. Using a construct-rating and psychometric refinement approach, a scale was developed that evidenced: (a) positive relations with interview-assessed psychopathology in the IMAGEN sample, both concurrently and prospectively and (b) positive associations with scale measures of disinhibition and reported psychopathology, and a robust negative correlation with P3 brain response, in a separate adult sample (Mage = 19.5). These findings demonstrate that a common scale measure can index this construct from adolescence through to early adulthood, and set the stage for systematic work directed at identifying neural and genetic biomarkers of this key liability construct using existing and future data from the IMAGEN project.

Risk profiles for heavy drinking in adolescence: differential effects of gender: Risk profiles for drinking

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi‐domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross‐sectional analyses on the large IMAGEN sample (N ≈ 1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19—for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19‐year‐olds bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

Addressing the reliability fallacy: Similar group effects may arise from unreliable individual effects

To cast valid predictions of future behavior or diagnose disorders, the reliable measurement of a “biomarker” such as the brain activation to prospective reward is a prerequisite. Surprisingly, only a small fraction of functional magnetic resonance imaging (fMRI) studies report or cite the reliability of brain activation maps involved in group analyses. Here, using simulations and exemplary longitudinal data of 126 healthy adolescents performing an intertemporal choice task, we demonstrate that reproducing a group activation map over time is not a sufficient indication of reliable measurements at the individual level. Instead, selecting regions based on significant main effects at the group level may yield estimates that fail to reliably capture individual variance in the subjective evaluation of an offer. Collectively, our results call for more attention on the reliability of supposed biomarkers at the level of the individual. Thus, caution is warranted in employing brain activation patterns prematurely for clinical applications such as diagnosis or tailored interventions before their reliability has been conclusively established by large-scale studies. To facilitate assessing and reporting of the reliability of fMRI contrasts in future studies, we provide a toolbox that incorporates common measures of global and local reliability.