Disentangling differing relationships between internalizing disorders and alcohol use.

Both internalizing disorders and alcohol use have dramatic, wide-spread implications for global health. Previous work has established common phenotypic comorbidity among these disorders, as well as shared genetic variation underlying them both. We used genomic structural equation modeling to investigate the shared genetics of internalizing, externalizing, and alcohol use traits, as well as to explore whether specific domains of internalizing symptoms mediate the contrasting relationships with problematic alcohol use compared to alcohol consumption. We also examined patterns of genetic correlations between similar traits within additional Finnish and East Asian ancestry groups. When the shared genetic influence of externalizing psychopathology was accounted for, the genetic effect of internalizing traits on alcohol use was reduced, suggesting the important role of common genetic factors underlying multiple psychiatric disorders and their genetic influences on comorbidity of internalizing and alcohol use traits. Individual internalizing domains had contrasting effects on frequency of alcohol consumption, which demonstrate the complex system of pleiotropy that exists, even within similar disorders, and can be missed when evaluating only relationships among formal diagnoses. Future work must consider the broad effects of shared psychopathology along with the fine-scale effects of heterogeneity within disorders to more fully understand the biology underlying complex traits.

Genetic and Environmental Influences on Stressful Life Events and their Associations with Executive Functions in Young Adulthood: A Longitudinal Twin Analysis.

Although stress is frequently considered an environmental factor, dependent stressful life events (SLEs)--stressors that result from one's actions or behaviors--may in fact be evoked by a genetic liability. It has been suggested that dependent SLEs may be partially caused by poor executive function (EFs), higher-level cognitive abilities that enable individuals to implement goal-directed behavior. We investigated the possibility of genetic and environmental overlap between SLEs and EFs in a longitudinal twin study. We found high genetic stability in the number of dependent SLEs from age 23 to age 29, suggesting that the number of dependent stressors show persistence across time due to their genetic etiology. In addition, there was a nominally significant negative genetic correlation between a Common EF latent factor and dependent SLEs at age 23. The genetic stability of dependent SLEs and association with Common EF provides insight into how some behaviors may lead to persistent stress.

Combining dimensional models of internalizing symptoms and repetitive negative thought: Systematic replication, model comparison, and external validation.

Despite the promise of transdiagnostic dimensional models of psychopathology, there have been few efforts to understand how distinct models can be combined to better capture the full range of psychopathology. The current report combines two prominent models of aspects of internalizing psychopathology, including a four-factor model of internalizing symptoms and a three-factor model of repetitive negative thought, to determine the degree to which these models are capturing distinct or isomorphic constructs. Employing model comparison techniques, we found that these models integrate into a single model which includes a general factor capturing covariance across internalizing dimensions (i.e., common internalizing), as well as specific factors for low positive affect, anxious arousal, anxious apprehension, and rumination. There was little evidence of a general repetitive negative thought factor over and above common internalizing, suggesting the two constructs are largely isomorphic. Importantly, all factors in the best-fitting model showed associations with diagnostic status across three psychiatric disorders, indicating external validity and potential clinical utility. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The dimensional structure of internalizing psychopathology: Relation to diagnostic categories.

Recent approaches aim to represent the dimensional structure of psychopathology, but relatively little research has rigorously tested sub-dimensions within internalizing psychopathology. This study tests pre-registered models of the dimensional structure of internalizing psychopathology, and their relations with current and lifetime depressive and anxiety disorders diagnostic data, in adult samples harmonized across three sites (n=427). Across S-1 bifactor and hierarchical models, we found converging evidence for both general and specific internalizing dimensions. Depression, generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic attacks were all associated with a general internalizing factor that we posit primarily represents motivational anhedonia. GAD was also associated with a specific anxious apprehension factor, and SAD with specific anxious apprehension and low positive affect factors. We suggest that dimensional approaches capturing shared and specific internalizing symptom facets more accurately describe the structure of internalizing psychopathology and provide useful alternatives to categorical diagnoses to advance clinical science.

Gray-Matter Morphometry of Internalizing-Symptom Dimensions During Adolescence.

Understanding the neuroanatomical correlates of internalizing psychopathology during adolescence may shed light on to neurodevelopmental processes that make this a critical period for the trajectory of mental illness. However, few studies have simultaneously examined co-occurring and dissociable features of internalizing psychopathology during this formative developmental stage. In the current study we identify the neuroanatomical correlates of four dimensions of internalizing psychopathology symptoms in adolescents: a common internalizing dimension capturing covariance in symptoms across internalizing disorders, as well as low positive affect-, anxious arousal-, and anxious apprehension-specific residuals. Our results suggest that these dimensions are associated with neuroanatomy across much of the brain, including prefrontal and limbic regions implicated in case-control studies, but also regions supporting visual processing. Importantly, results differed between males and females in regions that are sexually dimorphic in adulthood and the direction of the effects were largely opposite to what has been observed in adults and children.

Executive Functions and Impulsivity as Transdiagnostic Correlates of Psychopathology in Childhood: A Behavioral Genetic Analysis.

Executive functions (EFs) and impulsivity are dimensions of self-regulation that are both related to psychopathology. However, self-report measures of impulsivity and laboratory EF tasks typically display small correlations, and existing research indicates that impulsivity and EFs may tap separate aspects of self-regulation that independently statistically predict psychopathology in adulthood. However, relationships between EFs, impulsivity, and psychopathology may be different in childhood compared to adulthood. Here, we examine whether these patterns hold in the baseline assessment of the Adolescent Brain and Cognitive Development (ABCD) sample, a national sample of over 11,000 children (including 749 twin pairs) ages 9-10 years. We examine the phenotypic and genetic relationships among latent variables for different components of EFs and multiple facets of impulsivity. Additionally, we assess how EFs and impulsivity relate to composite measures and latent variables of psychopathology derived from parent report. EFs were weakly correlated with impulsivity, and the strength varied by impulsivity facet, emphasizing their separability. We did not identify significant genetic and environmental correlations between EFs and impulsivity. Moreover, controlling for their small relationships with each other, both EFs and some facets of impulsivity statistically predicted an Externalizing factor, attention problems, and social problems, and twin analyses suggested these relationships were genetic in origin. These findings indicate that EFs and impulsivity represent phenotypically and genetically separable aspects of self-regulation that are both transdiagnostic correlates of psychopathology in childhood.

The Emotional Word-Emotional Face Stroop task in the ABCD study: Psychometric validation and associations with measures of cognition and psychopathology.

Characterizing the interactions among attention, cognitive control, and emotion during adolescence may provide important insights into why this critical developmental period coincides with a dramatic increase in risk for psychopathology. However, it has proven challenging to develop a single neurobehavioral task that simultaneously engages and differentially measures these diverse domains. In the current study, we describe properties of performance on the Emotional Word-Emotional Face Stroop (EWEFS) task in the Adolescent Brain Cognitive Development (ABCD) Study, a task that allows researchers to concurrently measure processing speed/attentional vigilance (i.e., performance on congruent trials), inhibitory control (i.e., Stroop interference effect), and emotional information processing (i.e., difference in performance on trials with happy as compared to angry distracting faces). We first demonstrate that the task manipulations worked as designed and that Stroop performance is associated with multiple cognitive constructs derived from different measures at a prior time point. We then show that Stroop metrics tapping these three domains are preferentially associated with aspects of externalizing psychopathology and inattention. These results highlight the potential of the EWEFS task to help elucidate the longitudinal dynamics of attention, inhibitory control, and emotion across adolescent development, dynamics which may be altered by level of psychopathology.

Association of γ-aminobutyric acid and glutamate/glutamine in the lateral prefrontal cortex with patterns of intrinsic functional connectivity in adults.

This study examined how levels of neurotransmitters in the lateral prefrontal cortex (LPFC), a region underlying higher-order cognition, are related to the brain's intrinsic functional organization. Using magnetic resonance spectroscopy (MRS), GABA+ and Glx (glutamate + glutamine) levels in the left dorsal (DLPFC) and left ventral (VLPFC) lateral prefrontal cortex were obtained in a sample of 64 female adults (mean age = 48.5). We measured intrinsic connectivity via resting-state fMRI in three ways: (a) via seed-based connectivity for each of the two spectroscopy voxels; (b) via the spatial configurations of 17 intrinsic networks defined by a well-known template; and (c) via examination of the temporal inter-relationships between these intrinsic networks. The results showed that different neurotransmitter indexes (Glx-specific, GABA+-specific, Glx-GABA+ average and Glx-GABA+ ratio) were associated with distinct patterns of intrinsic connectivity. Neurotransmitter levels in the left LPFC are mainly associated with connectivity of right hemisphere prefrontal (e.g., DLPFC) or striatal (e.g., putamen) regions, two areas of the brain connected to LPFC via large white matter tracts. While the directions of these associations were mixed, in most cases, higher Glx levels are related to reduced connectivity. Prefrontal neurotransmitter levels are also associated with the degree of connectivity between non-prefrontal regions. These results suggest robust relationships between the brain's intrinsic functional organization and local neurotransmitters in the LPFC which may be constrained by white matter neuroanatomy.

Changes to information in working memory depend on distinct removal operations.

Holding information in working memory is essential for cognition, but removing unwanted thoughts is equally important. Here we use multivariate pattern analyses of brain activity to demonstrate the successful manipulation and removal of information from working memory using different strategies including suppressing a specific thought, replacing a thought with a different one, and clearing the mind of all thought. These strategies are supported by distinct brain regions and have differential consequences for allowing new information to be encoded.

Common and specific dimensions of internalizing disorders are characterized by unique patterns of brain activity on a task of emotional cognitive control.

Alterations in neural systems underlying cognitive control are well-documented across individuals with various internalizing disorders. The current study examined how individual differences in underlying traits related to internalizing disorders influence brain activation, as assessed by fMRI, when cognitive control must be exerted to make a decision about the emotional valence (positive, negative) of a task-relevant word displayed concurrently with a task-irrelevant emotional face. Taking a bi-factor model approach, fifty-five middle-aged female participants were characterized on symptom level on a common internalizing latent factor representing shared symptoms across anxiety and depression, as well as on specific factors remaining after taking the common internalizing factor into account: low positive affect, anxious arousal, and anxious apprehension. Contrasting activation on trials requiring higher vs. lower control revealed that higher levels of the Common Internalizing factor are associated with less deactivation of regions of the default mode network. Higher levels of the Low Positive Affect-specific factor are associated with less differentiation in engagement of portions of the fronto-parietal control network, while higher levels of the Anxious Arousal-specific factor are associated with less of a differentiation in activation of the thalamus. No effects were observed for level of the Anxious Apprehension-specific factor. These results suggest that prior findings of alterations in default mode activity associated with depression may not be specific to depressive symptoms per se but may characterize internalizing symptoms more generally. In addition, they suggest that reduced engagement of cognitive control regions may be more associated with low positive affect than depressive symptoms more generally.

Whole-cortex mapping of common genetic influences on depression and a social deficits dimension.

Social processes are associated with depression, particularly understanding and responding to others, deficits in which can manifest as callousness/unemotionality (CU). Thus, CU may reflect some of the genetic risk to depression. Further, this vulnerability likely reflects the neurological substrates of depression, presenting biomarkers to capture genetic vulnerability of depression severity. However, heritability varies within brain regions, so a high-resolution genetic perspective is needed. We developed a toolbox that maps genetic and environmental associations between brain and behavior at high resolution. We used this toolbox to estimate brain areas that are genetically associated with both depressive symptoms and CU in a sample of 258 same-sex twin pairs from the Colorado Longitudinal Twin Study (LTS). We then overlapped the two maps to generate coordinates that allow for tests of downstream effects of genes influencing our clusters. Genetic variance influencing cortical thickness in the right dorsal lateral prefrontal cortex (DLFPC) sulci and gyri, ventral posterior cingulate cortex (PCC), pre-somatic motor cortex (PreSMA), medial precuneus, left occipital-temporal junction (OTJ), parietal-temporal junction (PTJ), ventral somatosensory cortex (vSMA), and medial and lateral precuneus were genetically associated with both depression and CU. Split-half replication found support for both DLPFC clusters. Meta-analytic term search identified "theory of mind", "inhibit", and "pain" as likely functions. Gene and transcript mapping/enrichment analyses implicated calcium channels. CU reflects genetic vulnerability to depression that likely involves executive and social functioning in a distributed process across the cortex. This approach works to unify neuroimaging, neuroinformatics, and genetics to discover pathways to psychiatric vulnerability.

Turning down the heat: Neural mechanisms of cognitive control for inhibiting task-irrelevant emotional information during adolescence.

One major question in the cognitive neuroscience of cognitive control is whether prefrontal regions contribute to control by upregulating the processing of task-relevant material or by downregulating the processing of task-irrelevant material. Here we take a unique approach to addressing this question by using multi-voxel pattern analysis, which allowed us to determine the degree to which each of the task-relevant and task-irrelevant dimensions of a stimulus are being processed in posterior cortex on a trial-by-trial basis. In our study, adolescent participants performed an emotion word - emotional face Stroop task requiring them to determine the emotional valence (positive, negative) of a task-relevant word in the context of a task-irrelevant emotional face. Using mediation models, we determined whether activation of a major cognitive control region, the dorsolateral prefrontal cortex (DLPFC), influences reaction time on a trial-by-trial basis directly or if it does so indirectly by modulating processing of the task-relevant and/or task-irrelevant information in posterior brain regions. To examine the specificity of the effects observed for the DLPFC, similar analyses were performed for the amygdala, a brain region involved in processing of the salient task-irrelevant emotional information. For both congruent and incongruent trials, increased DLPFC activity on a given trial was associated with reduced perceptual processing of the task-irrelevant face, consistent with the idea that top-down cognitive control can modulate processing of task-irrelevant information. No effect of DLPFC activity was observed on processing of the task-relevant word. However, increased processing of the task-relevant word was associated with longer RT on congruent trials but not incongruent trials, which may reflect a need for greater processing of the task-relevant word to overcome any influence of the pre-potent task-irrelevant face. In a more exploratory aspect of our investigation, multi-level moderated mediation models were used to examine the influence of individual differences on the observed brain-behavior relationships. For congruent trials, the influence of task-irrelevant face processing on RT was decreased in individuals with higher self-reported Executive Control and increased in those with higher levels of self-reported Negative Affect. These results suggest that cognitive control regions in prefrontal cortex during adolescence can suppress the processing of task-irrelevant information in sensory cortex to influence performance (RT). The processing of task-relevant information may also influence performance, but such processing did not reveal evidence of being modulated by cognitive control regions. Moreover, these effects are sensitive to individual differences in the self-reported ability to exert cognitive and affective control. As such, we provide insights into the more precise mechanisms by which cognitive control influences task performance on a trial-by-trial basis during adolescence.

Neuroanatomical Correlates of the Unity and Diversity Model of Executive Function in Young Adults.

Understanding the neuroanatomical correlates of individual differences in executive function (EF) is integral to a complete characterization of the neural systems supporting cognition. While studies have investigated EF-neuroanatomy relationships in adults, these studies often include samples with wide variation in age, which may mask relationships between neuroanatomy and EF specific to certain neurodevelopmental time points, and such studies often use unreliable single task measures of EF. Here we address both issues. First, we focused on a specific age at which the majority of neurodevelopmental changes are complete but at which age-related atrophy is not likely (N = 251; mean age of 28.71 years, SD = 0.57). Second, we assessed EF through multiple tasks, deriving three factors scores guided by the unity/diversity model of EF, which posits a common EF factor that influences all EF tasks, as well as an updating-specific and shifting-specific factor. We found that better common EF was associated with greater volume and surface area of regions in right middle frontal gyrus/frontal pole, right inferior temporal gyrus, as well as fractional anisotropy in portions of the right superior longitudinal fasciculus (rSLF) and the left anterior thalamic radiation. Better updating-specific ability was associated with greater cortical thickness of a cluster in left cuneus/precuneus, and reduced cortical thickness in regions of right superior frontal gyrus and right middle/superior temporal gyrus, but no aspects of white matter diffusion. In contrast, better shifting-specific ability was not associated with gray matter characteristics, but rather was associated with increased mean diffusivity and reduced radial diffusivity throughout much of the brain and reduced axial diffusivity in distinct clusters of the left superior longitudinal fasciculus, the corpus callosum, and the right optic radiation. These results demonstrate that associations between individual differences in EF ability and regional neuroanatomical properties occur not only within classic brain networks thought to support EF, but also in a variety of other regions and white matter tracts. These relationships appear to differ from observations made in emerging adults (Smolker et al., 2015), which might indicate that the brain systems associated with EF continue to experience behaviorally relevant maturational process beyond the early 20s.

Organization of the Human Frontal Pole Revealed by Large-Scale DTI-Based Connectivity: Implications for Control of Behavior.

The goal of the current study was to examine the pattern of anatomical connectivity of the human frontal pole so as to inform theories of function of the frontal pole, perhaps one of the least understood region of the human brain. Rather than simply parcellating the frontal pole into subregions, we focused on examining the brain regions to which the frontal pole is anatomically and functionally connected. While the current findings provided support for previous work suggesting the frontal pole is connected to higher-order sensory association cortex, we found novel evidence suggesting that the frontal pole in humans is connected to posterior visual cortex. Furthermore, we propose a functional framework that incorporates these anatomical connections with existing cognitive theories of the functional organization of the frontal pole. In addition to a previously discussed medial-lateral distinction, we propose a dorsal-ventral gradient based on the information the frontal pole uses to guide behavior. We propose that dorsal regions are connected to other prefrontal regions that process goals and action plans, medial regions are connected to other brain regions that monitor action outcomes and motivate behaviors, and ventral regions connect to regions that process information about stimuli, values, and emotion. By incorporating information across these different levels of information, the frontal pole can effectively guide goal-directed behavior.

Individual differences in emotion-cognition interactions: emotional valence interacts with serotonin transporter genotype to influence brain systems involved in emotional reactivity and cognitive control.

The serotonin transporter gene (5-HTTLPR) influences emotional reactivity and attentional bias toward or away from emotional stimuli, and has been implicated in psychopathological states, such as depression and anxiety disorder. The short allele is associated with increased reactivity and attention toward negatively-valenced emotional information, whereas the long allele is associated with increased reactivity and attention toward positively-valenced emotional information. The neural basis for individual differences in the ability to exert cognitive control over these bottom-up biases in emotional reactivity and attention is unknown, an issue investigated in the present study. Healthy adult participants were divided into two groups, either homozygous carriers of the 5-HTTLPR long allele or homozygous carriers of the short allele, and underwent functional magnetic resonance imaging (fMRI) while completing an Emotional Stroop-like task that varied in the congruency of task-relevant and task-irrelevant information and the emotional valence of the task-irrelevant information. Behaviorally, participants demonstrated the classic "Stroop effect" (responses were slower for incongruent than congruent trials), which did not differ by 5-HTTLPR genotype. However, fMRI results revealed that genotype influenced the degree to which neural systems were engaged depending on the valence of the conflicting task-irrelevant information. While the "Long" group recruited prefrontal control regions and superior temporal sulcus during conflict when the task-irrelevant information was positively-valenced, the "Short" group recruited these regions during conflict when the task-irrelevant information was negatively-valenced. Thus, participants successfully engaged cognitive control to overcome conflict in an emotional context using similar neural circuitry, but the engagement of this circuitry depended on emotional valence and 5-HTTLPR status. These results suggest that the interplay between emotion and cognition is modulated, in part, by a genetic polymorphism that influences serotonin neurotransmission.