Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

An effort-based social feedback paradigm reveals aversion to popularity in socially anxious participants and increased motivation in adolescents.

We created a novel social feedback paradigm to study how motivation for potential social links is influenced in adolescents and adults. 88 participants (42F/46M) created online posts and then expended physical effort to show their posts to other users, who varied in number of followers and probability of positive feedback. We focused on two populations of particular interest from a social feedback perspective: adolescents relative to young adults (13-17 vs 18-24 years of age), and participants with social anxiety symptoms. Individuals with higher self-reported symptoms of social anxiety did not follow the typical pattern of increased effort to obtain social feedback from high status peers. Adolescents were more willing to exert physical effort on the task than young adults. Overall, participants were more likely to exert physical effort for high social status users and for users likely to yield positive feedback, and men were more likely to exert effort than women, findings that parallel prior results in effort-based tasks with financial rather than social rewards. Together the findings suggest social motivation is malleable, driven by factors of social status and the likelihood of a positive social outcome, and that age, sex, and social anxiety significantly impact patterns of socially motivated decision-making.

Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.

Meta-analyses have shown that digital mental health apps can be efficacious in reducing symptoms of depression and anxiety. However, real-world usage of apps is typically not sustained over time, and no studies systematically examine which features increase sustained engagement with apps or the relationship between engagement features and clinical efficacy. We conducted a systematic search of the literature to identify empirical studies that (1) investigate standalone apps for depression and/or anxiety in symptomatic participants and (2) report at least one measure of engagement. Features intended to increase engagement were categorized using the persuasive system design (PSD) framework and principles of behavioral economics. Twenty-five studies with 4159 participants were included in the analysis. PSD features were commonly used, whereas behavioral economics techniques were not. Smartphone apps were efficacious in treating symptoms of anxiety and depression in randomized controlled trials, with overall small-to-medium effects (g = 0.2888, SE = 0.0999, z(15) = 2.89, p = 0.0119, Q(df = 14) = 41.93, p < 0.0001, I2 = 66.6%), and apps that employed a greater number of engagement features as compared to the control condition had larger effect sizes (ß = 0.0450, SE = 0.0164, t(15) = 2.7344, p = 0.0161). We observed an unexpected negative association between PSD features and engagement, as measured by completion rate (ß = -0.0293, SE = 0.0121, t(17) = 02.4142, p = 0.0281). Overall, PSD features show promise for augmenting app efficacy, though engagement, as reflected in study completion, may not be the primary factor driving this association. The results suggest that expanding the use of PSD features in mental health apps may increase clinical benefits and that other techniques, such as those informed by behavioral economics, are employed infrequently.

Rapid Precision Functional Mapping of Individuals Using Multi-Echo fMRI.

Resting-state functional magnetic resonance imaging (fMRI) is widely used in cognitive and clinical neuroscience, but long-duration scans are currently needed to reliably characterize individual differences in functional connectivity (FC) and brain network topology. In this report, we demonstrate that multi-echo fMRI can improve the reliability of FC-based measurements. In four densely sampled individual humans, just 10 min of multi-echo data yielded better test-retest reliability than 30 min of single-echo data in independent datasets. This effect is pronounced in clinically important brain regions, including the subgenual cingulate, basal ganglia, and cerebellum, and is linked to three biophysical signal mechanisms (thermal noise, regional variability in the rate of T2∗ decay, and S0-dependent artifacts) with spatially distinct influences. Together, these findings establish the potential utility of multi-echo fMRI for rapid precision mapping using experimentally and clinically tractable scan times and will facilitate longitudinal neuroimaging of clinical populations.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

The impact of white matter hyperintensities on the structural connectome in late-life depression: Relationship to executive functions.

BACKGROUND: White matter hyperintensities (WMH) represent ischemic white matter damage in late-life depression (LLD) and are associated with cognitive control dysfunction. Understanding the impact of WMH on the structural connectivity of gray matter and the cognitive control correlates of WMH-related structural dysconnectivity can provide insight into the pathophysiology of LLD. METHODS: We compared WMH burden and performance on clinical measures of cognitive control in patients with LLD (N = 44) and a control group of non-depressed older adults (N = 59). We used the Network Modification (NeMo) Tool to investigate the impact of WMH on structural dysconnectivity in specific gray matter regions, and how such connectivity was related to cognitive control functions. RESULTS: Compared to the control group, LLD participants had greater WMH burden, poorer performance on Trail Making Test (TMT) A & B, and greater self-reported dysexecutive behavior on the Frosntal Systems Behavior Scale-Executive Function subscale (FrSBe-EF). Within the LLD group, disrupted connectivity in the left supramarginal gyrus, paracentral lobule, thalamus, and pallidum was associated with psychomotor slowing (TMT-A). Altered connectivity in the left supramarginal gyrus, paracentral lobule, precentral gyrus, postcentral gyrus, thalamus, and pallidum was associated with poor attentional set-shifting (TMT-B). A follow-up analysis that isolated set-shifting ability (TMT-B/A ratio) confirmed the association with dysconnectivity in the bilateral paracentral lobule, right thalamus, left precentral gyrus, postcentral gyrus, and pallidum; additionally, it revealed associations with dysconnectivity in the right posterior cingulate, and left anterior cingulate, middle frontal cortex, and putamen. CONCLUSIONS: In LLD, WMH are associated with region-specific disruptions in cortical and subcortical gray matter areas involved in attentional aspects of cognitive control systems and sensorimotor processing, which in turn are associated with slower processing speed, and reduced attentional set-shifting. CLINICAL TRIALS REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01728194.

Changes in Functional Connectivity Following Treatment With Emotion Regulation Therapy.

Emotion regulation therapy (ERT) is an efficacious treatment for distress disorders (i.e., depression and anxiety), predicated on a conceptual model wherein difficult to treat distress arises from intense emotionality (e.g., neuroticism, dispositional negativity) and is prolonged by negative self-referentiality (e.g., worry, rumination). Individuals with distress disorders exhibit disruptions in two corresponding brain networks including the salience network (SN) reflecting emotion/motivation and the default mode network (DMN) reflecting self-referentiality. Using resting-state functional connectivity (rsFC) analyses, seeded with primary regions in each of these networks, we investigated whether ERT was associated with theoretically consistent changes across nodes of these networks and whether these changes related to improvements in clinical outcomes. This study examined 21 generalized anxiety disorder (GAD) patients [with and without major depressive disorder (MDD)] drawn from a larger intervention trial (Renna et al., 2018a), who completed resting state fMRI scans before and after receiving 16 sessions of ERT. We utilized seed-based connectivity analysis with seeds in the posterior cingulate cortex (PCC), right anterior insula, and right posterior insula, to investigate whether ERT was associated with changes in connectivity of nodes of the DMN and SN networks to regions across the brain. Findings revealed statistically significant treatment linked changes in both the DMN and SN network nodes, and these changes were associated with clinical improvement corresponding to medium effect sizes. The results are discussed in light of a nuanced understanding of the role of connectivity changes in GAD and MDD, and begin to provide neural network support for the hypothesized treatment model predicated by ERT.

Prefrontal Executive Control Rescues Risk for Anxiety Associated with High Threat and Low Reward Brain Function.

Compared with neural biomarkers of risk for mental illness, little is known about biomarkers of resilience. We explore if greater executive control-related prefrontal activity may function as a resilience biomarker by "rescuing" risk associated with higher threat-related amygdala and lower reward-related ventral striatum activity. Functional MRI was used to assay baseline threat-related amygdala, reward-related ventral striatum, and executive control-related prefrontal activity in 120 young adult volunteers. Participants provided self-reported mood and anxiety ratings at baseline and follow-up. A moderation model revealed a significant three-way interaction wherein higher amygdala and lower ventral striatum activity predicted increases in anxiety in those with average or low but not high prefrontal activity. This effect was specific to anxiety, with the neural biomarkers explaining ~10% of the variance in change over time, above and beyond baseline symptoms, sex, age, IQ, presence or absence of DMS-IV diagnosis, and both early and recent stress. Our findings are consistent with the importance of top-down executive control in adaptive regulation of negative emotions, and highlight a unique combination of neural biomarkers that may identify at-risk individuals for whom the adoption of strategies to improve executive control of negative emotions may prove particularly beneficial.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

A Link Between Childhood Adversity and Trait Anger Reflects Relative Activity of the Amygdala and Dorsolateral Prefrontal Cortex.

BACKGROUND: Trait anger, or the dispositional tendency to experience a wide range of situations as annoying or frustrating, is associated with negative mental and physical health outcomes. The experience of adversity during childhood is one risk factor for the later emergence of high trait anger. This association has been hypothesized to reflect alterations in neural circuits supporting bottom-up threat processing and top-down executive control. METHODS: Here, using functional magnetic resonance imaging and self-report questionnaire data from 220 volunteers, we examined how individual differences in top-down prefrontal executive control and bottom-up amygdala threat activity modulate the association between childhood adversity and trait anger during young adulthood. RESULTS: We report that the association between childhood adversity and trait anger is attenuated specifically in young adults who have both relatively low threat-related amygdala activity and high executive control-related dorsolateral prefrontal cortex activity. CONCLUSIONS: These brain activity patterns suggest that simultaneous consideration of their underlying cognitive processes-namely, threat processing and executive control-may be useful in strategies designed to mitigate the negative mental health consequences of childhood adversity.

A BRIEF INTRODUCTION TO THE NEUROGENETICS OF COGNITION-EMOTION INTERACTIONS.

Neuroscience research has demonstrated that cognition, emotion, and their dynamic interactions emerge from complex and flexible patterns of activity across distributed neural circuits. A parallel branch of research in genetics has begun to identify common variation in the human DNA sequence (i.e., genome) that may shape individual differences in cognition-emotion interactions by altering molecular and cellular pathways that modulate the activity of these neural circuits. Here we provide a brief introduction to such neurogenetics research and how it may usefully inform our understanding of the biological mechanisms through which dynamic cognition-emotion interactions emerge and, subsequently, help shape normal and abnormal behavior.

Effects of Schizophrenia Polygenic Risk Scores on Brain Activity and Performance During Working Memory Subprocesses in Healthy Young Adults.

Recent work has begun to shed light on the neural correlates and possible mechanisms of polygenic risk for schizophrenia. Here, we map a schizophrenia polygenic risk profile score (PRS) based on genome-wide association study significant loci onto variability in the activity and functional connectivity of a frontoparietal network supporting the manipulation versus maintenance of information during a numerical working memory (WM) task in healthy young adults (n = 99, mean age = 19.8). Our analyses revealed that higher PRS was associated with hypoactivity of the dorsolateral prefrontal cortex (dlPFC) during the manipulation but not maintenance of information in WM (r2 = .0576, P = .018). Post hoc analyses revealed that PRS-modulated dlPFC hypoactivity correlated with faster reaction times during WM manipulation (r2 = .0967, P = .002), and faster processing speed (r2 = .0967, P = .003) on a separate behavioral task. These PRS-associated patterns recapitulate dlPFC hypoactivity observed in patients with schizophrenia during central executive manipulation of information in WM on this task.

Is low cognitive functioning a predictor or consequence of major depressive disorder? A test in two longitudinal birth cohorts.

Cognitive impairment has been identified as an important aspect of major depressive disorder (MDD). We tested two theories regarding the association between MDD and cognitive functioning using data from longitudinal cohort studies. One theory, the cognitive reserve hypothesis, suggests that higher cognitive ability in childhood decreases risk of later MDD. The second, the scarring hypothesis, instead suggests that MDD leads to persistent cognitive deficits following disorder onset. We tested both theories in the Dunedin Study, a population-representative cohort followed from birth to midlife and assessed repeatedly for both cognitive functioning and psychopathology. We also used data from the Environmental Risk Longitudinal Twin Study to test whether childhood cognitive functioning predicts future MDD risk independent of family-wide and genetic risk using a discordant twin design. Contrary to both hypotheses, we found that childhood cognitive functioning did not predict future risk of MDD, nor did study members with a past history of MDD show evidence of greater cognitive decline unless MDD was accompanied by other comorbid psychiatric conditions. Our results thus suggest that low cognitive functioning is related to comorbidity, but is neither an antecedent nor an enduring consequence of MDD. Future research may benefit from considering cognitive deficits that occur during depressive episodes from a transdiagnostic perspective.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

Correction: Genomic and Clinical Effects Associated with a Relaxation Response Mind-Body Intervention in Patients with Irritable Bowel Syndrome and Inflammatory Bowel Disease.

[This corrects the article DOI: 10.1371/journal.pone.0123861.].

Thinking and Feeling: Individual Differences in Habitual Emotion Regulation and Stress-Related Mood are Associated with Prefrontal Executive Control.

Calculating math problems from memory may seem unrelated to everyday processing of emotions, but they have more in common than one might think. Prior research highlights the importance of the dorsolateral prefrontal cortex (dlPFC) in executive control, intentional emotion regulation, and experience of dysfunctional mood and anxiety. While it has been hypothesized that emotion regulation may be related to 'cold' (ie. not emotion-related) executive control, this assertion has not been tested. We address this gap by providing evidence that greater dlPFC activity during 'cold' executive control is associated with increased use of cognitive reappraisal to regulate emotions in everyday life. We then demonstrate that in the presence of increased life stress, increased dlPFC activity is associated with lower mood and anxiety symptoms and clinical diagnoses. Collectively, our results encourage ongoing efforts to understand prefrontal executive control as a possible intervention target for improving emotion regulation in mood and anxiety disorders.

Individual differences in regulatory focus predict neural response to reward.

Although goal pursuit is related to both functioning of the brain's reward circuits and psychological factors, the literatures surrounding these concepts have often been separate. Here, we use the psychological construct of regulatory focus to investigate individual differences in neural response to reward. Regulatory focus theory proposes two motivational orientations for personal goal pursuit: (1) promotion, associated with sensitivity to potential gain, and (2) prevention, associated with sensitivity to potential loss. The monetary incentive delay task was used to manipulate reward circuit function, along with instructional framing corresponding to promotion and prevention in a within-subject design. We observed that the more promotion oriented an individual was, the lower their ventral striatum response to gain cues. Follow-up analyses revealed that greater promotion orientation was associated with decreased ventral striatum response even to no-value cues, suggesting that promotion orientation may be associated with relatively hypoactive reward system function. The findings are also likely to represent an interaction between the cognitive and motivational characteristics of the promotion system with the task demands. Prevention orientation did not correlate with ventral striatum response to gain cues, supporting the discriminant validity of regulatory focus theory. The results highlight a dynamic association between individual differences in self-regulation and reward system function.