Male-specific, replicable and functional roles of genetic variants and cerebral gray matter volumes in ADHD: a gene-wide association study across KTN1 and a region-wide functional validation across brain.

Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10-5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10-22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Gray matter volumetric correlates of attention deficit and hyperactivity traits in emerging adolescents.

Previous research has demonstrated reduction in cortical and subcortical, including basal ganglia (BG), gray matter volumes (GMV) in individuals with attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition that is more prevalent in males than in females. However, the volumetric deficits vary across studies. Whether volumetric reductions are more significant in males than females; to what extent these neural markers are heritable and relate to cognitive dysfunction in ADHD remain unclear. To address these questions, we followed published routines and performed voxel-based morphometry analysis of a data set (n = 11,502; 5,464 girls, 9-10 years) curated from the Adolescent Brain Cognition Development project, a population-based study of typically developing children. Of the sample, 634 and 2,826 were identified as monozygotic twins and dizygotic twins/siblings, respectively. In linear regressions, a cluster in the hypothalamus showed larger GMV, and bilateral caudate and putamen, lateral orbitofrontal and occipital cortex showed smaller GMVs, in correlation with higher ADHD scores in girls and boys combined. When examined separately, boys relative to girls showed more widespread (including BG) and stronger associations between GMV deficits and ADHD scores. ADHD traits and the volumetric correlates demonstrated heritability estimates (a2) between 0.59 and 0.79, replicating prior findings of the genetic basis of ADHD. Further, ADHD traits and the volumetric correlates (except for the hypothalamus) were each negatively and positively correlated with N-back performance. Together, these findings confirm volumetric deficits in children with more prominent ADHD traits. Highly heritable in both girls and boys and potentially more significant in boys than in girls, the structural deficits underlie diminished capacity in working memory and potentially other cognitive deficits in ADHD.

Gray matter volumetric correlates of dimensional impulsivity traits in children: Sex differences and heritability.

Previous research investigated the cerebral volumetric correlates of impulsivity largely in moderate-sized samples and few have examined the distinct correlates of dimensions of impulsivity, sex differences, or heritability of the correlates. Here, we performed voxel-based morphometry analysis of data (n = 11,474; 5,452 girls, 9-10 years) curated from the Adolescent Brain Cognition Development project. In a linear regression with all five UPPS-P subscores as regressors and age in months, total intracranial volume, study site, and scanner model as covariates, higher levels of lack of premeditation, and sensation seeking were correlated with larger cortical and subcortical gray matter volumes (GMVs). In contrast, higher positive urgency was correlated with smaller GMVs in many of the same regions. The dimensional impulsivity traits also involved distinct volumetric correlates, with, for instance, sensation seeking and positive urgency specifically implicating bilateral caudate head/mid-cingulate cortex and bilateral lateral orbitofrontal cortex/left precentral gyrus, respectively. Boys relative to girls scored higher in all impulsivity dimensions. Girls relative to boys showed significantly stronger positive and negative correlations between sensation seeking and insula, putamen, and inferior frontal gyrus (IFG) GMVs and between positive urgency and cingulate cortex, insula, and IFG GMVs, respectively. With a subsample of twins, the dimensional impulsivity traits were weakly to moderately heritable in both girls and boys, and the GMV correlates were highly heritable in girls and boys combined. These findings collectively suggest shared and nonshared as well as sex differences in the cerebral volumetric bases of dimensional impulsivity traits and may facilitate research of externalizing psychopathology in children.

Endocytosis and the Participation of Glycosaminoglycans Are Important to the Mechanism of Cell Death Induced by ß-Hairpin Antimicrobial Peptides.

The cytotoxic mode of action of four antimicrobial peptides (AMPs) (gomesin, tachyplesin, protegrin, and polyphemusin) against a HeLa cell tumor model is discussed. A study of cell death by AMP stimulation revealed some similarities, including annexin-V externalization, reduction of mitochondrial potential, insensitivity against inhibitors of cell death, and membrane permeabilization. Evaluation of signaling proteins and gene expression that control cell death revealed wide variation in the responses to AMPs. However, the ability to cross cell membranes emerged as an important characteristic of AMP-dependent cell death, where endocytosis mediated by dynamin is a common mechanism. Furthermore, the affinity between AMPs and glycosaminoglycans (GAGs) and GAG participation in the cytotoxicity of AMPs were verified. The results show that, despite their primary and secondary structure homology, these peptides present different modes of action, but endocytosis and GAG participation are an important and common mechanism of cytotoxicity for ß-hairpin peptides.

Gray matter volumetric correlates of behavioral activation and inhibition system traits in children: An exploratory voxel-based morphometry study of the ABCD project data.

Approach and avoidance represent two fundamental behavioral traits that develop early in life. Previous studies have examined the neural correlates of approach and avoidance traits in adults and adolescents. Here, using the data set of the Adolescent Brain Cognition Development project, we investigated the structural cerebral bases of behavioral activation system (BAS) and behavioral inhibition system (BIS) in children. We employed voxel-based morphometry to examine how gray matter volumes (GMV) related specifically to BAS and BIS traits in 11,542 children (5491 girls, age 9-10 years) with 648 and 2697 identified as monozygotic twins (MZ) and dizygotic twins/siblings (DZ), respectively. After accounting for the BIS score, higher BAS scores (residuals) were positively correlated with the GMV of the ventral striatum (VS), and the correlation was stronger in MZ than in DZ and unrelated children, with a heritability (h2) of 0.8463. Higher BAS scores were negatively correlated with the GMV of bilateral visual, lateral orbitofrontal, temporal, and inferior frontal cortex, as well as the precuneus. Higher BIS (after accounting for BAS) scores were negatively correlated with the GMVs of the ventral caudate and bilateral putamen/pallidum, hypothalamus, and right anterior insula, and the correlation was stronger in MZ than in DZ and unrelated children, with a heritability of 0.8848. A cluster in the VS showed positive and negative correlation with the BAS and BIS scores, respectively. These findings suggest shared and distinct cerebral volumetric bases of the BAS and BIS traits in children. Whereas both traits have a strong genetic basis, the BAS relative to BIS appears to be more amenable to environmental influences. These findings add to the literature of developmental neuroscience and may help identify genetic risk factors of externalizing and internalizing psychopathology.

Cerebral responses to self-initiated action during social interactions.

Social interaction involves self-initiated actions that engage subjective awareness of one's own volition. Individuals with social communication needs or social anxiety find it particularly difficult to initiate social interactions. However, extant studies have not specifically addressed how perceived exclusion may influence self-initiated actions during social interaction. As a first step to address this question, we scanned 24 healthy adults participating in a Cyberball game with two fictive players. By contrasting events of observing, receiving, and initiating ball toss during a scenario of fair game (FG) and of exclusion (EX), we examined the neural correlates of self-initiated action during social interactions. Behaviorally, participants were faster in catching but slower in tossing the ball in EX compared with FG, suggesting a burden during self-initiated actions during social exclusion. Tossing versus receiving (or observing) engaged higher activity during EX than FG in the precuneus and angular gyrus, regions that have been widely implicated in theory of mind processing and social emotions. Across subjects these cortical activities correlated positively with the difference between EX and FG in the percentage of trials where participants tossed the ball back to the same player (r = 0.69, p < 0.001). Together, the results suggested that, in healthy adults, social exclusion encumbered and engaged higher posterior cortical activations during self-initiated actions. The findings may facilitate future research of neural markers of social behavioral disorders.

Alcohol Expectancy and Cerebral Responses to Cue-Elicited Craving in Adult Nondependent Drinkers.

BACKGROUND: Positive alcohol expectancy (AE) contributes to excessive drinking. Many imaging studies have examined cerebral responses to alcohol cues and how these regional processes related to problem drinking. However, it remains unclear how AE relates to cue response and whether AE mediates the relationship between cue response and problem drinking. METHODS: A total of 61 nondependent drinkers were assessed with the Alcohol Expectancy Questionnaire and Alcohol Use Disorder Identification Test and underwent functional magnetic resonance imaging while exposed to alcohol and neutral cues. Imaging data were processed and analyzed with published routines, and mediation analyses were conducted to examine the interrelationships among global positive score of the Alcohol Expectancy Questionnaire, Alcohol Use Disorder Identification Test score, and regional responses to alcohol versus neutral cues. RESULTS: Alcohol as compared with neutral cues engaged the occipital, retrosplenial, and medial orbitofrontal cortex as well as the left caudate head and red nucleus. The bilateral thalamus showed a significant correlation in cue response and in left superior frontal cortical connectivity with global positive score in a linear regression. Mediation analyses showed that global positive score completely mediated the relationship between thalamic cue activity as well as superior frontal cortical connectivity and Alcohol Use Disorder Identification Test score. The alternative models that AE contributed to problem drinking and, in turn, thalamic cue activity and connectivity were not supported. CONCLUSIONS: The findings suggest an important role of the thalamic responses to alcohol cues in contributing to AE and at-risk drinking in nondependent drinkers. AEs may reflect a top-down modulation of the thalamic processing of alcohol cues, influencing the pattern of alcohol use.

Model testing for distinctive functional connectivity gradients with resting-state fMRI data.

In accordance with the concept of topographic organization of neuroanatomical structures, there is an increased interest in estimating and delineating continuous changes in the functional connectivity patterns across neighboring voxels within a region of interest using resting-state fMRI data. Fundamental to this functional connectivity gradient analysis is the assumption that the functional organization is stable and uniform across the region of interest. To evaluate this assumption, we developed a statistical model testing procedure to arbitrate between overlapping, shifted, or different topographic connectivity gradients across subdivisions of a structure. We tested the procedure using the striatum, a subcortical structure consisting of the caudate nucleus and putamen, in which an extensive literature, primarily from rodents and non-human primates, suggest to have a shared topographic organization of a single diagonal gradient. We found, across multiple resting state fMRI data samples of different spatial resolutions in humans, and one macaque resting state fMRI data sample, that the models with different functional connectivity gradients across the caudate and putamen was the preferred model. The model selection procedure was validated in control conditions of checkerboard subdivisions, demonstrating the expected overlapping gradient. More specifically, while we replicated the diagonal organization of the functional connectivity gradients in both the caudate and putamen, our analysis also revealed a medial-lateral organization within the caudate. Not surprisingly, performing the same analysis assuming a unitary gradient obfuscates the medial-lateral organization of the caudate, producing only a diagonal gradient. These findings demonstrate the importance of testing basic assumptions and evaluating interpretations across species. The significance of differential topographic gradients across the putamen and caudate and the medial-lateral gradient of the caudate in humans should be tested in future studies.

Problem Drinking, Alcohol Expectancy, and Thalamic Resting-State Functional Connectivity in Nondependent Adult Drinkers.

Alcohol misuse is associated with thalamic dysfunction. The thalamus comprises subnuclei that relay and integrate information between cortical and subcortical structures. However, it is unclear how the subnuclei contribute to thalamic dysfunctions in problem drinking. We investigated resting-state functional connectivity (rsFC) of thalamic subregions in 107 nondependent drinkers (57 women), using masks delineated by white matter tractography. Thalamus was parceled into motor, somatosensory, visual, premotor, frontal association, parietal association, and temporal association subregions. Whole-brain linear regression, each against Alcohol Use Disorders Identification Test (AUDIT) and positive alcohol expectancy (AE) score with age as a covariate, was performed for each seed, for men and women combined, and separately. Overall, problem drinking was associated with increased thalamic connectivities, whereas AE was associated with a mixed pattern of increased and decreased connectivities. Motor, premotor, somatosensory, and frontal association thalamic connectivity with bilateral caudate head was positively correlated with AUDIT score in men and women combined. Connectivity of the right caudate head with frontal association and premotor thalamus was also positively correlated with AE score in men and women combined. In contrast, motor and premotor thalamic connectivity with a number of cortical and subcortical structures showed sex differences in the correlation each with AUDIT and AE score. In mediation analyses, AE score completely mediated the correlation between thalamic caudate connectivity and AUDIT score, whereas the model where AE contributed to problem drinking and, in turn, altered thalamic caudate connectivity was not supported. To conclude, thalamic subregional rsFCs showed both shared and distinct changes and sex differences in association with problem drinking and AE. Increased thalamic caudate connectivity may contribute to problem drinking via enhanced AE. The findings suggest the importance of examining thalamic subdivisions and sex in investigating the functional roles of thalamus in problem drinking.

Structural and functional cerebral bases of diminished inhibitory control during healthy aging.

Inhibitory control or the ability to refrain from incorrect responses is a critical executive function known to diminish during aging. Imaging studies have elucidated cerebral changes that may underlie the age-related deficits. However, it remains unclear whether the structural and functional changes occur in the same brain regions and whether reduced gray matter volumes (GMV) mediate decreased activation during inhibition. Here, in a sample of 149 participants, we addressed the issues using structural and functional magnetic resonance imaging. Individual's response inhibition was evaluated by the stop signal reaction time (SSRT) in a stop signal task. The results showed that age was associated with prolonged SSRT across participants. Many cortical and subcortical regions demonstrated age-related reduction in GMV and activation to response inhibition. Additionally, age-related diminution in inhibitory control, as indexed by the SSRT, was associated with both shared and distinct morphometric and functional changes. Voxel-based morphometry demonstrated age-related reduction in GMV in the right dorsolateral prefrontal cortex and caudate head as well as bilateral insula, in association with prolonged SSRT. In a contrast of stop success versus go success trials, age was associated with lower activation in the medial and inferior frontal cortex and inferior parietal cortex. Further, reduction in GMV mediated age-related differences in activations only of the medial prefrontal cortex, providing limited evidence for structure function association. Thus, the decline in inhibitory control, as evidenced in the stop signal task, manifest with both shared and distinct structural and functional processes during aging.

Dynamic network dysfunction in cocaine dependence: Graph theoretical metrics and stop signal reaction time.

Graphic theoretical metrics have become increasingly popular in characterizing functional connectivity of neural networks and how network connectivity is compromised in neuropsychiatric illnesses. Here, we add to this literature by describing dynamic network connectivities of 78 cocaine dependent (CD) and 85 non-drug using healthy control (HC) participants who underwent fMRI during performance of a stop signal task (SST). Compared to HC, CD showed prolonged stop signal reaction time (SSRT), consistent with deficits in response inhibition. In graph theoretical analysis of dynamic functional connectivity, we examined temporal flexibility and spatiotemporal diversity of 14 networks covering the whole brain. Temporal flexibility quantifies how frequently a brain region interacts with regions of other communities across time, with high temporal flexibility indicating that a region interacts predominantly with regions outside its own community. Spatiotemporal diversity quantifies how uniformly a brain region interacts with regions in other communities over time, with high spatiotemporal diversity indicating that the interactions are more evenly distributed across communities. Compared to HC, CD exhibited decreased temporal flexibility and increased spatiotemporal diversity in the great majority of neural networks. The graph metric measures of the default mode network negatively correlated with SSRT in CD but not HC. The findings are consistent with diminished temporal flexibility and a compensatory increase in spatiotemporal diversity, in association with impairment of a critical executive function, in cocaine addiction. More broadly, the findings suggest that graph theoretical metrics provide new insights for connectivity analyses to elucidate network dysfunction that may elude conventional measures.

Thalamic Cortical Error-Related Responses in Adult Social Drinkers: Sex Differences and Problem Alcohol Use.

BACKGROUND: Error-related brain activities are altered in individuals with substance use disorders. Here we examined error-related activities in relation to problem drinking in nondependent alcohol drinkers. In particular, we investigated sex differences and whether altered error responses are related to post-error behavioral control. METHODS: A sample of 145 nondependent drinkers (77 women) performed the stop-signal task during functional magnetic resonance imaging. Imaging data were processed and modeled using statistical parametric mapping. Independent sample t test and linear regression were employed to examine sex differences in error response and relationship between error response and problem drinking. RESULTS: Compared with men, women showed greater error-related (stop error > go success) activations in the bilateral thalamus, right middle/superior temporal cortex, and bilateral dorsal anterior cingulate cortex. In whole-brain linear regression of error responses against the Alcohol Use Disorders Identification Test score, a wide swath of cortical and subcortical regions, including the thalamus, showed decreased activation in association with problem drinking in women but not in men. However, men and women were not different in the extent of post-error slowing and decreased thalamic error response in association with problem drinking was not related to the extent of post-error slowing in women. CONCLUSIONS: The results suggest sex differences in error-related activations with heavier drinking associated with reduced error activations in women but not in men. These differences in cerebral activations may reflect higher physiological arousal in response to errors and greater vulnerability of saliency-related arousal response to problem drinking in female as compared with male social drinkers.

Motor Preparation Disrupts Proactive Control in the Stop Signal Task.

In a study of the stop signal task (SST) we employed Bayesian modeling to compute the estimated likelihood of stop signal or P(Stop) trial by trial and identified regional processes of conflict anticipation and response slowing. A higher P(Stop) is associated with prolonged go trial reaction time (goRT)-a form of sequential effect-and reflects proactive control of motor response. However, some individuals do not demonstrate a sequential effect despite similar go and stop success (SS) rates. We posited that motor preparation may disrupt proactive control more in certain individuals than others. Specifically, the time interval between trial and go signal onset-the fore-period (FP)-varies across trials and a longer FP is associated with a higher level of motor preparation and shorter goRT. Greater motor preparatory activities may disrupt proactive control. To test this hypothesis, we compared brain activations and Granger causal connectivities of 81 adults who demonstrated a sequential effect (SEQ) and 35 who did not (nSEQ). SEQ and nSEQ did not differ in regional activations to conflict anticipation, motor preparation, goRT slowing or goRT speeding. In contrast, SEQ and nSEQ demonstrated different patterns of Granger causal connectivities. P(Stop) and FP activations shared reciprocal influence in SEQ but FP activities Granger caused P(Stop) activities unidirectionally in nSEQ, and FP activities Granger caused goRT speeding activities in nSEQ but not SEQ. These findings support the hypothesis that motor preparation disrupts proactive control in nSEQ and provide direct neural evidence for interactive go and stop processes.

Oxytocin attenuates trust as a subset of more general reinforcement learning, with altered reward circuit functional connectivity in males.

Oxytocin (OT) is an endogenous neuropeptide that, while originally thought to promote trust, has more recently been found to be context-dependent. Here we extend experimental paradigms previously restricted to de novo decision-to-trust, to a more realistic environment in which social relationships evolve in response to iterative feedback over twenty interactions. In a randomized, double blind, placebo-controlled within-subject/crossover experiment of human adult males, we investigated the effects of a single dose of intranasal OT (40 IU) on Bayesian expectation updating and reinforcement learning within a social context, with associated brain circuit dynamics. Subjects participated in a neuroeconomic task (Iterative Trust Game) designed to probe iterative social learning while their brains were scanned using ultra-high field (7T) fMRI. We modeled each subject's behavior using Bayesian updating of belief-states ("willingness to trust") as well as canonical measures of reinforcement learning (learning rate, inverse temperature). Behavioral trajectories were then used as regressors within fMRI activation and connectivity analyses to identify corresponding brain network functionality affected by OT. Behaviorally, OT reduced feedback learning, without bias with respect to positive versus negative reward. Neurobiologically, reduced learning under OT was associated with muted communication between three key nodes within the reward circuit: the orbitofrontal cortex, amygdala, and lateral (limbic) habenula. Our data suggest that OT, rather than inspiring feelings of generosity, instead attenuates the brain's encoding of prediction error and therefore its ability to modulate pre-existing beliefs. This effect may underlie OT's putative role in promoting what has typically been reported as 'unjustified trust' in the face of information that suggests likely betrayal, while also resolving apparent contradictions with regard to OT's context-dependent behavioral effects.

Resting state functional connectivity of the amygdala and problem drinking in non-dependent alcohol drinkers.

Alcohol misuse is associated with dysfunction of the amygdala-prefrontal cortical circuit. The amygdala and its cortical targets show decreased activity during a variety of task challenges in individuals engaged in problem drinking. On the other hand, it is less clear how amygdala resting state functional connectivity (rsFC) may be altered in association with alcohol misuse and whether such changes are restricted to prefrontal cortical structures. Further, the influences of comorbid substance use and depression and potential sex differences have not been assessed in earlier work. Here, with fMRI data from a Nathan Kline Institute/Rockland sample of 83 non-dependent alcohol drinkers (26 men), we addressed changes in whole brain rsFC of the amygdala in association with problem drinking as indexed by an alcohol involvement score. Imaging data were processed with Statistical Parametric Mapping following standard routines and all results were examined at voxel p < 0.001 uncorrected in combination with cluster p < 0.05 corrected for false discovery rate. Alcohol misuse was correlated with decreased amygdala connectivity with the dorsal anterior cingulate cortex (dACC) irrespective of depression and other substance use. Changes in amygdala-dACC connectivity manifested in the latero-basal subdivision of the amygdala. Further, men as compared to women showed a significantly stronger relationship in decreased amygdala-dACC connectivity and problem drinking, although it should be noted that men also showed a trend toward higher alcohol involvement score than women. The findings add to a growing literature documenting disrupted amygdala-prefrontal cortical functions in relation to alcohol misuse.

Time scale properties of task and resting-state functional connectivity: Detrended partial cross-correlation analysis.

Functional connectivity analysis is an essential tool for understanding brain function. Previous studies showed that brain regions are functionally connected through low-frequency signals both within the default mode network (DMN) and task networks. However, no studies have directly compared the time scale (frequency) properties of network connectivity during task versus rest, or examined how they relate to task performance. Here, using fMRI data collected from sixty-eight subjects at rest and during a stop signal task, we addressed this issue with a novel functional connectivity measure based on detrended partial cross-correlation analysis (DPCCA). DPCCA has the advantage of quantifying correlations between two variables in different time scales while controlling for the influence of other variables. The results showed that the time scales of within-network connectivity of the DMN and task networks are modulated in opposite directions across rest and task, with the time scale increased during rest vs. task in the DMN and vice versa in task networks. In regions of interest analysis, the within-network connectivity time scale of the pre-supplementary motor area - a medial prefrontal cortical structure of the task network and critical to proactive inhibitory control - correlated inversely with Barratt impulsivity and stop signal reaction time. Together, these findings demonstrate that time scale properties of brain networks may vary across mental states and provide evidence in support of a role of low frequency fluctuations of BOLD signals in behavioral control.

Proactive Control: Neural Oscillatory Correlates of Conflict Anticipation and Response Slowing.

Proactive control allows us to anticipate environmental changes and adjust behavioral strategy. In the laboratory, investigators have used a number of different behavioral paradigms, including the stop-signal task (SST), to examine the neural processes of proactive control. Previous functional MRI studies of the SST have demonstrated regional responses to conflict anticipation-the likelihood of a stop signal or P(stop) as estimated by a Bayesian model-and reaction time (RT) slowing and how these responses are interrelated. Here, in an electrophysiological study, we investigated the time-frequency domain substrates of proactive control. The results showed that conflict anticipation as indexed by P(stop) was positively correlated with the power in low-theta band (3-5 Hz) in the fixation (trial onset)-locked interval, and go-RT was negatively correlated with the power in delta-theta band (2-8 Hz) in the go-locked interval. Stimulus prediction error was positively correlated with the power in the low-beta band (12-22 Hz) in the stop-locked interval. Further, the power of the P(stop) and go-RT clusters was negatively correlated, providing a mechanism relating conflict anticipation to RT slowing in the SST. Source reconstruction with beamformer localized these time-frequency activities close to brain regions as revealed by functional MRI in earlier work. These are the novel results to show oscillatory electrophysiological substrates in support of trial-by-trial behavioral adjustment for proactive control.

Distinct neural processes support post-success and post-error slowing in the stop signal task.

Executive control requires behavioral adaptation to environmental contingencies. In the stop signal task (SST), participants exhibit slower go trial reaction time (RT) following a stop trial, whether or not they successfully interrupt the motor response. In previous fMRI studies, we demonstrated activation of the right-hemispheric ventrolateral prefrontal cortex, in the area of inferior frontal gyrus, pars opercularis (IFGpo) and anterior insula (AI), during post-error slowing (PES). However, in similar analyses we were not able to identify regional activities during post-success slowing (PSS). Here, we revisited this issue in a larger sample of participants (n=100) each performing the SST for 40 min during fMRI. We replicated IFGpo/AI activation to PES (p≤0.05, FWE corrected). Further, PSS engages decreased activation in a number of cortical regions including the left inferior frontal cortex (IFC; p≤0.05, FWE corrected). We employed Granger causality mapping to identify areas that provide inputs each to the right IFGpo/AI and left IFC, and computed single-trial amplitude (STA) of stop trials of these input regions as well as the STA of post-stop trials of the right IFGpo/AI and left IFC. The STAs of the right inferior precentral sulcus and supplementary motor area (SMA) and right IFGpo/AI were positively correlated and the STAs of the left SMA and left IFC were positively correlated (slope>0, p's≤0.01, one-sample t test), linking regional responses during stop success and error trials to those during PSS and PES. These findings suggest distinct neural mechanisms to support PSS and PES.

Barratt Impulsivity in Healthy Adults Is Associated with Higher Gray Matter Concentration in the Parietal Occipital Cortex that Represents Peripheral Visual Field.

Impulsivity is a personality trait of clinical importance. Extant research focuses on fronto-striatal mechanisms of impulsivity and how executive functions are compromised in impulsive individuals. Imaging studies employing voxel based morphometry highlighted impulsivity-related changes in gray matter concentrations in a wide array of cerebral structures. In particular, whereas prefrontal cortical areas appear to show structural alterations in individuals with a neuropsychiatric condition, the findings are less than consistent in the healthy population. Here, in a sample (n = 113) of young adults assessed for Barratt impulsivity, we controlled for age, gender and alcohol use, and showed that higher impulsivity score is associated with increased gray matter volume (GMV) in bilateral medial parietal and occipital cortices known to represent the peripheral visual field. When impulsivity components were assessed, we observed that this increase in parieto-occipital cortical volume is correlated with inattention and non-planning but not motor subscore. In a separate behavioral experiment of 10 young adults, we demonstrated that impulsive individuals are more vulnerable to the influence of a distractor on target detection in an attention task. If replicated, these findings together suggest aberrant visual attention as a neural correlate of an impulsive personality trait in neurotypical individuals and need to be reconciled with the literature that focuses on frontal dysfunctions.

Sex differences in the interacting roles of impulsivity and positive alcohol expectancy in problem drinking: A structural brain imaging study.

Alcohol expectancy and impulsivity are implicated in alcohol misuse. However, how these two risk factors interact to determine problem drinking and whether men and women differ in these risk processes remain unclear. In 158 social drinkers (86 women) assessed for Alcohol Use Disorder Identification Test (AUDIT), positive alcohol expectancy, and Barratt impulsivity, we examined sex differences in these risk processes. Further, with structural brain imaging, we examined the neural bases underlying the relationship between these risk factors and problem drinking. The results of general linear modeling showed that alcohol expectancy best predicted problem drinking in women, whereas in men as well as in the combined group alcohol expectancy and impulsivity interacted to best predict problem drinking. Alcohol expectancy was associated with decreased gray matter volume (GMV) of the right posterior insula in women and the interaction of alcohol expectancy and impulsivity was associated with decreased GMV of the left thalamus in women and men combined and in men alone, albeit less significantly. These risk factors mediated the correlation between GMV and problem drinking. Conversely, models where GMV resulted from problem drinking were not supported. These new findings reveal distinct psychological factors that dispose men and women to problem drinking. Although mediation analyses did not determine a causal link, GMV reduction in the insula and thalamus may represent neural phenotype of these risk processes rather than the consequence of alcohol consumption in non-dependent social drinkers. The results add to the alcohol imaging literature which has largely focused on dependent individuals and help elucidate alterations in brain structures that may contribute to the transition from social to habitual drinking.