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.

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.

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.

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.

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.

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.

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.

Dissociable Fronto-Operculum-Insula Control Signals for Anticipation and Detection of Inhibitory Sensory Cue.

The ability to anticipate and detect behaviorally salient stimuli is important for virtually all adaptive behaviors, including inhibitory control that requires the withholding of prepotent responses when instructed by external cues. Although right fronto-operculum-insula (FOI), encompassing the anterior insular cortex (rAI) and inferior frontal cortex (rIFC), involvement in inhibitory control is well established, little is known about signaling mechanisms underlying their differential roles in detection and anticipation of salient inhibitory cues. Here we use 2 independent functional magnetic resonance imaging data sets to investigate dynamic causal interactions of the rAI and rIFC, with sensory cortex during detection and anticipation of inhibitory cues. Across 2 different experiments involving auditory and visual inhibitory cues, we demonstrate that primary sensory cortex has a stronger causal influence on rAI than on rIFC, suggesting a greater role for the rAI in detection of salient inhibitory cues. Crucially, a Bayesian prediction model of subjective trial-by-trial changes in inhibitory cue anticipation revealed that the strength of causal influences from rIFC to rAI increased significantly on trials in which participants had higher anticipation of inhibitory cues. Together, these results demonstrate the dissociable bottom-up and top-down roles of distinct FOI regions in detection and anticipation of behaviorally salient cues across multiple sensory modalities.

The Right Superior Frontal Gyrus and Individual Variation in Proactive Control of Impulsive Response.

A hallmark of cognitive control is the ability to rein in impulsive responses. Previously, we used a Bayesian model to describe trial-by-trial likelihood of the stop signal or p(Stop) and related regional activations to p(Stop) to response slowing in a stop signal task. Here, we characterized the regional processes of conflict anticipation in association with intersubject variation in impulse control in 114 young adults. We computed the stop signal reaction time (SSRT) and a measure of motor urgency, indexed by the reaction time (RT) difference between go and stop error trials or "GoRT - SERT," where GoRT is the go trial RT and SERT is the stop error RT. Motor urgency and SSRT were positively correlated across subjects. A linear regression identified regional activations to p(Stop), each in correlation with SSRT and motor urgency. We hypothesized that shared neural activities mediate the correlation between motor urgency and SSRT in proactive control of impulsivity. Activation of the ventromedial prefrontal cortex, posterior cingulate cortex and right superior frontal gyrus (SFG) during conflict anticipation correlated negatively with the SSRT. Activation of the right SFG also correlated negatively with GoRT - SERT. Therefore, activation of the right SFG was associated with more efficient response inhibition and less motor urgency. A mediation analysis showed that right SFG activation to conflict anticipation mediates the correlation between SSRT and motor urgency bidirectionally. The current results highlight a specific role of the right SFG in translating conflict anticipation to the control of impulsive response, which is consistent with earlier studies suggesting its function in action restraint. SIGNIFICANCE STATEMENT: Individuals vary in impulse control. However, the neural bases underlying individual variation in proactive control of impulsive responses remain unknown. Here, in a large sample of young adults, we showed that activation of the right superior frontal gyrus (SFG) during conflict anticipation is positively correlated with the capacity of inhibitory control and negatively with motor urgency in the stop signal task. Importantly, activity of the right SFG mediates the counteracting processes of inhibitory control and motor urgency across subjects. The results support a unique role of the right SFG in individual variation in cognitive control.

Comparison of Cytotoxic Activity in Leukemic Lineages Reveals Important Features of ß-Hairpin Antimicrobial Peptides.

Several reports described different modes of cell death triggered by antimicrobial peptides (AMPs) due to direct effects on membrane disruption, and more recently by apoptosis and necrosis-like patterns. Cytotoxic curves of four ß-hairpin AMPs (gomesin, protegrin, tachyplesin, and polyphemusin) were obtained from several human leukemic lineages and normal monocytes and Two cell lines were then selected based on their cytotoxic sensitivity. One was sensitive to AMPs (K562) and the other resistant (KG-1) and their effect compared between these lineages. Thus, these lineages were chosen to further investigate biological features related with their cytotoxicities to AMPs. Stimulation with AMPs produced cell death, with activation of caspase-3, in K562 lineage. Increase on the fluidity of plasmatic membrane by reducing cholesterol potentiated cytotoxicity of AMPs in both lineages. Quantification of internal and external gomesin binding to the cellular membrane of both K562 and KG-1 cells showed that more peptide is accumulated inside of K562 cells. Additionally, evaluation of multi-drug resistant pumps activity showed that KG-1 has more activity than K562 lineage. A comparison of intrinsic gene patterns showed great differences between K562 and KG-1, but stimulation with gomesin promoted few changes in gene expression patterns. Differences in internalization process through the plasma membrane, multidrug resistance pumps activity, and gene expression pattern are important features to AMPs regulated cell death. J. Cell. Biochem. 118: 1764-1773, 2017. © 2016 Wiley Periodicals, Inc.

Abnormal reward circuitry in anorexia nervosa: A longitudinal, multimodal MRI study.

Anorexia nervosa (AN) is a debilitating illness and existing interventions are only modestly effective. This study aimed to determine whether AN pathophysiology is associated with altered connections within fronto-accumbal circuitry subserving reward processing. Diffusion and resting-state functional MRI scans were collected in female inpatients with AN (n = 22) and healthy controls (HC; n = 18) between the ages of 16 and 25 years. Individuals with AN were scanned during the acute, underweight phase of the illness and again following inpatient weight restoration. HC were scanned twice over the same timeframe. Based on univariate and multivariate analyses of fronto-accumbal circuitry, underweight individuals with AN were found to have increased structural connectivity (diffusion probabilistic tractography), increased white matter anisotropy (tract-based spatial statistics), increased functional connectivity (seed-based correlation in resting-state fMRI), and altered effective connectivity (spectral dynamic causal modeling). Following weight restoration, fronto-accumbal structural connectivity continued to be abnormally increased bilaterally with large (partial η2 = 0.387; right NAcc-OFC) and moderate (partial η2 = 0.197; left NAcc-OFC) effect sizes. Increased structural connectivity within fronto-accumbal circuitry in the underweight state correlated with severity of eating disorder symptoms. Taken together, the findings from this longitudinal, multimodal neuroimaging study offer converging evidence of atypical fronto-accumbal circuitry in AN. Hum Brain Mapp 37:3835-3846, 2016. © 2016 Wiley Periodicals, Inc.

Anticipating conflict: Neural correlates of a Bayesian belief and its motor consequence.

Previous studies have examined the neural correlates of proactive control using a variety of behavioral paradigms; however, the neural network relating the control process to its behavioral consequence remains unclear. Here, we applied a dynamic Bayesian model to a large fMRI data set of the stop signal task to address this issue. By estimating the probability of the stop signal - p(Stop) - trial by trial, we showed that higher p(Stop) is associated with prolonged go trial reaction time (RT), indicating proactive control of motor response. In modeling fMRI signals at trial and target onsets, we distinguished activities of proactive control, prediction error, and RT slowing. We showed that the anterior pre-supplementary motor area (pre-SMA) responds specifically to increased stop signal likelihood, and its activity is correlated with activations of the posterior pre-SMA and bilateral anterior insula during prolonged response times. This directional link is also supported by Granger causality analysis. Furthermore, proactive control, prediction error, and time-on-task are each mapped to distinct areas in the medial prefrontal cortex. Together, these findings dissect regional functions of the medial prefrontal cortex in cognitive control and provide system level evidence associating conflict anticipation with its motor consequence.

Using network dynamic fMRI for detection of epileptogenic foci.

BACKGROUND: Epilepsy is one of the most prevalent neurological disorders. It remains medically intractable for about one-third of patients with focal epilepsy, for whom precise localization of the epileptogenic zone responsible for seizure initiation may be critical for successful surgery. Existing fMRI literature points to widespread network disturbances in functional connectivity. Per previous scalp and intracranial EEG studies and consistent with excessive local synchronization during interictal discharges, we hypothesized that, relative to same regions in healthy controls, epileptogenic foci would exhibit less chaotic dynamics, identifiable via entropic analyses of resting state fMRI time series. METHODS: In order to first validate this hypothesis on a cohort of patients with known ground truth, here we test individuals with well-defined epileptogenic foci (left mesial temporal lobe epilepsy). We analyzed voxel-wise resting-state fMRI time-series using the autocorrelation function (ACF), an entropic measure of regulation and feedback, and performed follow-up seed-to-voxel functional connectivity analysis. Disruptions in connectivity of the region exhibiting abnormal dynamics were examined in relation to duration of epilepsy and patients' cognitive performance using a delayed verbal memory recall task. RESULTS: ACF analysis revealed constrained (less chaotic) functional dynamics in left temporal lobe epilepsy patients, primarily localized to ipsilateral temporal pole, proximal to presumed focal points. Autocorrelation decay rates differentiated, with 100 % accuracy, between patients and healthy controls on a subject-by-subject basis within a leave-one-subject out classification framework. Regions identified via ACF analysis formed a less efficient network in patients, as compared to controls. Constrained dynamics were linked with locally increased and long-range decreased connectivity that, in turn, correlated significantly with impaired memory (local left temporal connectivity) and epilepsy duration (left temporal - posterior cingulate cortex connectivity). CONCLUSIONS: Our current results suggest that data driven functional MRI methods that target network dynamics hold promise in providing clinically valuable tools for identification of epileptic regions.

Bayesian prediction and evaluation in the anterior cingulate cortex.

The dorsal anterior cingulate cortex (dACC) has been implicated in a variety of cognitive control functions, among them the monitoring of conflict, error, and volatility, error anticipation, reward learning, and reward prediction errors. In this work, we used a Bayesian ideal observer model, which predicts trial-by-trial probabilistic expectation of stop trials and response errors in the stop-signal task, to differentiate these proposed functions quantitatively. We found that dACC hemodynamic response, as measured by functional magnetic resonance imaging, encodes both the absolute prediction error between stimulus expectation and outcome, and the signed prediction error related to response outcome. After accounting for these factors, dACC has no residual correlation with conflict or error likelihood in the stop-signal task. Consistent with recent monkey neural recording studies, and in contrast with other neuroimaging studies, our work demonstrates that dACC reports at least two different types of prediction errors, and beyond contexts that are limited to reward processing.

Resting state functional connectivity of the basal nucleus of Meynert in humans: in comparison to the ventral striatum and the effects of age.

The basal nucleus of Meynert (BNM) provides the primary cholinergic inputs to the cerebral cortex. Loss of neurons in the BNM is linked to cognitive deficits in Alzheimer's disease and other degenerative conditions. Numerous animal studies described cholinergic and non-cholinergic neuronal responses in the BNM; however, work in humans has been hampered by the difficulty of defining the BNM anatomically. Here, on the basis of a previous study that delineated the BNM of post-mortem human brains in a standard stereotaxic space, we sought to examine functional connectivity of the BNM, as compared to the nucleus accumbens (or ventral striatum, VS), in a large resting state functional magnetic resonance imaging data set. The BNM and VS shared but also showed a distinct pattern of cortical and subcortical connectivity. Compared to the VS, the BNM showed stronger positive connectivity with the putamen, pallidum, thalamus, amygdala and midbrain, as well as the anterior cingulate cortex, supplementary motor area and pre-supplementary motor area, a network of brain regions that respond to salient stimuli and orchestrate motor behavior. In contrast, compared to the BNM, the VS showed stronger positive connectivity with the ventral caudate and medial orbitofrontal cortex, areas implicated in reward processing and motivated behavior. Furthermore, the BNM and VS each showed extensive negative connectivity with visual and lateral prefrontal cortices. Together, the distinct cerebral functional connectivities support the role of the BNM in arousal, saliency responses and cognitive motor control and the VS in reward related behavior. Considering the importance of BNM in age-related cognitive decline, we explored the effects of age on BNM and VS connectivities. BNM connectivity to the visual and somatomotor cortices decreases while connectivity to subcortical structures including the midbrain, thalamus, and pallidum increases with age. These findings of age-related changes of cerebral functional connectivity of the BNM may facilitate research of the neural bases of cognitive decline in health and illness.

Gray matter volume correlates of global positive alcohol expectancy in non-dependent adult drinkers.

Alcohol use and misuse is known to involve structural brain changes. Numerous imaging studies have examined changes in gray matter (GM) volumes in dependent drinkers, but there is little information on whether non-dependent drinking is associated with structural changes and whether these changes are related to psychological factors-such as alcohol expectancy-that influence drinking behavior. We used voxel-based morphometry (VBM) to examine whether the global positive scale of alcohol expectancy, as measured by the Alcohol Expectancy Questionnaire-3, is associated with specific structural markers and whether such markers are associated with drinking behavior in 113 adult non-dependent drinkers (66 women). Alcohol expectancy is positively correlated with GM volume of left precentral gyrus (PCG) in men and women combined and bilateral superior frontal gyri (SFG) in women, and negatively correlated with GM volume of the right ventral putamen in men. Furthermore, mediation analyses showed that the GM volume of PCG mediate the correlation of alcohol expectancy and the average number of drinks consumed per occasion and monthly total number of drinks in the past year. When recent drinking was directly accounted for in multiple regressions, GM volume of bilateral dorsolateral prefrontal cortices correlated positively with alcohol expectancy in the combined sample. To our knowledge, these results are the first to identify the structural brain correlates of alcohol expectancy and its mediation of drinking behaviors. These findings suggest that more studies are needed to investigate increased GM volume in the frontal cortices as a neural correlate of alcohol expectancy.

Gray matter volumetric correlates of the polygenic risk of depression: A study of the Human Connectome Project data.

Genetic factors confer risks for depression. Understanding the neural endophenotypes, including brain morphometrics, of genetic predisposition to depression would help in unraveling the pathophysiology of depression. We employed voxel-based morphometry (VBM) to examine how gray matter volumes (GMVs) were correlated with the polygenic risk score (PRS) for depression in 993 young adults of the Human Connectome Project. The phenotype of depression was quantified with a DSM-oriented scale of the Achenbach Adult Self-Report. The PRS for depression was computed for each subject using the Psychiatric Genomics Association Study as the base sample. In multiple regression with age, sex, race, drinking severity, and total intracranial volume as covariates, regional GMVs in positive correlation with the PRS were observed in bilateral hippocampi and right gyrus rectus. Regional GMVs in negative correlation with the PRS were observed in a wide swath of brain regions, including bilateral frontal and temporal lobes, anterior cingulate cortex, thalamus, lingual gyri, cerebellum, and the left postcentral gyrus, cuneus, and parahippocampal gyrus. We also found sex difference in anterior cingulate volumes in manifesting the genetic risk of depression. In addition, the GMV of the right cerebellum crus I partially mediated the link from PRS to depression severity. These findings add to the literature by highlighting 1) a more diverse pattern of the volumetric markers of depression, with most regions showing lower but others higher GMVs in association with the genetic risks of depression, and 2) the cerebellar GMV as a genetically informed neural phenotype of depression, in neurotypical individuals.

Characterization of dual effects induced by antimicrobial peptides: regulated cell death or membrane disruption.

BACKGROUND: Some reports describe lysis mechanisms by antimicrobial peptides (AMPs), while others describe the activation of regulated cell death. In this study, we compare the cell death-inducing activities of four ß-hairpin AMPs (gomesin, protegrin, tachyplesin and polyphemusin II) along with their linear analogs in the human erythroleukemia K562 cell line to investigate the relationship between their structure and activity. METHODS: K562 cells were exposed to AMPs. Morphological and biochemistry alterations were evaluated using light microscopy, confocal microscopy and flow cytometry. RESULTS: Gomesin and protegrin displayed cytotoxic properties that their linear counterparts did not. Tachyplesin and polyphemusin II and also their linear analogs induced cell death. We were able to distinguish two ways in which these AMPs induced cell death. Lower concentrations of AMPs induced controlled cell death mechanisms. Gomesin, tachyplesin and linear-tachyplesin promoted apoptosis that was characterized by annexin labeling, sensitivity to Z-VAD, and caspase-3 activation, but was also inhibited by necrostatin-1. Gomesin and protegrin induced cell death was dependent on intracellular Ca2+ mechanisms and the participation of free radicals was observed in protegrin induced cell death. Polyphemusin II and its linear analog mainly induced necrosis. Conversely, treatment with higher concentrations of AMPs primarily resulted in cell membrane disruption, but with clearly different patterns of action for each AMP tested. CONCLUSION: Different actions by ß-hairpin AMPs were observed at low concentrations and at higher concentrations despite the structure similarity. GENERAL SIGNIFICANCE: Controlled intracellular mechanism and direct membrane disruption were clearly distinguished helping to understand the real action of AMPs in mammalian cells.

Resting-state functional connectivity of the medial superior frontal cortex.

The medial superior frontal cortex (SFC), including the supplementary motor area (SMA) and presupplementary motor area (preSMA), is implicated in movement and cognitive control, among other functions central to decision making. Previous studies delineated the anatomical boundaries and functional connectivity of the SMA. However, it is unclear whether the preSMA, which responds to a variety of behavioral tasks, comprises functionally distinct areas. With 24 seed regions systematically demarcated throughout the anterior and posterior medial SFC, we examined here the functional divisions of the medial SFC on the basis of the "correlograms" of resting-state functional magnetic resonance imaging data of 225 adult individuals. In addition to replicating segregation of the SMA and posterior preSMA, the current results elucidated functional connectivities of anterior preSMA-the most anterior part of the medial SFC. In contrast to the caudal medial SFC, the anterior preSMA is connected with most of the prefrontal but not with somatomotor areas. Overall, the SMA is strongly connected to the thalamus and epithalamus, the posterior preSMA to putamen, pallidum, and subthalamic nucleus, and anterior preSMA to the caudate, with the caudate showing significant hemispheric asymmetry. These findings may provide a useful platform for future studies to investigate frontal cortical functions.

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.