Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

ezAlign: A Tool for Converting Coarse-Grained Molecular Dynamics Structures to Atomistic Resolution for Multiscale Modeling.

Soft condensed matter is challenging to study due to the vast time and length scales that are necessary to accurately represent complex systems and capture their underlying physics. Multiscale simulations are necessary to study processes that have disparate time and/or length scales, which abound throughout biology and other complex systems. Herein we present ezAlign, an open-source software for converting coarse-grained molecular dynamics structures to atomistic representation, allowing multiscale modeling of biomolecular systems. The ezAlign v1.1 software package is publicly available for download at github.com/LLNL/ezAlign. Its underlying methodology is based on a simple alignment of an atomistic template molecule, followed by position-restraint energy minimization, which forces the atomistic molecule to adopt a conformation consistent with the coarse-grained molecule. The molecules are then combined, solvated, minimized, and equilibrated with position restraints. Validation of the process was conducted on a pure POPC membrane and compared with other popular methods to construct atomistic membranes. Additional examples, including surfactant self-assembly, membrane proteins, and more complex bacterial and human plasma membrane models, are also presented. By providing these examples, parameter files, code, and an easy-to-follow recipe to add new molecules, this work will aid future multiscale modeling efforts.

An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.

BACKGROUND: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. METHODS: In silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether 'hindered' variants of 26DTB-P (wherein a hydrophilic 'anchor' is attached in the para-position of 26DTB-P via an acyl chain 'tether') had the desired properties. RESULTS: Molecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. CONCLUSIONS: These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.

Rewards weaken cross-modal inhibition of return with visual targets.

Previous studies have shown that rewards weaken visual inhibition of return (IOR). However, the specific mechanisms underlying the influence of rewards on cross-modal IOR remain unclear. Based on the Posner exogenous cue-target paradigm, the present study was conducted to investigate the effect of rewards on exogenous spatial cross-modal IOR in both visual cue with auditory target (VA) and auditory cue with visual target (AV) conditions. The results showed the following: in the AV condition, the IOR effect size in the high-reward condition was significantly lower than that in the low-reward condition. However, in the VA condition, there was no significant IOR in either the high- or low-reward condition and there was no significant difference between the two conditions. In other words, the use of rewards modulated exogenous spatial cross-modal IOR with visual targets; specifically, high rewards may have weakened IOR in the AV condition. Taken together, our study extended the effect of rewards on IOR to cross-modal attention conditions and demonstrated for the first time that higher motivation among individuals under high-reward conditions weakened the cross-modal IOR with visual targets. Moreover, the present study provided evidence for future research on the relationship between reward and attention.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

Computer Simulations on a pH-Responsive Anticancer Drug Delivery System Using Zwitterion-Grafted Polyamidoamine Dendrimer Unimolecular Micelles.

Unimolecular micelles have attracted wide attention in the field of drug delivery because of their thermodynamic stability and uniform size distribution. However, their drug loading/release mechanisms at the molecular level have been poorly understood. In this work, the stability and drug loading/release behaviors of unimolecular micelles formed using generation-5 polyamidoamine-graft-poly(carboxybetaine methacrylate) (PAMAM(G5)-PCBMA) were studied by dissipative particle dynamics simulations. In addition, the unimolecular micelles formed using generation-5 polyamidoamine-graft-poly(ethyleneglycol methacrylate) (PAMAM(G5)-PEGMA) were used as a comparison. The simulation results showed that PAMAM(G5)-PCBMA can spontaneously form core-shell unimolecular micelles. The PAMAM(G5) dendrimer constitutes a hydrophobic core to load the doxorubicin (DOX), while the zwitterionic PCBMA serves as a protective shell to improve the stability of the unimolecular micelle. The DOX can be encapsulated into the cavity of PAMAM(G5) at the physiological pH 7.4. The drug loading efficiency and drug loading content showed some regularities with the increase in the drug concentration. At the acidic pH 5.0, the loaded DOX can be released gradually from the hydrophobic core. The comparison of DOX-loaded morphologies between the PAMAM(G5)-PCBMA system and PAMAM(G5)-PEGMA system showed that the former has better monodisperse stability. This work could offer theoretical guidance for the design and development of promising unimolecular micelles for drug delivery.

Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels.

Voltage-gated sodium channels are essential for carrying electrical signals throughout the body, and mutations in these proteins are responsible for a variety of disorders, including epilepsy and pain syndromes. As such, they are the target of a number of drugs used for reducing pain or combatting arrhythmias and seizures. However, these drugs affect all sodium channel subtypes found in the body. Designing compounds to target select sodium channel subtypes will provide a new therapeutic pathway and would maximize treatment efficacy while minimizing side effects. Here, we examine the binding preferences of nine compounds known to be sodium channel pore blockers in molecular dynamics simulations. We use the approach of replica exchange solute tempering (REST) to gain a more complete understanding of the inhibitors' behavior inside the pore of NavMs, a bacterial sodium channel, and NavPas, a eukaryotic sodium channel. Using these simulations, we are able to show that both charged and neutral compounds partition into the bilayer, but neutral forms more readily cross it. We show that there are two possible binding sites for the compounds: (i) a site on helix 6, which has been previously determined by many experimental and computational studies, and (ii) an additional site, occupied by protonated compounds in which the positively charged part of the drug is attracted into the selectivity filter. Distinguishing distinct binding poses for neutral and charged compounds is essential for understanding the nature of pore block and will aid the design of subtype-selective sodium channel inhibitors.

Predicting Small Molecule Transfer Free Energies by Combining Molecular Dynamics Simulations and Deep Learning.

Accurately predicting small molecule partitioning and hydrophobicity is critical in the drug discovery process. There are many heterogeneous chemical environments within a cell and entire human body. For example, drugs must be able to cross the hydrophobic cellular membrane to reach their intracellular targets, and hydrophobicity is an important driving force for drug-protein binding. Atomistic molecular dynamics (MD) simulations are routinely used to calculate free energies of small molecules binding to proteins, crossing lipid membranes, and solvation but are computationally expensive. Machine learning (ML) and empirical methods are also used throughout drug discovery but rely on experimental data, limiting the domain of applicability. We present atomistic MD simulations calculating 15,000 small molecule free energies of transfer from water to cyclohexane. This large data set is used to train ML models that predict the free energies of transfer. We show that a spatial graph neural network model achieves the highest accuracy, followed closely by a 3D-convolutional neural network, and shallow learning based on the chemical fingerprint is significantly less accurate. A mean absolute error of ∼4 kJ/mol compared to the MD calculations was achieved for our best ML model. We also show that including data from the MD simulation improves the predictions, tests the transferability of each model to a diverse set of molecules, and show multitask learning improves the predictions. This work provides insight into the hydrophobicity of small molecules and ML cheminformatics modeling, and our data set will be useful for designing and testing future ML cheminformatics methods.

Integrated Analysis of the Water-Energy-Environmental Pollutant Nexus in the Petrochemical Industry.

China has set high water-conservation, energy-saving, and pollutant-reduction goals for the petrochemical industry. This represents a challenge to petrochemical enterprises because of the complex coupling between water, energy, and environmental pollutant (WEE) subsystems, elements (different types of WEE), and production units. However, there has been little research on the element-level coupling relationship. The connection and difference between the coupling relationships of the system, element, and unit levels are not well understood. Therefore, an integrated analysis method was developed to quantify the petrochemical WEE nexus (WEEN) at these three levels, including a generic WEEN model, material and energy flow analysis, and a WEEN analysis matrix. Three indicators were proposed to analyze three-level coupling quantitatively and to formulate improvement strategies for water-conservation, energy-saving, and pollutant-reduction. A case study demonstrated significant three-level coupling. The coupled percentage of WEE subsystems were 95.87%, 61.97%, and 54.99%, respectively. The dominant energy subsystem was the root of high consumption and pollution. Based on synergies and trade-offs, we proposed element optimization priorities: High priority (deoxidized water and fuel), medium priority (steam, circulating water, and wastewater), and low priority (fresh water, demineralized water, waste gas, and electricity). The identified unit improvement potential revealed overestimation (hydrotreating and delayed coking units) and underestimation (crude distillation units) of conventional methods that overlook three-level coupling.

Impact of electronic polarizability on protein-functional group interactions.

Interactions of proteins with functional groups are key to their biological functions, making it essential that they be accurately modeled. To investigate the impact of the inclusion of explicit treatment of electronic polarizability in force fields on protein-functional group interactions, the additive CHARMM and Drude polarizable force field are compared in the context of the Site-Identification by Ligand Competitive Saturation (SILCS) simulation methodology from which functional group interaction patterns with five proteins for which experimental binding affinities of multiple ligands are available, were obtained. The explicit treatment of polarizability produces significant differences in the functional group interactions in the ligand binding sites including overall enhanced binding of functional groups to the proteins. This is associated with variations of the dipole moments of solutes representative of functional groups in the binding sites relative to aqueous solution with higher dipole moments systematically occurring in the latter, though exceptions occur with positively charged methylammonium. Such variation indicates the complex, heterogeneous nature of the electronic environments of ligand binding sites and emphasizes the inherent limitation of fixed charged, additive force fields for modeling ligand-protein interactions. These effects yield more defined orientation of the functional groups in the binding pockets and a small, but systematic improvement in the ability of the SILCS method to predict the binding orientation and relative affinities of ligands to their target proteins. Overall, these results indicate that the physical model associated with the explicit treatment of polarizability along with the presence of lone pairs in a force field leads to changes in the nature of the interactions of functional groups with proteins versus that occurring with additive force fields, suggesting the utility of polarizable force fields in obtaining a more realistic understanding of protein-ligand interactions.

Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness.

Membrane protein functions can be altered by subtle changes in the host lipid bilayer physical properties. Gramicidin channels have emerged as a powerful system for elucidating the underlying mechanisms of membrane protein function regulation through changes in bilayer properties, which are reflected in the thermodynamic equilibrium distribution between nonconducting gramicidin monomers and conducting bilayer-spanning dimers. To improve our understanding of how subtle changes in bilayer thickness alter the gramicidin monomer and dimer distributions, we performed extensive atomistic molecular dynamics simulations and fluorescence-quenching experiments on gramicidin A (gA). The free-energy calculations predicted a nonlinear coupling between the bilayer thickness and channel formation. The energetic barrier inhibiting gA channel formation was sharply increased in the thickest bilayer (1,2-dierucoyl-sn-glycero-3-phosphocholine). This prediction was corroborated by experimental results on gramicidin channel activity in bilayers of different thickness. To further explore the mechanism of channel formation, we performed extensive unbiased molecular dynamics simulations, which allowed us to observe spontaneous gA dimer formation in lipid bilayers. The simulations revealed structural rearrangements in the gA subunits and changes in lipid packing, as well as water reorganization, that occur during the dimerization process. Together, the simulations and experiments provide new, to our knowledge, insights into the process and mechanism of gramicidin channel formation, as a prototypical example of the bilayer regulation of membrane protein function.

Resting-state brain fluctuation and functional connectivity dissociate moral injury from posttraumatic stress disorder.

Moral injury is closely associated with posttraumatic stress disorder (PTSD) and characterized by disturbances in social and moral cognition. Little is known about the neural underpinnings of moral injury, and whether the neural correlates are different between moral injury and PTSD. A sample of 26 U.S. military veterans (two females: 28-55 years old) were investigated to determine how subjective appraisals of morally injurious events measured by Moral Injury Event Scale (MIES) and PTSD symptoms are differentially related to spontaneous fluctuations indexed by amplitude of low frequency fluctuation (ALFF) as well as functional connectivity during resting-state functional magnetic resonance imaging scanning. ALFF in the left inferior parietal lobule (L-IPL) was positively associated with MIES subscores of transgressions, negatively associated with subscores of betrayals, and not related with PTSD symptoms. Moreover, functional connectivity between the L-IPL and bilateral precuneus was positively related with PTSD symptoms and negatively related with MIES total scores. Our results provide the first evidence that morally injurious events and PTSD symptoms have dissociable neural underpinnings, and behaviorally distinct subcomponents of morally injurious events are different in neural responses. The findings increase our knowledge of the neural distinctions between moral injury and PTSD and may contribute to developing nosology and interventions for military veterans afflicted by moral injury.

Molecular mechanism of HIV-1 TAT peptide and its conjugated gold nanoparticles translocating across lipid membranes.

The trans-acting activator of transcription (TAT) peptide, which is derived from human immunodeficiency virus-1 (HIV-1), has been widely used as an effective nanocarrier to transport extracellular substances into cells. However, the underlying translocation mechanism of TAT peptide across cell membranes still remains controversial. Besides, the molecular process of TAT peptide facilitating the transport of extracellular substances into cells is largely unknown. In this study, we explore the interactions of TAT peptides and their conjugated gold nanoparticles with lipid membranes by coarse-grained molecular dynamics simulations. It is found that the TAT peptides can hardly penetrate through the membrane at low peptide concentrations; after the concentration increases to a threshold value, they can cross the membrane through an induced nanopore due to the transmembrane electrostatic potential difference. The translocation of TAT peptides is mainly caused by the overall structural changes of membranes. Furthermore, we demonstrate that the translocation of gold nanoparticles (AuNPs) across the membrane is significantly affected by the number of grafted TAT peptides on the particle surface. The transmembrane efficiency of AuNPs may even be reduced when a small number of peptides modify them; whereas, when the number of grafted peptides increases to a certain value, the TAT-AuNP complex can translocate across the membrane in a pore-mediated way. Based on our findings, an effective strategy has been proposed to enhance the delivery efficiency of AuNPs. The present study can improve our understanding of the interactions between TAT peptides and cell membranes; it may also give some insightful suggestions on the design and development of nanocarriers with high efficiency for the delivery of nanoparticles and drugs.

Computer simulations of the adsorption of an N-terminal peptide of statherin, SN15, and its mutants on hydroxyapatite surfaces.

Statherin is a 43 amino acid long protein, which plays an important role in the process of biomineralization of enamel. In this work, we investigated the solvent effect on the adsorption of a peptide from the N-terminus of statherin, SN15, and its mutants SNA15 and SNS15 on the (001) face of hydroxyapatite [Ca10(PO4)6(OH)2, or HAP] with molecular dynamics simulations. The simulation results showed that the adsorption of the three peptides onto the HAP(001) surface was primarily driven by salt-bridge and electrostatic attraction in calcium phosphate (Ca/P) and sodium chloride (NaCl) solutions, respectively. SN15 adsorbs on the HAP surface with the strongest electrostatic interaction, while SNS15 is the weakest. Besides, Ca2+ around SN15 can form an equilateral triangle, which resembles the structure formed by Ca(2) ions in the HAP(001) crystal face, and this looks like the initial stage of HAP nucleation. The conformational changes of SN15 on HAP are analyzed by the root-mean-square deviation. It shows that SN15 is more stable in Ca/P solution while SNS15 is more stable in NaCl solution; the stability of SNA15 is almost the same in both solutions. This work reveals the adsorption mechanism of a series of SN peptides on the HAP surface and provides guidelines for the design of biomaterials for restoring etched enamel and regulating biomineralization.

Brain structural covariance network centrality in maltreated youth with PTSD and in maltreated youth resilient to PTSD.

Child maltreatment is a major cause of pediatric posttraumatic stress disorder (PTSD). Previous studies have not investigated potential differences in network architecture in maltreated youth with PTSD and those resilient to PTSD. High-resolution magnetic resonance imaging brain scans at 3 T were completed in maltreated youth with PTSD (n = 31), without PTSD (n = 32), and nonmaltreated controls (n = 57). Structural covariance network architecture was derived from between-subject intraregional correlations in measures of cortical thickness in 148 cortical regions (nodes). Interregional positive partial correlations controlling for demographic variables were assessed, and those correlations that exceeded specified thresholds constituted connections in cortical brain networks. Four measures of network centrality characterized topology, and the importance of cortical regions (nodes) within the network architecture were calculated for each group. Permutation testing and principle component analysis method were employed to calculate between-group differences. Principle component analysis is a methodological improvement to methods used in previous brain structural covariance network studies. Differences in centrality were observed between groups. Larger centrality was found in maltreated youth with PTSD in the right posterior cingulate cortex; smaller centrality was detected in the right inferior frontal cortex compared to youth resilient to PTSD and controls, demonstrating network characteristics unique to pediatric maltreatment-related PTSD. Larger centrality was detected in right frontal pole in maltreated youth resilient to PTSD compared to youth with PTSD and controls, demonstrating structural covariance network differences in youth resilience to PTSD following maltreatment. Smaller centrality was found in the left posterior cingulate cortex and in the right inferior frontal cortex in maltreated youth compared to controls, demonstrating attributes of structural covariance network topology that is unique to experiencing maltreatment. This work is the first to identify cortical thickness-based structural covariance network differences between maltreated youth with and without PTSD. We demonstrated network differences in both networks unique to maltreated youth with PTSD and those resilient to PTSD. The networks identified are important for the successful attainment of age-appropriate social cognition, attention, emotional processing, and inhibitory control. Our findings in maltreated youth with PTSD versus those without PTSD suggest vulnerability mechanisms for developing PTSD.

Smaller hippocampal CA1 subfield volume in posttraumatic stress disorder.

BACKGROUND: Smaller hippocampal volume in patients with posttraumatic stress disorder (PTSD) represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD-associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features. METHODS: Case-control cross-sectional studies of U.S. military veterans (n = 282) from the Iraq and Afghanistan era were grouped into PTSD (n = 142) and trauma-exposed controls (n = 140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3 T. Segmentation with FreeSurfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus-amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model. RESULTS: Significantly lower subfield volumes were associated with PTSD in left CA1 (P = 0.01; d = 0.21; uncorrected), CA3 (P = 0.04; d = 0.08; uncorrected), and right CA3 (P = 0.02; d = 0.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L-CA1 with PTSD (F4, 221  = 3.32, P = 0.07) is present and the other subfield findings are nonsignificant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD-associated differences in global hippocampal shape were nonsignificant. CONCLUSIONS: The present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety-like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.

Development of New Diagnostic Techniques - Machine Learning.

Traditional diagnoses on addiction reply on the patients' self-reports, which are easy to be dampened by false memory or malingering. Machine learning (ML) is a data-driven procedure that learns algorithms from training data and makes predictions. It is quickly developed and is more and more utilized into clinical applications including diagnoses of addiction. This chapter reviewed the basic concepts and processes of ML. Some studies utilizing ML to classify addicts and non-addicts, separate different types of addiction, and evaluate the effects of treatment are also reviewed. Both advantages and shortcomings of ML in diagnoses of addiction are discussed.

The interaction of perceived control and Gambler's fallacy in risky decision making: An fMRI study.

Limited recent evidence implicates the anterior/posterior cingulate (ACC/PCC) and lateral prefrontal networks as the neural substrates of risky decision-making biases such as illusions of control (IoC) and gambler's fallacy (GF). However, investigation is lacking on the dynamic interactive effect of those biases during decision making. Employing a card-guessing game that independently manipulates trial-by-trial perceived control and gamble outcome among 29 healthy female participants, we observed both IoC- and GF-type behaviors, as well as an interactive effect of previous control and previous outcome, with GF-type behaviors only following computer-selected, but not self-selected, outcomes. Imaging results implicated the ACC and left dorsolateral prefrontal cortex (DLPFC) in agency processing, and the cerebellum and right DLPFC in previous outcome processing, in accordance with past literature. Critically, the right inferior parietal lobule (IPL) exhibited significant betting-related activities to the interaction of previous control and previous outcome, showing more positive signals to previous computer-selected winning versus losing outcomes but the reverse pattern following self-selected outcomes, as well as responding to the interactive effect of control and outcome during feedback. Associations were also found between participants' behavioral sensitivity to the interactive effect of previous control and previous outcome, and right IPL signals, as well as its functional connectivity with neural networks implicated in agency and previous outcome processing. We propose that the right IPL provides the neural substrate for the interaction of perceived control and GF, through coordinating activities in the anterior and posterior cingulate cortices and working conjunctively with lateral PFC and other parietal networks.

Unfolding the spatial and temporal neural processing of lying about face familiarity.

To understand the neural processing underpinnings of deception, this study employed both neuroimaging (functional magnetic resonance imaging, fMRI) and neurophysiological (event-related potential, ERP) methodologies to examine the temporal and spatial coupling of the neural correlates and processes that occur when one lies about face familiarity. This was performed using simple directed lying tasks. According to cues provided by the researchers, the 17 participants were required to respond truthfully or with lies to a series of faces. The findings confirmed that lie and truth conditions are associated with different fMRI activations in the ventrolateral, dorsolateral, and dorsal medial-frontal cortices; premotor cortex, and inferior parietal gyrus. They are also associated with different amplitudes within the time interval between 300 and 1000 ms post face stimulus, after the initiation (270 ms) of face familiarity processing. These results support the cognitive model that suggests representations of truthful information are first aroused and then manipulated during deception. Stronger fMRI activations at the left inferior frontal gyrus and more positive-going ERP amplitudes within [1765, 1800] ms were observed in the contrast between lie and truth for familiar than for unfamiliar faces. The fMRI and ERP findings, together with ERP source reconstruction, clearly delineate the neural processing of face familiarity deception.