Distinctively different human neurobiological responses after trauma exposure and implications for posttraumatic stress disorder subtyping.

Trauma elicits various adaptive and maladaptive responses among all exposed people. There may be distinctively different patterns of adaptation/maladaptation or types according to neurobiological predisposition. The present study aims to dissect the heterogeneity of posttraumatic conditions in order to identify clinically meaningful subtypes in recently traumatized individuals and evaluate their neurobiological correlates and long-term prognosis. We implemented a data-driven classification approach in both discovery (n = 480) and replication (n = 220) datasets of trauma-exposed and trauma-unexposed individuals based on the clinical data across a wide range of assessments. Subtype-specific patterns of functional connectivity in higher-order cortical networks, longitudinal clinical outcomes, and changes in functional connectivity were also evaluated. We identified four distinct and replicable subtypes for trauma-exposed individuals according to posttraumatic stress symptoms. Each subtype was distinct in clinical characteristics, brain functional organization, and long-term trajectories for posttraumatic symptoms. These findings help enhance current understanding of mechanisms underlying the human-specific heterogeneous responses to trauma. Furthermore, this study contributes data towards the development of improved interventions, including targeting of subtype-specific characteristics, for trauma-exposed individuals and those with PTSD.

Hippocampal subregional alterations and verbal fluency in the early stage of type 2 diabetes mellitus.

Growing evidence indicates that type 2 diabetes mellitus (T2DM)-related cognitive dysfunction may develop in the early stage of the disease and is often accompanied by hippocampal structural alterations. In the current study, we investigated volume and shape alterations of the hippocampus at a subregional level in patients with T2DM. With the use of high-resolution brain structural images that were obtained from 30 T2DM patients with less than 5 years of disease duration and 30 healthy individuals, volumetric and shape analyses were performed. We also assessed the relationship between T2DM-related hippocampal structural alterations and performance on verbal fluency. In volumetric analysis, total hippocampal volume was smaller in the T2DM group, relative to the control group. At a subregional level, T2DM patients showed significant inward deformation and volume reduction of the right dentate gyrus and cornu ammonis 2/3 subregions as compared with healthy individuals. In particular, T2DM patients with lower performance on verbal fluency had smaller right dentate gyrus volumes relative to those with higher performance. These findings suggest that the hippocampus may undergo atrophy at a subregional level even in the early stage of T2DM, and this subregion-specific atrophy may be associated with reduced performance on verbal fluency.

Multiphase acquisitions in pediatric abdominal-pelvic CT are a common practice and contribute to unnecessary radiation dose.

BACKGROUND: Many patients at our pediatric hospital have had a contrast-enhanced CT of the abdomen and pelvis performed by an outside imaging facility before admission. We have noticed that many of these exams are multiphase, which may contribute to unnecessary radiation dose. OBJECTIVE: To determine the frequency of multiphase acquisitions and radiation dose indices in contrast-enhanced CTs of the abdomen and pelvis performed by outside imaging facilities in patients who were subsequently transferred to our pediatric hospital for care, and compare these metrics to contrast-enhanced CTs of the abdomen and pelvis performed internally. MATERIALS AND METHODS: A retrospective analysis was performed of contrast-enhanced CTs of the abdomen and pelvis from outside imaging facilities uploaded to our picture archiving and communication system (PACS) between January 1, 2012, and December 31, 2015. CT images and dose pages were reviewed to determine the number of phases and dose indices (CT dose index-volume [CTDIvol], dose-length product, size-specific dose estimate). Exams for abdominal or pelvic mass, trauma or urinary leak indications were excluded. Data were compared to internally acquired contrast-enhanced CTs of the abdomen and pelvis by querying the American College of Radiology (ACR) Dose Index Registry. This review was institutional review board and HIPAA compliant. RESULTS: There were 754 contrast-enhanced CTs of the abdomen and pelvis from 104 outside imaging facilities. Fifty-three percent (399/754) had 2 phases, and 2% (14/754) had 3 or more phases. Of the 939 contrast-enhanced CTs of the abdomen and pelvis performed internally, 12% (115) were multiphase exams. Of 88% (664) contrast-enhanced CTs of the abdomen and pelvis from outside imaging facilities with dose data, CTDIvol was 2.7 times higher than our institution contrast-enhanced CTs of the abdomen and pelvis (939) for all age categories as defined by the ACR Dose Index Registry (mean: 9.4 vs. 3.5 mGy, P<0.0001). The majority (74%) of multiphase exams were performed by 9 of 104 outside imaging facilities. CONCLUSION: Multiphase acquisitions in routine contrast-enhanced CT of the abdomen and pelvis exams at outside imaging facilities are more frequent than those at a dedicated pediatric institution and contribute to unnecessary radiation dose. A contrast-enhanced CT of the abdomen and pelvis exam from an outside imaging facility with two passes may have as much as four times to six times the dose as the same exam performed with a single pass at a pediatric imaging center. We advocate for imaging facilities with high multiphase rates to eliminate multiple phases from routine contrast-enhanced CT of the abdomen and pelvis exams in children.

MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor.

RATIONALE: The bile acid receptor farnesoid X receptor (FXR) regulates many aspects of lipid metabolism by variouscomplex and incompletely understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. OBJECTIVE: To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. METHODS AND RESULTS: ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma high-density lipoprotein (HDL)-cholesterol levels. Here, we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lowers hepatic ABCA1 and plasma HDL levels. We identified 2 complementary sequences to miR-144 in the 3' untranslated region of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I protein, whereas overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL-cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL-cholesterol. In addition, we used tissue-specific FXR-deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal, FXR. Finally, we identified functional FXR response elements upstream of the miR-144 locus, consistent with direct FXR regulation. CONCLUSIONS: We have identified a novel pathway involving FXR, miR-144, and ABCA1 that together regulate plasma HDL-cholesterol.

Urine myo-inositol as a novel prognostic biomarker for diabetic kidney disease: a targeted metabolomics study using nuclear magnetic resonance.

BACKGROUND: As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. METHODS: We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. RESULTS: During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. CONCLUSION: Myo-inositol can be used as an additive biomarker of ESRD progression in DKD.

Altered functional activity in bipolar disorder: A comprehensive review from a large-scale network perspective.

BACKGROUND: Growing literature continues to identify brain regions that are functionally altered in bipolar disorder. However, precise functional network correlates of bipolar disorder have yet to be determined due to inconsistent results. The overview of neurological alterations from a large-scale network perspective may provide more comprehensive results and elucidate the neuropathology of bipolar disorder. Here, we critically review recent neuroimaging research on bipolar disorder using a network-based approach. METHODS: A systematic search was conducted on studies published from 2009 through 2019 in PubMed and Google Scholar. Articles that utilized functional magnetic resonance imaging technique to examine altered functional activity of major regions belonging to a large-scale brain network in bipolar disorder were selected. RESULTS: A total of 49 studies were reviewed. Within-network hypoconnectivity was reported in bipolar disorder at rest among the default mode, salience, and central executive networks. In contrast, when performing a cognitive task, hyperconnectivity among the central executive network was found. Internetwork functional connectivity in the brain of bipolar disorder was greater between the salience and default mode networks, while reduced between the salience and central executive networks at rest, compared to control. CONCLUSION: This systematic review suggests disruption in the functional activity of large-scale brain networks at rest as well as during a task stimuli in bipolar disorder. Disrupted intra- and internetwork functional connectivity that are also associated with clinical symptoms suggest altered functional connectivity of and between large-scale networks plays an important role in the pathophysiology of bipolar disorder.

Imaging of Benign Adnexal Disease.

This article provides an overview of the imaging evaluation of benign ovarian and adnexal masses in premenopausal and postmenopausal women and lesions discovered during pregnancy. Current imaging techniques are discussed, including pitfalls and differential diagnosis when necessary, as well as management. It also reviews the now well-established American College of Radiology (ACR)/Society of Radiologists in Ultrasound consensus guidelines and covers the more recently introduced Ovarian-Adnexal Reporting and Data System by the ACR and the recently published ADNEx Scoring System.

Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective.

Post-traumatic stress disorder (PTSD) is a chronic condition characterized by symptoms of physiological and psychosocial burden. While growing research demonstrated signs of inflammation in PTSD, specific biomarkers that may be representative of PTSD such as the detailed neural correlates underlying the inflammatory responses in relation to trauma exposure are seldom discussed. Here, we review recent studies that explored alterations in key inflammatory markers in PTSD, as well as neuroimaging-based studies that further investigated signs of inflammation within the brain in PTSD, as to provide a comprehensive summary of recent literature with a neurological perspective. A search was conducted on studies published from 2009 through 2019 in PubMed and Web of Science. Fifty original articles were selected. Major findings included elevated levels of serum proinflammatory cytokines in individuals with PTSD across various trauma types, as compared with those without PTSD. Furthermore, neuroimaging-based studies demonstrated that altered inflammatory markers are associated with structural and functional alterations in brain regions that are responsible for the regulation of stress and emotion, including the amygdala, hippocampus, and frontal cortex. Future studies that utilize both central and peripheral inflammatory markers are warranted to elucidate the underlying neurological pathway of the pathophysiology of PTSD.

Identification of Tendency to Alcohol Misuse From the Structural Brain Networks.

The propensity to engage in risky behaviors including excessive alcohol consumption may impose increased medical, emotional, and psychosocial burdens. Personality and behavioral traits of individuals may contribute in part to the involvement in risky behaviors, and therefore the classification of one's traits may help identify those who are at risk for future onset of the addictive disorder and related behavioral issues such as alcohol misuse. Personality and behavioral characteristics including impulsivity, anger, reward sensitivity, and avoidance were assessed in a large sample of healthy young adults (n = 475). Participants also underwent diffusion tensor imaging for the analysis of structural brain networks. A data-driven clustering using personality and behavioral traits of the participants identified four subtypes. As compared with individuals clustered into the neutral type, individuals with a high level of impulsivity (A subtype) and those with high levels of reward sensitivity, impulsivity, anger, and avoidance (B subtype) showed significant associations with problem drinking. In contrast, individuals with high levels of impulsivity, anger, and avoidance but not reward sensitivity (C subtype) showed a pattern of social drinking that was similar to those of the neutral subtype. Furthermore, logistic regression analysis with ridge estimators was applied to demonstrate the neurobiological relevance for the identified subtypes according to distinct patterns of structural brain connectivity within the addiction circuitry [neutral vs. A subtype, the area under the receiver operator characteristic curve (AUC) = 0.74, 95% CI = 0.67-0.81; neutral vs. B subtype, AUC = 0.74, 95% CI = 0.66-0.82; neutral vs. C subtype, AUC = 0.77, 95% CI = 0.70-0.84]. The current findings enable the characterization of individuals according to subtypes based on personality and behavioral traits that are also corroborated by neuroimaging data and may provide a platform to better predict individual risks for addictive disorders.

FKBP5-associated miRNA signature as a putative biomarker for PTSD in recently traumatized individuals.

The epigenetic regulation of microRNA (miRNA) expression related to the FK506-binding protein 5 (FKBP5) gene may contribute to the risk of stress-related disorders such as posttraumatic stress disorder (PTSD). Here, we identified candidate miRNAs derived from FKBP5 knockout mice as a potential diagnostic biomarker of PTSD. Using a translational approach, candidate miRNAs found to alter in expression within the medial prefrontal cortex of FKBP5 knockout mice were selected. Each candidate miRNA was examined in the serum of 48 recently traumatized individuals with PTSD and 47 healthy individuals. Multimodal imaging was also conducted to identify the neural correlates for the expression of candidate exosomal miRNAs in response to trauma exposure. Differential miRNA expression was found according to PTSD diagnosis in two composite marker groups. The differential miRNA expression between the composite marker groups contributed to PTSD symptom severity, which may be explained by differential recruitment of prefrontolimbic activity in brain imaging. The present study reveals that a set of circulating exosomal miRNAs showing altered expression in FKBP5 knockout mice play a potential role as epigenetic markers of PTSD. The corroborative evidence from multiple levels including molecular, brain, and behavioral indicates that these epigenetic biomarkers may serve as complementary measures for the diagnosis and prognosis prediction of PTSD in recently traumatized individuals.

Cognitive Enhancement in Neurological and Psychiatric Disorders Using Transcranial Magnetic Stimulation (TMS): A Review of Modalities, Potential Mechanisms and Future Implications.

Cognitive enhancement refers to the improvement of cognitive function related to deficits that occurred as part of a certain illness. However, the term cognitive enhancement does not yet have a definitive meaning, and its connotations often vary depending on the research of interest. Recently, research interests are growing towards enhancing human cognition beyond what has traditionally been considered necessary using various brain devices. The phenomenon of exceeding the cognitive abilities of individuals who are already functional has also introduced new terminologies as means to classify between cognitive enhancing procedures that are part of treatment versus simply supplementary. Of the many devices used to attain cognitive enhancement, transcranial magnetic stimulation (TMS) is a unique neurostimulatory device that has demonstrated significant improvements in various cognitive domains including memory and cognitive processing skills. While many studies have supported the safety and efficacy of TMS in treatment, there has yet to be an optimization in parameter for TMS that is catered to a certain target group. The current paper aims to review with perspective the many studies that have used TMS for the purpose of cognitive enhancement and provide further insight on the development of an optimal stimulation parameter. The paper reviews 41 peer-reviewed articles that used TMS for cognitive enhancement, summarizes the findings that were apparent for each distinct parameter, and discusses future directions regarding TMS as an elective tool for healthy individuals while considering some of the ethical perspectives that may be warranted.

Efficacy of Polygonatum sibiricum on Mild Insomnia: A Randomized Placebo-Controlled Trial.

Polygonatum sibiricum (PS) rhizome, which contains glyceryl-1-monolinoleate as its primary active component, has been shown to improve insomnia in animal models. Based on these findings, we aimed to investigate the safety and efficacy of PS rhizome extract in improving sleep quality in individuals with mild insomnia. Eighty individuals with mild insomnia were enrolled in a four-week, randomized, double-blind, placebo-controlled trial of PS rhizome extract (500 mg/day, n = 40, PS group) or placebo (n = 40, placebo group). The primary outcome measure was change in total score on the Athens Insomnia Scale (AIS) to indicate sleep quality. The secondary outcome measures included change in actigraphy data and perfusion levels in the brain regions within the default mode network (DMN), which is known to play a key role in insomnia. The PS group showed greater improvement in the total AIS score with a significant increase in total sleep time, relative to the placebo group. In addition, significant group-by-visit interactions were observed in the perfusion level of the medial prefrontal cortex within the DMN. Findings of the current study provide first evidence that PS rhizome extract could be an effective natural ingredient for improving sleep in mild insomnia using a human model.

Altered attentional control over the salience network in complex regional pain syndrome.

The degree and salience of pain have been known to be constantly monitored and modulated by the brain. In the case of maladaptive neural responses as reported in centralized pain conditions such as complex regional pain syndrome (CRPS), the perception of pain is amplified and remains elevated even without sustained peripheral pain inputs. Given that the attentional state of the brain greatly influences the perception and interpretation of pain, we investigated the role of the attention network and its dynamic interactions with other pain-related networks of the brain in CRPS. We examined alterations in the intra- and inter-network functional connectivities in 21 individuals with CRPS and 49 controls. CRPS-related reduction in intra-network functional connectivity was found in the attention network. Individuals with CRPS had greater inter-network connectivities between the attention and salience networks as compared with healthy controls. Furthermore, individuals within the CRPS group with high levels of pain catastrophizing showed greater inter-network connectivities between the attention and salience networks. Taken together, the current findings suggest that these altered connectivities may be potentially associated with the maladaptive pain coping as found in CRPS patients.

The BDNF Val66Met Polymorphism Affects the Vulnerability of the Brain Structural Network.

Val66Met, a naturally occurring polymorphism in the human brain-derived neurotrophic factor (BDNF) gene resulting in a valine (Val) to methionine (Met) substitution at codon 66, plays an important role in neuroplasticity. While the effect of the BDNF Val66Met polymorphism on local brain structures has previously been examined, its impact on the configuration of the graph-based white matter structural networks is yet to be investigated. In the current study, we assessed the effect of the BDNF polymorphism on the network properties and robustness of the graph-based white matter structural networks. Graph theory was employed to investigate the structural connectivity derived from white matter tractography in two groups, Val homozygotes (n = 18) and Met-allele carriers (n = 55). Although there were no differences in the global network measures including global efficiency, local efficiency, and modularity between the two genotype groups, we found the effect of the BDNF Val66Met polymorphism on the robustness properties of the white matter structural networks. Specifically, the white matter structural networks of the Met-allele carrier group showed higher vulnerability to targeted removal of central nodes as compared with those of the Val homozygote group. These findings suggest that the central role of the BDNF Val66Met polymorphism in regards to neuroplasticity may be associated with inherent differences in the robustness of the white matter structural network according to the genetic variants. Furthermore, greater susceptibility to brain disorders in Met-allele carriers may be understood as being due to their limited stability in white matter structural connectivity.

Network attributes underlying intellectual giftedness in the developing brain.

Brain network is organized to maximize the efficiency of both segregated and integrated information processing that may be related to human intelligence. However, there have been surprisingly few studies that focus on the topological characteristics of brain network underlying extremely high intelligence that is intellectual giftedness, particularly in adolescents. Here, we examined the network topology in 25 adolescents with superior intelligence (SI-Adol), 25 adolescents with average intelligence (AI-Adol), and 27 young adults with AI (AI-Adult). We found that SI-Adol had network topological properties of high global efficiency as well as high clustering with a low wiring cost, relative to AI-Adol. However, contrary to the suggested role that brain hub regions play in general intelligence, the network efficiency of rich club connection matrix, which represents connections among brain hubs, was low in SI-Adol in comparison to AI-Adol. Rather, a higher level of local connection density was observed in SI-Adol than in AI-Adol. The highly intelligent brain may not follow this efficient yet somewhat stereotypical process of information integration entirely. Taken together, our results suggest that a highly intelligent brain may communicate more extensively, while being less dependent on rich club communications during adolescence.