bluuebunny/crossref_metadata_2025 huggingface dataset:
Political Reform in Israel
Authors: Rahat Gideon
Published: June 2018

Israel has experienced both failed and successful attempts to reform its democratic institutions in the seventy years since its founding. The most noteworthy failure has been in the promotion of much-needed electoral reform that would moderate the “extreme” features of the hyper-representative, party-centered electoral system. Successes range from small modifications of the electoral system to wide-ranging reforms of the government system at the local and national levels and within political parties. These reforms injected doses of majoritarianism and personalism into the system. But they did not help to solve the problems in the functioning of the Israeli regime; in fact, they often made them worse.
State and Society Building in Early Israel
Authors: Rozin Orit
Published: June 2018

This chapter portrays the political and legal regime of Israel in its early years as the product of three factors: the conscious political effort of the Zionist movement; a nation-building process, which was a vast cultural endeavour aimed at constructing a new sovereign Jew; and decolonization in a territory where the British legacy still had significant political and legal influence. The chapter argues that notwithstanding its dependence on great powers and the Jewish Diaspora, and despite its weakness on the international stage, Israel displayed a not insignificant measure of political independence. On the level of intra-Jewish consciousness, the achievement was even greater. Diaspora Jews saw the establishment of the state as a transformative moment in Jewish history; its Jewish citizens felt that they were achieving political liberty.
Interest in Getting Help to Reduce or Stop Substance Use Among Syringe Exchange Clients Who Use Opioids
Authors: Frost Madeline C. , Williams Emily C. , Kingston Susan , Banta-Green Caleb J.
Published: June 2018

Objectives:

Opioid use is a growing problem in the United States. Despite existence of effective treatments (eg, opioid agonist medication), most people with opioid use disorder do not receive treatment. Increasing treatment receipt is an essential component of the response to the opioid crisis. We examined factors associated with interest in getting help to reduce or stop substance use among syringe exchange program (SEP) clients who reported using opioids.

Methods:

Surveys were administered at 17 SEPs across Washington State during 2015; 436 respondents who reported recent opioid use and not receiving current treatment were eligible for this analysis. Multivariable logistic regression was conducted to examine factors associated with being somewhat or very interested in getting help, including sociodemographic characteristics, substance use behaviors and outcomes, and use of health care services.

Results:

Most participants reported interest in getting help (77.5%). Factors positively associated with interest included female gender (adjusted odds ratio [AOR] = 1.79; 95% confidence interval [CI]: 1.03, 3.11), having an abscess (AOR = 1.87; 95% CI: 1.02, 3.40), and having received treatment (AOR = 4.83; 95% CI: 1.77, 13.14) or other services (AOR = 3.01; 95% CI: 1.06, 8.54) in the past year. Recent methamphetamine use was negatively associated with interest in getting help (AOR = 0.49; 95% CI: 0.26, 0.91).

Conclusions:

In this survey of SEP clients, interest in getting help to reduce or stop substance use was prevalent and varied across subpopulations of persons using opioids. Findings point to SEPs as an important venue for treatment engagement, and suggest subgroups who may be targeted for engagement interventions.
Evaluation of an Ion Trap Toxtyper Liquid Chromatography With An Ion Trap Mass Spectrometric Instrument (Toxtyper) for Drug of Abuse Screening in Oral Fluid
Authors: Plecko Thomas , Berbalk Kevin , Wieland Eberhard , Shipkova Maria
Published: June 2018

Background:

Oral fluid (OF) is increasingly used as an alternative sample matrix in drug of abuse screening. Screening is commonly performed by immunoassays and results confirmed using laborious gas chromatography–mass spectrometry (GC-MS)–based methods. Therefore, an easy to operate ion trap mass spectrometric (IT-MS) commercial screening method (Toxtyper; Bruker Daltronik, Bremen, Germany) combined with a laboratory-developed sample preparation procedure has been evaluated for their application to OF.

Methods:

OF samples were subjected to protein precipitation followed by HybridSPE-Phospholipid extraction. Chromatographic separation was achieved by ultra–high-performance liquid chromatography; MS2/MS3 spectra were recorded by IT-MS and analyzed using a library provided by the manufacturer (Bruker Daltronik). The lower limit of detection, linearity, imprecision, inaccuracy, and specificity (interferences and matrix effects) were investigated for methadone, buprenorphine, pregabalin, fentanyl, amphetamine, 3,4-methylendioxy-N-methylamphetamine, cocaine, acetylcodeine, and nordiazepam, after spiking drug-free OF with these test substances. In addition, concordance between IT-MS results and gas chromatography–tandem mass spectrometry, liquid chromatography–tandem mass spectrometry, or immunoassay (buprenorphine) results was investigated.

Results:

No interferences or matrix effects were observed. The lower limit of detection for acetylcodeine, amphetamine, benzoylecgonine, methadone, and nordiazepam was below the common cutoffs for immunological screening assays and comparable to that of GC-MS. Imprecision and inaccuracy, both in- and between-series, were consistently <25%, except for buprenorphine. Toxtyper screening for pregabalin and fentanyl was less sensitive than a targeted liquid chromatography–tandem mass spectrometry assay. A very good concordance was found between the previous analytical approach and the new IT-MS method.

Conclusions:

The Toxtyper IT-MS is easy to use and can be applied for the screening of drug of abuse and the qualitative confirmation analysis in OF in a clinical toxicology service. Although intended for qualitative analysis, performance data suggest that the methods investigated may also be applicable for semiquantitative longitudinal follow-up.
Performance of Noninvasive Assessment in the Diagnosis of Right Heart Failure After Left Ventricular Assist Device
Authors: Joly Joanna M. , El-Dabh Ashraf , Marshell Ramey , Chatterjee Arka , Smith Michelle G. , Tresler Margaret , Kirklin James K. , Acharya Deepak , Rajapreyar Indranee N. , Tallaj José A. , Pamboukian Salpy V.
Published: June 2018

Right heart failure (RHF) after left ventricular assist device (LVAD) is associated with poor outcomes. Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) defines RHF as elevated right atrial pressure (RAP) plus venous congestion. The purpose of this study was to examine the diagnostic performance of the noninvasive Intermacs criteria using RAP as the gold standard. We analyzed 108 patients with LVAD who underwent 341 right heart catheterizations (RHC) between January 1, 2006, and December 31, 2013. Physical exam, echocardiography, and laboratory data at the time of RHC were collected. Conventional two-by-two tables were used and missing data were excluded. The noninvasive Intermacs definition of RHF is 32% sensitive (95% cardiac index (CI), 0.21–0.44) and 97% specific (95% CI, 0.95–0.99) for identifying elevated RAP. Clinical assessment failed to identify two-thirds of LVAD patients with RAP > 16 mm Hg. More than half of patients with elevated RAP did not have venous congestion, which may represent a physiologic opportunity to mitigate the progression of disease before end-organ damage occurs. One-quarter of patients who met the noninvasive definition of RHF did not actually have elevated RAP, potentially exposing patients to unnecessary therapies. In practice, if any component of the Intermacs definition is present or equivocal, our data suggest RHC is warranted to establish the diagnosis.
Toxoplasmosis in the non-orthotopic heart transplant recipient population, how common is it? Any indication for prophylaxis?
Authors: Dhakal Reshika , Gajurel Kiran , Montoya Jose G.
Published: June 2018

Purpose of review

Unlike in orthotopic heart transplant (OHT) setting where toxoplasma prophylaxis is a standard practice in pretransplant toxoplasma seronegative recipients who have received donor hearts from seropositive donors (D+/R-), there is no consensus regarding prophylaxis in non-OHT recipients.

Recent findings

The incidence of toxoplasma disease in non-OHT recipients is less than 1% but its true burden is underestimated. Among 31 cases of toxoplasma disease reported from 2004 through 2017, renal and liver transplant recipients comprised of 90% of cases. A total of 94% of 18 recipients with known pretransplant serology were seronegative recipients (mostly D+/R-). Out of 16 recipients with adequate information, 10 (63%) and five (31%) were deemed to be donor derived and nondonor-derived primary toxoplasmosis respectively. Tissue invasive reactivation was uncommon. Almost all cases were described in patients not on prophylaxis at the time of presentation. Universal screening of donor/recipient toxoplasma serology for risk stratification is beneficial as illustrated by reports of fatal cases of toxoplasmosis due to unavailability of positive donor serology results.

Toxoplasma disease in non-OHT predominantly occurs in pretransplant seronegative recipients- mostly in D+/R- group and is rare in seropositive recipients. Posttransplant prophylaxis should be targeted against the high-risk D+/R- group and should be considered in seropositive recipients in whom unusually high immunosuppression is implemented. Toxoplasma serologies and PCR should be used in combination for the diagnosis of toxoplasmosis in non-OHT patients.
Nitroglycerin Ointment for Reducing the Rate of Mastectomy Flap Necrosis in Immediate Implant-Based Breast Reconstruction
Authors: Turin Sergey Y. , Li Daniel D. , Vaca Elbert E. , Fine Neil
Published: June 2018

Background:

Mastectomy flap necrosis remains a challenging complication in immediate tissue expander breast reconstruction. Nitroglycerin ointment has been shown to reduce the incidence of mastectomy flap necrosis in a randomized controlled study, using 45 g per breast and treating one side only in bilateral cases. This study was conducted to determine the efficacy of 15 g of nitroglycerin ointment per breast, therefore permitting application to both breasts in cases of bilateral mastectomy.

Methods:

A retrospective cohort study of patients undergoing immediate tissue expander breast reconstruction performed by a single reconstructive surgeon was conducted. The intervention cohort consisted of all patients between June 10, 2015, and June 9, 2016 (94 patients, 158 breasts), where 15 g of nitroglycerin ointment was routinely applied per breast. The control cohort consisted of all patients from June 10, 2014, to June 9, 2015 (107 patients, 170 breasts), where nitroglycerin was not applied. All complications were tracked, including minor wound healing problems.

Results:

There was an overall 22 percent decreased incidence of mastectomy flap necrosis in the nitroglycerin ointment cohort (47.5 percent versus 60.6 percent; p = 0.002), with a 44 percent reduction in full-thickness mastectomy flap necrosis that trended toward statistical significance (9.5 percent versus 16.5 percent; p = 0.06). On multivariate analysis, nitroglycerin application was independently associated with a decrease in mastectomy flap necrosis or need for mastectomy flap débridement. There was no significant difference in the incidence of postoperative hypotension (3.8 percent versus 2.9 percent) or headache among cohorts.

Conclusion:

Topical nitroglycerin ointment application to mastectomy skin flaps at 15 g per breast is a cost-effective means of decreasing the incidence of mastectomy flap necrosis in unilateral and bilateral immediate tissue expander breast reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Crossover to Bilateral Repetitive Transcranial Magnetic Stimulation
Authors: Cristancho Pilar , Trapp Nicholas T. , Siddiqi Shan H. , Dixon David , Miller J. Philip , Lenze Eric J.
Published: June 2018

Clinical trials using left-sided repetitive transcranial magnetic stimulation (rTMS) report remission rates of 14% to 32.6%. A large percentage of patients would not achieve remission with standard rTMS treatment. The question of what clinicians should do when a patient is not responding to standard high-frequency (HF) left-sided rTMS remains unanswered. This prospective case series examines whether crossover to bilateral stimulation enhances antidepressant outcomes in patients not responding to unilateral rTMS. Patients in a major depressive episode received an rTMS clinical protocol of 4 to 6 weeks' duration. Stimulation began with HF rTMS (10 Hz) over the left dorsolateral prefrontal cortex (range, 3000–5000 pulses per session). A total of 17 patients without sufficient clinical improvement early in their rTMS course received 1-Hz rTMS (range, 600–1200 pps) over the right dorsolateral prefrontal cortex (added to the HF left-sided stimulation). Hamilton Depression Rating Scale scores decreased from 13.9 ± 3.9 (mean ± SD) from the start of augmentation to 12.2 ± 5.8 at the end of acute treatment, a 1.7-point change, Cohen d effect size = −0.35, 95% confidence interval, −1.01 to − 0.34, suggesting improvement. Remission rate in this sample was 24% (4/17). This case series indicates that crossover to bilateral stimulation is a feasible and potentially effective strategy when patients are not improving with standard rTMS. A randomized controlled trial comparing crossover versus standard rTMS is needed to determine the efficacy of this paradigm.
Mesolimbic dopamine projections mediate cue-motivated reward seeking but not reward retrieval
Authors: Halbout Briac , Marshall Andrew T. , Azimi Ali , Liljeholm Mimi , Mahler Stephen V. , Wassum Kate M. , Ostlund Sean B.
Published: June 2018

Efficient foraging requires an ability to coordinate discrete reward-seeking and reward-retrieval behaviors. We used pathway-specific chemogenetic inhibition to investigate how mesolimbic and mesocortical dopamine circuits contribute to the expression and modulation of reward seeking and retrieval. Inhibiting ventral tegmental area dopamine neurons disrupted the tendency for reward-paired cues to motivate reward seeking, but spared their ability to increase attempts to retrieve reward. Similar effects were produced by inhibiting dopamine inputs to nucleus accumbens, but not medial prefrontal cortex. Inhibiting dopamine neurons spared the suppressive effect of reward devaluation on reward seeking, an assay of goal-directed behavior. Attempts to retrieve reward persisted after devaluation, indicating they were habitually performed as part of a fixed action sequence. Our findings show that complete bouts of reward seeking and retrieval are behaviorally and neurally dissociable from bouts of reward seeking without retrieval. This dichotomy may prove useful for uncovering mechanisms of maladaptive behavior.
Coordinated Turning Behaviour of Loitering Honeybees (Apis Mellifera)
Authors: Mahadeeswara Mandiyam Y. , Srinivasan Mandyam V.
Published: June 2018

Turning during flight is a complex behaviour that requires coordination to ensure that the resulting centrifugal force is never large enough to disrupt the intended turning trajectory. The centrifugal force during a turn increases with the curvature (sharpness) of the turn, as well as the speed of flight. Consequently, sharp turns would require lower flight speeds, in order to limit the centrifugal force to a manageable level and prevent unwanted sideslips. We have video-filmed honeybees flying near a hive entrance when the entrance is temporarily blocked. A 3D reconstruction and analysis of the flight trajectories executed during this loitering behaviour reveals that sharper turns are indeed executed at lower speeds. During a turn, the flight speed is matched to the curvature, moment to moment, in such a way as to maintain the centrifugal force at an approximately constant, low level of about 30% of the body weight, irrespective of the speed or the curvature of the turn. This ensures that turns are well coordinated, with few or no sideslips - as is evident from analysis of other properties of the flight trajectories.
On the overlap between scientific and societal taxonomic attention - insights for conservation
Authors: Jarić Ivan , Correia Ricardo A. , Roberts David L. , Gessner Jörn , Meinard Yves , Courchamp Franck
Published: June 2018

Attention directed at different species by society and science is particularly relevant within the field of conservation, as societal preferences will strongly impact support for conservation initiatives and their success. Here, we assess the association between societal and research interests in four charismatic and threatened species groups, derived from a range of different online sources and social media platforms as well as scientific publications. We found a high level of concordance between scientific and societal taxonomic attention, which was consistent among assessed species groups and media sources. Results indicate that research is apparently not as disconnected from the interests of society as it is often reproached, and that societal support for current research objectives should be adequate. While the high degree of similarity between scientific and societal interest is both striking and satisfying, the dissimilarities are also interesting, as new scientific findings may constitute a constant source of novel interest for the society.
Potentiation of cerebellar Purkinje cells facilitates whisker reflex adaptation through increased simple spike activity
Authors: Romano Vincenzo , Propris Licia De , Bosman Laurens W.J. , Warnaar Pascal , Brinke Michiel M. ten , Lindeman Sander , Ju Chiheng , Velauthapillai Arthiha , Spanke Jochen K. , Guerra Emily Middendorp , Hoogland Tycho M. , Negrello Mario , D’Angelo Egidio , De Zeeuw Chris I.
Published: June 2018

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading the behavioral response. Neuronal and behavior changes did not occur in two cell-specific mouse models with impaired long-term potentiation at parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.

Impact statement

Romano et al. show that expression of cerebellar whisker learning can be mediated by increases in simple spike activity, depending on LTP induction at parallel fiber to Purkinje cell synapses.
Predicting mutational routes to new adaptive phenotypes
Authors: Lind Peter A. , Libby Eric , Herzog Jenny , Rainey Paul B.
Published: June 2018

Predicting evolutionary change poses numerous challenges. Here we take advantage of the model bacteriumPseudomonas fluorescensin which the genotype-to-phenotype map determining evolution of the adaptive “wrinkly spreader” (WS) type is known. We present mathematical descriptions of three necessary regulatory pathways and use these to predict both the rate at which each mutational route is used and the expected mutational targets. To test predictions, mutation rates and targets were determined for each pathway. Unanticipated mutational hotspots caused experimental observations to depart from predictions but additional data led to refined models. A mismatch was observed between the spectra of WS-causing mutations obtained with and without selection due to low fitness of previously undetected WS-causing mutations. Our findings contribute toward the development of mechanistic models for forecasting evolution, highlight current limitations, and draw attention to challenges in predicting locus-specific mutational biases and fitness effects.

Impact statement

A combination of genetics, experimental evolution and mathematical modelling defines information necessary to predict the outcome of short-term adaptive evolution.
Using composite phenotypes to reveal hidden physiological heterogeneity and model oxygen saturation variation of high altitude acclimatization in a Chinese Han longitudinal cohort
Authors: Li Yi , Wang Yi , Zhang Menghan , Ma Yanyun , Wang Kun , Liu Xiaoyu , Hao Meng , Sun Chang , Wang Xiaofeng , Chen Xingdong , Zhang Yao , Duan Wenyuan , Kang Longli , Qiao Bin , Wang Jiucun , Jin Li
Published: June 2018

Altitude acclimatization is the physiological process of the human body adjusting to the decreased availability of oxygen. Since several physiological processes are involved and the relation among them is complicated, analyses of single-traits is insufficient in revealing the complex mechanism of high altitude acclimatization. In this study, we examined whether these physiological responses could be studied as composite phenotypes which are represented by a linear combination of physiological traits. We developed a strategy which combines both spectral clustering and Partial Least Squares Path Modeling (PLSPM) to define composite phenotypes based on a cohort study of 883 Chinese Han males. And we captured 14 composite phenotypes from 28 physiological traits of high altitude acclimatization. Using these composite phenotypes, we applied k-means clustering to reveal hidden population physiological heterogeneity in high altitude acclimatization. Furthermore, we employed multivariate linear regression to systematically model (Model 1 and Model 2) oxygen saturation (SpO2) changes in high altitude acclimatization and evaluated the model fitness performance. And composite phenotypes based Model 2 has better fitness than single-traits based Model 1 in all measurement indices. Therefore, this new strategy of defining and applying composite phenotypes can be considered as a general strategy of complex traits research, which may also shed light on genetic loci discovery and phenome analyses.
Turing-like patterns can arise from purely bioelectric mechanisms
Authors: Brodsky Micah
Published: June 2018

Turing-like patterns can potentially occur in non-neural (non-excitable) tissues through strictly bioelectric processes, without involving transcriptional (gene) regulation, cell migration, or traditional reaction-diffusion mechanisms. Small molecules that gate transmembrane ion channels are often charged and capable of passing through intercellular gap junctions, and their transport under the influence of trans-junction electric fields furnishes a bioelectric feedback loop. We develop an analytically tractable, circuit-based model of this phenomenon and show that it can lead to spontaneous formation of spatial patterns in ligand density and membrane voltage under physiologically plausible conditions. The process is distinct from Turing’s reaction-diffusion paradigm but closely analogous to the spontaneous formation of patterns in colonies of chemotactic bacteria.
Somatosensory responses to nothing: an MEG study of expectations during omission of tactile stimulations
Authors: Andersen Lau M. , Lundqvist Daniel
Published: June 2018

The brain builds up expectations to future events based on the patterns of past events. This function has been studied extensively in the auditory and visual domains using various oddball paradigms, but only little exploration of this phenomenon has been done in the somatosensory domain. In this study, we explore how expectations of somatosensory stimulations are established and expressed in neural activity as measured with magnetoencephalography. Using tactile stimulations to the index finger, we compared conditions with actual stimulation to conditions with omitted stimulations, both of which were either expected or unexpected.

Our results show that when a stimulation is expected but omitted, a time-locked response occurs ∼135 ms subsequent to the expected stimulation. This somatosensory response to “nothing” was source localized to the secondary somatosensory cortex and to the insula. This provides novel evidence of the capability of the brain of millisecond time-keeping of somatosensory patterns across intervals of 3000 ms.

Our results also show that when stimuli are repeated and expectations are established, there is associated activity in the theta and beta bands. These theta and beta band expressions of expectation were localized to the primary somatosensory area, inferior parietal cortex and cerebellum. Furthermore, there was gamma band activity in the right insula for the first stimulation after an omission, which indicates the detection of a new stimulation event after an expected pattern has been broken.

Finally, our results show that cerebellum play a crucial role in predicting upcoming stimulation and in predicting when stimulation may begin again.
Building a mechanistic mathematical model of hepatitis C virus entry
Authors: Kalemera Mphatso , Mincheva Dilyana , Grove Joe , Illingworth Christopher J. R.
Published: June 2018

The mechanism by which hepatitis C virus (HCV) gains entry into cells is a complex one, involving a broad range of host proteins. Entry is a critical phase of the viral lifecycle, and a potential target for therapeutic or vaccine-mediated intervention. However, the mechanics of HCV entry remain poorly understood. Here we describe a novel computational model of viral entry, encompassing the relationship between HCV and the key host receptors CD81 and SR-B1. We conduct experiments to thoroughly quantify the influence of an increase or decrease in receptor availability upon the extent of viral entry. We use these data to build and parameterise a mathematical model, which we then validate by further experiments. Our results are consistent with sequential HCV-receptor interactions, whereby initial interaction between the HCV E2 glycoprotein and SR-B1 facilitates the accumulation CD81 receptors, leading to viral entry. However, we also demonstrate that a small minority of virus can achieve entry in the absence of SR-B1. Our model estimates the impact of the different obstacles that viruses must surmount to achieve entry; among virus particles attaching to the cell surface, 20-35% accumulate sufficient CD81 receptors, of these 4-8% then complete the subsequent steps to achieve productive infection. Furthermore, we make estimates of receptor stoichiometry; between 3 and 6 CD81 receptors are likely to be required to achieve viral entry. Our model provides a tool to investigate the entry characteristics of HCV variants and outlines a framework for future quantitative studies of the multi-receptor dynamics of HCV entry.
Maternal cannabinoid exposure during lactation alters the developmental trajectory of prefrontal cortex GABA-currents in offspring
Authors: Scheyer Andrew F. , Wager-Miller Jim , Pelissier-Alicot Anne-Laure , Murphy Michelle N. , Mackie Ken , Manzoni Olivier J.J.
Published: June 2018

Cannabis is the most widely used illicit drug in the world, and its usage is increasing with its widespread legalization. Use of the drug by mothers during lactation may transfer active cannabinoids to the developing offspring, altering postnatal neurodevelopment during this critical period. During early life, GABA undergoes a functional switch from an excitatory to an inhibitory neurotransmitter due to reciprocal changes in expression of the K+/Cl- co-transporters KCC2 and NKCC1. Here, we characterize the functional GABA switch in the prefrontal cortex of both male and female rats. We show that treating rat dams with Δ9-THC or a synthetic cannabinoid during early lactation (PND01-10) retards KCC2 expression and delays the GABA switch in pups of both sexes via a CB1R-dependent mechanism. Our results indicate that the developmental trajectory of GABA in PFC neurons is significantly altered by perinatal exposure to cannabinoids through lactation during the early perinatal period.
Mapping the genetics of neuropsychological traits to the molecular network of the human brain using a data integrative approach
Authors: Yousaf Afsheen , Duketis Eftichia , Jarczok Tomas , Sachse Michael , Biscaldi Monica , Degenhardt Franziska , Herms Stefan , Cichon Sven , Klauck Sabine.M. , Ackermann Jörg , Freitag Christine M. , Chiocchetti Andreas G. , Koch Ina
Published: June 2018

Motivation

Complex neuropsychiatric conditions including autism spectrum disorders are among the most heritable neurodevelopmental disorders with distinct profiles of neuropsychological traits. A variety of genetic factors modulate these traits (phenotypes) underlying clinical diagnoses. To explore the associations between genetic factors and phenotypes, genome-wide association studies are broadly applied. Stringent quality checks and thorough downstream analyses for in-depth interpretation of the associations are an indispensable prerequisite. However, in the area of neuropsychology there is no framework existing, which besides performing association studies also affiliates genetic variants at the brain and gene network level within a single framework.

Results

We present a novel bioinformatics approach in the field of neuropsychology that integrates current state-of-the-art tools, algorithms and brain transcriptome data to elaborate the association of phenotype and genotype data. The integration of transcriptome data gives an advantage over the existing pipelines by directly translating genetic associations to brain regions and developmental patterns. Based on our data integrative approach, we identify genetic variants associated with Intelligence Quotient (IQ) in an autism cohort and found their respective genes to be expressed in specific brain areas.

Conclusion

Our data integrative approach revealed that IQ is related to early down-regulated and late up-regulated gene modules implicated in frontal cortex and striatum, respectively. Besides identifying new gene associations with IQ we also provide a proof of concept, as several of the identified genes in our analysis are candidate genes related to intelligence in autism, intellectual disability, and Alzheimer’s disease. The framework provides a complete extensive analysis starting from a phenotypic trait data to its association at specific brain areas at vulnerable time points within a timespan of four days.

Availability and Implementation

Our framework is implemented in R and Python. It is available as an in-house script, which can be provided on demand.

Contact

afsheen.yousaf@kgu.de
Functional decoupling of emotion coping network subserves automatic emotion regulation by implementation intention
Authors: Chen Shengdong , Ding Nanxiang , Biswal Bharat , Li Zhihao , Qin Shaozheng , Xie Chao , Chen Changming , Yuan Jiajin
Published: June 2018

Automatic emotion regulation (AER) aims at modifying emotional impact effortlessly. However, the effortless account and the neural mechanisms of AER are both undetermined. For this purpose, we collected functional neuroimages (fMRI) in thirty-one participants who attended to neutral and disgust pictures in three conditions: Watching, Goal Intention (GI) and Reappraisal by Implementation Intention (RII). RII decreased negative feelings and bilateral amygdala activity without eliciting cognitive efforts, evidenced by the reduced effort rating and less prefrontal engagement during RII compared to Watching and GI. These regulation effects should not be explained by emotional habituation, as Experiment 2 (n=40) observed no habituation to stimulus repetitions. Task-based network analysis showed similar functional connectivity (FC) of ventral anterior cingulate cortex to left insula and right precuneus during RII and GI conditions, both involving goal setup. Furthermore, RII relative to GI exhibited weaker FC in brain networks subserving effortful control (e.g. inferior-superior parietal FC), memory retrieval (e.g. inferior-middle temporal and lingual-putamen FCs), aversive anticipation and motor planning (e.g. Paracentral-superior temporal gyrus, putamen-operculum FCs). The FC strength of putamen to operculum/lingual, and paracentral to STG positively predicts regulatory difficulty. These results suggest that the setup of implementation intention automatizes emotion regulation, by reducing online mobilization of neural systems underlying the stream of emotion coping.
Childhood socioeconomic status moderates genetic predisposition for peak smoking
Authors: Bierut Laura , Biroli Pietro , Galama Titus J. , Thom Kevin
Published: June 2018

Smoking is the leading cause of preventable disease and death in the U.S., and it is strongly influenced both by genetic predisposition and childhood socioeconomic status (SES). Using genetic variants exhibiting credible and robust associations with smoking, we construct polygenic risk scores (PGS) and evaluate whether childhood SES mediates genetic risk in determining peak-cigarette consumption in adulthood. We find a substantial protective effect of childhood SES for those genetically at risk of smoking: adult smokers who grew up in high-SES households tend to smoke roughly the same amount of cigarettesper day at peak (∼ 23 for low and ∼ 25 for high genetic risk individuals, or about 8%more), while individuals from low-SES backgrounds tend to smoke substantially more ifgenetically at risk (∼ 25 for low and ∼ 32 for high genetic risk individuals, or about 28% more).
Functional diversity of brain networks supports consciousness and verbal intelligence
Authors: Naci Lorina , Haugg Amelie , MacDonald Alex , Anello Mimma , Houldin Evan , Naqshbandi Shakib , Gonzalez-Lara Laura E. , Arango Miguel , Harle Christopher , Cusack Rhodri , Owen Adrian M.
Published: June 2018

How are the myriad stimuli arriving at our senses transformed into conscious thought? To address this question, in a series of studies, we asked whether a common mechanism underlies loss of information processing in unconscious states across different conditions, which could shed light on the brain mechanisms of conscious cognition. With a novel approach, we brought together for the first time, data from the same paradigm—a highly engaging auditory-only narrative—in three independent domains: anesthesia-induced unconsciousness, unconsciousness after brain injury, and individual differences in intellectual abilities during conscious cognition. During external stimulation in the unconscious state, the functional differentiation between the auditory and fronto-parietal systems decreased significantly relatively to the conscious state. Conversely, we found that stronger functional differentiation between these systems in response to external stimulation predicted higher intellectual abilities during conscious cognition, in particular higher verbal acuity scores in independent cognitive testing battery. These convergent findings suggest that the responsivity of sensory and higher-order brain systems to external stimulation, especially through the diversification of their functional responses is an essential feature of conscious cognition and verbal intelligence.
Multiplex imaging of quantal glutamate release and presynaptic Ca2+ at multiple synapses in situ
Authors: Jensen Thomas P. , Zheng Kaiyu , Cole Nicholas , Marvin Jonathan S. , Looger Loren L. , Rusakov Dmitri A.
Published: June 2018

Information processing by brain circuits depends on Ca2+-dependent, stochastic release of the excitatory neurotransmitter glutamate. Optical glutamate sensors have enabled detection of evoked and spontaneous synaptic discharges. However, monitoring presynaptic function and its underpinning machinery in situ requires simultaneous readout of quantal glutamate release and nanomolar presynaptic Ca2+. Here, we find that the fluorescence lifetime of the red-shifted Ca2+ indicator Cal-590 is Ca2+-sensitive in the nanomolar range, and employ it in combination with green glutamate sensors to relate quantal neurotransmission to presynaptic Ca2+ kinetics. Imaging of multiple synapses in an identified neural circuit reveals that fluctuations both in spike-evoked Ca2+ transients and in resting presynaptic Ca2+ can affect release efficacy. At the sub-microscopic level within individual presynaptic boutons, we detected no consistent co-localisation of presynaptic Ca2+ entry and glutamate release sites, suggesting loose coupling between the two. The present approach broadens qualitatively our horizon in understanding release machinery of central synapses.
Stimulus-driven brain rhythms within the alpha band: The attentional-modulation conundrum
Authors: Keitel Christian , Keitel Anne , Benwell Christopher SY , Daube Christoph , Thut Gregor , Gross Joachim
Published: June 2018

Two largely independent research lines use rhythmic sensory stimulation to study visual processing. Despite the use of strikingly similar experimental paradigms, they differ crucially in their notion of the stimulus-driven periodic brain responses: One regards them mostly as synchronised (entrained) intrinsic brain rhythms; the other assumes they are predominantly evoked responses (classically termed steady-state responses, or SSRs) that add to the ongoing brain activity. This conceptual difference can produce contradictory predictions about, and interpretations of, experimental outcomes. The effect of spatial attention on brain rhythms in the alpha-band (8-13 Hz) is one such instance: alpha-range SSRs have typically been found to increase in power when participants focus their spatial attention on laterally presented stimuli, in line with a gain control of the visual evoked response. In nearly identical experiments, retinotopic decreases in entrained alpha-band power have been reported, in line with the inhibitory function of intrinsic alpha. Here we reconcile these contradictory findings by showing that they result from a small but far-reaching difference between two common approaches to EEG spectral decomposition. In a new analysis of previously published EEG data, recorded during bilateral rhythmic visual stimulation, we find the typical SSR gain effect when emphasising stimulus-locked neural activity and the typical retinotopic alpha suppression when focusing on ongoing rhythms. These opposite but parallel effects suggest that spatial attention may bias the neural processing of dynamic visual stimulation via two complementary neural mechanisms.
Habituation and individual variation in the endocrine stress response in the Trinidadian guppy (Poecilia reticulata)
Authors: Houslay T.M. , Earley R.L. , Young A.J. , Wilson A.J.
Published: June 2018

The vertebrate stress response enables individuals to react to and cope with environmental challenges. A crucial aspect of the stress response is the elevation of circulating glucocorticoids. However, continued activation of the stress response under repeated (or chronic) stress can be damaging to fitness. Under certain circumstances it may therefore be adaptive to habituate to repeated exposures to a particular stressor by reducing the magnitude of any associated release of glucocorticoids. Here, we investigate whether Trinidadian guppies (Poecilia reticulata) habituate to repeated exposure to a mild stressor, using a waterborne hormone sampling approach that has previously been shown to elicit a stress response in small fish. We also test for individual variation in the extent of habituation to this stressor. Concentrating on freely circulating cortisol, we found that the first exposure to the assay induced high cortisol release rates but that guppies tended to habituate quickly to subsequent exposures. There were consistent differences among individuals in their average cortisol release rate (after accounting for effects of variables such as body size) over repeated exposures. Our analyses did not find evidence of individual differences in habituation rate, although limitations in statistical power could account for this finding. We also present data on free 11-ketotestosterone, in addition to conjugated forms of both hormones. We discuss consistent individual differences around the general pattern of habituation in the flexible stress response, and highlight the potential for individual variation in habituation to facilitate selection against the deleterious effects of chronic stress.

Summary statement

Trinidadian guppies habituate quickly to repeated stress exposure, and exhibit consistent differences in their endocrine stress response. We provide a framework for analysing individual variation in habituation rate.
Disruption of cortical dopaminergic modulation impairs preparatory activity and delays licking initiation
Authors: Chen Ke , Vincis Roberto , Fontanini Alfredo
Published: June 2018

Dysfunction of motor cortices is thought to contribute to motor disorders such as Parkinson’s disease (PD). However, little is known on the link between cortical dopaminergic loss, abnormalities in motor cortex neural activity and motor deficits. We address the role of dopamine in modulating motor cortical activity by focusing on the anterior lateral motor cortex (ALM) of mice performing a cued-licking task. We first demonstrate licking deficits and concurrent alterations of spiking activity in ALM of mice with unilateral depletion of dopaminergic neurons (i.e., mice injected with 6-OHDA into the medial forebrain bundle). Hemi-lesioned mice displayed delayed licking initiation, shorter duration of licking bouts, and lateral deviation of tongue protrusions. In parallel with these motor deficits, we observed a reduction in the prevalence of cue responsive neurons and altered preparatory activity. Acute and local blockade of D1 receptors in ALM recapitulated some of the key behavioral and neural deficits observed in hemi-lesioned mice. Altogether, our data show a direct relationship between cortical D1 receptor modulation, cue-evoked and preparatory activity in ALM, and licking initiation.

SIGNIFICANCE STATEMENT

The link between dopaminergic signaling, motor cortical activity and motor deficits is not fully understood. This manuscript describes alterations in neural activity of the anterior lateral motor cortex (ALM) that correlate with licking deficits in mice with unilateral dopamine depletion or with intra-ALM infusion of dopamine antagonist. The findings emphasize the importance of cortical dopaminergic modulation in motor initiation. These results will appeal not only to researchers interested in cortical control of licking, but also to a broader audience interested in motor control and dopaminergic modulation in physiological and pathological conditions. Specifically, our data suggest that dopamine deficiency in motor cortex could play a role in the pathogenesis of the motor symptoms of Parkinson’s disease.
Smaller Hippocampal CA-1 Subfield Volume in Posttraumatic Stress Disorder
Authors: Chen Lyon W. , Sun Delin , Davis Sarah L. , Haswell Courtney C. , Dennis Emily L. , Swanson Chelsea A. , Whelan Christopher D. , Gutman Boris , Jahanshad Neda , Iglesias Juan Eugenio , Thompson Paul ,   Mid-Atlantic MIRECC Workgroup, Wagner H. Ryan , Saemann Philipp , LaBar Kevin S. , Morey Rajendra A.
Published: June 2018

Background

Smaller hippocampal volume in patients with 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 study of US 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-Tesla. Segmentation with Free Surfer 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=.01; d=.21; uncorrected), CA3 (p=.04; d=.08; uncorrected), and right CA3 (p=.02; d=.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 non-significant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD associated differences in global hippocampal shape were non-significant.

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.
Chronic intermittent ethanol exposure selectively increases synaptic excitability in the ventral domain of the rat hippocampus
Authors: Ewin Sarah E. , Morgan James W. , Niere Farr , McMullen Nate P. , Barth Samuel H. , Almonte Antoine G. , Raab-Graham Kimberly F. , Weiner Jeffrey L.
Published: June 2018

Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety-and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long-Evans rats were exposed to CIE or air for 10 days (12 hrs/day; targeting blood ethanol levels of 175-225 mg%) and recordings were made 24 hours into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, was dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal.

Highlights

Chronic intermittent ethanol exposure produces robust increases in anxiety-like behavior in male Long Evans rats.

Chronic intermittent ethanol exposure increases synaptic excitability in the ventral, but not the dorsal, domain of the hippocampus.

These changes in excitability are associated with alterations in synaptoneurosomal expression of small conductance calcium-activated potassium channels and the GluA2 AMPA receptor subunit that are also restricted to the ventral hippocampus.