Using Imagination to Integrate Contextual Effects in a Cue-Reactivity Paradigm in Patients with Alcohol Use Disorder: A Functional Magnetic Resonance Imaging Pilot Study.

INTRODUCTION: In individuals with alcohol use disorder (AUD), the brain areas underlying cue-induced reactions (e.g., cingulum, striatum, thalamus) and altered activation of these regions have been identified by functional neuroimaging. Neuronal responses to a complex alcohol-related context are yet to investigate. To better understand contextual effects as well as the interplay of cue-induced neural reactions and context exposure, the present study implemented an imagination procedure during functional magnetic resonance imaging (fMRI). METHODS: Thirteen patients with AUD and 13 healthy controls completed two rounds of a cue-reactivity paradigm inside an MRI scanner. Two individualized imagination tasks were conducted before each of the two cue reactivity tasks. A 2 (group) × 2 (imagination) × 2 (picture-type) analysis of variance (ANOVA) was performed. RESULTS: The ANOVA revealed a main effect for imagination with higher activation in bilateral thalamus and right caudate nucleus and an interaction effect between imagination and group in right thalamus and left caudate nucleus, due to the patient group reacting stronger during alcohol-related imagination. These structures are involved in relaying sensory information and habit learning. No main or interaction effects of picture type were observed. CONCLUSIONS: These results support the view that context effects alter the neural responses in thalamus and nucleus caudatus in patients with AUD, and that imagination tasks are suited to incorporate contextual influences in neurophysiological research designs. Future research needs to investigate whether the failure to observe a picture-type effect was due to limited statistical power and omission to individualize picture set, or whether an imagination procedure interferes with the evocation of picture-type effects.

Reduced structural connectivity of the amygdala is associated with childhood trauma in adult patients with alcohol use disorder.

Childhood trauma (CT) is frequent in patients with alcohol use disorder (AUD) and may impact on adult drinking behaviour and treatment outcome. This study aimed to investigate the structural correlates of CT in AUD, focusing on the amygdala, which plays a crucial role in the neurobiology of trauma. We hypothesized reduced amygdala volume and reduced structural connectivity as quantified by fractional anisotropy (FA) and by number of streamlines in those AUD patients with a history of moderate to severe CT (AUD-CT). T1-weighted MP2RAGE and diffusion-weighted imaging (DWI) 3-Tesla MRI-scans were acquired in 41 recently abstinent patients with AUD. We compared bilateral amygdala volume and structural connectivity (FA and number of streamlines) of pathways emanating from the amygdala between AUD-CT (n = 20) and AUD without CT (AUD-NT, n = 21) using a mixed model multivariate analysis of variance (MANCOVA) controlling for age and gender. AUD-CT displayed reduced FA and reduced number of streamlines of amygdalar tracts. There were no differences regarding amygdala volume. The severity of physical abuse, a subscale of the childhood trauma questionnaire, was negatively correlated with FA and with number of streamlines. AUD-CT and AUD-NT differ regarding structural connectivity of pathways projecting to and from the amygdala, but not regarding amygdala volume. Those alterations of structural connectivity in AUD-CT may represent a distinguishable neurobiological subtype of AUD, which might be associated with the complex clinical picture and poorer outcome that patients with CT and AUD often present.

EEG Microstates and Psychosocial Stress During an Exchange Year.

The well-known stress vulnerability model of psychosis assumes that psychotic episodes result from the coincidence of individual trait dispositions and triggering stressors. We thus hypothesized that a transient psychosocial stressor would not only increase the number of and stress caused by psychosis-like symptoms (like delusion-like symptoms or auditory hallucinations) in healthy subjects but also elicit changes in EEG microstates that have been related to the presence of psychotic symptoms in patients with schizophrenia. Considering a radical change of one's psychosocial environment as a significant stressor, we analyzed psychotic symptoms and EEG microstate data in teenage exchange-students at an early and a later phase of their stay. The subjects experienced a small and transient, but significant increase of stress by psychosis-like symptoms. These changes in mental state were associated with increases in microstate class A, which has previously been related to unspecific stress. microstate classes C and D, which have consistently been found to be altered in patients with psychosis, were found unaffected by the time of the recording and the subjective stress experiences. Therefore, we conclude that microstate class A appears to be a psychosis independent and rather general correlate of psychosocial stress, whereas changes in microstate classes C and D seem to be more specifically tied to the presence of psychotic symptoms.

The Neurophysiology of Implicit Alcohol Associations in Recently Abstinent Patients With Alcohol Use Disorder: An Event-Related Potential Study Considering Gender Effects.

BACKGROUND: Neuroscientific models of alcohol use disorders (AUDs) postulate an imbalance between automatic, implicit, and controlled (conscious) processes. Implicit associations towards alcohol indicate the automatically attributed appeal of alcohol-related stimuli. First, behavioral studies indicate that negative alcohol associations are less pronounced in patients compared to controls, but potential neurophysiological differences remain unexplored. This study investigates neurophysiological correlates of implicit alcohol associations in recently abstinent patients with AUD for the first time, including possible gender effects. METHODS: A total of 62 patients (40 males and 22 females) and 21 controls performed an alcohol valence Implicit Association Test, combining alcohol-related pictures with positive (incongruent condition) or negative (congruent condition) words, while brain activity was recorded using 64-channel electroencephalography. Event-related potentials (ERPs) for alcohol-negative and alcohol-positive trials were computed. Microstate analyses investigated the effects of group (patients, controls) and condition (incongruent, congruent); furthermore, possible gender effects in patients were analyzed. Significant effects were localized with standardized low-resolution brain electromagnetic topography analysis. RESULTS: Although no behavioral group differences were found, ERPs of patients and controls were characterized by distinct microstates from 320 ms onwards. ERPs between conditions differed only in patients with higher signal strength during incongruent trials. Around 600 ms, controls displayed higher signal strength than patients. A gender effect mirrored this pattern with enhanced signal strength in females as opposed to male patients. Around 690 ms, a group-by-valence interaction indicated enhanced signal strength in congruent compared to incongruent trials, which was more pronounced in controls. CONCLUSIONS: For patients with AUD, the pattern, timing, and source localization of effects suggest greater effort regarding semantic and self-relevant integration around 400 ms during incongruent trials and attenuated emotional processing during the late positive potential timeframe. Interestingly, this emotional attenuation seemed reduced in female patients, thus corroborating the importance of gender-sensitive research and potential treatment of AUD.

Context-Specific Inhibition is Related to Craving in Alcohol Use Disorders: A Dangerous Imbalance.

BACKGROUND: Most contemporary neuroscientific models of alcohol use disorders (AUD) incorporate an imbalance between enhanced cue reactivity, which results in a strong urge to consume, and the impaired inhibitory control of that urge. While these phenomena have been frequently investigated separately, studies involving both aspects and thus precisely investigating the postulated imbalance are rare. In this study, inhibition was investigated in an addiction-specific context and individual craving levels were also examined. METHODS: This study compared inhibition in alcohol-related and neutral contexts in patients with AUD and healthy controls, while also taking into account the individual amount of craving. All subjects performed a Go/NoGo task involving neutral and alcohol-related NoGo trials, while their brain activity was recorded using multichannel electroencephalography. The map strength and topography of the N2 and P3 components of the NoGo event-related potentials were compared between groups and contexts using whole-scalp randomization-based methods. The effects of interest were further investigated with sLORETA source analysis. RESULTS: For the N2 component, the context by craving interaction was strong for map strength and map topography. The source analysis indicated that in subjects with high craving, alcohol-related context led to enhanced and prolonged activation in the posterior cingulate and premotor cortical areas. This interaction was specific for craving, but not for diagnostic classification. The amplitude of the P3 component was reduced in subjects with AUD, which replicated previous findings. CONCLUSIONS: In subjects with strong craving, the conflict reflected in the NoGo-N2 was enhanced in the alcohol-related context. Such enhanced conflict probably makes the successful inhibition of the urge to drink in high-risk situations even more difficult for this subgroup of patients and should therefore be addressed in individualized treatment planning.

Focus on emotion as a catalyst of memory updating during reconsolidation.

We share the idea of Lane et al. that successful psychotherapy exerts its effects through memory reconsolidation. To support it, we add further evidence that a behavioral interference may trigger memory update during reconsolidation. Furthermore, we propose that - in addition to replacing maladaptive emotions - new emotions experienced in the therapeutic process catalyze reconsolidation of the updated memory structure.

A tutorial on data-driven methods for statistically assessing ERP topographies.

Dynamic changes in ERP topographies can be conveniently analyzed by means of microstates, the so-called "atoms of thoughts", that represent brief periods of quasi-stable synchronized network activation. Comparing temporal microstate features such as on- and offset or duration between groups and conditions therefore allows a precise assessment of the timing of cognitive processes. So far, this has been achieved by assigning the individual time-varying ERP maps to spatially defined microstate templates obtained from clustering the grand mean data into predetermined numbers of topographies (microstate prototypes). Features obtained from these individual assignments were then statistically compared. This has the problem that the individual noise dilutes the match between individual topographies and templates leading to lower statistical power. We therefore propose a randomization-based procedure that works without assigning grand-mean microstate prototypes to individual data. In addition, we propose a new criterion to select the optimal number of microstate prototypes based on cross-validation across subjects. After a formal introduction, the method is applied to a sample data set of an N400 experiment and to simulated data with varying signal-to-noise ratios, and the results are compared to existing methods. In a first comparison with previously employed statistical procedures, the new method showed an increased robustness to noise, and a higher sensitivity for more subtle effects of microstate timing. We conclude that the proposed method is well-suited for the assessment of timing differences in cognitive processes. The increased statistical power allows identifying more subtle effects, which is particularly important in small and scarce patient populations.

The experiences and perceptions of health-care professionals regarding assistive technology training: A systematic review.

Worldwide, there is an increasing demand for assistive technologies (ATs) that can support people to live independently for longer. Health-care professionals (HCPs) often recommend AT devices, however there exists a lack of availability of devices and appropriate training in the field. This systematic review aimed to synthesize the available evidence into the experiences and training needs of HCPs in relation to AT. Six electronic databases were searched without date restrictions: MEDLINE, PsycINFO, SPP, SSCI, CINAHL, and ASSIA. Journal handsearching, searching reference lists of included studies and relevant reviews, and contacting experts in the field of AT were also conducted. Findings were analyzed using narrative synthesis. Data from 7846 participants from 62 studies were synthesized, eliciting perceived challenges in access to and provision of training, resulting in knowledge gaps across disciplines and geographic locations. Mechanisms to mitigate these issues included ongoing support following training and tailoring education to meet individual needs since comprehensive training is essential to maintain and improve competence, knowledge, and confidence. Further research is required to explore the impact and effectiveness of AT training for HCPs to ensure that users of devices are supported to live independent and healthy lives.

Psychometric properties of the modified Suicide Stroop Task (M-SST) in patients with suicide risk and healthy controls.

The Cognitive Model of Suicide proposes a suicide attentional bias in individuals with suicidal thoughts and behavior (STBs). The Suicide Stroop Task (SST) was developed as a behavioral measure to assess this attentional bias. However, prior studies demonstrated poor psychometric properties of the SST. Methods: We developed a modified Suicide Stroop Task (M-SST) and tested its psychometric properties in a sample of healthy controls (n = 30) and inpatients with STBs (n = 24). Participants (50% female, aged 18 to 61 years) completed the M-SST with neutral, positive, negative, suicide-related positive and suicide-related negative words. Interference scores were calculated by subtracting the mean reaction time (mean RT) of the neutral words from the mean RT of the suicide-related positive words (mean RTSuicide-Positive-mean RTNeutral) and suicide-related negative words (mean RTSuicide-Negative-mean RTNeutral), resulting in two suicide-specific interference scores. Similarly, interference scores were calculated for the positive and negative words by subtracting the mean RT of neutral words from the mean RT of positive and negative words. Results: When analyzed separately, patients with STBs showed greater interferences for suicide-related positive words (p = 0.039), and for suicide-related negative words (p = 0.016), however, we found no group differences in interference scores for positive and negative words, suggesting a suicide attentional bias in patients with STBs. Controlling for the repeated measure design, a repeated measure ANOVA failed to detect a significant group × interference interaction effect (p = 0.176), which limits the generalizability of the findings. However, the interference score of suicide-related negative words showed an adequate classification accuracy (AUC = 0.72, 95% CI [0.58-0.86], p = 0.006) for differentiating between healthy controls and patients with STBs. Moreover, the interference scores showed acceptable internal reliability for the total sample and only suicide-related interference scores were correlated with clinical characteristics, thus demonstrating convergent validity. Conclusion: The results provide preliminary evidence for a suicide attentional bias in individuals with STBs compared to healthy controls. The M-SST represents a promising tool for assessing a suicide attentional bias by revealing adequate psychometric properties. Future studies with larger samples are needed to confirm these preliminary findings.

Implicit measures of suicide vulnerability: Investigating suicide-related information-processing biases and a deficit in behavioral impulse control in a high-risk sample and healthy controls.

OBJECTIVE: Relevant implicit markers of suicidal thoughts and behaviors (STBs) have only been studied in isolation with mixed evidence. This is the first study that investigated a suicide attentional bias, a death-identity bias and a deficit in behavioral impulsivity in a high-risk sample and healthy controls. METHOD: We administered the Death Implicit Association Test, the Modified Suicide Stroop Task, and a Go/No-Go Task to inpatient suicide ideators (n = 42), suicide attempters (n = 40), and community controls (n = 61). RESULTS: Suicide ideators and attempters showed a suicide attentional bias and a death-identity bias compared to healthy controls. Ideators and attempters did not differ in these implicit information-processing biases. Notably, only attempters were more behaviorally impulsive compared to controls; however, ideators and attempters did not significantly differ in behavioral impulsivity. Moreover, implicit scores were positively intercorrelated in the total sample. CONCLUSION: In line with the Cognitive Model of Suicide, ideators and attempters display suicide-related information processing biases, which can be considered as implicit cognitive markers of suicide vulnerability. Furthermore, attempters have elevated levels of behavioral impulsiveness. These results are highly relevant in the context of crisis intervention strategies and warrant further research.

Antibiotic resistance plasmids in Enterobacteriaceae isolated from fresh produce in northern Germany.

In this study, the genomes of 22 Enterobacteriaceae isolates from fresh produce and herbs obtained from retail markets in northern Germany were completely sequenced with MiSeq short-read and MinION long-read sequencing and assembled using a Unicycler hybrid assembly. The data showed that 17 of the strains harbored between one and five plasmids, whereas in five strains, only the circular chromosomal DNA was detected. In total, 38 plasmids were identified. The size of the plasmids detected varied between ca. 2,000 and 326,000 bp, and heavy metal resistance genes were found on seven (18.4%) of the plasmids. Eleven plasmids (28.9%) showed the presence of antibiotic resistance genes. Among large plasmids (>32,000 bp), IncF plasmids (specifically, IncFIB and IncFII) were the most abundant replicon types, while all small plasmids were Col-replicons. Six plasmids harbored unit and composite transposons carrying antibiotic resistance genes, with IS26 identified as the primary insertion sequence. Class 1 integrons carrying antibiotic resistance genes were also detected on chromosomes of two Citrobacter isolates and on four plasmids. Mob-suite analysis revealed that 36.8% of plasmids in this study were found to be conjugative, while 28.9% were identified as mobilizable. Overall, our study showed that Enterobacteriaceae from fresh produce possess antibiotic resistance genes on both chromosome and plasmid, some of which are considered to be transferable. This indicates the potential for Enterobacteriaceae from fresh produce that is usually eaten in the raw state to contribute to the transfer of resistance genes to bacteria of the human gastrointestinal system. IMPORTANCE: This study showed that Enterobacteriaceae from raw vegetables carried plasmids ranging in size from 2,715 to 326,286 bp, of which about less than one-third carried antibiotic resistance genes encoding resistance toward antibiotics such as tetracyclines, aminoglycosides, fosfomycins, sulfonamides, quinolones, and ß-lactam antibiotics. Some strains encoded multiple resistances, and some encoded extended-spectrum ß-lactamases. The study highlights the potential of produce, which may be eaten raw, as a potential vehicle for the transfer of antibiotic-resistant bacteria.

A suicide attentional bias as implicit cognitive marker of suicide vulnerability in a high-risk sample.

Introduction: Suicide risk assessment based on self-report questionnaires is considered as problematic because risk states are dynamic and at-risk individuals may conceal suicidal intentions for several reasons. Therefore, recent research efforts increasingly focus on implicit risk markers such as the suicide attentional bias (SAB) measured with the Suicide Stroop Task (SST). However, most SST studies failed to demonstrate a SAB in individuals with suicide risk and repeatedly demonstrated insufficient psychometrics of the SST. This study aimed to investigate a SAB using a modified SST (M-SST) and to test its psychometric properties. Method: We compared n = 61 healthy controls and a high-risk inpatient sample of n = 40 suicide ideators and n = 40 suicide attempters regarding interference scores of positive, negative and suicide-related words. Interference scores were calculated by subtracting the mean reaction time (mean RT) of the neutral words from the mean RT of the suicide-related words (mean RT Suicide -mean RT Neutral), resulting in a suicide-specific interference score. Similarly, interference scores were calculated for the positive and negative words by subtracting the mean RT of neutral words from the mean RT of positive and negative words. Results: A Group × Interference ANOVA showed a significant interaction effect (p <.001, ηp2 = .09), indicating that group effects significantly vary across interference type. Post hoc comparisons revealed that both ideators and attempters demonstrated greater interferences only for suicide-related words compared to healthy controls, indicating a SAB in patients, while a difference between ideators and attempters was lacking. The suicide interference score classified with an AUC = 0.73, 95% CI [0.65 - 0.82], p <.001, between controls and patients with STBs. The M-SST demonstrated good internal consistency and convergent validity. Discussion: The study adds evidence to the assumptions of the Cognitive Model of Suicide, viewing a SAB as a cognitive marker of suicide vulnerability independently of the engagement in suicidal behavior. The results' clinical implications are discussed in the context of recommended intervention strategies during an acute suicidal state. Future studies with the M-SST should include non-suicidal patient controls to investigate whether a SAB is uniquely related to suicidality.

Antidepressants and alcohol use disorder: A multicenter study on the mediating role of depression symptom changes.

BACKGROUND: Alcohol use disorder (AUD) and depression are highly prevalent and tied to significant psychological, physiological, social and economic consequences. Their co-occurrence presents a complex clinical challenge, as the impact of antidepressant medication on AUD outcomes remains equivocal. In this multicenter, longitudinal study we investigated the relationship between antidepressant medication and changes in depression symptoms and alcohol use in AUD patients. METHODS: We analyzed data from 153 detoxified AUD patients who attended a 12-week residential treatment program between 2015 and 2019. Within a mediation analysis, adopting a bootstrapping approach and a quasi-Bayesian framework, we estimated the total, direct, and mediated effects of antidepressants on the percentage of days abstinent to assess the role of changes in depression symptoms as a mediating factor. RESULTS: The mediation analysis revealed a dual impact pathway model with a negative direct effect of antidepressants on abstinence (p = 0.004) and a positive indirect effect, mediated through the reduction of depression symptoms (p = 0.002). CONCLUSIONS: The findings of the mediation analysis show that patients treated with antidepressants and whose depression symptoms do not improve over time show more relapses, while patients treated with antidepressants who achieve a reduction in depression symptoms show fewer relapses over time. Thus, to optimize treatment outcome, depression symptoms should be vigilantly monitored when antidepressants are prescribed during AUD treatment.

Tracking the implicit self using event-related potentials.

Negative biases in implicit self-evaluation are thought to be detrimental to subjective well-being and have been linked to various psychological disorders, including depression. An understanding of the neural processes underlying implicit self-evaluation in healthy subjects could provide a basis for the investigation of negative biases in depressed patients, the development of differential psychotherapeutic interventions, and the estimation of relapse risk in remitted patients. We thus studied the brain processes linked to implicit self-evaluation in 25 healthy subjects using event-related potential (ERP) recording during a self-relevant Implicit Association Test (sIAT). Consistent with a positive implicit self-evaluation in healthy subjects, they responded significantly faster to the congruent (self-positive mapping) than to the incongruent sIAT condition (self-negative mapping). Our main finding was a topographical ERP difference in a time window between 600 and 700 ms, whereas no significant differences between congruent and incongruent conditions were observed in earlier time windows. This suggests that biases in implicit self-evaluation are reflected only indirectly, in the additional recruitment of control processes needed to override the positive implicit self-evaluation of healthy subjects in the incongruent sIAT condition. Brain activations linked to these control processes can thus serve as an indirect measure for estimating biases in implicit self-evaluation. The sIAT paradigm, combined with ERP, could therefore permit the tracking of the neural processes underlying implicit self-evaluation in depressed patients during psychotherapy.

Associations of thalamocortical networks with reduced mindfulness in alcohol use disorder.

Background: Increased mindfulness is associated with reduced alcohol consumption in patients with alcohol use disorder (AUD) after residential treatment. However, the underlying neurobiological mechanism of mindfulness in AUD is unclear. Therefore, we investigate the structural and functional alterations of the thalamocortical system with a focus on the mediodorsal thalamic nucleus (MD-TN), the default mode and the salience network (DMN/SN) which has previously been associated with mindfulness in healthy subjects. We hypothesized lower mindfulness and reduced structural and functional connectivity (FC) of the thalamocortical system, particularly in the DMN/SN in AUD. We assumed that identified neurobiological alterations in AUD are associated with impairments of mindfulness. Methods: Forty-five abstinent patients with AUD during residential treatment and 20 healthy controls (HC) were recruited. Structural and resting-state functional MRI-scans were acquired. We analysed levels of mindfulness, thalamic volumes and network centrality degree of the MD-TN using multivariate statistics. Using seed-based whole brain analyses we investigated functional connectivity (FC) of the MD-TN. We performed exploratory correlational analyses of structural and functional DMN/SN measurements with levels of mindfulness. Results: In AUD we found significantly lower levels of mindfulness, lower bilateral thalamic and left MD-TN volumes, reduced FC between MD-TN and anterior cingulum/insula and lower network centrality degree of the left MD-TN as compared to HC. In AUD, lower mindfulness was associated with various reductions of structural and functional aspects of the MD-TN. Conclusion: Our results suggest that structural and functional alterations of a network including the MD-TN and the DMN/SN underlies disturbed mindfulness in AUD.

Alcohol-specific inhibition training in patients with alcohol use disorder: a multi-centre, double-blind randomized clinical trial examining drinking outcome and working mechanisms.

AIMS: For the first time, to our knowledge, in a clinical sample with alcohol use disorder (AUD), this study compared the effects of two versions of alcohol-specific inhibition training (Alc-IT) on drinking outcomes and on experimental parameters assessing two possible working mechanisms: stimulus devaluation and inhibitory enhancement. DESIGN: Multi-centre, double-blind, three-arm clinical RCT with 3-, 6- and 12-month follow-up comparing standard Alc-IT, improved Alc-IT and an active control condition. SETTING: Three specialized AUD treatment centres in Switzerland. PARTICIPANTS: A total of 242 detoxified, recently abstinent patients with severe AUD (18-60 years; 29.8% female). INTERVENTION AND COMPARATOR: Both interventions [standard Alc-IT (n = 84) and improved Alc-IT (n = 79)] and the comparator [unspecific inhibition training (n = 79)] consisted of six sessions of a modified inhibitory task (Go/NoGo task) with alcohol-related and neutral stimuli. Both versions of Alc-IT required response inhibition in alcohol-related trials but differed in Go/NoGo ratios (standard: 50/50; improved: 75/25), with improved Alc-IT posing higher inhibitory demands. The control condition, an unspecific inhibition training, featured alcohol-related pictures in Go as well as NoGo trials. MEASUREMENTS: The primary outcome, percentage of days abstinent, was assessed at 3-month follow-up with a time-line follow-back interview. FINDINGS: The group receiving improved Alc-IT showed a significantly higher percentage of days abstinent at 3-month follow-up compared with the control group [γcontrol = 74.30; γimproved = 85.78; ß = 11.48, 95% confidence interval (CI) = 2.57, 20.40, P = 0.012, adjusted r2 = 0.062], while for standard Alc-IT no effect significantly different from zero was detected (γstandard = 70.95; ß = -3.35, 95% CI = -12.20, 5.50, P = 0.457, adjusted r2 = -0.04). CONCLUSIONS: Alcohol-specific inhibition training with high inhibitory demands increased days abstinent at 3-month follow-up in patients with severe alcohol use disorder. Such an improved, inhibitory-demanding, alcohol-specific inhibition training outperformed the standard version of alcohol-specific inhibition training, suggesting an inhibitory working mechanism.

Activation of the WNT/ß-catenin pathway attenuates experimental emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: To characterize WNT/ß-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. METHODS: The expression, localization, and activity of WNT/ß-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/ß-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo. MEASUREMENTS AND MAIN RESULTS: No differences in the mRNA expression profile of the main WNT/ß-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear ß-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/ß-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/ß-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. CONCLUSIONS: Decreased WNT/ß-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/ß-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/ß-catenin activation as a future therapeutic approach for emphysema.

How is carer strain related to the recovery of stroke survivors with right hemisphere dysfunction? Implications for practice.

AIM: Right hemisphere strokes are associated with neuro-behavioural impairments including hemi-inattention, impulsiveness and anosognosia, which can impede stroke recovery and adversely affect carer health. This study explored the impact of associated impairments on carer strain and depression through a mixed methods approach. METHOD: Fifty-one carer-survivor dyads were recruited from inpatient rehabilitation units and followed-up for 6 months. Validated measures assessed survivors' physical and cognitive function and carers' strain and depression levels. Survey methods captured qualitative experiences of the caring role. Data collection occurred at baseline, discharge, 6 weeks post-discharge and 6 months. Multilevel-modelling and thematic data analysis, were employed. RESULTS: Carer strain median scores were within normal ranges of the Caregiver Strain Index scale. Carer strain was positively linked to carer depression, number of carers' concerns reported and survivors' anosognosia levels. Carer strain was negatively linked to the survivors' functional and cognitive abilities. Carers' experiences differed qualitatively with caring concerns increasing over time. CONCLUSION: Carer strain worsens with increases in significant concerns about the rehabilitation process and poor survivor functioning skills, which potentially increase risk of depression in carers. Consequently, improving right-hemisphere stroke survivors' recovery and nurturing the carer-survivor relationship are likely to enhance overall outcomes and caring experiences.IMPLICATIONS FOR REHABILITATIONIn the context of right hemisphere stroke: Carer assessment should be comprehensive and include a measure of perceived ability to care.Less strained carers tend to report fewer caring concerns and have lower depression levels.Education, training and practical support should be tailored to carer identified needs, abilities and the caring context.

Right Inferior Frontal Activation During Alcohol-Specific Inhibition Increases With Craving and Predicts Drinking Outcome in Alcohol Use Disorder.

Alcohol use disorder (AUD) is characterized by enhanced cue-reactivity and the opposing control processes being insufficient. The ability to inhibit reactions to alcohol-related cues, alcohol-specific inhibition, is thus crucial to AUD; and trainings strengthening this ability might increase treatment outcome. The present study investigated whether neurophysiological correlates of alcohol-specific inhibition (I) vary with craving, (II) predict drinking outcome in AUD and (III) are modulated by alcohol-specific inhibition training. A total of 45 recently abstinent patients with AUD and 25 controls participated in this study. All participants underwent functional magnetic resonance imaging (fMRI) during a Go-NoGo task with alcohol-related as well as neutral conditions. Patients with AUD additionally participated in a double-blind RCT, where they were randomized to either an alcohol-specific inhibition training or an active control condition (non-specific inhibition training). After the training, patients participated in a second fMRI measurement where the Go-NoGo task was repeated. Percentage of days abstinent was assessed as drinking outcome 3 months after discharge from residential treatment. Whole brain analyses indicated that in the right inferior frontal gyrus (rIFG), activation related to alcohol-specific inhibition varied with craving and predicted drinking outcome at 3-months follow-up. This neurophysiological correlate of alcohol-specific inhibition was however not modulated by the training version. Our results suggest that enhanced rIFG activation during alcohol-specific (compared to neutral) inhibition (I) is needed to inhibit responses when craving is high and (II) fosters sustained abstinence in patients with AUD. As alcohol-specific rIFG activation was not affected by the training, future research might investigate whether potential training effects on neurophysiology are better detectable with other methodological approaches.

Alcohol-related context modulates neural correlates of inhibitory control in alcohol dependent patients: Preliminary data from an fMRI study using an alcohol-related Go/NoGo-task.

Alcohol use disorder (AUD) is characterized by both impaired inhibitory control and heightened cue reactivity, including enhanced craving and drinking urges in response to alcohol-related stimuli. The interaction between these two mechanisms is thought to be crucial in the maintenance of addiction and relapse. The present study used a newly developed alcohol-related Go/NoGo-task to investigate how exposure to alcohol-related cues affects neural processing of inhibitory control in subjects with AUD. Functional magnetic resonance imaging (fMRI) was recorded during performance of a Go/NoGo task, which incorporated alcohol-related and neutral stimuli as Go and NoGo trials in abstinent AUD patients and healthy controls (HC). AUD patients exhibited increased activation of a fronto-striatal-parietal network during successful response inhibition relative to HC. Within the AUD group, activation for alcohol-related (relative to neutral) inhibition was enhanced in regions including bilateral anterior cingulate cortex (ACC), right medial frontal and precentral gyri, and right putamen. Activation differences in the right ACC increased with subjective craving. These preliminary findings suggest that AUD patients need to recruit enhanced neuronal resources for successful inhibition. In parts of the inhibitory network, this hyperactivation is enhanced when inhibition takes place in an alcohol-related context. Activation in the ACC increased stronger in patients experiencing high craving, possibly because of an enhanced conflict. The task introduced here thus allows to investigate neural processing of alcohol-related inhibition in an AUD sample. The preliminary results suggest that exposure to alcohol-related cues intensifies the demand on an already challenged inhibitory system in recently abstinent patients with AUD.