Analyzing fractal dimension in electroconvulsive therapy: Unraveling complexity in structural and functional neuroimaging.

BACKGROUND: Numerous studies show that electroconvulsive therapy (ECT) induces hippocampal neuroplasticity, but findings are inconsistent regarding its clinical relevance. This study aims to investigate ECT-induced plasticity of anterior and posterior hippocampi using mathematical complexity measures in neuroimaging, namely Higuchi's fractal dimension (HFD) for fMRI time series and the fractal dimension of cortical morphology (FD-CM). Furthermore, we explore the potential of these complexity measures to predict ECT treatment response. METHODS: Twenty patients with a current depressive episode (16 with major depressive disorder and 4 with bipolar disorder) underwent MRI-scans before and after an ECT-series. Twenty healthy controls matched for age and sex were also scanned twice for comparison purposes. Resting-state fMRI data were processed, and HFD was computed for anterior and posterior hippocampi. Group-by-time effects for HFD in anterior and posterior hippocampi were calculated and correlations between HFD changes and improvement in depression severity were examined. For FD-CM analyses, we preprocessed structural MRI with CAT12's surface-based methods. We explored group-by-time effects for FD-CM and the predictive value of baseline HFD and FD-CM for treatment outcome. RESULTS: Patients exhibited a significant increase in bilateral hippocampal HFD from baseline to follow-up scans. Right anterior hippocampal HFD increase was associated with reductions in depression severity. We found no group differences and group-by-time effects in FD-CM. After applying a whole-brain regression analysis, we found that baseline FD-CM in the left temporal pole predicted reduction of overall depression severity after ECT. Baseline hippocampal HFD did not predict treatment outcome. CONCLUSION: This study suggests that HFD and FD-CM are promising imaging markers to investigate ECT-induced neuroplasticity associated with treatment response.

Alcohol Biomarker Phosphatidylethanol as a Predictor of the Severity of Alcohol Withdrawal Syndrome.

AIMS: to investigate the relationship between phosphatidylethanol (PEth) and withdrawal severity in patients with alcohol use disorder (AUD). METHODS: in 34 patients with AUD admitted for treatment of acute alcohol withdrawal, data were available for initial blood PEth concentrations and scores throughout detoxification of symptoms of withdrawal assessed by trained medical staff using the alcohol withdrawal syndrome (AWS)-scale, a validated scale consisting of 11 items in the alcohol withdrawal syndrome (two subscales with seven physiological and five psychological symptoms). RESULTS: a significant positive correlation between PEth and the severity of alcohol withdrawal was found. When the sample was divided into two groups, according to whether or not AWS score at some point in the treatment reached 6 or more, the median PEth score was higher in those whose peak score had been 6 or more (score of 6 being the suggested cutoff to start medicating the withdrawal syndrome). Although there was a trend for some aspects of the clinical history to be more 'severe' in those with higher AWS, no differences reached significance. CONCLUSION: blood PEth on admission could have a role in identifying patients at risk of more severe AWS.

Brief Report: Protective or Risk Factor? Aftermath Effects of Perceived Social Support on Embitterment during the COVID-19 Pandemic.

There are indications for a raise in embitterment during the COVID-19 pandemic. As embitterment is related to felt social exclusion, pessimism, and a proneness toward COVID-19-related conspiracy beliefs, embitterment may be a key factor to consider in the current pandemic. However, perceived social support (PSS), which is associated with hope during the COVID-19 pandemic could serve as an important resilience factor for bitterness. We therefore investigated the effects of PSS on embitterment in aftermath of the second wave of the COVID-19 pandemic. 52 individuals participated in our follow-up online study in October 2020 (T1) and May 2021 (T2). Embitterment (measured with the Berne Embitterment Inventory) and PSS were repeatedly assessed at T1 and T2. A double moderation analysis was conducted, using the PROCESS macro to examine the effects of embitterment, PSS, and age on embitterment 6 months later. The results suggest that the prediction of embitterment at T2 by embitterment at T1 was altered by changes in PSS. Here, in particular participants with high embitterment at T1 and a gain in PSS had higher embitterment scores at T2, whereas participants with low embitterment were found to have lower embitterment scores. This interaction effect was further influenced by the age of the participants, where the effects were more pronounced among middle-aged participants than younger participants. As embittered individuals seem to grow in bitterness with a gain in PSS, support is found for the notion that embittered individuals seeking allies supporting their mindset.

The clinical course of comorbid substance use disorder and attention deficit/hyperactivity disorder: protocol and clinical characteristics of the INCAS study.

BACKGROUND: Substance use disorders (SUD) often co-occur with attention deficit hyperactivity disorder (ADHD). Although the short-term effects of some specific interventions have been investigated in randomized clinical trials, little is known about the long-term clinical course of treatment-seeking SUD patients with comorbid ADHD. AIMS: This paper presents the protocol and baseline clinical characteristics of the International Naturalistic Cohort Study of ADHD and SUD (INCAS) designed and conducted by the International Collaboration on ADHD and Substance Abuse (ICASA) foundation. The overall aim of INCAS is to investigate the treatment modalities provided to treatment-seeking SUD patients with comorbid ADHD, and to describe the clinical course and identify predictors for treatment outcomes. This ongoing study employs a multicentre observational prospective cohort design. Treatment-seeking adult SUD patients with comorbid ADHD are recruited, at 12 study sites in nine different countries. During the follow-up period of nine months, data is collected through patient files, interviews, and self-rating scales, targeting a broad range of cognitive and clinical symptom domains, at baseline, four weeks, three months and nine months. RESULTS: A clinically representative sample of 578 patients (137 females, 441 males) was enrolled during the recruitment period (June 2017-May 2021). At baseline, the sample had a mean age (SD) of 36.7 years (11.0); 47.5% were inpatients and 52.5% outpatients; The most prevalent SUDs were with alcohol 54.2%, stimulants 43.6%, cannabis 33.1%, and opioids 14.5%. Patients reported previous treatments for SUD in 71.1% and for ADHD in 56.9%. Other comorbid mental disorders were present in 61.4% of the sample: major depression 31.5%, post-traumatic stress disorder 12.1%, borderline personality disorder 10.2%. CONCLUSIONS: The first baseline results of this international cohort study speak to its feasibility. Data show that many SUD patients with comorbid ADHD had never received treatment for their ADHD prior to enrolment in the study. Future reports on this study will identify the course and potential predictors for successful pharmaceutical and psychological treatment outcomes. TRIAL REGISTRATION: ISRCTN15998989 20/12/2019.

Different Goals, Different Needs: The Effects of Telephone- and Text Message-Based Continuing Care for Patients with Different Drinking Goals After Residential Treatment for Alcohol Use Disorder.

AIMS: Drinking goal has emerged as a promising predictor variable for alcohol-related outcomes. Many patients with alcohol use disorder (AUD) choose another drinking goal than abstinence after residential AUD treatment program. We aimed to examine the effects of an abstinent drinking goal (ADG) and conditional abstinence drinking goal (CADG) 6 months after residential treatment on drinking outcomes in patients with severe AUD and investigate the effectiveness of telephone-based (TEL) or text message-based (TEX) continuing care according to the individual drinking goal. METHODS: A total of 240 patients from two specialized residential treatment programs for AUD were included in the study. Patients were randomly assigned to high-frequency (nine contacts) or low-frequency (two contacts) TEL, TEX (nine contacts), or control group (no contact) from treatment discharge to the 6-month follow-up. RESULTS: Patients with an ADG were significantly more often abstinent (58%) at the 6-month follow-up compared to patients with a CADG (32.1%), and in the case of relapse, showed a significantly longer time to the first drink. Patients with a CADG of the high-frequency TEL showed a tendency to be more abstinent at the 6-month follow-up and reported significantly higher alcohol-related self-efficacy compared to the CADG patients of the control group. CONCLUSIONS: Patients with CADG are more vulnerable to relapse, and therefore may benefit more from high-frequency telephone contacts to deal with alcohol-related problems and reach their goal. In the case of relapse, the high-frequent contacts may help patients stay connected to health services, preventing chronification and facilitating recovery from AUD.

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.

Telephone- and Text Message-Based Continuing Care After Residential Treatment for Alcohol Use Disorder: A Randomized Clinical Multicenter Study.

BACKGROUND: Alcohol use disorder (AUD) is characterized by extremely high rates of postresidential treatment relapse, and as such, continuing care to prevent relapse has become an important element in AUD treatment. In this regard, research has yielded heterogeneous evidence on telephone-based (TEL) and text message-based (TEX) continuing care. We aimed to compare the effectiveness of TEL and TEX continuing care provided in different frequencies by psychotherapists for patients from residential treatments in mitigating the occurrence of posttreatment relapse in patients who completed a 12-week abstinence-oriented residential treatment program for AUD. METHODS: A total of 240 patients from 2 residential treatment programs for AUD were included in the study. Patients were randomly assigned to high- (10 contacts) or low-frequency (3 contacts) TEL, TEX (10 contacts) continuing care, or control group (1 contact) from discharge to 6-month follow-up. The TEL was intended to be supportive and consisted of several cognitive behavioral therapy components, whereas the TEX was based on behavioral self-monitoring techniques and additional calls in case of relapse or as needed. Sociodemographic, clinical, and alcohol-specific variables at residential treatment discharge and at 5-month follow-up were assessed through interviews and questionnaires. RESULTS: Compared with the control group, patients in the high-frequency TEL were significantly more likely to be abstinent at 6-month follow-up and, in case of relapse, showed a tendency toward a longer time to first drink. Moreover, the high-frequency TEL and TEX groups had significantly higher alcohol-related self-efficacy 6 months after residential treatment. CONCLUSION: High-frequency proactive telephone contact by psychotherapists known to the patient may help patients to surmount the vulnerable phase after residential treatment and, in case of relapse, might help patients stay connected to health services, which in turn prevents chronification and facilitates recovery from AUD.

Trail Making Test: Normative Data for Patients with Severe Alcohol Use Disorder.

Background: Patients with alcohol use disorders (AUD) often show cognitive impairment, particularly in executive functions that has been linked to poor treatment outcomes. The Trail Making Test (TMT) is the most widely used neuropsychological test to investigate executive functions with available normative data. However, no such norms exist for patients with AUD, although there is extensive evidence that TMT performance is altered in AUD patients. Purpose: To provide normative data for patients with AUD and compare the performance of AUD patients with already existing normative data from healthy subjects. Methods: Data of 494 recently detoxified patients with AUD who entered an abstinence-oriented residential treatment program were analyzed. Patients completed a standardized diagnostic procedure and the TMT Parts A and B at treatment admission. Results: AUD patients' performance on the TMT was impaired compared to the normative data of healthy individuals and decreased with increasing age and lower levels of education, with stronger effects in Part B assessing more complex executive functioning. Alcohol-related variables showed no direct associations with TMT performance. Conclusions: The results replicate the association of age and education with TMT performance, suggesting that AUD may be associated with impaired cognitive functioning earlier in life in abstinent patients shortly after withdrawal from alcohol compared to healthy individuals. The presented normative data for patients with AUD particularly improve the examination of executive deficits, and may enable clinicians to evaluate patients' cognitive functioning in treatment more precisely.

Symptom-Triggered Detoxification Using the Alcohol-Withdrawal-Scale Reduces Risks and Healthcare Costs.

AIMS: As there are only a few existing experimental studies on symptom-triggered therapy for patients with alcohol withdrawal, we investigated the effectiveness of symptom-triggered detoxification regarding the use and dosage of benzodiazepine and withdrawal complications in a naturalistic clinical setting of a specialized treatment center for alcohol use disorder. METHODS: In total, 301 charts of patients who entered residential treatment for alcohol withdrawal were included in the retrospective analysis. Charts of 176 patients treated with the Alcohol Withdrawal-Scale (AWS) were compared to the charts of 125 patients treated with treatment as usual (TAU) before the implementation of AWS. Sociodemographical and clinical variables, previous detoxifications and complications, duration of treatment, use and dose of benzodiazepine and other withdrawal medication, complications and premature discontinuation of treatment were abstracted from the patients' medical records. RESULTS: The two groups did not differ in any demographical or clinical variables measured upon treatment admission. The total percentage of patients being treated with benzodiazepines during detoxification decreased from 78.4 to 38.6% after the implementation of the AWS. The implementation of the AWS significantly reduced the duration of the acute detoxification from 136 to 66 h, and the use, duration and dose of benzodiazepine by nearly two-thirds while complications and treatment discontinuation remained unvaryingly. Healthcare costs for detoxification were reduced by half per patient. CONCLUSIONS: The findings indicate that symptom-triggered treatment for alcohol withdrawal is safe and effective in a naturalistic clinical setting and significantly reduces healthcare costs and the risk for overmedicating patients.

Prestimulus default mode activity influences depth of processing and recognition in an emotional memory task.

Low self-referential thoughts are associated with better concentration, which leads to deeper encoding and increases learning and subsequent retrieval. There is evidence that being engaged in externally rather than internally focused tasks is related to low neural activity in the default mode network (DMN) promoting open mind and the deep elaboration of new information. Thus, reduced DMN activity should lead to enhanced concentration, comprehensive stimulus evaluation including emotional categorization, deeper stimulus processing, and better long-term retention over one whole week. In this fMRI study, we investigated brain activation preceding and during incidental encoding of emotional pictures and on subsequent recognition performance. During fMRI, 24 subjects were exposed to 80 pictures of different emotional valence and subsequently asked to complete an online recognition task one week later. Results indicate that neural activity within the medial temporal lobes during encoding predicts subsequent memory performance. Moreover, a low activity of the default mode network preceding incidental encoding leads to slightly better recognition performance independent of the emotional perception of a picture. The findings indicate that the suppression of internally-oriented thoughts leads to a more comprehensive and thorough evaluation of a stimulus and its emotional valence. Reduced activation of the DMN prior to stimulus onset is associated with deeper encoding and enhanced consolidation and retrieval performance even one week later. Even small prestimulus lapses of attention influence consolidation and subsequent recognition performance.

Resistance to temptation: the interaction of external and internal control on alcohol use during residential treatment for alcohol use disorder.

BACKGROUND: There is evidence that drinking during residential treatment is related to various factors, such as patients' general control beliefs and self-efficacy, as well as to external control of alcohol use by program's staff and situations where there is temptation to drink. As alcohol use during treatment has been shown to be associated with the resumption of alcohol use after discharge from residential treatment, we aimed to investigate how these variables are related to alcohol use during abstinence-oriented residential treatment programs for alcohol use disorders (AUD). METHODS: In total, 509 patients who entered 1 of 2 residential abstinence-oriented treatment programs for AUD were included in the study. After detoxification, patients completed a standardized diagnostic procedure including interviews and questionnaires. Drinking was assessed by patients' self-report of at least 1 standard drink or by positive breathalyzer testing. The 2 residential programs were categorized as high or low control according to the average number of tests per patient. RESULTS: Regression analysis revealed a significant interaction effect between internal and external control suggesting that patients with high internal locus of control and high frequency of control by staff demonstrated the least alcohol use during treatment (16.7%) while patients with low internal locus of control in programs with low external control were more likely to use alcohol during treatment (45.9%). No effects were found for self-efficacy and temptation. CONCLUSIONS: As alcohol use during treatment is most likely associated with poor treatment outcomes, external control may improve treatment outcomes and particularly support patients with low internal locus of control, who show the highest risk for alcohol use during treatment. High external control may complement high internal control to improve alcohol use prevention while in treatment.

Glucocorticoids enhance in vivo exposure-based therapy of spider phobia.

BACKGROUND: Preclinical and clinical studies indicate that the administration of glucocorticoids may promote fear extinction processes. In particular, it has been shown that glucocorticoids enhance virtual reality based exposure therapy of fear of heights. Here, we investigate whether glucocorticoids enhance the outcome of in vivo exposure-based group therapy of spider phobia. METHODS: In a double blind, block-randomized, placebo-controlled, between-subject study design, 22 patients with specific phobia of spiders were treated with two sessions of in vivo exposure-based group therapy. Cortisol (20 mg) or placebo was orally administered 1 hr before each therapy session. Patients returned for a follow-up assessment one month after therapy. RESULTS: Exposure-based group therapy led to a significant decrease in phobic symptoms as assessed with the Fear of Spiders Questionnaire (FSQ) from pretreatment to immediate posttreatment and to follow-up. The administration of cortisol to exposure therapy resulted in increased salivary cortisol concentrations and a significantly greater reduction in fear of spiders (FSQ) as compared to placebo at follow-up, but not immediately posttreatment. Furthermore, cortisol-treated patients reported significantly less anxiety during standardized exposure to living spiders at follow-up than placebo-treated subjects. Notably, groups did not differ in phobia-unrelated state-anxiety before and after the exposure sessions and at follow-up. CONCLUSIONS: These findings indicate that adding cortisol to in vivo exposure-based group therapy of spider phobia enhances treatment outcome.

Spider phobia is associated with decreased left amygdala volume: a cross-sectional study.

BACKGROUND: Evidence from animal and human studies imply the amygdala as the most critical structure involved in processing of fear-relevant stimuli. In phobias, the amygdala seems to play a crucial role in the pathogenesis and maintenance of the disorder. However, the neuropathology of specific phobias remains poorly understood. In the present study, we investigated whether patients with spider phobia show altered amygdala volumes as compared to healthy control subjects. METHODS: Twenty female patients with spider phobia and twenty age-matched healthy female controls underwent magnetic resonance imaging to investigate amygdala volumes. The amygdalae were segmented using an automatic, model-based segmentation tool (FSL FIRST). Differences in amygdala volume were investigated by multivariate analysis of covariance with group as between-subject factor and left and right amygdala as dependent factors. The relation between amygdala volume and clinical features such as symptom severity, disgust sensitivity, trait anxiety and duration of illness was investigated by Spearman correlation analysis. RESULTS: Spider phobic patients showed significantly smaller left amygdala volume than healthy controls. No significant difference in right amygdala volume was detected. Furthermore, the diminished amygdala size in patients was related to higher symptom severity, but not to higher disgust sensitivity or trait anxiety and was independent of age. CONCLUSIONS: In summary, the results reveal a relation between higher symptom severity and smaller left amygdala volume in patients with spider phobia. This relation was independent of other potential confounders such as the disgust sensitivity or trait anxiety. The findings suggest that greater spider phobic fear is associated with smaller left amygdala. However, the smaller left amygdala volume may either stand for a higher vulnerability to develop a phobic disorder or emerge as a consequence of the disorder.

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.

Distinct and shared patterns of brain plasticity during electroconvulsive therapy and treatment as usual in depression: an observational multimodal MRI-study.

Electroconvulsive therapy (ECT) is a highly effective treatment for depression. Previous studies point to ECT-induced volume increase in the hippocampi and amygdalae, and to increase in cortical thickness. However, it is unclear if these neuroplastic changes are associated with treatment response. This observational study aimed to address this research question by comparing neuroplasticity between patients with depression receiving ECT and patients with depression that respond to treatment as usual (TAU-responders). Twenty ECT-patients (16 major depressive disorder (MDD), 4 depressed bipolar disorder), 20 TAU-responders (20 MDD) and 20 healthy controls (HC) were scanned twice with multimodal magnetic resonance imaging (structure: MP2RAGE; perfusion: arterial spin labeling). ECT-patients were scanned before and after an ECT-index series (ECT-group). TAU-responders were scanned during a depressive episode and following remission or treatment response. Volumes and cerebral blood flow (CBF) of the hippocampi and amygdalae, and global mean cortical thickness were compared between groups. There was a significant group × time interaction for hippocampal and amygdalar volumes, CBF in the hippocampi and global mean cortical thickness. Hippocampal and amygdalar enlargements and CBF increase in the hippocampi were observed in the ECT-group but neither in TAU-responders nor in HC. Increase in global mean cortical thickness was observed in the ECT-group and in TAU-responders but not in HC. The co-occurrence of increase in global mean cortical thickness in both TAU-responders and in ECT-patients may point to a shared mechanism of antidepressant response. This was not the case for subcortical volume and CBF increase.

Electroconvulsive therapy induces remodeling of hippocampal co-activation with the default mode network in patients with depression.

INTRODUCTION: Electroconvulsive therapy (ECT) is a highly efficient treatment for depression. Previous studies repeatedly reported an ECT-induced volume increase in the hippocampi. We assume that this also affects extended hippocampal networks. This study aims to investigate the structural and functional interplay between hippocampi, hippocampal pathways and core regions of the default mode network (DMN). Twenty patients with a current depressive episode receiving ECT-treatment and twenty age and sex matched healthy controls (HC) were included in the study. ECT-patients underwent multimodal magnetic resonance imaging (MRI)-scans (diffusion weighted imaging, resting state functional MRI) before and after an ECT-index series. HC were also scanned twice in a similar between-scan time-interval. Parahippocampal cingulum (PHC) and uncinate fasciculus (UF) were reconstructed for each participant using manual tractography. Fractional anisotropy (FA) was averaged across tracts. Furthermore, we investigated seed-based functional connectivity (FC) from bilateral hippocampi and from the PCC, a core region of the DMN. At baseline, FA in PHC and UF did not differ between groups. There was no baseline group difference of hippocampal-FC. PCC-FC was decreased in ECT-patients. ECT induced a decrease in FA in the left PHC in the ECT group. No longitudinal changes of FA were found in the UF. Furthermore, there was a decrease in hippocampal-PCC-FC, an increase in hippocampal-supplementary motor area-FC, and an increase in PCC-FC in the ECT-group, reversing group differences at baseline. Our findings suggest that ECT induces structural and functional remodeling of a hippocampal-DMN. Those changes may contribute to ECT-induced clinical response in patients with depression.

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.

In- and Out-Group Effects on Social Perception and Empathy in Cocaine Use Disorder.

Earlier research revealed that cocaine users display impairments in emotional but not necessarily in cognitive empathy. However, no study to date has tested whether empathy is generally altered or whether impairments are restricted to specific social targets. The current investigation addresses this open question. In addition, we examined whether attributions of warmth and competence as well as personal future expectancies differed between cocaine users and substance-naïve controls. Twenty-two chronic cocaine users and 40 stimulant-naïve controls specified their perceived warmth and competence for four social targets [in-group member, opposite consumption out-group member (cocaine user for controls and non-user for cocaine user), opposite consumption out-group member of opposite gender, and elderly person]. They also specified their cognitive and emotional empathy for these four targets facing eight desirable and eight undesirable events. Finally, they rated the likelihood of these scenarios happening to themselves. Both cocaine users and controls attributed lower warmth to cocaine-using than non-using targets. Comparably, no in-group preference was observed in cocaine user's emotional empathy ratings, and greater denigration of the in-group was associated with higher frequency and doses of cocaine consumption. In addition, cocaine users rated both desirable and undesirable events as more likely to happen to themselves than did controls. Results show that substance-naïve individuals stigmatize cocaine users. They further point to compromised self-esteem in cocaine users resulting from such stigmatization. Interventions should address stigmatization processes to break the vicious circle of mutual social distancing and stronger dedication to the drug.

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.

Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users.

Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response.