Neuropsychological Testing and Machine Learning Distinguish Alzheimer’s Disease from Other Causes for Cognitive Impairment

With promising results in recent treatment trials for Alzheimer’s disease (AD), it becomes increasingly important to distinguish AD at early stages from other causes for cognitive impairment. However, existing diagnostic methods are either invasive (lumbar punctures, PET) or inaccurate Magnetic Resonance Imaging (MRI). This study investigates the potential of neuropsychological testing (NPT) to specifically identify those patients with possible AD among a sample of 158 patients with Mild Cognitive Impairment (MCI) or dementia for various causes. Patients were divided into an early stage and a late stage group according to their Mini Mental State Examination (MMSE) score and labeled as AD or non-AD patients based on a post-mortem validated threshold of the ratio between total tau and beta amyloid in the cerebrospinal fluid (CSF; Total tau/Aβ(1–42) ratio, TB ratio). All patients completed the established Consortium to Establish a Registry for Alzheimer’s Disease—Neuropsychological Assessment Battery (CERAD-NAB) test battery and two additional newly-developed neuropsychological tests (recollection and verbal comprehension) that aimed at carving out specific Alzheimer-typical deficits. Based on these test results, an underlying AD (pathologically increased TB ratio) was predicted with a machine learning algorithm. To this end, the algorithm was trained in each case on all patients except the one to predict (leave-one-out validation). In the total group, 82% of the patients could be correctly identified as AD or non-AD. In the early group with small general cognitive impairment, classification accuracy was increased to 89%. NPT thus seems to be capable of discriminating between AD patients and patients with cognitive impairment due to other neurodegenerative or vascular causes with a high accuracy, and may be used for screening in clinical routine and drug studies, especially in the early course of this disease

Acceptance Towards LGB Persons Is an Independent Protective Factor Against Suicide on a Country Level

Background: Sexual minorities such as lesbian, gay, and bisexual (LGB) people have an increased risk for suicide, whose reasons are not sufficiently understood. We aimed to test if differences in LGB acceptance explain variations in general suicide rates on a country level. Methods: We used linear regression models to explain the variation in age-standardized suicide rates in 34 OECD countries based on LGB acceptance, which was recently assessed in large international surveys polling the general population about their attitude towards homosexuality. We included economic and sociological variables, which have been shown to be related to suicide rates in previous work, as covariates. We then used backward elimination, leave-one-out cross-validation, and the Bayesian information criterion to identify best-fitting models (i.e., to select relevant predictors). Results: All employed model selection methods favored a 4-predictor model, where higher LGB acceptance, fertility rate, religiosity, and unemployment rate were significantly related to lower suicide rates. Suicide rates were well explained by this sparse model (R2 adjusted = 0.442). In the full model with all predictors, as well as in the selected four-predictor model, higher LGB acceptance was significantly related to lower suicide rates. Conclusions: Our findings suggest that low LGB acceptance, as measured by international surveys, might be a risk factor for suicide

A predictive coding account of bistable perception - a model-based fMRI study

In bistable vision, subjective perception wavers between two interpretations of a constant ambiguous stimulus. This dissociation between conscious perception and sensory stimulation has motivated various empirical studies on the neural correlates of bistable perception, but the neurocomputational mechanism behind endogenous perceptual transitions has remained elusive. Here, we recurred to a generic Bayesian framework of predictive coding and devised a model that casts endogenous perceptual transitions as a consequence of prediction errors emerging from residual evidence for the suppressed percept. Data simulations revealed close similarities between the model’s predictions and key temporal characteristics of perceptual bistability, indicating that the model was able to reproduce bistable perception. Fitting the predictive coding model to behavioural data from an fMRI-experiment on bistable perception, we found a correlation across participants between the model parameter encoding perceptual stabilization and the behaviourally measured frequency of perceptual transitions, corroborating that the model successfully accounted for participants’ perception. Formal model comparison with established models of bistable perception based on mutual inhibition and adaptation, noise or a combination of adaptation and noise was used for the validation of the predictive coding model against the established models. Most importantly, model-based analyses of the fMRI data revealed that prediction error time-courses derived from the predictive coding model correlated with neural signal time-courses in bilateral inferior frontal gyri and anterior insulae. Voxel-wise model selection indicated a superiority of the predictive coding model over conventional analysis approaches in explaining neural activity in these frontal areas, suggesting that frontal cortex encodes prediction errors that mediate endogenous perceptual transitions in bistable perception. Taken together, our current work provides a theoretical framework that allows for the analysis of behavioural and neural data using a predictive coding perspective on bistable perception. In this, our approach posits a crucial role of prediction error signalling for the resolution of perceptual ambiguities

Evidence for a hijacked brain reward system but no desensitized threat system in quitting‐motivated smokers: An fMRI study

Background and aims: Several aspects of how quitting-motivated tobacco use disorder (TUD) subjects and never-smokers differ in terms of reward and threat processing remain unresolved. We aimed to examine aberrant reward and threat processes in TUD and the association with smoking characteristics. Design: A between- and within-subjects functional magnetic resonance imaging (fMRI) experiment with a 2 (groups) × 4 (stimulus type) factorial design. The experimental paradigm had four conditions: pictures of (1) cigarettes served as drug-related-positive cues, (2) food as alternative reward cues, (3) long-term consequences of smoking as drug-related-negative cues and (4) neutral pictures as control. Setting/participants: Adult participants (n = 38 TUD subjects and n = 42 never-smokers) were recruited in Berlin, Germany. Measurements: As contrasts of primary interest, the interactions of group × stimulus-type were assessed. Significance threshold correction for multiple testing was carried out with the family-wise error method. Correlation analyses were used to test the association with smoking characteristics. Findings: The 2 × 2 interaction of smoking status and stimulus type revealed activations in the brain reward system to drug-related-positive cues in TUD subjects (between-subjects effect: P-values ≤ 0.036). As a response to drug-related-negative cues, TUD subjects showed no reduced activation of the aversive brain network. Within the TUD group, a significant negative association was found between response of the aversive brain system to drug-related-negative cues (within-subjects effect: P-values ≤ 0.021) and the number of cigarettes smoked per day (right insula r = -0.386, P = 0.024; left insula r = -0.351, P = 0.042; right ACC r = -0.359, P = 0.037). Conclusions: Moderate smokers with tobacco use disorder appear to have altered brain reward processing of drug-related-positive (but not negative) cues compared with never smokers

Aversive drug cues reduce cigarette craving and increase prefrontal cortex activation during processing of cigarette cues in quitting motivated smokers

Aversive drug cues can be used to support smoking cessation and create awareness of negative health consequences of smoking. Better understanding of the effects of aversive drug cues on craving and the processing of appetitive drug cues in abstinence motivated smokers is important to further improve their use in cessation therapy and smoking-related public health measures. In this study, 38 quitting motivated smokers underwent functional magnetic resonance imaging (fMRI) scanning while performing a novel extended cue-reactivity paradigm. Pictures of cigarettes served as appetitive drug cues, which were preceded by either aversive drug cues (e.g., smokers' leg) or other cues (neutral or alternative reward cues). Participants were instructed to rate their craving for cigarettes after presentation of drug cues. When aversive drug cues preceded the presentation of appetitive drug cues, behavioural craving was reduced and activations in prefrontal (dorsolateral prefrontal cortex) and paralimbic (dorsal anterior cingulate cortex [dACC] and anterior insulae) areas were enhanced. A positive association between behavioural craving reduction and neurofunctional activation changes was shown for the right dACC. Our results suggest that aversive drug cues have an impact on the processing of appetitive drug cues, both on a neurofunctional and a behavioural level. A proposed model states that aversive drug-related cues activate control-associated brain areas (e.g., dACC), leading to increased inhibitory control on reward-associated brain areas (e.g., putamen) and a reduction in subjective cravings

comparison of methadone and levomethadone in long-term treatment

Background This study aimed to investigate the development of opioid tolerance in patients receiving long-term methadone maintenance treatment (MMT). Methods A region-wide cross-sectional study was performed focusing on dosage and duration of treatment. Differences between racemic methadone and levomethadone were examined. All 20 psychiatric hospitals and all 110 outpatient clinics in Berlin licensed to offer MMT were approached in order to reach patients under MMT fulfilling the DSM IV criteria of opiate dependence. In the study, 720 patients treated with racemic methadone or levomethadone gave information on the dosage of treatment. Out of these, 679 patients indicated the duration of MMT. Results Treatment with racemic methadone was reported for 370 patients (54.5 %), with levomethadone for 309 patients (45.5 %). Mean duration of MMT was 7.5 years. We found a significant correlation between dosage and duration of treatment, both in a conjoint analysis for the two substances racemic methadone and levomethadone and for each substance separately. These effects remained significant when only patients receiving MMT for 1 year or longer were considered, indicating proceeding tolerance development in long-term treatment. When correlations were compared between racemic methadone and levomethadone, no significant difference was found. Conclusions Our data show a tolerance development under long-term treatment with both racemic methadone and levomethadone. Tolerance development did not differ significantly between the two substances

Predicting outcome of daycare cognitive behavioural therapy in a naturalistic sample of patients with PTSD: a machine learning approach

Background: Identifying predictors for treatment outcome in patients with posttraumatic stress disorder (PTSD) is important in order to provide an effective treatment, but robust and replicated treatment outcome predictors are not available up to now. Objectives: We investigated predictors of treatment outcome in a naturalistic sample of patients with PTSD admitted to an 8-week daycare cognitive behavioural therapy programme following a wide range of traumatic events. Method: We used machine learning (linear and non-linear regressors and cross-validation) to predict outcome at discharge for 116 patients and sustained treatment effects 6 months after discharge for 52 patients who had a follow-up assessment. Predictions were based on a wide selection of demographic and clinical assessments including age, gender, comorbid psychiatric disorders, trauma history, posttraumatic symptoms, posttraumatic cognitions, depressive symptoms, general psychopathology and psychosocial functioning. Results: We found that demographic and clinical variables significantly, but only modestly predicted PTSD treatment outcome at discharge (r = 0.21, p = .021 for the best model) and follow-up (r = 0.31, p = .026). Among the included variables, more severe posttraumatic cognitions were negatively associated with treatment outcome. Early response in PTSD symptomatology (percentage change of symptom scores after 4 weeks of treatment) allowed more accurate predictions of outcome at discharge (r = 0.56, p < .001) and follow-up (r = 0.43, p = .001). Conclusion: Our results underscore the importance of early treatment response for short- and long-term treatment success. Nevertheless, it remains an unresolved challenge to identify variables that can robustly predict outcome before the initiation of treatment

Patterns of Alcohol Consumption Among Individuals With Alcohol Use Disorder During the COVID-19 Pandemic and Lockdowns in Germany

Importance Alcohol consumption (AC) leads to death and disability worldwide. Ongoing discussions on potential negative effects of the COVID-19 pandemic on AC need to be informed by real-world evidence. Objective To examine whether lockdown measures are associated with AC and consumption-related temporal and psychological within-person mechanisms. Design, Setting, and Participants This quantitative, intensive, longitudinal cohort study recruited 1743 participants from 3 sites from February 20, 2020, to February 28, 2021. Data were provided before and within the second lockdown of the COVID-19 pandemic in Germany: before lockdown (October 2 to November 1, 2020); light lockdown (November 2 to December 15, 2020); and hard lockdown (December 16, 2020, to February 28, 2021). Main Outcomes and Measures Daily ratings of AC (main outcome) captured during 3 lockdown phases (main variable) and temporal (weekends and holidays) and psychological (social isolation and drinking intention) correlates. Results Of the 1743 screened participants, 189 (119 [63.0%] male; median [IQR] age, 37 [27.5-52.0] years) with at least 2 alcohol use disorder (AUD) criteria according to the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) yet without the need for medically supervised alcohol withdrawal were included. These individuals provided 14 694 smartphone ratings from October 2020 through February 2021. Multilevel modeling revealed significantly higher AC (grams of alcohol per day) on weekend days vs weekdays (β = 11.39; 95% CI, 10.00-12.77; P < .001). Alcohol consumption was above the overall average on Christmas (β = 26.82; 95% CI, 21.87-31.77; P < .001) and New Year’s Eve (β = 66.88; 95% CI, 59.22-74.54; P < .001). During the hard lockdown, perceived social isolation was significantly higher (β = 0.12; 95% CI, 0.06-0.15; P < .001), but AC was significantly lower (β = −5.45; 95% CI, −8.00 to −2.90; P = .001). Independent of lockdown, intention to drink less alcohol was associated with lower AC (β = −11.10; 95% CI, −13.63 to −8.58; P < .001). Notably, differences in AC between weekend and weekdays decreased both during the hard lockdown (β = −6.14; 95% CI, −9.96 to −2.31; P = .002) and in participants with severe AUD (β = −6.26; 95% CI, −10.18 to −2.34; P = .002). Conclusions and Relevance This 5-month cohort study found no immediate negative associations of lockdown measures with overall AC. Rather, weekend-weekday and holiday AC patterns exceeded lockdown effects. Differences in AC between weekend days and weekdays evinced that weekend drinking cycles decreased as a function of AUD severity and lockdown measures, indicating a potential mechanism of losing and regaining control. This finding suggests that temporal patterns and drinking intention constitute promising targets for prevention and intervention, even in high-risk individuals

Goal-oriented decision making in regular alcohol consumption

In sogenannten Zwei-System-Theorien wird die Entstehung und Aufrechterhaltung von Abhängigkeitserkrankungen als Resultat einer veränderten Balance zwischen einem (überaktiven) Belohungssystem und einem (dysfunktionalen) Kontrollsystem verstanden. In der vorliegenden Publikationspromotion wurde die Beteiligung beider Systeme an Entscheidungen für Alkoholkonsum, an der Entstehung von Suchtdruck und kognitiver Kontrollfähigkeit sowie an der Wirksamkeit eines neuartigen suchtdruckreduzierenden Therapieansatzes, des Cognitive Bias Modification Trainings (CBM), untersucht. Hierfür kam funktionelle und strukturelle Magnetresonanztomographie zum Einsatz. Es fand sich ein überaktives Belohnungssystem im Zusammenhang mit Entscheidungen für den Alkoholkonsum, sowie im Zusammenhang mit subjektivem Suchtdruck. Diese Überaktivierung konnte durch CBM erfolgreich reduziert werden. Eine reduzierte kognitive Kontrollfähigkeit war bei alkoholabhängigen Patienten mit einer zunehmenden Atrophie inferiorer frontaler Hirnareale assoziiert. Die präsentierten Arbeiten unterstreichen die Bedeutung eines überaktiven Belohnungssystems für die Entstehung von Suchtdruck und suchttypischem Entscheidungsverhalten und damit auch als potenzielle Zielpathologie für innovative Therapiekonzepte.Dual system theories state an altered interaction between an (overactive) reward and a (dysfunctional) control system in substance use disorders. In the present work, the role of both systems is investigated regarding pro-alcohol decisions, craving and cognitive control as well as the effect mechanism of new craving-reducing treatment strategies (cognitive bias modification training, CBM). To this end, functional and structural magnet resonance imaging was used. We found an association between craving, decisions in favor of alcohol and an hyperactivation of reward-associated circuits. This hyperactivation was shown to be successfully reduced by cognitive bias modification training. Growing atrophy of the inferior frontal gyrus was related to increasing disinhibition in alcohol-dependent patients. Hence, the results underscore the importance of an hyperactivated reward system for the development of craving and addictive decision behavior. Targeting automatic tendencies and associated hyperactivations of reward areas may therefore be a promising direction for future therapies in alcohol use disorder