Using Drift Diffusion and RL Models to Disentangle Effects of Depression On Decision-Making vs. Learning in the Probabilistic Reward Task.

The Probabilistic Reward Task (PRT) is widely used to investigate the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), and recent studies have used it to provide insight into decision-making mechanisms affected by MDD. The current project used PRT data from unmedicated, treatment-seeking adults with MDD to extend these efforts by: (1) providing a more detailed analysis of standard PRT metrics-response bias and discriminability-to better understand how the task is performed; (2) analyzing the data with two computational models and providing psychometric analyses of both; and (3) determining whether response bias, discriminability, or model parameters predicted responses to treatment with placebo or the atypical antidepressant bupropion. Analysis of standard metrics replicated recent work by demonstrating a dependency between response bias and response time (RT), and by showing that reward totals in the PRT are governed by discriminability. Behavior was well-captured by the Hierarchical Drift Diffusion Model (HDDM), which models decision-making processes; the HDDM showed excellent internal consistency and acceptable retest reliability. A separate "belief" model reproduced the evolution of response bias over time better than the HDDM, but its psychometric properties were weaker. Finally, the predictive utility of the PRT was limited by small samples; nevertheless, depressed adults who responded to bupropion showed larger pre-treatment starting point biases in the HDDM than non-responders, indicating greater sensitivity to the PRT's asymmetric reinforcement contingencies. Together, these findings enhance our understanding of reward and decision-making mechanisms that are implicated in MDD and probed by the PRT.

Cognitive Signatures of Depressive and Anhedonic Symptoms and Affective States Using Computational Modeling and Neurocognitive Testing.

BACKGROUND: Deeper phenotyping may improve our understanding of depression. Because depression is heterogeneous, extracting cognitive signatures associated with severity of depressive symptoms, anhedonia, and affective states is a promising approach. METHODS: Sequential sampling models decomposed behavior from an adaptive approach-avoidance conflict task into computational parameters quantifying latent cognitive signatures. Fifty unselected participants completed clinical scales and the approach-avoidance conflict task by either approaching or avoiding trials offering monetary rewards and electric shocks. RESULTS: Decision dynamics were best captured by a sequential sampling model with linear collapsing boundaries varying by net offer values, and with drift rates varying by trial-specific reward and aversion, reflecting net evidence accumulation toward approach or avoidance. Unlike conventional behavioral measures, these computational parameters revealed distinct associations with self-reported symptoms. Specifically, passive avoidance tendencies, indexed by starting point biases, were associated with greater severity of depressive symptoms (R = 0.34, p = .019) and anhedonia (R = 0.49, p = .001). Depressive symptoms were also associated with slower encoding and response execution, indexed by nondecision time (R = 0.37, p = .011). Higher reward sensitivity for offers with negative net values, indexed by drift rates, was linked to more sadness (R = 0.29, p = .042) and lower positive affect (R = -0.33, p = .022). Conversely, higher aversion sensitivity was associated with more tension (R = 0.33, p = .025). Finally, less cautious response patterns, indexed by boundary separation, were linked to more negative affect (R = -0.40, p = .005). CONCLUSIONS: We demonstrated the utility of multidimensional computational phenotyping, which could be applied to clinical samples to improve characterization and treatment selection.

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala.

Neuroticism/Negative Emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment and divorce to mental illness and premature death. Work in animals suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to the human brain and temperament have remained unclear. Here we used a combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is selectively associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to 'threat-related' faces. Implicit in much of the neuroimaging literature is the assumption that different threat paradigms are statistically interchangeable probes of individual differences in neural function, yet our results revealed negligible evidence of convergence between popular threat-anticipation and emotional-face tasks. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing the next generation of mechanistic research.

Low-load blood flow restriction strength training in patients with COPD: a randomised single-blind pilot study.

OBJECTIVE: The objective of this study is to compare the effectiveness of lower limb low-load blood flow restriction training (LL-BFRT) with high-load strength training (HL-ST) as part of an outpatient pulmonary rehabilitation programme on leg strength in patients with chronic obstructive pulmonary disease (COPD). METHODS: Participants were randomised to LL-BFRT or HL-ST (24 sessions). LL-BFRT was done at 30% 1-repetition maximum (1-RM) with 70% arterial occlusion pressure. HL-ST was done at 70% 1-RM. Primary outcome was isometric strength of knee extensors and flexors. Secondary outcomes were 1-RM, functional exercise capacity, physical activity, symptom burden and health-related quality of life. Perceptions of dyspnoea and leg fatigue were recorded after every exercise. We compared groups with t-tests. RESULTS: We included 30 participants (13 women, 17 men, 64 (9) years, forced expiratory volume in 1 s 47 (18)% pred.), 24 completed the study. Isometric knee extensor strength improved to a clinically relevant degree in both legs in both groups (LL-BFRT: right leg 9 (20) Nm, left leg 10 (18) Nm; HL-ST: right leg 15 (26) Nm, left leg 16 (30) Nm, data are mean (SD)), without statistically significant or clinically relevant between-group differences (right leg mean difference= -6.4, 95% CI= -13.20 to 25.92 Nm, left leg mean difference= -5.6, 95% CI= -15.44 to 26.55 Nm). 1 min sit-to-stand test performance improved to a clinically relevant degree only in the LL-BFRT group (4 (4) vs 1 (5) repetitions). Interestingly, physical activity improved to a clinically relevant degree only in the LL-BFRT group (1506 (2441) vs -182 (1971) steps/day). LL-BFRT lowered perceived in-exercise dyspnoea and increased leg fatigue compared with HL-ST in the initial 12 trainings. CONCLUSION: In patients with stable COPD undergoing outpatient pulmonary rehabilitation, LL-BFRT was not superior to HL-ST in improving leg strength. LL-BFRT led to similar strength gains as HL-ST while reducing perceptions of dyspnoea in the initial training phase. TRIAL REGISTRATION NUMBER: NCT04151771.

Predicting Fear Extinction in Posttraumatic Stress Disorder.

Fear extinction is the basis of exposure therapies for posttraumatic stress disorder (PTSD), but half of patients do not improve. Predicting fear extinction in individuals with PTSD may inform personalized exposure therapy development. The participants were 125 trauma-exposed adults (96 female) with a range of PTSD symptoms. Electromyography, electrocardiogram, and skin conductance were recorded at baseline, during dark-enhanced startle, and during fear conditioning and extinction. Using a cross-validated, hold-out sample prediction approach, three penalized regressions and conventional ordinary least squares were trained to predict fear-potentiated startle during extinction using 50 predictor variables (5 clinical, 24 self-reported, and 21 physiological). The predictors, selected by penalized regression algorithms, were included in multivariable regression analyses, while univariate regressions assessed individual predictors. All the penalized regressions outperformed OLS in prediction accuracy and generalizability, as indexed by the lower mean squared error in the training and holdout subsamples. During early extinction, the consistent predictors across all the modeling approaches included dark-enhanced startle, the depersonalization and derealization subscale of the dissociative experiences scale, and the PTSD hyperarousal symptom score. These findings offer novel insights into the modeling approaches and patient characteristics that may reliably predict fear extinction in PTSD. Penalized regression shows promise for identifying symptom-related variables to enhance the predictive modeling accuracy in clinical research.

Recent advances in studying brain-behavior interactions using functional imaging: The primary startle response pathway and its affective modulation in humans.

The startle response is a cross-species defensive reflex that is considered a key tool for cross-species translational emotion research. While the neural pathway mediating (affective) startle modulation has been extensively studied in rodents, human work on brain-behavior interactions has lagged in the past due to technical challenges, which have only recently been overcome through non-invasive simultaneous EMG-fMRI assessments. We illustrate key paradigms and methodological tools for startle response assessment in rodents and humans and review evidence for primary and modulatory neural circuits underlying startle responses and their affective modulation in humans. Based on this, we suggest a refined and integrative model for primary and modulatory startle response pathways in humans concluding that there is strong evidence from human work on the neurobiological pathway underlying the primary startle response while evidence for the modulatory pathway is still sparse. In addition, we provide methodological considerations to guide future work and provide an outlook on new and exciting perspectives enabled through technical and theoretical advances outlined in this work.

The effects of standardised versus individualised seat height on 1-minute sit-to-stand test performance in healthy individuals: a randomised crossover trial.

PURPOSE: We aimed to (i) investigate differences in 1-minute sit-to-stand test (1MSTST) performance (i.e., the number of repetitions) between a standardised modality (i.e., starting from a conventional chair with 46 cm seat height) and an individualised modality (i.e., starting with a knee joint flexion angle of 90°), and to (ii) quantify the influence of tibia and femur length on 1MSTST performance. METHODS: Healthy participants were recruited for this randomised crossover study, performing each 1MSTST modality twice in a randomised order. The primary outcome was the number of repetitions in the 1MSTST. Secondary endpoints were the acute responses in peripheral oxygen saturation, heart rate, and leg fatigue and dyspnoea. Additionally, we investigated correlations of performance with knee extensor strength in both modalities. RESULTS: Thirty participants were recruited and completed the study. They achieved significantly less repetitions in the standardised 1MSTST compared to the individualised 1MSTST (B = - 12.1, 95% confidence interval [95% CI] = - 14.8/- 9.4, p < 0.001). We found a significant effect of femur length on 1MSTST performance (B = - 1.6, 95% CI = - 2.6/- 0.7, p = 0.01), tibia length showed significant interaction with the 1MSTST modality (B = 1.2, 95% CI = 0.2/2.2, p = 0.03). CONCLUSION: An individualisation of the 1MSTST starting position to 90° knee flexion angle leads to more repetitions compared to the traditional starting position. The higher repetition count is explained by controlling for differences in tibia length. We recommend individualisation of the 1MSTST, enabling more valid comparisons across populations and study samples. TRIAL REGISTRATION NUMBER: http://www. CLINICALTRIALS: gov , NCT04772417. TRIAL REGISTRATION DATE: February 26, 2021.

Watching with Argus eyes: Characterization of emotional and physiological responding in adults exposed to childhood maltreatment and/or recent adversity.

Exposure to adverse experiences is a well-established major risk factor for affective psychopathology. The vulnerability of deleterious sequelae is assumed in maladaptive processes of the defensive system, particularly in emotional processing. More specifically, childhood maltreatment has been suggested to be associated with the recruitment of specific and distinct defensive response profiles. To date, it remains unclear whether these are specific or generalizable to recent adversity in adulthood. This pre-registered study aimed to investigate the impact of exposure to childhood and recent adversity on emotional processing in 685 healthy adults with the "Affective Startle Modulation" Paradigm (ASM). First, we replicated higher trait anxiety and depression levels in individuals exposed to both types of adversity. Second, we observed increased general skin conductance reactivity in individuals exposed to recent adversity. Third, individuals exposed to childhood maltreatment showed reduced, while individuals exposed to recent adversity showed increased discrimination between pictures of negative and neutral valence, compared with non-exposed individuals in SCR. No association between exposure to adversity and fear potentiated startle was observed. Furthermore, explorative analyses revealed moderate dimensional and categorical agreement between two childhood maltreatment questionnaires and provide insight into potential adversity-type specific effects. Our results support experience-dependent plasticity in sympathetic nervous system reactivity and suggest distinct response profiles in affective modulation in individuals exposed to early versus recent adversity. We emphasize the need to further explore distinct adversity profiles to further our understanding on specific psychophysiological profiles and their potential implication for prevention and intervention.

Validation of a small cough detector.

Research question: The assessment of cough frequency in clinical practice relies predominantly on the patient's history. Currently, objective evaluation of cough is feasible with bulky equipment during a brief time (i.e. hours up to 1 day). Thus, monitoring of cough has been rarely performed outside clinical studies. We developed a small wearable cough detector (SIVA-P3) that uses deep neural networks for the automatic counting of coughs. This study examined the performance of the SIVA-P3 in an outpatient setting. Methods: We recorded cough epochs with SIVA-P3 over eight consecutive days in patients suffering from chronic cough. During the first 24 h, the detector was validated against cough events counted by trained human listeners. The wearing comfort and the device usage were assessed using a questionnaire. Results: In total, 27 participants (mean±sd age 50±14 years) with either chronic unexplained cough (n=12), COPD (n=4), asthma (n=5) or interstitial lung disease (n=6) were studied. During the daytime, the sensitivity of SIVA-P3 cough detection was 88.5±2.49% and the specificity was 99.97±0.01%. During the night-time, the sensitivity was 84.15±5.04% and the specificity was 99.97±0.02%. The wearing comfort and usage of the device was rated as very high by most participants. Conclusion: SIVA-P3 enables automatic continuous cough monitoring in an outpatient setting for objective assessment of cough over days and weeks. It shows comparable sensitivity or higher sensitivity than other devices with fully automatic cough counting. Thanks to its wearing comfort and the high performance for cough detection, it has the potential for being used in routine clinical practice.

Robust group- but limited individual-level (longitudinal) reliability and insights into cross-phases response prediction of conditioned fear.

Here, we follow the call to target measurement reliability as a key prerequisite for individual-level predictions in translational neuroscience by investigating (1) longitudinal reliability at the individual and (2) group level, (3) internal consistency and (4) response predictability across experimental phases. One hundred and twenty individuals performed a fear conditioning paradigm twice 6 months apart. Analyses of skin conductance responses, fear ratings and blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) with different data transformations and included numbers of trials were conducted. While longitudinal reliability was rather limited at the individual level, it was comparatively higher for acquisition but not extinction at the group level. Internal consistency was satisfactory. Higher responding in preceding phases predicted higher responding in subsequent experimental phases at a weak to moderate level depending on data specifications. In sum, the results suggest that while individual-level predictions are meaningful for (very) short time frames, they also call for more attention to measurement properties in the field.

Increasing Daily Physical Activity and Its Effects on QTc Time in Severe to Very Severe COPD: A Secondary Analysis of a Randomised Controlled Trial.

Approximately, half of COPD patients die from cardiovascular diseases. A prolongation of cardiac repolarization (measured as QTc interval) is associated with cardiovascular events or cardiovascular deaths in populations of older adults and COPD. One way to reduce the QTc could be to increase physical activity (PA). We investigated whether QTc can be reduced by an increase in PA in patients with severe COPD. This is a secondary outcome analysis from a randomized controlled trial investigating the effects of a 3 months pedometer based program to improve PA. 12-lead ECG was assessed at baseline and after 3 months. We measured PA using a validated triaxial accelerometer. Data were analyzed from 59 participants. Multiple regression modeling, including adjustment for baseline QTc, sex, QT prolonging medications, BMI, smoking status and FEV1%, showed no evidence for an association between an improvement of ≥15% PA and QTc reduction. A 15% improvement in PA according to step counts over 3 months seems not to reduce QTc interval by its MCID of 20 ms in patients with severe to very severe COPD.

A data multiverse analysis investigating non-model based SCR quantification approaches.

Electrodermal signals are commonly used outcome measures in research on arousal, emotion, and habituation. Recently, we reported on heterogeneity in skin conductance response quantification approaches and its impact on replicability. Here we provide complementary work focusing on within-approach heterogeneity of specifications for skin conductance response quantification. We focus on heterogeneity within the baseline-correction approach (BLC) which appeared as particularly heterogeneous-for instance with respect to the pre-CS baseline window duration, the start, and end of the peak detection window. We systematically scrutinize the robustness of results when applying different BLC approach specifications to one representative pre-existing data set (N = 118) in a (partly) pre-registered study. We report high agreement between different BLC approaches for US and CS+ trials, but moderate to poor agreement for CS- trials. Furthermore, a specification curve of the main effect of CS discrimination during fear acquisition training from all potential and reasonable combinations of specifications (N = 150) and a prototypical trough-to-peak (TTP) approach indicates that resulting effect sizes are largely comparable. A second specification curve (N = 605 specific combinations) highlights a strong impact of different transformation types. Crucially, however, we show that BLC approaches often misclassify the peak value-particularly for CS- trials, leading to stimulus-specific biases and challenges for post-processing and replicability of CS discrimination across studies applying different approaches. Lastly, we investigate how negative skin conductance values in BLC, appearing most frequently for CS- (CS- > CS+ > US), correspond to values in TTP quantification. We discuss the results considering prospects and challenges of the multiverse approach and future directions.

Anxiety-Related Frontocortical Activity Is Associated With Dampened Stressor Reactivity in the Real World.

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes, from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys have begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here, we used a combination of approaches-including neuroimaging assays of threat anticipation and emotional-face perception and more than 10,000 momentary assessments of emotional experience-to demonstrate that individuals who showed greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experienced lower levels of stressor-dependent distress in their daily lives (ns = 202-208 university students). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world.

Navigating the manyverse of skin conductance response quantification approaches - A direct comparison of trough-to-peak, baseline correction, and model-based approaches in Ledalab and PsPM.

Raw data are typically required to be processed to be ready for statistical analyses, and processing pipelines are often characterized by substantial heterogeneity. Here, we applied seven different approaches (trough-to-peak scoring by two different raters, script-based baseline correction, Ledalab as well as four different models implemented in the software PsPM) to two fear conditioning data sets. Selection of the approaches included was guided by a systematic literature search by using fear conditioning research as a case example. Our approach can be viewed as a set of robustness analyses (i.e., same data subjected to different processing pipelines) aiming to investigate if and to what extent these different quantification approaches yield comparable results given the same data. To our knowledge, no formal framework for the evaluation of robustness analyses exists to date, but we may borrow some criteria from a framework suggested for the evaluation of "replicability" in general. Our results from seven different SCR quantification approaches applied to two data sets with different paradigms suggest that there may be no single approach that consistently yields larger effect sizes and could be universally considered "best." Yet, at least some of the approaches employed show consistent effect sizes within each data set indicating comparability. Finally, we highlight substantial heterogeneity also within most quantification approaches and discuss implications and potential remedies.

Multisensory Home-Monitoring in Individuals With Stable Chronic Obstructive Pulmonary Disease and Asthma: Usability Study of the CAir-Desk.

BACKGROUND: Research integrating multisensory home-monitoring in respiratory disease is scarce. Therefore, we created a novel multisensory home-monitoring device tailored for long-term respiratory disease management (named the CAir-Desk). We hypothesize that recent technological accomplishments can be integrated into a multisensory participant-driven platform. We also believe that this platform could improve chronic disease management and be accessible to large groups at an acceptable cost. OBJECTIVE: This study aimed to report on user adherence and acceptance as well as system functionality of the CAir-Desk in a sample of participants with stable chronic obstructive pulmonary disease (COPD) or asthma. METHODS: We conducted an observational usability study. Participants took part in 4 weeks of home-monitoring with the CAir-Desk. The CAir-Desk recorded data from all participants on symptom burden, physical activity, spirometry, and environmental air quality; data on sputum production, and nocturnal cough were only recorded for participants who experienced symptoms. After the study period, participants reported on their perceptions of the usability of the monitoring device through a purpose-designed questionnaire. We used descriptive statistics and visualizations to display results. RESULTS: Ten participants, 5 with COPD and 5 with asthma took part in this study. They completed symptom burden questionnaires on a median of 96% (25th percentile 14%, 75th percentile 96%), spirometry recordings on 55% (20%, 94%), wrist-worn physical activity recordings on 100% (97%, 100%), arm-worn physical activity recordings on 45% (13%, 63%), nocturnal cough recordings on 34% (9%, 54%), sputum recordings on 5% (3%, 12%), and environmental air quality recordings on 100% (99%, 100%) of the study days. The participants indicated that the measurements consumed a median of 13 (10, 15) min daily, and that they preferred the wrist-worn physical activity monitor to the arm-worn physical activity monitor. CONCLUSIONS: The CAir-Desk showed favorable technical performance and was well-accepted by our sample of participants with stable COPD and asthma. The obtained insights were used in a redesign of the CAir-Desk, which is currently applied in a randomized controlled trial including an interventional program.

Longitudinal Smartphone-Based Post-hospitalisation Symptom Monitoring in SARS-CoV-2 Associated Respiratory Failure: A Multi-Centre Observational Study.

Background: We aimed to longitudinally monitor the recovery in breathlessness, symptom burden, health-related quality-of-life, and mental health status in individuals hospitalised due to SARS-CoV-2 associated respiratory failure. Methods: Individuals hospitalised due to SARS-CoV-2 associated respiratory failure were recruited at hospital discharge in three participating centres. During the 90 day follow-up, European Quality of Life-5 Dimensions-5 Levels Instrument (EQ-5D-5L), modified Medical Research Council (mMRC) Dyspnoea Scale, COPD Assessment Test (CAT), and weekly Hospital Anxiety and Depression Scale (HADS) questionnaires were assessed using a smartphone application. The results were presented using descriptive statistics and graphics. Linear mixed models with random intercept were fitted to analyse differences of intensive-care unit status on the recovery course in each outcome. Results: We included 58 participants, 40 completed the study. From hospital discharge until 90 days post-discharge, EQ-5D-5L index changed from 0.83 (0.66, 0.92) to 0.96 (0.82, 1.0), VAS rating on general health status changed from 62 (50, 75) % to 80 (74, 94) %, CAT changed from 13 (10, 21) to 7 (3, 11) points, mMRC changed from 1 (0, 2) to 0 (0, 1) points, HADS depression subscale changed from 6 (4, 9) to 5 (1, 6) points, HADS anxiety subscale changed from 7 (3, 9) to 2 (1, 8) points. Differences in the recovery courses were observed between intensive-care and ward participants. Participants that were admitted to an intensive-care unit during their hospitalisation (n = 16) showed increases in CAT, mMRC, HADS scores, and decreases in EQ-5D-5L 30 days after hospital discharge. Conclusion: Being admitted to an ICU led to statistically significant reductions in recovery in the EQ-5D-5L and the CAT. Furthermore, the flare-up in symptom burden and depression scores, accompanied by an attenuated recovery in HrQoL and general health status in the ICU-group suggests that a clinical follow-up 1 month after hospital discharge can be recommended, evaluating further treatments. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04365595].

Revisiting potential associations between brain morphology, fear acquisition and extinction through new data and a literature review.

Inter-individual differences in defensive responding are widely established but their morphological correlates in humans have not been investigated exhaustively. Previous studies reported associations with cortical thickness of the dorsal anterior cingulate cortex, insula and medial orbitofrontal cortex as well as amygdala volume in fear conditioning studies. However, these associations are partly inconsistent and often derived from small samples. The current study aimed to replicate previously reported associations between physiological and subjective measures of fear acquisition and extinction and brain morphology. Structural magnetic resonance imaging was performed on 107 healthy adults who completed a differential cued fear conditioning paradigm with 24 h delayed extinction while skin conductance response (SCR) and fear ratings were recorded. Cortical thickness and subcortical volume were obtained using the software Freesurfer. Results obtained by traditional null hypothesis significance testing and Bayesians statistics do not support structural brain-behavior relationships: Neither differential SCR nor fear ratings during fear acquisition or extinction training could be predicted by cortical thickness or subcortical volume in regions previously reported. In summary, the current pre-registered study does not corroborate associations between brain morphology and inter-individual differences in defensive responding but differences in experimental design and analyses approaches compared to previous work should be acknowledged.

Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation.

When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.

The Neurofunctional Basis of Affective Startle Modulation in Humans: Evidence From Combined Facial Electromyography and Functional Magnetic Resonance Imaging.

BACKGROUND: The startle eye-blink is the cross-species translational tool to study defensive behavior in affective neuroscience with relevance to a broad range of neuropsychiatric conditions. It makes use of the startle reflex, a defensive response elicited by an immediate, unexpected sensory event, which is potentiated when evoked during threat and inhibited during safety. In contrast to skin conductance responses or pupil dilation, modulation of the startle reflex is valence specific. Rodent models implicate a modulatory pathway centering on the brainstem (i.e., nucleus reticularis pontis caudalis) and the centromedial amygdala as key hubs for flexibly integrating valence information into differential startle magnitude. Technical advances now allow for the investigation of this pathway using combined facial electromyography and functional magnetic resonance imaging in humans. METHODS: We employed a multimethodological approach combining trial-by-trial facial eye-blink startle electromyography and brainstem- and amygdala-specific functional magnetic resonance imaging in humans. Validating the robustness and reproducibility of our findings, we provide evidence from two different paradigms (fear-potentiated startle, affect-modulated startle) in two independent studies (N = 43 and N = 55). RESULTS: We provide key evidence for a conserved neural pathway for acoustic startle modulation between humans and rodents. Furthermore, we provide the crucial direct link between electromyography startle eye-blink magnitude and neural response strength. Finally, we demonstrate a dissociation between arousal-specific amygdala responding and triggered valence-specific amygdala responding. CONCLUSIONS: We provide neurobiologically based evidence for the strong translational value of startle responding and argue that startle-evoked amygdala responding and its affective modulation may hold promise as an important novel tool for affective neuroscience and its clinical translation.

Development of an ICF-based questionnaire for urinary and/or fecal incontinence (ICF-IAF): The female patients' perspective using focus groups (subproject).

AIMS: The aim of this study was to identify the problems and resources of women with urinary or fecal incontinence based on the International Classification of Function and Health (ICF) framework and detecting the impact on the personal environment and quality of life. This study forms part of a project with an overall goal to enable standardized planning and evaluation of interventions in multi-professional settings. METHODS: To answer the study question a mixed-method sequential design with a priority to the quantitative approach was considered appropriate. Regarding methods, focus groups were chosen to collect data. Transcripts were analyzed with content analysis and identified concepts linked to the corresponding ICF categories by two different raters. Cohen's kappa was calculated for interrater reliability. RESULTS: Thirteen women with a mean age of 69.9 years were recruited. Four focus groups were conducted, whereas saturation was reached after two focus groups. Overall transcripts 99 defined ICF categories at second level could be linked (body functions = 31, body structures = 5, activities and participation = 33, and environmental factors = 30) whereas 4 categories were not sufficiently covered by the ICF (3 = personal factors, 1 = not covered). CONCLUSIONS: This study has determined 103 resources and problems based on the ICF model of women with urinary and/or fecal incontinence. In spite of these results, it was shown that four concepts are not fully covered by the ICF framework. The current data highlight the importance of an extension of the ICF model, especially towards the personal factors of patients.