Quantifying brain-functional dynamics using deep dynamical systems: Technical considerations.

Both mental health and mental illness unfold in complex and unpredictable ways. Novel artificial intelligence approaches from the area of dynamical systems reconstruction can characterize such dynamics and help understand the underlying brain mechanisms, which can also be used as potential biomarkers. However, applying deep learning to model dynamical systems at the individual level must overcome numerous computational challenges to be reproducible and clinically useful. In this study, we performed an extensive analysis of these challenges using generative modeling of brain dynamics from fMRI data as an example and demonstrated their impact on classifying patients with schizophrenia and major depression. This study highlights the tendency of deep learning models to identify functionally unique solutions during parameter optimization, which severely impacts the reproducibility of downstream predictions. We hope this study guides the future development of individual-level generative models and similar machine learning approaches aimed at identifying reproducible biomarkers of mental illness.

Application of the grading system for "nociplastic pain" in chronic primary and chronic secondary pain conditions: a field study.

ABSTRACT: The concept "nociplastic pain" has been developed for patients with features of nociceptive system sensitization that are not explained as nociceptive or neuropathic. Here, we tested how well the recently published grading system differentiates between chronic primary and secondary pain conditions. We recruited patients with fibromyalgia (FMS, n = 41), complex regional pain syndrome (CRPS, n = 11), osteoarthritis (OA, n = 21), or peripheral nerve injury (PNI, n = 8). We used clinical history, pain drawings, quantitative sensory testing (QST), and questionnaires to classify their pains as possibly or probably "nociplastic." All patients with chronic primary pain exhibited widespread/regional pain not explainable by either nociceptive or neuropathic mechanisms. Widespread pain occurred in 12 patients with OA but was identified as nociceptive in 11 of 12. Regional pain occurred in 4 patients with PNI but was identified as neuropathic in 3 of 4. At this step, the grading system had 100% sensitivity and 93% specificity. Clinical evidence for pain hypersensitivity by QST, and history of hypersensitivity and mental comorbidities did not differentiate between chronic primary pain (QST: 36/52 = 69%, history: 43/52 = 83%) and secondary pain conditions (QST: 20/29 = 69%, history: 24/29 83%). Based on these data, specificity remained excellent (93%), but sensitivity dropped substantially (60%) due to lacking evidence for pain hypersensitivity in many patients with FMS. This low sensitivity suggests that the published grading system is not suitable for screening purposes. We suggest structural and content modifications to improve sensitivity, including placement of patient history before clinical examination and addition of a high tender point count as evidence for widespread pain hypersensitivity.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Parkinsonism, Psychomotor Slowing, Negative and Depressive Symptoms in Schizophrenia Spectrum and Mood Disorders: Exploring Their Intricate Nexus Using a Network Analytic Approach.

BACKGROUND AND HYPOTHESIS: Parkinsonism, psychomotor slowing, negative and depressive symptoms show evident phenomenological similarities across different mental disorders. However, the extent to which they interact with each other is currently unclear. Here, we hypothesized that parkinsonism is an independent motor abnormality showing limited associations with psychomotor slowing, negative and depressive symptoms in schizophrenia spectrum (SSD), and mood disorders (MOD). STUDY DESIGN: We applied network analysis and community detection methods to examine the interplay and centrality (expected influence [EI] and strength) between parkinsonism, psychomotor slowing, negative and depressive symptoms in 245 SSD and 99 MOD patients. Parkinsonism was assessed with the Simpson-Angus Scale (SAS). We used the Positive and Negative Syndrome Scale (PANSS) to examine psychomotor slowing (item #G7), negative symptoms (PANSS-N), and depressive symptoms (item #G6). STUDY RESULTS: In SSD and MOD, PANSS item #G7 and PANSS-N showed the largest EI and strength as measures of centrality. Parkinsonism had small or no influence on psychomotor slowing, negative and depressive symptoms in SSD and MOD. In SSD and MOD, exploratory graph analysis identified one community, but parkinsonism showed a small influence on its occurrence. Network Comparison Test yielded no significant differences between the SSD and MOD networks (global strength p value: .396 and omnibus tests p value: .574). CONCLUSIONS: The relationships between the individual domains followed a similar pattern in both SSD and MOD highlighting their transdiagnostic relevance. Despite evident phenomenological similarities, our results suggested that parkinsonism is more independent of negative and depressive symptoms than psychomotor slowing in both SSD and MOD.

Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits.

BACKGROUND: Understanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. METHODS: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. RESULTS: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Measuring interpersonal trauma: Development and validation of the German version of the victimization experience schedule (VES).

OBJECTIVE: Interpersonal victimization experiences (VEs) significantly affect mental and physical health, particularly in disorders associated with life-time adversities, like fibromyalgia syndrome (FMS) and major depressive disorder (MDD). However, assessing VEs comprehensively remains challenging due to limited tools that encompass sub-traumatic events, such as bullying or discrimination, and contextual dimensions. We aimed to address this gap by validating the Victimization Experience Schedule (VES) in German, examining its reliability, and assessing VEs in clinical populations with FMS and MDD. METHODS: We investigated the relationship between VEs and clinical symptoms in individuals with FMS, MDD and healthy controls (N = 105) in a case-control study. We also analyzed correlations between different types of VEs and categories of early childhood abuse and posttraumatic-stress-disorder instruments. Additionally, we validated our findings in an independent sample of individuals with FMS (N = 97) from a clinical study. RESULTS: We observed excellent inter-rater reliability (Kw = 0.90-0.99), and VEs assessed using the VES were in alignment with subcategories of early childhood abuse. The prevalence of VEs extended beyond the categories covered by traditional survey instruments and was higher in individuals with MDD (4.0 ± 2.6) and FMS (5.9 ± 3.1) compared to controls (1.5 ± 1.7). We consistently identified a significant association between the number of VEs, the associated subjective distress, and clinical scores. Furthermore, distinct correlation patterns between VEs and clinical outcomes emerged across different cohorts. CONCLUSION: Our study emphasizes the VES's value in understanding VEs within MDD and FMS. These experiences span from traumatic to sub-traumatic and correlate with posttraumatic-stress and clinical symptoms, underscoring the VES's importance as an assessment tool.

[Diagnosis and admission center : Establishment and evaluation of an integrated translational infrastructure for clinical psychiatric research]. / Diagnose- und Aufnahmezentrum : Etablierung und Evaluation einer integrierten translationalen Infrastruktur für die klinisch-psychiatrische Forschung.

The routine in-depth characterization of patients with methods of clinical and scale-based examination, neuropsychology, based on biomaterials, and sensor-based information opens up transformative possibilities on the way to personalized diagnostics, treatment and prevention in psychiatry, psychotherapy, and psychosomatics. Effective integration of the additional temporal and logistical effort into everyday care as well as the acceptance by patients are critical to the success of such an approach but there is little evidence on this to date. We report here on the establishment of the Diagnosis and Admission Center (DAZ) at the Central Institute of Mental Health (ZI) in Mannheim. The DAZ is an outpatient unit upstream of other care structures for clinical and scientific phenotyping across diagnoses as a starting point for data-driven, individualized pathways to further treatment, diagnostics or research. We describe the functions, goals, and implementation of the newly created clinical scientific translational structure, provide an overview of the patient populations it has reached, and provide data on its acceptance. In this context, the close integration with downstream clinical processes enables a better coordinated and demand-oriented allocation. In addition, DAZ enables a faster start of disorder-specific diagnostics and treatment. Since its launch in April 2021 up to the end of 2022, 1021 patients underwent psychiatric evaluation at DAZ during a pilot phase. The patient sample corresponded to a representative sample from standard care and the newly established processes were regarded as helpful by patients. In summary, the DAZ uniquely combines the interests and needs of patient with the collection of scientifically relevant data.

Stress-Induced Sensitization of Insula Activation Predicts Alcohol Craving and Alcohol Use in Alcohol Use Disorder.

BACKGROUND: Stress and alcohol cues trigger alcohol consumption and relapse in alcohol use disorder. However, the neurobiological processes underlying their interaction are not well understood. Thus, we conducted a randomized, controlled neuroimaging study to investigate the effects of psychosocial stress on neural cue reactivity and addictive behaviors. METHODS: Neural alcohol cue reactivity was assessed in 91 individuals with alcohol use disorder using a validated functional magnetic resonance imaging (fMRI) task. Activation patterns were measured twice, at baseline and during a second fMRI session, prior to which participants were assigned to psychosocial stress (experimental condition) or a matched control condition or physical exercise (control conditions). Together with fMRI data, alcohol craving and cortisol levels were assessed, and alcohol use data were collected during a 12-month follow-up. Analyses tested the effects of psychosocial stress on neural cue reactivity and associations with cortisol levels, craving, and alcohol use. RESULTS: Compared with both control conditions, psychosocial stress elicited higher alcohol cue-induced activation in the left anterior insula (familywise error-corrected p < .05) and a stress- and cue-specific dynamic increase in insula activation over time (F22,968 = 2.143, p = .007), which was predicted by higher cortisol levels during the experimental intervention (r = 0.310, false discovery rate-corrected p = .016). Cue-induced insula activation was positively correlated with alcohol craving during fMRI (r = 0.262, false discovery rate-corrected p = .032) and alcohol use during follow-up (r = 0.218, false discovery rate-corrected p = .046). CONCLUSIONS: Results indicate a stress-induced sensitization of cue-induced activation in the left insula as a neurobiological correlate of the effects of psychosocial stress on alcohol craving and alcohol use in alcohol use disorder, which likely reflects changes in salience attribution and goal-directed behavior.

Female sex and burden of depressive symptoms predict insufficient response to telemedical treatment in adult attention-deficit/hyperactivity disorder: results from a naturalistic patient cohort during the COVID-19 pandemic.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder, that typically manifests itself during childhood and persists in a majority of the affected individuals into adulthood, negatively affecting physical and mental health. Previous studies have shown detrimental effects of the COVID-19 pandemic on mental health in individuals with ADHD. Thus, telemedicine could be a useful tool for optimizing treatment-outcomes in adult ADHD by improving treatment adherence and persistence. However, data on telemedical treatment outcomes in adult patients with ADHD is scarce. Methods: We report here the sub-cohort analysis of a naturalistic cohort of adult patients (N = 254) recruited between April 2020-April 2021, comparing the effects of telemedical treatment on participants either clinically diagnosed with depression (N = 54) or ADHD (N = 67). Participants were asked to fill out the WHO-5 repetitively during >12 weeks of telemedical treatment. Furthermore scores of WHO-5, SCL-90R and BDI-II, psychopathology, psychosocial functioning, sociodemographic data, medical records and a feedback survey were analyzed for both groups and compared. Participants with ADHD were further stratified according to the development of well-being during the study period in order to identify factors associated with a satisfactory treatment outcome. Results: Participants with depression reported a significant improvement of well-being during the course of the study, while no such effect could be seen in participants with ADHD on a group level. Despite the good outcome, participants with depression were more severely affected at baseline, with significantly worse psychopathology and a more precarious labor and financial situation. A detailed analysis of ADHD participants without clinical improvement revealed significantly higher BDI-II scores than for ADHD participants with a satisfactory outcome (p = 0.03, Mann-Whitney-U-Test), suggesting successful treatment was hampered by the combination of ADHD and depressive symptoms. Furthermore, female sex among ADHD patients was correlated with an unfavorable treatment outcome during the course of the study (p = 0.001, Spearman correlation) as well as living with children (p = 0.02, Spearman correlation). Conclusion: Besides screening for depressive symptoms before telemedical treatment, future research should address the specific needs of female ADHD patients as these patients may be at a particularly high risk of being overburdened with family work.

Psychomotor slowing in schizophrenia is associated with cortical thinning of primary motor cortex: A three cohort structural magnetic resonance imaging study.

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ.