Association of Unc-51-like Kinase 4 (ULK4) with the reactivity of the extended reward system in response to conditioned stimuli.

OBJECTIVES: ULK4 is an established candidate gene for mental disorders and antipsychotic treatment response. We investigated the association of functional genetic variation at the ULK4 locus with the human extended dopaminergic reward system using fMRI during the performance of a well-established reward paradigm. METHODS: Two hundred and thirty-four patients were included in this study. Association of genetic variation in the ULK4 gene with reward system functioning were determined using the Desire-Reason-Dilemma (DRD) paradigm which allows to assess brain activation in response to conditioned reward stimuli. RESULTS: Variant prioritisation revealed the strongest functional signatures for the ULK4 variant rs17215589, coding for amino acid exchange Ala715Thr. For rs17215589 minor allele carriers, we detected increased activation responses to conditioned reward stimuli in the ventral tegmental area, nucleus accumbens and several cortical brain regions of the extended reward system. CONCLUSIONS: Our findings provide further evidence in humans that genetic variation in ULK4 may increase the vulnerability to mental disorders, by modulating the extended reward system function. Future studies are needed to confirm the modulation of the extended reward system by ULK4 and to specify the role of this mechanism in the pathogenesis of psychiatric disorders.

The neoliberal leaning of the neuroscience discourse when it deals with mental health and learning disorders.

Neuroscience attracted increasing attention in mass media during the last decades. Indeed, neuroscience advances raise high expectations in society concerning major societal issues such as mental health and learning difficulties. Unfortunately, according to leading experts, neuroscience advances have not yet benefited patients, students and socially deprived families. Yet, neuroscience findings are widely overstated and misrepresented in the media. Academic studies, briefly described here, showed that most data misrepresentations were already present in the neuroscience literature before spreading in mass media. This triumphalist neuroscience discourse reinforces a neuro-essentialist conception of mental disorders and of learning difficulties. By emphasizing brain plasticity, this discourse fuels the neoliberal ethics that overvalue autonomy, rationality, flexibility and individual responsibility. According to this unrealistic rhetoric, neuroscience-based techniques will soon bring inexpensive private solutions to enduring social problems. When considering the social consequences of this rhetoric, neuroscientists should refrain from overstating the interpretation of their observations in their scientific publications and in their exchanges with journalists.

Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

AIM: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. METHODS: We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. RESULTS: In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. CONCLUSION: Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

New role of platelets in schizophrenia: predicting drug response.

Background: Elevated platelet count (PLTc) is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis. However, the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear. Aims: We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables. Methods: A total of 2985 patients with schizophrenia were randomised into seven groups. Each group received one of seven antipsychotic treatments and was assessed at 2, 4 and 6 weeks. Clinical symptoms were evaluated using the positive and negative syndrome scale (PANSS). Additionally, we measured blood cell counts and metabolic parameters, such as blood lipids. Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes, while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes. Results: PLTc significantly increased in patients treated with aripiprazole (F=6.00, p=0.003), ziprasidone (F=7.10, p<0.001) and haloperidol (F=3.59, p=0.029). It exhibited a positive association with white blood cell count and metabolic indicators. Higher baseline PLTc was observed in non-responders, particularly in those defined by the PANSS-negative subscale. In the structural equation model, PLTc, white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores. Moreover, higher baseline PLTc was observed in individuals with less metabolic change, although this association was no longer significant after accounting for baseline metabolic values. Conclusions: Platelet parameters, specifically PLTc, are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia. Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation. Given PLTc's easy measurement and clinical relevance, it warrants increased attention from psychiatrists. Trial registration number: ChiCTR-TRC-10000934.

Large-Scale Neuroimaging of Mental Illness.

Neuroimaging has provided important insights into the brain variations related to mental illness. Inconsistencies in prior studies, however, call for methods that lead to more replicable and generalizable brain markers that can reliably predict illness severity, treatment course, and prognosis. A paradigm shift is underway with large-scale international research teams actively pooling data and resources to drive consensus findings and test emerging methods aimed at achieving the goals of precision psychiatry. In parallel with large-scale psychiatric genomics studies, international consortia combining neuroimaging data are mapping the transdiagnostic brain signatures of mental illness on an unprecedented scale. This chapter discusses the major challenges, recent findings, and a roadmap for developing better neuroimaging-based tools and markers for mental illness.

The Signature Biobank: A longitudinal biopsychosocial repository of psychiatric emergency patients.

The Signature Biobank is a longitudinal repository of biospecimen, psychological, sociodemographic, and diagnostic data that was created in 2012. The Signature Consortium represents a group of approximately one hundred Quebec-based transdisciplinary clinicians and research scientists with various expertise in the field of psychiatry. The objective of the Signature Biobank is to investigate the multi-faceted underpinnings of psychiatric disorders among patients in crisis. The Signature Consortium is expanding and includes new active members that seek to highlight the contributions made by Signature Biobank since its inception. This article details our research protocol, directions, and summarizes contributions. To date, we have collected biological samples (n = 1,986), and questionnaire data (n = 2,085) from psychiatric emergency patients of the Institut universitaire en santé mentale de Montréal (Quebec, Canada), with a large proportion from whom both data types were collected (n = 1,926). In addition to this, a subsample of patients was followed-up at hospital discharge, and two additional outpatient clinic appointments (n = 958 with at least one follow-up). In addition, a socio-demographically matched comparison group of individuals who were not hospitalized for psychiatric disorders (n = 149) was recruited from the surrounding catchment area. To summarize, a systematic review of the literature shows that the Signature Biobank has contributed to better characterizing psychiatric comorbidities, biological profiles, and psychosocial functioning across some of the most common psychiatric disorders, including psychosis, mood, anxiety, and substance use disorders. The Signature Biobank is now one of the world's largest repositories of data collected from patients receiving care at a psychiatric emergency unit.

Edward Trautner (1890-1978), a pioneer of psychopharmacology.

This article examines the scientific career of Edward Trautner, who did pioneering research in the 1950s on lithium treatment for psychiatric disorders. Trautner was the first scientist to study the mechanism of action of lithium as a psychiatric medication. His research established that lithium could be used safely and rationally, and anticipated by a decade the large volume of research in the 1960s and 1970s that led to international acceptance of lithium treatment for mood disorders. Trautner was a pioneer of biological psychiatry who considered pharmacology to be a useful therapeutical tool rather than a permanent cure for putative chemical imbalances. His research involved cross-disciplinary collaborations that combined clinical and laboratory research in the disciplines of psychiatry, physiology, biochemistry, teratology, and even oncology. Trautner himself had a multidisciplinary background that included publications in literature and philosophy.

Deconstructing depression by machine learning: the POKAL-PSY study.

Unipolar depression is a prevalent and disabling condition, often left untreated. In the outpatient setting, general practitioners fail to recognize depression in about 50% of cases mainly due to somatic comorbidities. Given the significant economic, social, and interpersonal impact of depression and its increasing prevalence, there is a need to improve its diagnosis and treatment in outpatient care. Various efforts have been made to isolate individual biological markers for depression to streamline diagnostic and therapeutic approaches. However, the intricate and dynamic interplay between neuroinflammation, metabolic abnormalities, and relevant neurobiological correlates of depression is not yet fully understood. To address this issue, we propose a naturalistic prospective study involving outpatients with unipolar depression, individuals without depression or comorbidities, and healthy controls. In addition to clinical assessments, cardiovascular parameters, metabolic factors, and inflammatory parameters are collected. For analysis we will use conventional statistics as well as machine learning algorithms. We aim to detect relevant participant subgroups by data-driven cluster algorithms and their impact on the subjects' long-term prognosis. The POKAL-PSY study is a subproject of the research network POKAL (Predictors and Clinical Outcomes in Depressive Disorders; GRK 2621).

A long and winding road: My personal journey to oxytocin with no return.

The present paper is the personal narration of the author reviewing her scientific pathways that led her toward the study of oxytocin. My work began with a pioneering study showing a decreased number of the serotonin transporter proteins in romantic lovers. This unexpected finding promoted my interest in the neurobiology of human emotions and feelings, and significantly shifted my research focus from diseases to physiological states that underlie "love." During this time increasing experimental data broadened the spectrum of activities of oxytocin from female functions, such as parturition and lactation, to modulation of the stress and immune system. The literature also began to reveal an important role for oxytocin in a sense of safety and wellbeing, processes that are critical to both love and survival. I suggest here that future studies should disentangle different emerging questions regarding the exact role of oxytocin within human nature, as well as its possible therapeutic applications in different physiological conditions and pathological states. Understanding these, in turn, holds the potential to improve the lives of both individuals and societies.

Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy.

As psychedelic compounds gain traction in psychiatry, there is a need to consider the active mechanism to explain the effect observed in randomized clinical trials. Traditionally, biological psychiatry has asked how compounds affect the causal pathways of illness to reduce symptoms and therefore focus on analysis of the pharmacologic properties. In psychedelic-assisted psychotherapy (PAP), there is debate about whether ingestion of the psychedelic alone is thought to be responsible for the clinical outcome. A question arises how the medication and psychotherapeutic intervention together might lead to neurobiological changes that underlie recovery from illness such as post-traumatic stress disorder (PTSD). This paper offers a framework for investigating the neurobiological basis of PAP by extrapolating from models used to explain how a pharmacologic intervention might create an optimal brain state during which environmental input has enduring effects. Specifically, there are developmental "critical" periods (CP) with exquisite sensitivity to environmental input; the biological characteristics are largely unknown. We discuss a hypothesis that psychedelics may remove the brakes on adult neuroplasticity, inducing a state similar to that of neurodevelopment. In the visual system, progress has been made both in identifying the biological conditions which distinguishes the CP and in manipulating the active ingredients with the idea that we might pharmacologically reopen a critical period in adulthood. We highlight ocular dominance plasticity (ODP) in the visual system as a model for characterizing CP in limbic systems relevant to psychiatry. A CP framework may help to integrate the neuroscientific inquiry with the influence of the environment both in development and in PAP. Appeared originally in Front Neurosci 2021; 15:710004.

45 years German Society of Biological Psychiatry (DGBP).

The foundation of a German Society of Biological Psychiatry (DGBP) was initiated at the Second World Congress of Biological Psychiatry of the WFSBP in Barcelona in 1978. Its mission was and is to promote interdisciplinary research on the biology of mental disorders and to translate results of biological research into clinical practice. During the presidency of Peter Falkai, its tasks were defined to improve the quality and support of biologically oriented research in Germany by the DFG (Deutsche Forschungsgemeinschaft; German Research Foundation), BMBF (Bundesministerium für Bildung und Forschung) and EU (European Union), to promote young researchers doing biologically oriented research, to improve on the diagnosis and therapy of mental disorders and to advise policy makers by taking part in legal processes. The DGBP has been a corporate member of the WFSBP from its beginning, became a cooperative member of the DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde), later of the German Brain Council, and fostered relationships with other scientific societies. Over the past 45 years, more than twenty congresses were held in Germany and neighboring countries. Emerging from the pandemic, the DGBP is ready to continue its mission to promote interdisciplinary research on the biology of mental disorders with a focus on the development of young scientists and to translate results of biological research into clinical practice, with regard to pharmacotherapy in close cooperation with the Arbeitsgemeinschaft Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). In this sense, this article also aims to stimulate the cooperation of the society with other national and international partners and to foster new relationships with young scientists and professionals interested in the aims and goals of the DGBP.

Biofeedback and Treatment for Borderline Personality Disorder.

Empirically validated treatments for borderline personality disorder rely on fostering self-awareness of one's internal experience for treatment success, yet these treatments do not include objective tools to assess self-awareness. Integrating biofeedback into empirically supported treatments provides a way to objectively measure physiological correlates of emotional states, thereby enhancing accurate self-assessment. By using biofeedback, individuals with borderline personality disorder may gain skills to increase self-awareness, improve emotion regulation, and enhance behavioral control. The authors propose that biofeedback can be used to objectively measure fluctuating emotional intensity, thereby facilitating structured self-assessment of emotions and enabling more effective use of interventions for emotion regulation; can be delivered by trained mental health professionals; and may even be considered as a stand-alone intervention replacing alternative, more costly, treatments.

Investigation of the Relationship Between Cognitive Functions and Retinal Findings From Spectral Optical Coherence Tomography in Patients With Schizophrenia and Their Healthy Siblings.

OBJECTIVE: Retinal structural changes which were investigated by optical coherence tomography (OCT) have been reported in schizophrenia. Since cognitive dysfunction is a core feature of schizophrenia, the correlations between retinal findings and cognitive functions of patients and their healthy siblings may provide insight into the pathophysiological processes of the disorder. We aimed to investigate the relationship between neuropsychiatric tests and retinal changes in schizophrenia patients and their healthy siblings. METHODS: We measured OCT parameters and cognitive performance (via Trail Making Tests, verbal fluency tests, and The Digit Span Tests) of 72 participants (36 patients with schizophrenia and 36 healthy siblings) and disease severity (with Positive and Negative Syndrome Scale, Global Assessment of Functioning, and Clinical Global Impression scales) in patients with schizophrenia and evaluated the relationship between retinal findings and clinical parameters, especially neurocognitive tests. RESULTS: We found decreased ganglion cell layer-inner plexiform layer thickness and macular volume in the patient group. There were strong correlations between neurocognitive tests and OCT findings in both groups. On the other hand, there was not any correlation between retinal findings and disease parameters. CONCLUSION: The cognitive symptoms of schizophrenia may be more closely related to structural changes in the retina.

A Longitudinal Investigation of Blood Neurofilament Light Chain Levels in Chronic Cocaine Users.

The identification of a blood marker of brain pathology that is sensitive to substance-induced neurotoxicity and dynamically responds to longitudinal changes in substance intake would substantially improve clinical monitoring in the field of substance use and addiction. Here, we explored the hypothesis that plasma levels of neurofilament light chain (NfL), a promising marker of neuroaxonal pathology, are elevated in chronic cocaine users and longitudinally associated with changes in cocaine use. Plasma NfL levels were determined using single molecule array (SIMOA) technology at baseline and at a 4-month follow-up. Substance use was subjectively assessed with an extensive interview and objectively measured via toxicological analysis of urine and 4-month hair samples. In a generalized linear model corrected for sex, age, and body mass index, NfL plasma levels were elevated in cocaine users (n=35) compared to stimulant-naïve healthy controls (n=35). A positive correlation between cocaine hair concentration and NfL levels was also found. Changes in cocaine hair concentration (group analysis of increasers vs. decreasers) over the 4-month interval predicted NfL levels at follow-up, indicating a rise in NfL with increased cocaine use and a reduction with decreased use. No associations between use or change of use of other substances (including the neurotoxic cocaine adulterant levamisole) and NfL levels were found. Our findings demonstrate that NfL is a sensitive marker for assessing cocaine-related neuroaxonal pathology, supporting the utility of blood NfL analysis in addiction research but also suggesting the detailed assessment of substance use in neurological studies and diagnostics.

Gender and sex in eating disorders: A narrative review of the current state of knowledge, research gaps, and recommendations.

INTRODUCTION: Eating disorders (EDs) have long been considered conditions exclusively affecting women, and studies in the ED field regularly exclude men. Research efforts are needed to better understand the role of gender and sex in EDs. This review describes the role of gender and sex in the development of EDs from a biopsychosocial perspective. METHODS: The primary hypothesis of this narrative review is that gender and sex interact to influence ED risk. The literature review was conducted using the PubMed database. RESULTS: This review first presents the general characteristics and prevalence of EDs according to gender and sex. Next, neurodevelopmental processes, neurobiology, gender roles, body image, and the minority stress model are addressed. Lastly, research perspectives to better include gender and sex in the field of EDs are discussed (e.g., representation of gender and sex diversities, development of appropriate assessment tools, and increasing awareness). CONCLUSION: Although substantial knowledge gaps remain, there is a growing recognition of the importance of integrating gender and sex in ED research that holds promise for further development in the field.

The decoupling of structural and functional connectivity of auditory networks in individuals at clinical high-risk for psychosis.

OBJECTIVES: Disrupted auditory networks play an important role in the pathophysiology of psychosis, with abnormalities already observed in individuals at clinical high-risk for psychosis (CHR). Here, we examine structural and functional connectivity of an auditory network in CHR utilising state-of-the-art electroencephalography and diffusion imaging techniques. METHODS: Twenty-six CHR subjects and 13 healthy controls (HC) underwent diffusion MRI and electroencephalography while performing an auditory task. We investigated structural connectivity, measured as fractional anisotropy in the Arcuate Fasciculus (AF), Cingulum Bundle, and Superior Longitudinal Fasciculus-II. Gamma-band lagged-phase synchronisation, a functional connectivity measure, was calculated between cortical regions connected by these tracts. RESULTS: CHR subjects showed significantly higher structural connectivity in the right AF than HC (p < .001). Although non-significant, functional connectivity between cortical areas connected by the AF was lower in CHR than HC (p = .078). Structural and functional connectivity were correlated in HC (p = .056) but not in CHR (p = .29). CONCLUSIONS: We observe significant differences in structural connectivity of the AF, without a concomitant significant change in functional connectivity in CHR subjects. This may suggest that the CHR state is characterised by a decoupling of structural and functional connectivity, possibly due to abnormal white matter maturation.

Poststroke psychosis: a case report.

BACKGROUND: Stroke is currently the second leading cause of death in the elderly population. Neuropsychiatric complications following stroke are common, can be overlooked, and are associated with low quality of life, increase in the burden of caregiving and impaired functional status. METHODS: We report a case of poststroke psychosis in a woman without prior psychiatric history. In addition, a brief, nonsystematic review of the pertinent literature was performed. RESULTS: Psychosis can present in almost 5% of stroke survivors. Many patients with poststroke psychosis have no previous psychiatric history and the most common lesion locations include the right frontal, temporal and parietal lobes, the white matter connecting those areas, as well as the right caudate nucleus. Compared to other stroke survivors, patients with poststroke psychosis are more likely to depend on assistance in their everyday lives, can have more difficulty coping with the sequelae of stroke, and have an increased 10-year mortality risk. Guidelines for diagnosing and managing poststroke psychosis are needed. CONCLUSION: Psychosis is a possible complication of stroke and is associated with impairment and increased mortality. Guidelines for diagnosing and managing poststroke psychosis are currently lacking. To assure evidence-based care, further research is needed.

Connectome-based predictive modelling can predict follow-up craving after abstinence in individuals with opioid use disorders.

Background: Individual differences have been detected in individuals with opioid use disorders (OUD) in rehabilitation following protracted abstinence. Recent studies suggested that prediction models were effective for individual-level prognosis based on neuroimage data in substance use disorders (SUD). Aims: This prospective cohort study aimed to assess neuroimaging biomarkers for individual response to protracted abstinence in opioid users using connectome-based predictive modelling (CPM). Methods: One hundred and eight inpatients with OUD underwent structural and functional magnetic resonance imaging (fMRI) scans at baseline. The Heroin Craving Questionnaire (HCQ) was used to assess craving levels at baseline and at the 8-month follow-up of abstinence. CPM with leave-one-out cross-validation was used to identify baseline networks that could predict follow-up HCQ scores and changes in HCQ (HCQfollow-up-HCQbaseline). Then, the predictive ability of identified networks was tested in a separate, heterogeneous sample of methamphetamine individuals who underwent MRI scanning before abstinence for SUD. Results: CPM could predict craving changes induced by long-term abstinence, as shown by a significant correlation between predicted and actual HCQfollow-up (r=0.417, p<0.001) and changes in HCQ (negative: r=0.334, p=0.002；positive: r=0.233, p=0.038). Identified craving-related prediction networks included the somato-motor network (SMN), salience network (SALN), default mode network (DMN), medial frontal network, visual network and auditory network. In addition, decreased connectivity of frontal-parietal network (FPN)-SMN, FPN-DMN and FPN-SALN and increased connectivity of subcortical network (SCN)-DMN, SCN-SALN and SCN-SMN were positively correlated with craving levels. Conclusions: These findings highlight the potential applications of CPM to predict the craving level of individuals after protracted abstinence, as well as the generalisation ability; the identified brain networks might be the focus of innovative therapies in the future.

Corrigendum to "Schizophrenia: a narrative review of etiological and diagnostic issues" (Consortium Psychiatricum, 2022, Volume 3, Issue 3, doi: 10.17816/CP132).

[This corrects the article DOI: 10.17816/CP132.].