Journal of psychiatry and brain science最新文献

High titers of anti-NMDAR1 IgG autoantibodies were found in the brains of patients with anti-NMDAR1 encephalitis that exhibits psychosis, impaired memory, and many other psychiatric symptoms in addition to neurological symptoms. Low titers of blood circulating anti-NMDAR1 IgG autoantibodies are sufficient to robustly impair spatial working memory in mice with intact blood-brain barriers (BBB). On the other hand, anti-NMDAR1 autoantibodies were reported to protect against neuronal excitotoxicity caused by excessive glutamate in neurological diseases. Activation of extrasynaptic NMDARs is responsible for neuronal excitotoxicity, whereas activation of synaptic NMDARs within the synaptic cleft is pro-survival and essential for NMDAR-mediated neurotransmission. Unlike small IgG, IgM antibodies are large and pentameric (diameter of ~30 nm). It is plausible that IgM anti-NMDAR1 autoantibodies may be restricted to bind extrasynaptic NMDARs and thereby specifically inhibit neuronal excitotoxicity, but physically too large to enter the synaptic cleft (width: 20-30 nm) to suppress synaptic NMDAR-mediated neurotransmission in modulation of cognitive function and neuronal pro-survival signaling. Hence, blood circulating anti-NMDAR1 IgM autoantibodies are both neuroprotective and pro-cognitive, whereas blood circulating anti-NMDAR1 IgG and IgA autoantibodies are detrimental to cognitive function. Investigation of anti-NMDAR1 IgM autoantibodies may open up a new avenue for the development of long-lasting preventive and therapeutic IgM anti-NMDAR1 autoantibodies that protect from neuronal excitotoxicity in many neurological diseases and psychiatric disorders.

The risk for developing schizophrenia is increased among first-degree relatives of those with psychotic disorders, but the risk is even higher in those meeting established criteria for clinical high risk (CHR), a clinical construct most often comprising of attenuated psychotic experiences. Conversion to psychosis among CHR youth has been reported to be about 15-35% over three years. Accurately identifying individuals whose psychotic symptoms will worsen would facilitate earlier intervention, but this has been difficult to do using behavior measures alone. Brain-based risk markers have the potential to improve the accuracy of predicting outcomes in CHR youth. This narrative review provides an overview of neuroimaging studies used to investigate psychosis risk, including studies involving structural, functional, and diffusion imaging, functional connectivity, positron emission tomography, arterial spin labeling, magnetic resonance spectroscopy, and multi-modality approaches. We present findings separately in those observed in the CHR state and those associated with psychosis progression or resilience. Finally, we discuss future research directions that could improve clinical care for those at high risk for developing psychotic disorders.

Astrocytes, despite some shared features as glial cells supporting neuronal function in gray and white matter, participate and adapt their morphology and neurochemistry in a plethora of distinct regulatory tasks in specific neural environments. In the white matter, a large proportion of the processes branching from the astrocytes' cell bodies establish contacts with oligodendrocytes and the myelin they form, while the tips of many astrocyte branches closely associate with nodes of Ranvier. Stability of myelin has been shown to greatly depend on astrocyte-to-oligodendrocyte communication, while the integrity of action potentials that regenerate at nodes of Ranvier has been shown to depend on extracellular matrix components heavily contributed by astrocytes. Several lines of evidence are starting to show that in human subjects with affective disorders and in animal models of chronic stress there are significant changes in myelin components, white matter astrocytes and nodes of Ranvier that have direct relevance to connectivity alterations in those disorders. Some of these changes involve the expression of connexins supporting astrocyte-to-oligodendrocyte gap junctions, extracellular matrix components produced by astrocytes around nodes of Ranvier, specific types of astrocyte glutamate transporters, and neurotrophic factors secreted by astrocytes that are involved in the development and plasticity of myelin. Future studies should further examine the mechanisms responsible for those changes in white matter astrocytes, their putative contribution to pathological connectivity in affective disorders, and the possibility of leveraging that knowledge to design new therapies for psychiatric disorders.

Endogenous neuropeptide Oxytocin (OXT) plays a crucial role in modulating pro-social behavior and the neural response to social/emotional stimuli. Intranasal administration is the most common method of delivering OXT. Intranasal OXT has been implemented in clinical studies of various psychiatric disorders with mixed results, mainly related to lack of solid pharmacodynamics and pharmacokinetics model. Due to intranasal OXT's mechanism of reducing the activation of neural areas implicated in emotional responding and emotion regulation, a psychopathology with this target mechanism could be potentially excellent candidate for future clinical trial. In this regard, irritability in youth may be a very promising target for clinical studies of intranasal OXT. Here we provide a mini-review of fifteen randomized controlled trials in pediatric patients with diagnoses of autism spectrum disorder (ASD), Prader-Willi syndrome (PWS), or Phelan-McDermid syndrome (PMS). Most studies had small sample sizes and varying dosages, with changes in irritability, mainly as adverse events (AEs). Neuroimaging results showed modulation of the reward processing system and the neural areas implicated in social-emotional information processing by intranasal OXT administration. Further research is needed to determine the most effective dose and duration of OXT treatment, carefully select target psychopathologies, verify target engagement, and measure adverse event profiles.

Depression is the most common mental illness in the U.S. affecting nearly 40 million adults age 18 years and older. Depression has both genetic and environmental influences. In addition, women are more likely to be affected by depression than men. However, the relationship between genes and depression is complex and may be influenced by sex. Understanding the genetic basis of sex-specific differences for depression has the potential to lead to new biological understanding of the etiology of depression in females compared to males and to promote the development of novel and more effective pharmacotherapies. This review examines the role of sex in genetic associations with depression for both genome-wide association and candidate gene studies. While the genetic association signals of depression differ by sex, the role of sex in the heritability of depression is complex and warrants further investigation.

Affective reactions to acute stressors often evoke exacerbations of psychotic symptoms and sometimes de novo psychotic symptoms and initial psychotic episodes. Across the lifespan, affective reactions to acute stressors are enhanced by successive adverse childhood experiences (ACEs), in a process called "behavioral sensitization". The net effects of behavioral sensitization of acute stress responses are to alter responsivity to positive and negative feedback and to unexpected events, regardless of valence, leading to the maladaptive assignment of salience to stimuli and events. The assignment of "aberrant" salience to stimuli and events has profound consequences for learning and decision-making, which can influence both the positive and negative symptoms of psychosis. In this review, we discuss some of the psychological and neural mechanisms by which affective reactivity to acute stress, and its sensitization through the experience of stress and trauma across the lifespan, impact both the positive and negative symptoms of psychosis. We recount how the reward and salience networks of the brain, together with inputs from the dopamine and serotonin neurotransmitter systems, are implicated in both affective reactivity to stress and the symptoms of psychosis, likely mediate the effects of stress and trauma on the symptoms of psychosis and could serve as targets for interventions.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by early-onset repetitive behaviors, restricted interests, sensory and motor difficulties, and impaired social interactions. Converging evidence from neuroimaging, lesion and postmortem studies, and rodent models suggests cerebellar involvement in ASD and points to promising targets for therapeutic interventions for the disorder. This review elucidates understanding of cerebellar mechanisms in ASD by integrating and contextualizing recent structural and functional cerebellar research.