Journal of psychiatry and brain science最新文献

Comorbid posttraumatic stress disorder and major depressive disorder (PTSD + MDD) is the most common pathological response to trauma, yet despite their synergistic detriment to health, knowledge regarding the neurobiological mechanism underlying PTSD + MDD is extremely limited. This study proposes a novel model of PTSD + MDD that is built on biological systems shown to underlay PTSD + MDD and takes advantage of ketamine's unique suitability to probe PTSD + MDD due to its rescue of stress-related neuroplasticity deficits. The central hypothesis is that changes in PTSD + MDD clinical symptoms are associated with functional connectivity changes and cognitive dysfunction and that ketamine infusions improve clinical symptoms by correction of functional connectivity changes and improvement in cognition. Participants with PTSD + MDD (n = 42) will be randomized to receive a series of six ketamine infusions or saline-placebo over three weeks. Pre/post-measures will include: (1) neuroimaging; (2) cognitive functioning task performance; and (3) PTSD, MDD, and rumination self-report measures. These measures will also be collected once in a trauma-exposed group including PTSD-only (n = 10), trauma-exposed-MDD (TE-MDD; n = 10), and healthy controls (HC, n = 21). Successful completion of the study will strongly support the concept of a biologically-based model of PTSD + MDD. The results will (1) identify functional imaging signatures of the mechanisms underpinning pathological responses to trauma, (2) shift focus from mono-diagnostic silos to unified biological and behavioral disease processes and, thus, (3) inform interventions to correct dysregulation of PTSD + MDD symptom clusters thereby supporting more precise treatments and better outcomes.

The prevalence of non-suicidal self-injury (NSSI) is high in adolescents and young adults. However, there is a paucity of evidence-based treatments to address this clinical problem. An open-label, pilot study in the target population showed that treatment with oral N-acetylcysteine (NAC), a widely available dietary supplement, was associated with reduction in NSSI frequency. In preparation for a biologically informed design of an efficacy trial, a critical preliminary step is to clarify NAC's biological signatures, or measures of the mechanisms underlying its clinical effects. Toward that end, we propose a 2-stage project to investigate NAC's biological signatures (changes in glutathione (GSH) and/or glutamate (Glu)) in women with NSSI. The first stage; a double-blind randomized placebo-controlled study will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term (4 weeks) NAC treatment in 36 women aged 16-24 years with NSSI. Go/No-go criteria to determine if the study will progress to the second stage include pre-specified changes in brain and blood measures of GSH. Changes in the brain GSH are measured through magnetic resonance spectroscopy (MRS). The dose for the stage 2 will be selected based on the biological changes and the tolerability observed in the stage 1. The stage 2 will seek to replicate the biological signature findings in an 8-week trial in a new patient cohort, and examine the relationships among biological signatures, NAC pharmacokinetics and clinical response. This 2-stage project is unique as it unifies clinical psychiatric measurements, quantitative MRS and pharmacological approaches in the first placebo-controlled clinical trial of NAC in young women with NSSI.

Trial registration: The stage 1 trial protocol has been registered on https://clinicaltrials.gov/ with ClinicalTrials.gov ID "NCT04005053" (Registered on 02 July 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04005053).

Reminders of loved ones have long been avoided during extinction-based treatments because of their assumed status as safety signals, which, by inhibiting fear in the moment, impair the long-term outcomes of fear extinction. Yet, recent work has demonstrated that in contrast to standard safety signals, social support reminders actually enhance fear extinction and lead to lasting reduction of fear, suggesting that they may have beneficial effects during exposure therapy that have before-now been overlooked. Here, we argue for a revision of the assumption that social support is detrimental to fear extinction processes and propose that future work should focus on the potential of social support reminders to improve treatment outcomes in those with anxiety disorders.

Over the last two decades, neuroscientists have used antidepressant placebo probes to examine the biological mechanisms implicated in antidepressant placebo effects. However, findings from these studies have not yet elucidated a model-based theory that would explain the mechanism through which antidepressant expectancies evolve to induce persistent mood changes. Emerging evidence suggests that antidepressant placebo effects may be informed by models of reinforcement learning (RL). Such that an individual's expectation of improvement is updated with the arrival of new sensory evidence, by incorporating a reward prediction error (RPE), which signals the mismatch between the expected (expected value) and perceived improvement. Consistent with this framework, neuroimaging studies of antidepressant placebo effects have demonstrated placebo-induced μ-opioid activation and increased blood-oxygen-level dependent (BOLD) responses in regions tracking expected values (e.g., ventromedial prefrontal cortex (vmPFC)) and RPEs (e.g., ventral striatum (VS)). In this study, we will demonstrate the causal contribution of reward learning signals (expected values and RPEs) to antidepressant placebo effects by experimentally manipulating expected values using transcranial magnetic stimulation (TMS) targeting the vmPFC and μ-opioid striatal RPE signal using pharmacological approaches. We hypothesized that antidepressant placebo expectancies are represented in the vmPFC (expected value) and updated by means of μ-opioid-modulated striatal learning signal. In a 3 × 3 factorial double-blind design, we will randomize 120 antidepressant-free individuals with depressive symptoms to one of three between-subject opioid conditions: the μ-opioid agonist buprenorphine, the μ-opioid antagonist naltrexone, or an inert pill. Within each arm, individuals will be assigned to receive three within-subject counterbalanced forms of TMS targeting the vmPFC-intermittent Theta Burst Stimulation (TBS) expected to potentiate the vmPFC, continuous TBS expected to de-potentiate the vmPFC, or sham TBS. These experimental manipulations will be used to modulate trial-by-trial reward learning signals and related brain activity during the Antidepressant Placebo functional MRI (fMRI) Task to address the following aims: (1) investigate the relationship between reward learning signals within the vmPFC-VS circuit and antidepressant placebo effects; (2) examine the causal contribution of vmPFC expected value computations to antidepressant placebo effects; and (3) investigate the causal contribution of μ-opioid-modulated striatal RPEs to antidepressant placebo effects. The proposed study will be the first to investigate the causal contribution of μ-opioid-modulated vmPFC-VS learning signals to antidepressant placebo responses, paving the way for developing novel treatments modulating learning processes and objective means of quantifying and potentially reducing placebo effects during drug development.

Schizophrenia is a disorder of the self. In particular, patients show cardinal deficits in self-agency (i.e., the experience and awareness of being the agent of one's own thoughts and actions) that directly contribute to positive psychotic symptoms of hallucinations and delusions and distort reality monitoring (defined as distinguishing self-generated information from externally-derived information). Predictive coding models suggest that the experience of self-agency results from a minimal prediction error between the predicted sensory consequence of a self-generated action and the actual outcome. In other words, the experience of self-agency is thought to be driven by making reliable predictions about the expected outcomes of one's own actions. Most of the agency literature has focused on the motor system; here we present a novel viewpoint that examines agency from a different lens using distinct tasks of reality monitoring and speech monitoring. The self-prediction mechanism that leads to self-agency is necessary for reality monitoring in that self-predictions represent a critical precursor for the successful encoding and memory retrieval of one's own thoughts and actions during reality monitoring to enable accurate self-agency judgments (i.e., accurate identification of self-generated information). This self-prediction mechanism is also critical for speech monitoring where we continually compare auditory feedback (i.e., what we hear ourselves say) with what we expect to hear. Prior research has shown that the medial prefrontal cortex (mPFC) may represent one potential neural substrate of this self-prediction mechanism. Unfortunately, patients with schizophrenia (SZ) show mPFC hypoactivity associated with self-agency impairments on reality and speech monitoring tasks, as well as aberrant mPFC functional connectivity during intrinsic measures of agency during resting states that predicted worsening psychotic symptoms. Causal neurostimulation and neurofeedback techniques can move the frontiers of schizophrenia research into a new era where we implement techniques to manipulate excitability in key neural regions, such as the mPFC, to modulate patients' reliance on self-prediction mechanisms on distinct tasks of reality and speech monitoring. We hypothesize these findings will show that mPFC provides a unitary basis for self-agency, driven by reliance on self-prediction mechanisms, which will facilitate the development of new targeted treatments in patients with schizophrenia.

Antibodies persist months and years in blood. Chronic presence of low titers of blood circulating anti-NMDAR1 autoantibodies are sufficient to impair cognitive function in the integrity of the BBB in mice, suggesting potential cognitive damaging effects of low titers of blood circulating anti-NMDAR1 autoantibodies in the general human population and psychiatric patients. Investigation of anti-NMDAR1 autoantibodies against individual NMDAR1 antigenic epitopes may potentially provide risk biomarkers and therapeutic targets for development of immunotherapy as a precision medicine for psychiatric patients in the future.

In the following grant report, we describe initial and planned work supported by our National Institute of Mental Health R01-funded, Research Domain Criteria (RDoc) informed project, "Dimensional Brain Behavior Predictors of CBT Outcomes in Pediatric Anxiety". This project examines response to cognitive behavioral therapy (CBT) in a large sample of anxiety-affected and low-anxious youth ages 7 to 18 years using multiple levels of analysis, including brain imaging, behavioral performance, and clinical measures. The primary goal of the project is to understand how brain-behavioral markers of anxiety-relevant constructs, namely acute threat, cognitive control, and their interaction, associate with CBT response in youth with clinically significant anxiety. A secondary goal is to determine whether child age influences how these markers predict, and/or change, across varying degrees of CBT response. Now in its fourth year, data from this project has informed the examination of (1) baseline (i.e., pre-CBT) anxiety severity as a function of brain-behavioral measures of cognitive control, and (2) clinical characteristics of youth and parents that associate with anxiety severity and/or predict response to CBT. Analysis of brain-behavioral markers before and after CBT will assess mechanisms of CBT effect, and will be conducted once the data collection in the full sample has been completed. This knowledge will help guide the treatment of clinically anxious youth by informing for whom and how does CBT work.

We report on the ongoing project "The New Tics Study: A Novel Approach to Pathophysiology and Cause of Tic Disorders," describing the work completed to date, ongoing studies and long-term goals. The overall goals of this research are to study the pathophysiology of Provisional Tic Disorder, and to study tic remission (or improvement) in a prospective fashion. Preliminary data collection for the project began almost 10 years ago. The current study is nearing completion of its third year, and has already reported several novel and important results. First, surprisingly, at least 90% of children who had experienced tics for only a mean of 3 months still had tics at the 12-month anniversary of their first tic, though in some cases tics were seen only with remote video observation of the child sitting alone. Thus almost all of them now had a DSM-5 diagnosis of Tourette's Disorder or Persistent (Chronic) Tic Disorder. Baseline clinical features that predicted 12-month outcome included tic severity, subsyndromal autism spectrum symptoms, an anxiety disorder, and a history of 3 or more phonic tics. Second, we found that poorer tic suppression ability when immediately rewarded for suppression predicted greater tic severity at follow-up. Third, striatal volumes did not predict outcome as hypothesized, but a larger hippocampus at baseline predicted worse severity at follow-up. Enrollment and data collection continue, including functional connectivity MRI (fcMRI) imaging, and additional analyses are planned once the full sample is enrolled.