Journal of psychiatry and brain science最新文献

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.

We report on the ongoing R21 project "Social Reward Learning in Schizophrenia". Impairments in social cognition are a hallmark of schizophrenia. However, little work has been done on social reward learning deficits in schizophrenia. The overall goal of the project is to assess social reward learning in schizophrenia. A probabilistic reward learning (PRL) task is being used in the MRI scanner to evaluate reward learning to negative and positive social feedback. Monetary reward learning is used as a comparison to assess specificity. Behavioral outcomes and brain areas, included those involved in reward, are assessed in patients with schizophrenia or schizoaffective disorder and controls. It is also critical to determine whether decreased expected value (EV) of social stimuli and/or reward prediction error (RPE) learning underlie social reward learning deficits to inform potential treatment pathways. Our central hypothesis is that the pattern of social learning deficits is an extension of a more general reward learning impairment in schizophrenia and that social reward learning deficits critically contribute to deficits in social motivation and pleasure. We hypothesize that people with schizophrenia will show impaired behavioral social reward learning compared to controls, as well as decreased ventromedial prefrontal cortex (vmPFC) EV signaling at time of choice and decreased striatal RPE signaling at time of outcome, with potentially greater impairment to positive than negative feedback. The grant is in its second year. It is hoped that this innovative approach may lead to novel and more targeted treatment approaches for social cognitive impairments, using cognitive remediation and/or brain stimulation.

Background: Results from studies using medical record data indicate chronic (>90 days) opioid analgesic use (OAU) is associated with new depressive episodes (NDE), worsening depression and risk for depression recurrence. This body of evidence is based on retrospective cohort studies and medical record data. Limitations of existing research are overcome in a new prospective cohort study of the opioid-depression relationship.

Methods: Prospective cohort of 1500 adult patients recruited from two health care systems. Eligible subjects started a new period of OAU and have 30 to 90 days of OAU at baseline. Diagnostic assessments for psychiatric disorders, structured measures of pain, pain functioning, opioid use, social support, sleep and impulsivity will be obtained at baseline, 6-month and 12-month follow-up. Baseline participants will be invited to 12 monthly brief assessments of pain-related functioning, depression symptoms and opioid use.

Innovation: Robust control for confounding by indication and detailed phenotyping of depression and opioid use disorder.

Anticipated results: Chronic OAU will be associated with new onset of a depression phenotype characterized by anhedonia and somatic symptoms. This relationship will be partly, but not completely explained by impaired functioning and low social support.

Conclusions: Although the annual number of opioid prescriptions in the United States has decreased, over 190 million patients have OAU each year. If chronic OAU leads to a clinically meaningful affective disorder, independent of pain, then we need to consider depression an important adverse effect of chronic OAU and adjust care for chronic pain accordingly.

ADHD is defined by behavioral symptoms that are not well characterized in relation to ADHD's neurobiological mechanisms. This approach has limited our ability to define ADHD nosology and predict outcomes because it does not systematically examine facets of the disorder such as the inability to maintain cognitively effortful activities, as promoted in the NIMH RDoC approach. Existing data indicate ADHD is associated with differences in reward valuation and processing, but we do not know whether ADHD is also associated with higher levels of aversion to exerting cognitive effort and/or altered reward x effort interactions. Our ongoing study addresses this knowledge gap by examining individuals' preferences between rewards associated with minimal effort and reward alternatives with a higher payoff but higher effort costs ("effort discounting"); thereby permitting us to characterize differences in biases and tradeoffs during effort-related decision-making in ADHD. The study takes advantage of a well-defined sample of ADHD-diagnosed and healthy control individuals to address three aims. First, we determine whether ADHD is associated with steeper discounting of larger, more effortful rewards. Second, we examine the subjective perception of effort in youth diagnosed with ADHD and healthy controls using tasks requiring varying levels of cognitive effort. Third, we explore relationships amongst indices of effort discounting, theoretically-related traits (e.g., grit, distress tolerance), biomarkers of effort-related decision-making (eye movements and pupil size), and various cognitive measures. Successful completion of the aims will permit us to better characterize ADHD-healthy control differences and lay a foundation for more computational approaches to ADHD diagnostic criteria.

Schizophrenia and other psychotic disorders are serious psychiatric disorders that are associated with substantial societal, family, and individual costs/distress. Evidence suggests that early intervention can improve prognostic outcomes; therefore, it is essential to accurately identify those at risk for psychosis before full psychotic symptoms emerge. The purpose of our study is to develop a brief, valid screening questionnaire to identify individuals at risk for psychosis in non-clinical populations across 3 large, community catchment areas with diverse populations. This is a needed study, as the current screening tools for at-risk psychotic populations in the US have been validated only in clinical and/or treatment seeking samples, which are not likely to generalize beyond these specialized settings. The specific aims are as follows: (1) to determine norms and prevalence rates of attenuated positive psychotic symptoms across 3 diverse, community catchment areas and (2) to develop a screening questionnaire, inclusive of both symptom-based and risk factor-based questions. Our study will develop an essential screening tool that will identify which individuals have the greatest need of follow-up with structured interviews in both research and clinical settings. Our study has the potential for major contributions to the early detection and prevention of psychotic disorders.

We report on the ongoing project "A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use." Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world's population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an "epidemic" of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a novel chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. In our initial preclinical studies, we demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain in five animal models. The overall goal of the project is to complete the investigational new drug (IND)-enabling preclinical studies of Kindolor, and once IND approval is gained, we will proceed to the clinical Phase Ia and 1b safety studies and a Phase 2a efficacy study. The work is in its second year, and the present report describes progress toward our overall goal of bringing our compound to a full Phase 2 ready stage.

Major depressive disorder (MDD) is a serious public health problem that has, at best, modest treatment response-potentially due to its heterogeneous clinical presentation. One way to parse the heterogeneity is to investigate the role of particular features of MDD, an endeavor that can also help identify novel and focal targets for treatment and prevention efforts. Our R01 focuses on the feature of psychomotor disturbance (e.g., psychomotor agitation (PmA) and retardation (PmR)), a particularly pernicious feature of MDD, that has not been examined extensively in MDD. Aim 1 is comparing three groups of individuals-those with current MDD (n = 100), remitted MDD (n = 100), and controls (n = 50)-on multiple measures of PmR and PmA (assessed both in the lab and in the subjects' natural environment). Aim 2 is examining the structural (diffusion MRI) and functional (resting state fMRI) connectivity of motor circuitry of the three groups as well as the relation between motor circuitry and the proposed indicators of PmR and PmA. Aim 3 is following up with subjects three times over 18 months to evaluate whether motor symptoms change in tandem with overall depressive symptoms and functioning over time and/or whether baseline PmR/PmA predicts course of depression and functioning. Aim 3 is particularly clinically significant. Finding that motor functioning and overall depression severity co-vary over time, or that motor variables predict subsequent change in overall depression severity, would support the potential clinical utility of these novel, reliable, and easily administered motor assessments.