Pub Date : 2021-01-01Epub Date: 2021-04-08DOI: 10.20900/jpbs.20210005
Carol B Peterson, Ann F Haynos, Bryon A Mueller, Ross D Crosby, Stephen A Wonderlich, Lisa M Anderson, Carolyn M Pearson, Molly Fennig, Erin Gallagher, Kathryn R Cullen
The purpose of this investigation is to identify the anticipatory reward mechanisms that maintain binge eating and purging in bulimia nervosa. Emerging data indicate the importance of reward and anticipatory processes as maintenance mechanisms of bulimia nervosa that can be targeted in treatment. The proposed research will identify neurobiological and psychological anticipatory mechanisms of binge eating and purging using functional magnetic resonance imaging (fMRI), and ecological momentary assessment (EMA) in the natural environment. In this investigation, 60 adults (30 with bulimia nervosa and 30 matched comparison participants) will undergo negative and positive mood inductions followed by an fMRI food selection task (and a comparison shopping task) to examine neurobiological and affective responses to food and non-food reward anticipation. Participants with bulimia nervosa will complete two weeks of EMA examining real-time affect changes in relation to the anticipation of binge eating and purging. These methods will facilitate rigorous assessment of the links between neurobiological (fMRI) and naturalistic (EMA) data in anticipatory reward processes. Findings from this investigation will inform the conceptualization and treatment of bulimia nervosa by identifying the role of reward anticipation in symptom maintenance, providing a crucial framework for targeting these anticipatory processes in existing and novel interventions.
{"title":"Neurobiological and Psychological Maintenance Mechanisms Associated with Anticipatory Reward in Bulimia Nervosa.","authors":"Carol B Peterson, Ann F Haynos, Bryon A Mueller, Ross D Crosby, Stephen A Wonderlich, Lisa M Anderson, Carolyn M Pearson, Molly Fennig, Erin Gallagher, Kathryn R Cullen","doi":"10.20900/jpbs.20210005","DOIUrl":"https://doi.org/10.20900/jpbs.20210005","url":null,"abstract":"<p><p>The purpose of this investigation is to identify the anticipatory reward mechanisms that maintain binge eating and purging in bulimia nervosa. Emerging data indicate the importance of reward and anticipatory processes as maintenance mechanisms of bulimia nervosa that can be targeted in treatment. The proposed research will identify neurobiological and psychological anticipatory mechanisms of binge eating and purging using functional magnetic resonance imaging (fMRI), and ecological momentary assessment (EMA) in the natural environment. In this investigation, 60 adults (30 with bulimia nervosa and 30 matched comparison participants) will undergo negative and positive mood inductions followed by an fMRI food selection task (and a comparison shopping task) to examine neurobiological and affective responses to food and non-food reward anticipation. Participants with bulimia nervosa will complete two weeks of EMA examining real-time affect changes in relation to the anticipation of binge eating and purging. These methods will facilitate rigorous assessment of the links between neurobiological (fMRI) and naturalistic (EMA) data in anticipatory reward processes. Findings from this investigation will inform the conceptualization and treatment of bulimia nervosa by identifying the role of reward anticipation in symptom maintenance, providing a crucial framework for targeting these anticipatory processes in existing and novel interventions.</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38954751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-02-26DOI: 10.20900/jpbs.20210004
Munirul M Haque, Masud Rabbani, Dipranjan Das Dipal, Md Ishrak Islam Zarif, Anik Iqbal, Shaheen Akhter, Shahana Parveen, Mohammad Rasel, Golam Rabbani, Faruq Alam, Tanjir Rashid Soron, Syed Ishtiaque Ahmed, Sheikh Iqbal Ahamed
In low- and middle-income countries, especially in Bangladesh, Autism Spectrum Disorder (ASD) may be considered an anathema, and social-cultural-financial constraints mean that there are few facilities available for treatment for ASD children. The revolution in the use of the mobile phone (~80%) by the majority of people in Bangladesh in recent years has created an opportunity to improve the overall scenario in the treatment or remote monitoring process for children with ASD. In this grant project, we planned and developed a mobile phone-based system to remotely monitor children with ASD and help their treatment process both at the caregiver and care practitioner ends. In developing mCARE, we utilized a Remote Experience Sampling Method to design, build, deploy, and study the impact of mobile based monitoring and treatment of children with ASD in Bangladesh. We developed a mobile application using the Experience Sampling Method (ESM). A caregiver routinely reported the behavioral and milestone parameters of their children with ASD. The care practitioners monitored the longitudinal data that helped them in decision-making in a particular patient's treatment process. The Value Sensitive Design (VSD) was used to make this mobile application more user friendly with consideration of the local economic, social, and cultural values in Bangladesh.
{"title":"Grant Report on mCARE: Mobile-Based Care for Children with Autism Spectrum Disorder (ASD) for Low- and Middle-Income Countries (LMICs).","authors":"Munirul M Haque, Masud Rabbani, Dipranjan Das Dipal, Md Ishrak Islam Zarif, Anik Iqbal, Shaheen Akhter, Shahana Parveen, Mohammad Rasel, Golam Rabbani, Faruq Alam, Tanjir Rashid Soron, Syed Ishtiaque Ahmed, Sheikh Iqbal Ahamed","doi":"10.20900/jpbs.20210004","DOIUrl":"https://doi.org/10.20900/jpbs.20210004","url":null,"abstract":"<p><p>In low- and middle-income countries, especially in Bangladesh, Autism Spectrum Disorder (ASD) may be considered an anathema, and social-cultural-financial constraints mean that there are few facilities available for treatment for ASD children. The revolution in the use of the mobile phone (~80%) by the majority of people in Bangladesh in recent years has created an opportunity to improve the overall scenario in the treatment or remote monitoring process for children with ASD. In this grant project, we planned and developed a mobile phone-based system to remotely monitor children with ASD and help their treatment process both at the caregiver and care practitioner ends. In developing mCARE, we utilized a Remote Experience Sampling Method to design, build, deploy, and study the impact of mobile based monitoring and treatment of children with ASD in Bangladesh. We developed a mobile application using the Experience Sampling Method (ESM). A caregiver routinely reported the behavioral and milestone parameters of their children with ASD. The care practitioners monitored the longitudinal data that helped them in decision-making in a particular patient's treatment process. The Value Sensitive Design (VSD) was used to make this mobile application more user friendly with consideration of the local economic, social, and cultural values in Bangladesh.</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25537615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-06-29DOI: 10.20900/jpbs.20210012
C Sophia Albott, Sey Lee, Kathryn R Cullen, Paul Thuras, Shmuel Lissek, Joseph Wels, Katrina J Friedrich, Alyssa M Krueger, Kelvin O Lim
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.
{"title":"Characterization of Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder Using Ketamine as an Experimental Medicine Probe <sup>†</sup>.","authors":"C Sophia Albott, Sey Lee, Kathryn R Cullen, Paul Thuras, Shmuel Lissek, Joseph Wels, Katrina J Friedrich, Alyssa M Krueger, Kelvin O Lim","doi":"10.20900/jpbs.20210012","DOIUrl":"https://doi.org/10.20900/jpbs.20210012","url":null,"abstract":"<p><p>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 (<i>n</i> = 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 (<i>n</i> = 10), trauma-exposed-MDD (TE-MDD; <i>n</i> = 10), and healthy controls (HC, <i>n</i> = 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.</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39504314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-04-29DOI: 10.20900/jpbs.20210007
Siddhee A Sahasrabudhe, Thanharat Silamongkol, Young Woo Park, Alanna Colette, Lynn E Eberly, Bonnie Klimes-Dougan, Lisa D Coles, James C Cloyd, Gülin Öz, Bryon A Mueller, Reena V Kartha, Kathryn R Cullen
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).
{"title":"Identifying Biological Signatures of N-Acetylcysteine for Non-Suicidal Self-Injury in Adolescents and Young Adults.","authors":"Siddhee A Sahasrabudhe, Thanharat Silamongkol, Young Woo Park, Alanna Colette, Lynn E Eberly, Bonnie Klimes-Dougan, Lisa D Coles, James C Cloyd, Gülin Öz, Bryon A Mueller, Reena V Kartha, Kathryn R Cullen","doi":"10.20900/jpbs.20210007","DOIUrl":"10.20900/jpbs.20210007","url":null,"abstract":"<p><p>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.</p><p><strong>Trial registration: </strong>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).</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39032651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-06-28DOI: 10.20900/jpbs.20210010
Erica A Hornstein, Naomi I Eisenberger
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.
{"title":"An Argument for Reconsidering the Role of Social Support in Treating Anxiety Disorders.","authors":"Erica A Hornstein, Naomi I Eisenberger","doi":"10.20900/jpbs.20210010","DOIUrl":"https://doi.org/10.20900/jpbs.20210010","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39221251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-02-15DOI: 10.20900/jpbs.20210001
Marta Peciña, Alexandre Y Dombrovski, Rebecca Price, Helmet T Karim
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.
{"title":"Understanding the Neurocomputational Mechanisms of Antidepressant Placebo Effects.","authors":"Marta Peciña, Alexandre Y Dombrovski, Rebecca Price, Helmet T Karim","doi":"10.20900/jpbs.20210001","DOIUrl":"10.20900/jpbs.20210001","url":null,"abstract":"<p><p>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.","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25490895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-10-14DOI: 10.20900/jpbs.20210017
Karuna Subramaniam
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.
{"title":"The Role of the Medial Prefontal Cortex in Self-Agency in Schizophrenia.","authors":"Karuna Subramaniam","doi":"10.20900/jpbs.20210017","DOIUrl":"https://doi.org/10.20900/jpbs.20210017","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39609948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-06-28DOI: 10.20900/jpbs.20210009
Xianjin Zhou
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.
{"title":"Cognitive Impact by Blood Circulating Anti-NMDAR1 Autoantibodies.","authors":"Xianjin Zhou","doi":"10.20900/jpbs.20210009","DOIUrl":"10.20900/jpbs.20210009","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39221252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. Tso, Carly A. Lasagna, K. Fitzgerald, C. Colombi, C. Sripada, S. Peltier, T. Johnson, Katharine N. Thakkar
Social dysfunction is an intractable problem in a wide spectrum of psychiatric illnesses, undermining patients’ capacities for employment, independent living, and maintaining meaningful relationships. Identifying common markers of social impairment across disorders and understanding their mechanisms are prerequisites to developing targeted neurobiological treatments that can be applied productively across diagnoses and illness stages to improve functional outcome. This project focuses on eye gaze perception, the ability to accurately and efficiently discriminate others’ gaze direction, as a potential biomarker of social functioning that cuts across psychiatric diagnoses. This premise builds on both the monkey and human literatures showing gaze perception as a basic building block supporting higher-level social communication and social development, and reports of abnormal gaze perception in multiple psychiatric conditions accompanied by prominent social dysfunction (e.g., psychosis-spectrum disorders, autism-spectrum disorders, social phobia). A large sample (n = 225) of adolescent and young adult (age 14–30) psychiatric patients (regardless of diagnosis) with various degrees of impaired social functioning, and demographically-matched healthy controls (n = 75) will be recruited for this study. Participant’s psychiatric phenotypes, cognition, social cognition, and community functioning will be dimensionally characterized. Eye gaze perception will be assessed using a psychophysical task, and two metrics (precision, self-referential bias) that respectively tap into gaze perception disturbances at the visual perceptual and interpretation levels, independent of general deficits, will be derived using hierarchical Bayesian modeling. A subset of the participants (150 psychiatric patients, 75 controls) will additionally undergo multimodal fMRI to determine the functional and structural brain network features of altered gaze perception. The specific aims of this project are three-fold: (1) Determine the generality of gaze perception disturbances in psychiatric patients with prominent social dysfunction; (2) Map behavioral indices of gaze perception disturbances to dimensions of psychiatric phenotypes and core functional domains; and (3) Identify the neural correlates of altered gaze perception in psychiatric patients with social dysfunction. Successfully completing these specific aims will identify the specific basic deficits, clinical profile, and underlying neural circuits associated with social dysfunction that can be used to guide targeted, personalized treatments, thus advancing NIMH’s Strategic Objective 1 (describe neural circuits associated with mental illnesses and map the connectomes for mental illnesses) and Objective 3 (develop new treatments based on discoveries in neuroscience and behavioral science).
{"title":"Disrupted Eye Gaze Perception as a Biobehavioral Marker of Social Dysfunction: An RDoC Investigation","authors":"I. Tso, Carly A. Lasagna, K. Fitzgerald, C. Colombi, C. Sripada, S. Peltier, T. Johnson, Katharine N. Thakkar","doi":"10.20900/JPBS.20200021","DOIUrl":"https://doi.org/10.20900/JPBS.20200021","url":null,"abstract":"Social dysfunction is an intractable problem in a wide spectrum of psychiatric illnesses, undermining patients’ capacities for employment, independent living, and maintaining meaningful relationships. Identifying common markers of social impairment across disorders and understanding their mechanisms are prerequisites to developing targeted neurobiological treatments that can be applied productively across diagnoses and illness stages to improve functional outcome. This project focuses on eye gaze perception, the ability to accurately and efficiently discriminate others’ gaze direction, as a potential biomarker of social functioning that cuts across psychiatric diagnoses. This premise builds on both the monkey and human literatures showing gaze perception as a basic building block supporting higher-level social communication and social development, and reports of abnormal gaze perception in multiple psychiatric conditions accompanied by prominent social dysfunction (e.g., psychosis-spectrum disorders, autism-spectrum disorders, social phobia). A large sample (n = 225) of adolescent and young adult (age 14–30) psychiatric patients (regardless of diagnosis) with various degrees of impaired social functioning, and demographically-matched healthy controls (n = 75) will be recruited for this study. Participant’s psychiatric phenotypes, cognition, social cognition, and community functioning will be dimensionally characterized. Eye gaze perception will be assessed using a psychophysical task, and two metrics (precision, self-referential bias) that respectively tap into gaze perception disturbances at the visual perceptual and interpretation levels, independent of general deficits, will be derived using hierarchical Bayesian modeling. A subset of the participants (150 psychiatric patients, 75 controls) will additionally undergo multimodal fMRI to determine the functional and structural brain network features of altered gaze perception. The specific aims of this project are three-fold: (1) Determine the generality of gaze perception disturbances in psychiatric patients with prominent social dysfunction; (2) Map behavioral indices of gaze perception disturbances to dimensions of psychiatric phenotypes and core functional domains; and (3) Identify the neural correlates of altered gaze perception in psychiatric patients with social dysfunction. Successfully completing these specific aims will identify the specific basic deficits, clinical profile, and underlying neural circuits associated with social dysfunction that can be used to guide targeted, personalized treatments, thus advancing NIMH’s Strategic Objective 1 (describe neural circuits associated with mental illnesses and map the connectomes for mental illnesses) and Objective 3 (develop new treatments based on discoveries in neuroscience and behavioral science).","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44398257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natalie de la Garrigue, Juliana Glasser, P. Sehatpour, D. Iosifescu, E. Dias, Marlene Carlson, Constance B. Shope, T. Sobeih, Tse-Hwei Choo, M. Wall, L. Kegeles, James E. Gangwisch, Megan R Mayer, Stephanie Brazis, Heloise M. De Baun, S. Wolfer, D. Bermudez, Molly S. Arnold, Danielle N. Rette, A. Meftah, M. Conant, J. Lieberman, Joshua T. Kantrowitz
We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a “gold-standard”.
{"title":"Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia †","authors":"Natalie de la Garrigue, Juliana Glasser, P. Sehatpour, D. Iosifescu, E. Dias, Marlene Carlson, Constance B. Shope, T. Sobeih, Tse-Hwei Choo, M. Wall, L. Kegeles, James E. Gangwisch, Megan R Mayer, Stephanie Brazis, Heloise M. De Baun, S. Wolfer, D. Bermudez, Molly S. Arnold, Danielle N. Rette, A. Meftah, M. Conant, J. Lieberman, Joshua T. Kantrowitz","doi":"10.20900/JPBS.20200018","DOIUrl":"https://doi.org/10.20900/JPBS.20200018","url":null,"abstract":"We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a “gold-standard”.","PeriodicalId":73912,"journal":{"name":"Journal of psychiatry and brain science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41841004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}