All symposium themes and talk titles are tentative and subject to change.
Risk and Resilience in PTSD: Analyzing Trajectories and New Treatment Approaches
Chair: Eric Vermetten (Leiden University Medical Center)
- Emerging Approaches and Interventions to PTSD
Speaker: Lisa Burback (University of Alberta)
Novel Trajectory Analyses in PTSD in large Japanese Cohorts
Speaker: Masanori Nagamine (National Defense Medical College Reseach Institute)
Emerging Approaches to Veterans after War in Ukraine - Novel Use of Ketamine in PTSD
Speaker: Iryna Frankova (Bogolometz Medical University)
Over the last four decades, the scientific landscape of PTSD has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. It is apparent that chronic PTSD is a systemic disorder with high allostatic load. The disorder poses a complex and heterogeneous challenge, is often resistant to conventional evidence-based treatments. Recent advances in PTSD research shed light on how staging approaches and trajectory analyses may help in tailoring interventions. A phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and recent recognition of a staging model position interventions in step with the progression of the pathophysiology. This symposium delves into these multifaceted challenges, introducing emerging treatment approaches and innovative pathways for PTSD management. First, Dr. Lisa Burback reviews emerging interventions arising from preclinical and clinical research, encompassing secondary prevention efforts, pharmacological and psychotherapeutic innovations, augmentation strategies, psychedelics, and neuromodulation interventions. She will present a PTSD staging model and phase orientation to guide rational treatment selection, enhancing personalized care.Second, Dr. Masanori Nagamine presents novel insights into PTSD heterogeneity by exploring unique symptom trajectories of risk and resilience in large longitudinal cohort of first responders after Great East JApan Earhtquake in Fukushima and veterans after participation in peacekeeping mission in South Sudan (UNMISS). Utilizing innovative analytic tools, his research deepens the understanding of diverse PTSD presentations.Third, Dr. Iryna Frankova shares her pioneering work on digital mental health interventions for PTSD in the context of war in Ukraine. She will also review novel combined use of ketamine and EMDR in war veterans in the war, presenting promising prospects for overcoming treatment barriers.The symposium endeavors to present these novel approaches to understanding PTSD, offering valuable opportunities for optimizing treatment outcomes. By highlighting leading-edge advancements, this symposium aims to rise to the challenges inherent in addressing PTSD and guides a new decade towards novel understandings and effective patient-centered care.
- Learning about importance of staging models in PTSD for better understanding how symptom progression can vary and impact treatment response
- Appraise innovative approaches to trajectory analyses in PTSD, including novel analytic tools and predictive pathways
- Discover emerging interventions for PTSD arising from preclinical and clinical research, including digital mental health strategies, pharmacological and psychotherapeutic innovations, psychedelics, and neuromodulation techniques
#PTSD #trajectories #pharmacotherapy #risk #resilience
Time for a Serotonin Rethink: New Discoveries in Serotonin Neuron Heterogeneity
Chair: Yu Ohmura (Chinese Institute for Brain Research (CIBR))
New Discoveries in 5-HT Neuron Diversity and Function Revealed Through Large Scale Neurophysiological Recordings
Speaker: Trevor Sharp (University of Oxford)
Contrasting Roles of Serotonin Neurons in the Dorsal and Median Raphe in Positive and Negative Emotions
Speaker: Kazuki Nagayasu (Kyoto University)
Activity Patterns of Serotonergic Neurons in Vivo During Emotional Behaviors
Speaker: Bradley Miller (Columbia University Irving Medical Center)
The neurotransmitter serotonin (5-HT) is crucially involved in regulating physiological and psychological processes linked to a wide range of neuropsychiatric disorders, and serotonin-targeted drugs play a central role in their clinical management (Sharp and Barnes, 2020). Many attempts have been made to uncover a unified mechanism that could account for serotonin’s many roles. However, recent research has revealed a remarkable and unexpected heterogeneity within the serotonin system, spanning from the cellular through to the integrated neural network levels. Thus, evidence suggests that the serotonin system does not contain a single unified code but that heterogeneous subsystems may account for serotonin’s diverse functions. This thinking has important implications for the way we envisage serotonin contributes to neuropsychiatric disorders and for developing better treatments. Thus, a future vision is that specific serotonin subsystems underpin different disorders and treatments that target these subsystems will have improved efficacy and fewer side effects. To this end, we need a comprehensive understanding of the heterogeneity in the serotonin system. Our symposium will delve into serotonin subsystems, providing a display of cutting-edge serotonin research and a platform for vibrant scientific discussions of the meaning of serotonin heterogeneity. Dr. Sharp will present the latest news on the population of serotonin-glutamate co-releasing neurons and the use of large-scale recordings to illustrate the complexity of serotonin neuron networks and their response to aversive stimuli or pharmacological manipulation. Dr. Nagayasu will present experiments utilizing optogenetics and fiber photometry combined with novel biosensors which uncover distinct roles of specific serotonin pathways in regulating emotional responding (Kawai et al., 2022). Dr. Miller will report his recent advances applying miniature microscopy to directly image the activity of serotonergic neurons in mice during emotional behaviors (Paquelet et al., 2022; 2023). With that approach, his group imaged the activity of over 2,000 genetically identified DRN-5HT neurons across a range of emotional behaviors spanning positive and negative valence. This revealed that, as a population, serotonergic neurons show large responses to both positive and negative valence stimuli, and their responses increase with the intensity (salience) of stimuli. However, at the individual neuron level, these studies found a great deal of heterogeneity in the specific stimuli that activate serotonergic neurons. As a whole, this symposium plans to reconcile earlier ideas on the global neuromodulatory role of serotonin neurons with new findings of a high level of diversity within these neurons and their role in emotional and cognitive functions. Through this, it aims to deepen our understanding of the role of serotonergic signaling in the cause and treatment of psychiatric disorders.
- Although attempts have been made to understand the role of the serotonergic nervous system in a unified manner, the serotonergic system is far from being a homogeneous entity. Our symposium aims to delve into these intricate subsystems, providing a platform for cutting-edge research and vibrant scientific discussions.
- Through this symposium, we aim to organize the role of the serotonergic nervous system in emotional and cognitive functions in light of its heterogeneity. By doing so, we will be able to elaborate strategies for developing drugs for treating psychiatric disorders.
#5-HT #serotonergic system
Targeting Autoantibodies: A Precision Medicine Approach in Psychotic Disorders
Chair: Belinda Lennox (University of Oxford)
•Prevalence of Serum Auto-Antibodies in Patients with Psychosis and Seizures
Speaker: Steven Siegel (University Southern California)
Anti-gliadin antibodies in severe mental illness
Speaker: Robert Yolken (Johns Hopkins University)
A novel targeted therapy for anti-NMDA receptor autoantibody-related disorders
Speaker: Mitsuyuki Matsumoto (Arialys Therapeutics)
Antipsychotics palliate, but do not cure, psychotic disorders. Moreover, up to a third of individuals with schizophrenia are considered treatment resistant. Despite the evident need for new and better treatments, biological heterogeneity in schizophrenia and related psychotic disorders has impeded therapeutic drug discovery. This session will review historical views and recent discoveries in the field of autoimmunity and psychotic disorders. Autoimmune-autoantibodies are a clear causal factor for certain specific autoimmune CNS diseases, such as anti-NMDAR encephalitis and neuromyelitis optica. Epidemiologic studies in genetically distinct populations consistently show an association between autoimmunity and psychotic disorders. Comorbid autoimmunity and severe infection further increase an individual’s risk for schizophrenia, highlighting the potential contribution of immune responses to the psychotic state. Evidence for autoimmunity in schizophrenia has also emerged from large genomic studies that have mapped a number of risk loci to gene enhancer regions in antibody-secreting B lymphocytes. Additionally, studies have found increased B cell numbers in acute psychosis, and elevated circulating autoantibodies in schizophrenia. Immunologic disturbances, such as elevated autoantibodies, could provide a strategy for subclassifying individuals with psychotic disorders. This session will provide you with updates on new findings in autoimmunity and psychotic disorders. The panelists will present unpublished subgroup profiling data in the context of autoimmunity and psychotic disorders. Robert Yolken (JHU) will present studies exploring the influence of gliadin antibodies in individuals with a range of serious psychiatric disorders. IgG antibodies to gliadin were measured in individuals with schizophrenia, bipolar disorder, major depressive disorder as well as control individuals without a psychiatric disorder. Increased odds of elevated levels of IgG gliadin antibodies were found in individuals with major depressive disorder (OR 2.93. 95% CI 1.65-5.22, p<.00013) and, to a lesser extent, in individuals with schizophrenia (OR 1.75, 95% CI 1.05-2.91, p<.03). Elevated levels of antibodies to gliadin were also found in individuals with a psychiatric disorder who had undergone a recent suicide attempt (OR 2.25, 95% CI 1.2-4.2, p<.011). The suppression of gliadin antibodies may provide a therapeutic approach for the prevention and treatment of serious psychiatric disorders. Steven Siegel (USC) will describe data from a current study exploring the prevalence and associated symptoms of neuronal auto-antibodies in patients with psychosis and seizures. Serum auto-antibodies were present in psychotic patients, with D1R antibodies present in higher levels than healthy controls. There were symptomatic differences between psychotic patients with and without a neuronal auto-antibody. These data indicate that immune etiologies of psychosis and autistic behaviors may be more prevalent than is currently understood. Mitsuyuki Matsumoto (Arialys) will present data on a novel monoclonal humanized one-armed antibody blocking therapy for anti-NMDAR autoantibody-related disorders to treat the spectrum of neurological and psychiatric manifestations of these disorders. The detection of autoantibodies indicates novel approaches for identifying and treating autoimmune subgroups of patients with psychiatric disorders. Immunotherapies targeting well-curated subgroups may ultimately benefit treatment-resistant individuals or even be curative in some cases.
- Participants will be able to describe the evidence and implications of increased anti-Dopamine Type 1 Receptor (D1R) antibodies in subjects with psychosis as compared to healthy controls and seizure disorder.
- Participants will be able to describe the relevance of gliadin antibodies in severe mental illness
- Recent progresses in anti-NMDA receptor autoantibody-related disorders and new treatment approaches
#neuroimmunology #IgG antibodies #autoimmunity #NMDAR antibodies #psychoimmunology
Targeting Neural Circuits for Therapeutic Intervention in Altered Salience and Reward Related Psychiatric Conditions
Chair: Huai-Hsuan Tseng (National Cheng Kung University)
Alteration of Salience and Reward Processing, Cognitive and Social Cognitive Deficits in Bipolar Disorder and Schizophrenia
Speaker: Huai-Hsuan Tseng (National Cheng Kung University)
Neural Circuits for Jumping to Conclusions, Cognition/Metacognition, and Ego-disturbance in Psychosis/Schizophrenia
Speaker: Jun Miyata (Kyoto University)
Altered Triple-Network Resting-State Functional Connectivity in Adolescents with Problematic Internet Use
Speaker: Kristiana Siste (University of Indonesia)
A hyper-dopaminergic state in the hippocampus-midbrain-striatal circuit is observed across different psychiatric conditions, including schizophrenia, bipolar disorder, substance use, and behavioral addiction. This aberrant dopaminergic activity is further associated with altered functional connectivity within and between the salience network, which presents a potential target for developing novel therapeutic interventions.In the first session, Dr. Huai-Hsuan Tseng will discuss the altered nigral-striatal-cortical dopamine pathway in those with a first episode and those at clinical high risk for psychosis (CHR). An elevated dopamine responsiveness to stress is observed, though it's less prominent in CHR. Intriguingly, an increased response in the caudate nucleus during the processing of emotional stimuli was also noted in CHR. Dr. Tseng further examines frontostriatal connectivity in patients with euthymic bipolar disorders and found that stronger dorsal striatum-ventrolateral prefrontal cortex connectivity correlated with poorer cognitive and social cognitive function in the euthymic BD group. Moreover, frontostriatal connectivity significantly correlated with higher levels of peripheral inflammation.The second speaker, Dr. Jun Miyata, delves into the aberrant salience hypothesis and examines the relationship between delusions, hallucinations, and the jumping-to-conclusions (JTC) bias, which refers to requiring a lesser amount of evidence for decision-making compared to healthy individuals. Dr. Miyata revealed that the functional connectivity of the striatum was associated with both JTC and delusions/hallucinations. People with schizophrenia often exhibit mild yet broad cognitive issues, while delusion is a metacognition problem. The commonalities and specifics of the neural correlates of cognition and metacognition remained elusive. Dr. Miyata demonstrated that the default mode network (DMN) may contribute to both. Finally, experiences deemed as delusion in English/American psychiatry are considered ego-disturbance in German psychiatry and are studied as the sense of agency/self. The relationship between aberrant salience and ego disturbance was unclear. Dr. Miyata identified an association between the subjective experience of aberrant salience and a sense of self.The alarming rise in Problematic Internet Use (PIU) cases among adolescents warrants attention. The final speaker, Dr. Kristiana Siste, employs the triple-network model (comprising the Central Executive Network (CEN), DMN, and Salience Network (SN)) to understand the underlying neurobiological processes of PIU. Dr. Kristiana found that adolescents with PIU exhibited heightened functional connectivity between the left lateral prefrontal cortex (LPFC(L)) and the left anterior insula (aIns(L)), but reduced connectivity between the LPFC(L) and the medial PFC (MPFC), as well as the right lateral parietal cortex (LP(R)), compared to those without PIU. These findings imply that adolescents with PIU possess enhanced connectivity between the CEN and SN, but diminished connectivity between the CEN and DMN. Mediation analysis showed that the functional connectivity between the LPFC(L) and MPFC was influenced by emotional dysregulation. In summary, the early engagement of the midbrain-striatal-frontal circuits underpins emotional processing, regulation, and neurocognitive and social cognitive deficits across various psychiatric conditions. Pharmacological and non-pharmacological interventions focusing on emotion and cognitive functions, targeting the functional connectivity of these circuits, might be precise strategies for these susceptible populations.
- Alteration of the salience and reward pathway in different clinical disorder
- Resting state functional MRI as an instrument in investigating neurofunctional changes in brain pathways
- Salience and reward pathway as a targeting neural circuits for therapeutic intervention
#Salience network #corticostriatal circuitry #Schizophrenia #Bipolar disorder #Internet addiction
Optimizing Repetitive Transcranial Magnetic Stimulation Therapies for Depression and Addiction: Challenges and Pitfalls
Chair: Georg S. Kranz (Medical University of Vienna/The Hong Kong Polytechnic University)
Harnessing Simultaneous rTMS/fNIRS to Optimize rTMS Treatment Efficacy
Speaker: Georg S. Kranz (Medical University of Vienna/The Hong Kong Polytechnic University)
Targeting Cortical Plasticity in Drug Addiction
Speaker: Ti-Fei Yuan (Jiao Tong University School of Medicine)
Real World Study on Maintenance TMS Therapy for Recurrent Depressive Disorder and Bipolar Depression
Speaker: Yoshihiro Noda (Keio University School of Medicine)
Knowledge on the effectiveness of repetitive transcranial magnetic stimulation (rTMS) is quickly accumulating, with more and more clinicians administering it on a daily basis as an efficacious alternative or adjunct to pharmacological treatments . Of note, the recently FDA-approved Stanford Neuromodulation Therapy protocol for treatment-resistant depression is attracting a great deal of attention for its astounding antidepressant outcomes (78%-90% response rates) – such accelerated forms of rTMS may mitigate the delay of response to treatment, as seen for first-line pharmacological treatments. The aim of this symposium is to provide the latest results on these highly promising treatment approaches and to bridge the gap between scientific data and the application of rTMS in daily clinical routine. The first talk, given by Dr. Georg S Kranz, will cover research on the simultaneous application of rTMS and neuroimaging. This setup allows for the investigation of rTMS-induced excitability changes of the prefrontal cortex, elucidating intra- and inter-individual differences underlying therapeutic responses to guide treatment optimization . In the second talk, Dr. Ti-Fei Yuan will provide evidence showing how synaptic plasticity alterations underlie addictive behavior, and that erasing the plasticity abolishes such behaviors. This is then translated to noninvasive measurements of human cortical plasticity, and how targeting aberrant changes in the human cortex can restore brain networks to treat addicted patients [3-5]. The third talk, given by Dr. Yoshihiro Noda, will focus on the important issue of maintaining brain stimulation treatment success using maintenance theta-burst stimulation (TBS). Dr. Noda will report on longitudinal research that was conducted within the framework of the TMS Database Registry Consortium Research Project in Japan (TReC-J). He will argue that maintenance TBS treatment is a clinically meaningful relapse prevention strategy for patients with recurrent depressive disorder and/or bipolar depression who have responded to acute TBS treatment [6-8].
- To provide an updated understanding of the effectiveness of rTMS for depression and substance use disorders.
- To explore new protocols of rTMS that accelerate treatment response.
- To discuss the mechanism of action of therapeutic rTMS.
#repetitive transcranial magnetic stimulation #theta-burst stimulation
Novel Therapies to Treat Bipolar Disorder: Translation and Back-translation Between Preclinical and Clinical Studies
Chair: Michael Berk (Deakin University)
Search for New Treatment Options of Bipolar Disorder Using Model Mice
Speaker: Tadafumi Kato (Juntendo University)
Trimetazidine to Treat the Brain and the Heart in Bipolar Depression
Speaker: Jee Hyun Kim (Deakin University)
Modulating Dopamine Transporter as a Therapeutic Target for Bipolar Disorder
Speaker: Lakshmi Yatham (University of British Columbia)
Amongst the top 10 causes of disability in the world, bipolar disorder is the most poorly resourced in research and threadbare in treatment options (Grande et al., 2016). Sadly, bipolar disorder’s cost measured by global disability-adjusted life years has worsened from 6 to 9 million in the last 3 decades (He et al., 2020). Mortality in bipolar disorder is the highest compared to any other psychiatric illness (Grande et al., 2016), outcomes that have been unchanged for decades. Therefore, developing more effective therapies for bipolar disorder is an urgent imperative that requires translation and back-translation between preclinical and clinical research. Prof. Tadafumi Kato is a global leader in preclinical and clinical research in metabolic processes in bipolar disorder, who will open the symposium by presenting his latest research on the research approach of back-translation of clinical research to develop and confirm rodent models (Nakamura et al., 2021) to test potential treatments. Based on the finding of GWAS, they developed an animal model with heterozygous loss of Fads1/2, encoding enzymes synthesizing polyunsaturated fatty acids such as DHA/EPA and showed that they show both mania- and depression-like episodes which were prevented by lithium treatment (Yamamoto et al., 2023). He will also discuss the drug development using animal models. Dr Jee Hyun Kim is an emerging leader in drug discovery research who is currently co-leading the international phase II clinical trial to test the efficacy of a heart medication, trimetazidine, in treating bipolar depression. She will present the complex pathophysiology of bipolar depression (Khanra et al., 2023), and the atheoretical cross-disciplinary approach that led to the discovery of trimetazidine to be tested in rodent models to reduce depression-like behaviors (Bortolasci et al., 2023). Translation of preclinical findings to the preliminary outcomes of the clinical trial will also be presented. The final speaker Prof. Lakshmi Yatham is the current president of the World Federation of Societies of Biological Psychiatry who is leading the guidelines for the treatment of bipolar disorder. He will present the latest neurobiological understanding of bipolar disorder based on imaging studies (e.g., (Yatham et al., 2022)) and describe the work that outlines the therapeutic potential of novel agents for treating mood episodes in bipolar disorder (e.g., (Keramatian et al., 2023)). The chairperson Prof. Michael Berk will then lead the discussion on biomarker research for precision medicine in bipolar disorder.
- To understand the genetic, transcriptomic, and proteomic findings on different phases of bipolar disorder
- To understand back-translation approaches in developing useful rodent models to test novel therapies to treat bipolar disorder and translational approaches in drug discovery by using ethologically valid rodent models that can be applied to the clinical trial setting
- To understand the latest developments in potential therapeutics for bipolar disorder
#Bipolar disorder #translation #mitochondria #dopamine #biomarker
Decoding Ketamine's Enigma: Unravelling the Role of Specific NMDA Receptor Subunits in Its Antidepressant and Cognitive Functions.
Chair: Rachel A. Hill (Monash University)
The GluN2D NMDA Receptor Subunit Mediates S-ketamine Induced Disruptions to Hippocampal Gamma Power During Working Memory Maintenance.
Speaker: Rachel A. Hill (Monash University)
The Role of NMDA Receptor GluN2D Subunit in GABA Neurons on the Long-lasting Antidepressant Effects of Ketamine Enantiomers and Their Metabolites
Speaker: Soichiro Ide (Tokyo Metropolitan Institute of Medical Sciences)
The Role of GluN2A-Containing NMDAR in the Antidepressant Actions of Ketamine
Speaker: Panos Zanos (University of Cyprus)
Ketamine, an equal racemic mixture of (S)-ketamine and (R)-ketamine, acts as a non-competitive NMDA receptor antagonist. A single subanesthetic dose of ketamine demonstrates rapid and long-lasting antidepressant effects, particularly in treatment-resistant patients [1-5], leading to recent global approval of (S)-ketamine for depression treatment. However, similar to the racemic drug, (S)-ketamine also negatively impacts working memory in humans, primates, and rodents [6-8]. Therefore, it is essential to comprehend the distinct behavioural and cognitive outcomes regulated by ketamine enantiomers to improve their clinical utility and develop novel therapeutics. This symposium presents ground-breaking new data on the role of subunit-specific NMDARs underlying ketamine's antidepressant and cognitive properties. Speaker 1. Associate Professor Rachel Hill (Monash University, Melbourne, Australia) will present novel data on the effects of both (S)-ketamine and (R)-ketamine on working memory performance and task-induced cortical and hippocampal gamma power recorded during the Trial-unique-non-match to location (TUNL) touchscreen task in wild type as well as GluN2D subunit knockout mice. We will show data indicating that neither ketamine enantiomers impact overall accuracy on the TUNL task. However, (S)-ketamine increases the time taken to complete the task, in WT, but not GluN2DKO mice. Furthermore, (S)-ketamine disrupts hippocampal gamma power during the maintenance phase of the working memory task specifically in WT mice, but not GluN2DKO mice. These world-first data shed new light on task-induced neural network dysfunction caused by (S)-ketamine and mediated by the GluN2D subunit. Speaker 2. Investigator. Soichiro Ide (Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) will present recent data on the role of GluN2D on the GABA (Gad1) neurons, as well as subtypes expressing parvalbumin (Pvalb), in the expression of the antidepressant effect of ketamine and its metabolites using conditioned GluN2D-knockout (GluN2D-cKO) mice. We show that long-lasting antidepressant effects of (R)-ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) were not observed in GluN2D(Gad1)-cKO mice, although acute effects of the drugs and the effects of the (S)-ketamine enantiomer remain intact. Furthermore, we show that GluN2D in Pvalb-positive neurons is responsible for the sustained antidepressant effects of (R)-ketamine, but not (2R,6R)-HNK. These findings indicate a critical and distinct role of the GluN2D-NMDARs in the pharmacological effects of ketamine’s optical isomers and metabolites. Speaker 3. Assistant Prof. Panos Zanos (University of Cyprus, Cyprus) will present new data demonstrating, for the first time, that NMDA receptor activation (rather than inhibition) is necessary for the beneficial effects of ketamine and other potential rapid-acting antidepressant compounds. Activation of the NMDA receptor is essential for inducing canonical long-term potentiation (LTP) at excitatory glutamatergic synapses, resulting in sustained upregulation of synaptic strength, which has been directly linked to the sustained rapid antidepressant action. Ketamine acts synergistically with NMDAR positive allosteric modulators to produce antidepressant-like behavioral effects, and the activation of the NMDAR subunit GluN2A is necessary and sufficient for such relevant effects. Therefore, promoting GluN2A-NMDA receptor activation-dependent LTP-like processes in vivo may prove to be a novel and effective rapid-acting antidepressant strategy.
- Recent global approvals of (S)-ketamine for treatment-resistant depression have ignited excitement in the field, yet the underlying antidepressant mechanism and potential cognitive effects remain poorly understood. This symposium will provide ground-breaking insights into ketamine's actions on synaptic, cellular, and neural network pathways relevant to depression and cognition.
- A further learning objective from the symposium is deeper understanding of the subunit specific mechanisms by which ketamine, ketamine enantiomers and ketamine metabolites act to produce antidepressant and cognitive disrupting effects.
- Additionally, this symposium aims to foster discussions on advancing ketamine's clinical utility and developing improved therapeutics, ultimately enhancing treatment strategies and outcomes for depression and related cognitive disturbances. The symposium promises to shed light on unexplored aspects of ketamine's potential and open new avenues for more effective treatment options.
#ketamine #antidepressant #cognition #NMDA receptor subunit #working memory
The Impact of Early Life Adversity on Brain and Behavior
Chair: Zijun Wang (University of Kansas)
Juvenile Social Isolation Affects the Development of Excitatory and Inhibitory Neuronal Circuits in Medial Prefrontal Cortex
Speaker: Hiroki Yoshino (Nara Medical University)
Early Social Isolation Stress Potentiates Heroin Seeking by Aggravating the Dysfunction of Prelimbic Cortex to Ventral Tegmental Area Projection
Speaker: Zijun Wang (University of Kansas)
Nutritional Strategies to Combat the Long-term Impact of Early-life Adversity on Cognitive Decline and Alzheimer’s Disease Progression
Speaker: Aniko Korosi (University of Amsterdam)
Early life adversity (ELA) refers to stressful experiences or adverse events that occur during early developmental stages, including prenatal and early postnatal periods. Studies have shown that exposure to ELA has long-lasting and profound effects on an individual's physical and mental health, including increased susceptibility to various brain illnesses and metabolic disorders. ELA induces persistent changes in the brain and periphery system. For example, ELA affects brain development (e.g., key regions involved in emotional regulation and cognitive functions)1-5, neuroplasticity5, immune responses6,7, and metabolic homeostasis8. These persistent changes contribute to the progress of mental and metabolic diseases. Therefore, understanding the impact of ELA is crucial for developing effective interventions and preventive strategies. However, the molecular and neural mechanisms underlying ELA-induced disease vulnerability are still unclear. In this proposed symposium, the speakers will investigate the impact of ELA on the brain and behavior by focusing on three different topics: 1) Dr. Hiroki Yoshino will elucidate how ELA influences the development of excitatory and inhibitory neuronal circuits in the medial prefrontal cortex (mPFC). mPFC is one of the key brain regions that regulate higher-order cognitive functions, emotional processing, decision-making, and impulse control, and are implicated in multiple psychiatric and neurodegenerative disorders. Dr. Yoshino’s group found that juvenile social isolation stress disrupts the developmental trajectory of mPFC pyramidal neurons and parvalbumin interneurons, which renders later adulthood mPFC dysfunction. 2) Dr. Zijun Wang will clarify how ELA increases vulnerability to opioid addiction by changing the connectivity and molecular signatures within the projection from the PFC to the ventral tegmental area (VTA). Opioid addiction is a chronic psychiatric disorder affecting about 53 million people worldwide. Dr. Wang’s group showed that early social isolation stress (during adolescence) potentiates heroin relapse-related behaviors and aggravates heroin abstinence-induced neuronal dysfunction in the PFC->VTA circuits. Moreover, this neuronal dysfunction is accompanied by gene transcriptional changes within PFC->VTA circuits. 3) Dr. Aniko Korosi will unravel how ELA affects the progression of cognitive decline and Alzheimer’s disease. Alzheimer’s disease is expected to affect 153 million people worldwide by 2050. Dr. Korosi’s group found that ELA leads to cognitive decline associated with primed neuroimmune system altering how microglia respond to secondary challenges and amyloid accumulation later in life, and that ELA alters the trajectory of AD-related synaptic changes. They also demonstrated that early nutritional supplementation with anti-inflammatory fatty acids can mitigate the long-term impact of ELA on cognitive decline, neuroimmune alterations and slow down Alzheimer’s disease progression in a transgenic AD mouse model. These studies showcase a wide range of functional and mechanistic approaches and unveil complex mechanisms of ELA-induced vulnerability for multiple diseases, which underscores the enormous potential of these basic research programs in combating health problems highlighted by The CINP World Congress of Neuropsychopharmacology. Furthermore, these translational studies use novel methods at the crossroads of systems neuroscience and bioinformatics by integrating transgenic mouse models, behaviors, electrophysiology, and molecular techniques, which reveal novel information about the molecular and neural mechanisms underlying the impact of ELA.
#early life adversity #prefrontal cortex #opioid addiction #Alzheimer’s disease
Sociability, Motivation and Pleasure in Mental Disorders: From Molecular Understanding to Therapeutic Strategies.
Chair: Marco A. Riva (University of Milan), Eri Hashimoto (Sapporo Medical University)
Vulnerability and Resilience to Prenatal Stress Exposure in Rodents: from Neurobiological Mechanisms and Circuits to Psychopathologic Domains.
Speaker: Marco A. Riva (University of Milan)
Disorders of the Social Behavior: Neuronal Circuits and Treatments with Psychedelics.
Speaker: Gabriella Gobbi (McGill University)
New Therapeutic Approach for Treatment of Refractory Psychiatric Disorders: Recoveries of Behavior/GABAergic Interneuron Genetic Function Using Drugs and Stem Cells.
Speaker: Wataru Ukai (Sapporo Medical University)
The present symposium will summarize authoritatively recent advances on the functional mechanisms contributing to the etiology of specific behavioral domains, including sociability, motivation and pleasure that represent critical elements in mental disorders. The symposium will unfold upon the discussion of preclinical and translational studies addressing different aspects related to psychiatric disorders and how a proper understanding of the molecular substrates and brain circuits involved in such alterations may be instrumental to test and develop effective treatments for the cure of mental disorders, including depression and schizophrenia. Prof. M.A. Riva (University of Milan, Italy) will focus on stress as one of the major causative elements for mental disorders, and in particular on how early in life stress exposure may produce behavioral and functional consequences spanning from adolescence to adulthood. More specifically Prof. Riva will show how exposure to prenatal stress (PNS) in rodents produces emotional dysregulation, characterized by reduced sociability and anxiety-like behavior in a percentage of adolescent offspring, whereas others appear to be resilient. Such vulnerability to PNS is associated with differences in the activity state of specific brain regions and with changes in the expression of immune and glucocorticoid-related markers that may represent an important target for therapeutic intervention. Prof. G. Gobbi (Mc Gill University) will present the neuronal circuits underlying social behavior in rodents, focusing on the role of the prefrontal cortex (PFC) as well as reticular thalamus. Moreover, she will present how psychedelics drugs such as LSD can enhance social behaviors through the stimulation of the 5-HT2A and AMPA receptor responses located in the PFC glutamatergic neurons as well as the activation of the mTOR complex. The psychedelics may be a novel treatment for social behavior dysfunctions such as autism spectrum disorders. Dr. Ukai (Sapporo Medical University) will present his recent data on GABAergic interneuron and trophic mechanisms in the recovery effect of treatments with psychotropic medicines and stem cells for social and empathy-like behavior dysfunction caused by exposure to adversities during development. He will specifically focus on the alterations of the adult genetic mechanism of parvalbumin (+) interneuron and trophic mechanism in the local translation and spine/synapse formation regulated by neuronal RNA granules. All in all, the understanding of mechanisms and circuits that contribute to the onset and manifestation of different psychopathologic domains may be pivotal to optimizing individual intervention aimed at counteracting disrupted mechanisms as well as in promoting resilience.
- Using a Research Domain Criteria (RDoC), the circuits underlying stress, anhedonia, amotivation and social dysfunction will be presented.
- To understand how psychedelics, by acting through cortical circuits may modify social behavior.
- 3)To show how characterizing the link between early life adversities and mental illness may lead to novel therapeutic approaches aimed at mitigating or preventing the outburst of psychopathologies.
#psychopathologic domains #psychedelics #brain circuits #GABA #stress
The Antidepressant Effect and Mode of Action of Psilocybin – Clinical Trial and Molecular Imaging Data from Studies in Man and Pig
Chair: Johan Lundberg (Karolinska Institutet/European College of Psychiatry; The Psychedelic research Thematic Working Group)
The Clinical Effect and Side-effects of Psilocybin in Treatment Resistant Depression
Speaker: Guy Goodwin (University of Oxford/Compass Pathways/European College of Psychiatry; The Psychedelic research Thematic Working Group)
The Relation Between Acute Effects of Altered State, 5-HT2A Binding and Synaptic Plasticity in Large Animals and Healthy Control Subjects
Speaker: Gitte Moos Knudsen (University of Copenhagen/European College of Psychiatry; The Psychedelic research Thematic Working Group)
Translational Response Biomarkers Examined in an RCT of Psilocybin Treatment of Depression
Speaker: Johan Lundberg (Karolinska Institutet/European College of Psychiatry; The Psychedelic research Thematic Working Group)
Current antidepressant treatment regimens are mostly slow in onset and leave a substantial group of patients with major depressive disorder (MDD) without remission. Thus, depressed patients have a more than doubled all-cause mortality and nine times more work loss than matched non-depression controls1. The outcomes are even worse in subgroups of treatment resistant (TRD) patients2. Development of better treatments are hampered by the lack of translatable biomarkers of antidepressant response. Here, we present novel data on the clinical effect and side-effects of single-dose psilocybin both in TRD and non-TRD patients as well as translatable biomarkers of antidepressant effect in pig brain, healthy volunteers, and MDD-patients.The clinical effect and side-effects of psilocybin in Treatment Resistant Depression (Goodwin) The investigational drug COMP360 is a proprietary, synthetic formulation of psilocybin being developed for TRD. Here, we expand on the outcomes from a phase 2 study of COMP360 in individuals with TRD -the largest randomized controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints3. In COMP360 we randomly assigned adults with TRD to receive a single dose of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001). The apparently mechanistic association of the acute effects of altered state with the primary clinical outcomes will be described.The relation between acute effects of altered state, 5-HT2A binding and synaptic plasticity in large animals and healthy control subjects (Knudsen) A single dose of psilocybin, a classical psychedelic serotonin 2A receptor (5-HT2AR) agonist, is associated with intriguing sustainable effects on mood and creativity. The exact mechanism(s) behind antidepressive actions of both SSRI's and classical psychedelics is still under investigation but we have novel data to suggest that the duration of SSRI intervention is associated with increase presynaptic density (SV2A) in the human brain, as measured with [11C]UCB-J PET. In contrast, after just a single dose of psilocybin, we see increased SV2A density and a down-regulation of cerebral 5-HT2AR in the pig brain one week4. We now have preliminary data that support similar findings in healthy humans.Translational response biomarkers examined in an RCT of psilocybin treatment of depression (Lundberg) PSIPET is an academic RCT in 34 MDD patients where biomarkers are examined in blood, CSF and using [11C]UCB-J for quantification of synaptic density before and 1-2 weeks after a single dose of single dose psilocybin versus niacin. Results of the clinical effect from day 8 to day 360, side-effects and relation to biomarkers will be presented and contextualized based on the previous talks.
- 1.The talks will give an understanding for the current evidence of single-dose psilocybin’s antidepressant effect and side-effects in two different populations. Various outcomes will be discussed as well as their relation to the acute effect of psilocybin dosing.
- 2.Also, the pharmacology of psilocybin will be described based on ex-vivo and in vivo experiments. The acute clinical effects related to interaction with the 5-HT2A receptor will be related in detail as will the relation between acute 5-HT2A binding and delayed SV2A density as a marker for synaptic plasticity.
- 3.The potential causal relationship between single dose psilocybin and SV2A binding as a marker for synaptic plasticity in MDD patients will be described. The potential benefit of various biomarkers of psilocybin response will be contextualized.
#psilocybin #major depressive disorder #5-HT2A #SV2A #synaptic plasticity
Understanding Molecular, Cellular, and Circuit Mechanisms and Development of Therapeutic Methods for PTSD
Chair: Satoshi Kida (The University of Tokyo)
The Molecular Mechanism of PTSD and Development of Treatment to Improve PTSD
Speaker: Satoshi Kida (The University of Tokyo)
Translational Evidence for Endocannabinoid Modulation of Fear and Extinction
Speaker: Andrew Holmes (National Institute on Alcohol Abuse and Alcoholism)
Microglia-dependent Regulation of Fear Memory Extinction
Speaker: Paul Frankland (University of Toronto/Hospital for Sick Children)
Posttraumatic stress disorder (PTSD) is a psychiatric disorder associated with traumatic memory. Mechanisms of PTSD are still unknown at the neural circuitry, cellular, and molecular levels. Therefore, effective drug-based treatments based on molecular mechanisms have not been developed. Paul Frankland, one of the speakers in this symposium, has shown that the promotion of adult hippocampal neurogenesis enhances memory forgetting in mice. Satoshi Kida, a chair of this symposium, has proposed a new treatment for PTSD using memantine (an antagonist of NMDA glutamate receptor), which accelerates memory forgetting by promoting adult hippocampus neurogenesis. Importantly, ongoing clinical trials have shown that the administration of memantine improves symptoms of PTSD. In this symposium, we will introduce brand new research clarifying the mechanisms of PTSD and further developing a new therapeutic approach for PTSD by targeting the fear memory processes.Satoshi Kida will talk about the molecular mechanism of PTSD and the development of methods to improve PTSD. He compared the transcriptomes of the peripheral blood of PTSD patients showing severe reexperiencing symptoms and the mouse hippocampus after fear memory retrieval and found that the level of mRNA encoding a protein inactivating the cAMP signal transduction pathway is reduced in the hippocampus of fear memory-activated mice and blood of PTSD patients with reexperiencing symptoms, suggesting that PTSD patients show upregulation of cAMP signaling pathway. Consistent with that notion, pharmacological and optogenetic upregulation or downregulation of cAMP signaling transduction enhanced or impaired, respectively, the retrieval and subsequent maintenance of fear memory in mice. These observations suggest that the facilitation of cAMP signaling mediating the downregulation of PDE4B expression enhances traumatic memory, thereby playing a key role in the reexperiencing of symptoms of PTSD patients. Additionally, he will introduce the effects of memantine on PTSD patients. Andrew Holmes will talk about “Evidence from clinical and preclinical studies show that endocannabinoids modulate extinction”. Endocannabinoids have been known to play critical roles in the extinction of fear memory. He will show new evidence describing the neural circuits and cellular mechanisms underlying these effects of endocannabinoids and endocannabinoid-signal transduction is a therapeutic target of PTSD. Paul Frankland will talk about “Microglia-dependent regulation of fear memory extinction”. He will show that microglia shape circuit formation during development and provide evidence that they play a similar role in adulthood. Interestingly, he found that during extinction learning microglia are recruited to fear memory engram cells and suggests that microglia play an active role in reducing fear memory expression through silencing and synaptic remodeling mechanisms.As described above, this symposium will cover basic research to understand the mechanisms of fear memory and PTSD, as well as applied research leading to clinical applications.
- The audience will learn the molecular mechanisms of PTSD in which the activation of the cAMP-signaling pathway is associated with reexperiencing symptoms of PTSD and therapeutic methods to improve the symptoms of PTSD through hippocampal neurogenesis by memantine.
- The audience will learn from this presentation how translational evidence suggests that pharmacotherapeutically targeting endocannabinoids is a novel approach to improving extinction in neuropsychiatric disorders.
- The audience will be provided with an overview of microglia biology, and present novel evidence for a role of microglia in the extinction of fear memories.
#PTSD #fear memory #cAMP signaling pathway #endocannabinoid #Microglia
Digital Phenotype to Guide Clinical Interventions for Suicide Treatment
Chair: Enrique Baca-Garcia (Fundacion Jimenez Diaz. Universidad Autonoma de Madrid)
A Neurosignature of Emotion Regulation Predicts Suicidal Ideation in Response to Stressors
Speaker: Maria A. Oquendo (Perelman School of Medicine, University of Pennsylvania)
Phenotypes of Suicidal Behaviour Found in Clinical, Epidemiological and Neurocognitive Research
Speaker: Philipe Courtet (Montpelier University)
Smartcrisis 3.0: Use the EMA Suicide Behiovior Data in Real Time to Treat Suicide Behaviour
Speaker: Maria Barrigon-Estevez (Hospital Gregorio Marañon)
With more than 700,000 deaths per year worldwide, suicide and suicidal behaviour remain an unresolved public health problem (WHO, 2019). Suicide prevention needs precision medicine. Digital health represents an opportunity for precision medicine. (from Barrigon et al).The emergence of experience sampling method technologies and, in particular, the incorporation of mass data collection using ecological momentary assessment (EMA) and smartphones’ sensor monitoring and new analysis technologies such as machine learning, has provided an opportunity to improve the definition of phenotype. (Barrigon et al., 2019). In this way, by analyzing digital data coming from mobile devices, we can gather information about a person's behavior, cognitive function, and emotional state.This symposium will focus on new approaches to suicidal behaviour. First, Dr Oquendo (USA) will share her group's experience with ecological momentary assessment (EMA) as a novel instrument to identify digital risk phenotypes and recent advances suggesting that EMA based patterns of suicidal ideation may be underpinned by a specific pathophysiology.Second, Dr Courtet (France) will propose that 1) combining EMA and fMRI could provide a better understanding of the triggering role of social adversity in suicidal behaviour and 2) assessing the emotional and cardiovascular response to experimental social stress task may refine suicidal phenotypes and their specific biological roots. Finally, Dr Baca/Barrigon (Spain) will discuss the experience of using ecological momentary interventions (EMI) to prevent suicide re-attempts in high-risk populations, opening up the possibility of personalizing interventions in real time and in this way empowering patients.
- To update the state of the art of the internal elements of suicidal behavior (psychological pain, section meaking
- To review the use of sampling extraction technologies for the definition of digital phenotypes in suicidal behavior
- To present evidence of the usefulness of EMA (ecological momentary assessment) EMI (ecological momentary intervention) for prevention, treatment, and follow-up of suicide risk
#Suicide behavior #Digital phenotype #EMA (ecological momentary assessment) #EMI (ecological momentary intervention) #Decision-making
Improving Outcomes in Mental Illness: From Neuroimaging and Digital Technology to Implementation Science
Chair: John M. Kane (Donald and Barbara Zucker School of Medicine at Hofstra/Northwell)
The Neuromorphological Correlates of Treatment Response Following the First Psychotic Episode: The Need for New Approaches
Speaker: Paola Dazzan (King's College London)
Exploring Wearables and Machine Learning for Depression Screening and Monitoring
Speaker: Taishiro Kishimoto (Keio University, Tokyo)
The Underutilization of LAIs and Clozapine: The Role of Implementation Science
Speaker: John M. Kane (Donald and Barbara Zucker School of Medicine at Hofstra/Northwell)
Though considerable progress has been made in the acute and long-term treatment of mental illness outcomes remain heterogeneous and often both unpredictable and difficult to measure in real time. Few biomarkers exist with which to predict treatment or to stratify patients in clinical trials. In routine clinical care health care professionals often see patients infrequently and do not have a fully informed perspective on day-to-day clinical outcomes, including overall functioning. In addition, even when new evidence emerges from clinical trials, etc. it often takes many years to be implemented in routine clinical care. All these factors impede our progress in improving outcomes. This symposium chaired by J. Kane (New York, U.S.A.) will discuss the use of neuroimaging as a biomarker, the role digital technology in providing phenotypic data as well as real time monitoring of symptoms and functioning, and the need for implementation science to facilitate adoption of new/novel strategies. P. Dazzan (London, UK) will discuss the relationship between brain morphology and response to antipsychotics as well as the overall potential of structural and functional neuroimaging to inform the diagnostic process, predict treatment response and better identify those at risk for relapse despite ongoing pharmacotherapy. T. Kishimoto (Tokyo, Japan) will discuss the role of digital technology in enhancing access to care, facilitating the diagnostic process, and providing tools to monitor patients in real time. J. Kane (New York, U.S.A.) will provide perspective on implementing new technologies and new evidence from clinical trials into routine clinical care. He will discuss the need for implementation science to understand disparities in the application of evidenced based medicine and obstacles to improving outcomes with examples such as long-acting injectable antipsychotics and clozapine, particularly in early phase patients.
- The attendees will learn about the potential use of neuroimaging to facilitate patient management and improve outcomes.
- The attendees will better understand the potential role of digital technology, digital phenotyping, and digital monitoring of patient outcomes.
- The attendees will gain further perspective on obstacles to the implementation of new knowledge and new tools in day-to-day clinical practice, and how those obstacles can be overcome.
#Neuroimaging #Digital Technology #Implementation Science
Understanding the Mechanisms of Social Stress and Autism-linked Social Deficits
Chair: Zhen Yan (State University of New York at Buffalo)
Circuitry and Molecular Mechanisms of Mental Disturbance by Social Isolation Stress
Speaker: Zhen Yan (State University of New York at Buffalo)
Brain-Periphery Interplay of Inflammation in Social Defeat Stress
Speaker: Tomoyuki Furuyashiki (Kobe University)
Mechanisms of Social Impairments in Mouse Models of Autism Spectrum Disorders
Speaker: Eunjoon Kim (Korea Advanced Institute of Science and Technology)
Positive social interactions provide a wide range of physical and mental benefits. Exposure to chronic social isolation stress or prolonged social defeat stress can have profound effects on the neurobiology of the brain, leading to alterations in social behavior and cognitive functions, and the heightened vulnerability to emotional disorders. The session provides an opportunity to explore the neurobiological mechanisms of social stress derived from social deprivation or hostile social interactions, as well as the underlying causes of social deficits in neuropsychiatric diseases such as autism spectrum disorders (ASD). The three speakers will share their important discoveries in this field, shedding light on various aspects of social stress and its impact on mental health. One aspect that will be discussed is the neuronal circuits that are causally linked to different mental disturbances in males and females following chronic social isolation stress (Zhen Yan, speaker and organizer; State University of New York at Buffalo, USA). By using cutting-edge techniques, such as in vivo multichannel recordings, optogenetics, chemogenetics, and in vivo calcium imaging, researchers have been able to dissect the specific neuronal populations and circuit pathways that play key roles in mediating the effects of social isolation. This research will help uncover how social isolation affects the brain and potentially contributes to divergent mental health outcomes between genders (1, 2). Another topic of focus will be the inflammatory and neurometabolic mechanisms of social defeat stress (Tomoyuki Furuyashiki, speaker; Kobe, Japan). By using state-of-the-art approaches, including single-cell transcriptome, epigenome, proteome, and metabolome analyses, three-dimensional electron and expansion microscopy, and cell-type-specific genetic manipulations, researchers have been able to elucidate the roles and mechanisms of microglial activation and leukocyte mobilization in social defeat stress-induced emotional disturbances and their link to neurometabolic alterations in the brain. This research will help uncover how social defeat stress causes persistent neurocircuitry alterations via the interaction of inflammation in the brain and periphery partly as a response to brain energy expenditure (3, 4). Additionally, the session will address the molecular determinants that play a crucial role in ASD-like social impairment and other phenotypes (Eunjoon Kim, speaker; Korea Advanced Institute of Science and Technology, Korea). By uncovering these underlying molecular mechanisms, researchers can gain insights into the pathophysiology of behavioral deficits in ASD, potentially paving the way for the development of more precise and effective therapeutic strategies (5, 6). Overall, these preclinical studies hold promise for translating into therapeutic interventions that can address social aberrations and promote improved mental well-being.References 1. Wang ZJ, … Yan Z (2022) Molecular Psychiatry 27:3056-3068. PMID: 35449296 2. Tan T, … Yan Z (2021) Cell Reports 34:108874. PMID: 33761364 3. Ishikawa Y, … Furuyashiki T (2021) British Journal of Pharmacology 178:827-844. PMID: 32678951 4. Nie X, … Furuyashiki T (2018) Neuron 99:464-479. PMID: 30033154 5. Lee E, … and Kim E (2021). Nature Communications, 12:5116. PMID: 34433814 6. Kim H, … and Kim E (2022). Nature Communications 13:5051. PMID: 36030255
- In this session, the audience will learn about recent advancements in our understanding of neurobiological mechanisms underlying social isolation stress, social defeat stress, and social impairment in ASD models. Three leading groups in this field will demonstrate the neural circuits, biological processes, and molecular targets involved in social aberrations.
- The audience will also learn translational values of these preclinical studies. By identifying specific molecular targets and neural circuits, these studies provides insights for developing novel therapeutic strategies, such as pharmacological interventions or brain stimulation techniques, that could potentially alleviate social stress-induced mental disorders or social deficits in ASD.
#social isolation stress #social defeat stress #autistic social deficits #neural circuits #molecular mechanisms
New Insights on Cannabis Use and Clinical Implications: Translational Perspective
Chair: Deepak C. D'Souza (Yale University)
The Significance of THC and CBD on the Lipidome
Speaker: Marcus Leweke (The University of Sydney)
In Vivo Imaging of Translocator Protein in Long-term Cannabis Users
Speaker: Romina Mizrahi (McGill University)
THC Alters Single Cell Transcriptome in Immune Cells
Speaker: Ke Xu (Yale University)
Cannabis is the most widely used drug, particularly by adolescents and youth, making it a growing public health concern1. However, the mechanisms of cannabinoids in humans are understudied. Using cutting-edge imaging technology and an omics approach, here, we propose a symposium to present the new findings from in vivo human studies. We will discuss the cannabinoids’ effects on lipidome, brain function, and transcriptome, and provide new insights on how cannabinoids affect the peripheral and central nervous system, which may be translated to clinical treatment in the future.Chair: Deepak C D’Souza, MD, Professor of Psychiatry, Yale School of Medicine Speaker 1. Markus Leweke, M.D. The significance of THC and CBD on the lipidome. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) influence brain function through the endocannabinoid systems' lipid-mediated network2. However, their impact on the lipidome remains unknown. Dr. Leweke will present the data from relative expression patterns of > 3,000 lipids in the brain, blood, and cerebrospinal fluid through novel imaging methods, and a broader lipid network in response to THC and CBD administration. He will also show how aligning lipid-induced abnormalities occurring in brain regions of interest with peripheral systems can refine the selection of the latter for use as surrogate markers of cannabinoid exposure. Speaker 2. Romina Mizrahi M.D., Ph.D. In Vivo Imaging of Translocator Protein in Long-term Cannabis Users. Cannabis increases the risk of schizophrenia in vulnerable individuals3. Using Positron Emission Tomography (PET) molecular imaging, Dr. Mizrahi will present complementary studies on cannabis showing a) significant effects of cannabis use on neuroimmune function (translocator Protein, TSPO) in cannabis users, with no effect in those in the psychosis spectrum, and b) novel unpublished data on Monoamino Oxidase B (MAO-B) in psychosis patients with and without cannabis use, a ~24.0 % reduction in MAO-B in patients with early psychosis compared to controls, with a ~19.5% lower MAO-B in cannabis use than no use. This discovery together with the novel TSPO data may explain the exacerbated psychotic experiences in vulnerable patients using cannabis, earlier disease onset and higher relapse rates in patients with schizophrenia.Speaker 3. Ke Xu, M.D., Ph.D. THC alters single cell transcriptome in immune cells.Cannabinoids’ anti-inflammatory effects in humans show inconsistent findings4, partially due to cell type heterogeneity. Dr. Xu will present how THC changes single cell gene expression in human immune cell types. Differential gene expression (DEG) at each cell type between prior and post-THC infusion is identified. THC-induced DEG varies significantly in different cell types with the largest number of DEGs in CD4+ T cells. Pathways involved in inflammatory functions also show cell-type differences. These results provide new insights into the THC’s effects on immune suppression for future treatment. The panel is highly diverse. The speakers are from three different countries, including 50% women, different ethnicities, and at their different career stages.
- Identify how THC and CBD impact brain function through the endocannabinoid systems’ lipid-mediated network.
- Understand how cannabis use affects neuroimmune function and learn about the role of MAO-B in psychosis patients with and without cannabis use.
- Understand how THC changes single cell gene expression in human immune cell types.
#tetrahydrocannabinol #cannabidiol #gene expression #lipidome #neuroimmune
Targeting Neurotransmitter Systems in Addiction: Advances and Future Directions
Chair: Kazutaka Ikeda (Tokyo Metropolitan Institute of Medical Science)
Intricate Role of Acetylcholine Receptors (AChRs) in Addiction and Psychiatric Disorders
Speaker: Marina Picciotto (Yale School of Medicine)
Neuropsychopharmacological Factors that Influence Drug Choice
Speaker: Serge H. Ahmed (Universit de Bordeaux)
G-Protein-activated Inwardly Rectifying Potassium (GIRK) Channel as a Therapeutic Target for Addiction
Speaker: Kazutaka Ikeda (Tokyo Metropolitan Institute of Medical Science)
Addiction remains a significant global challenge, necessitating the development of innovative therapeutic approaches. This symposium aims to showcase cutting-edge research on the pharmacological modulation of neurotransmitter systems involved in addiction and discuss future directions in addiction research. Dr. Marina Picciotto, a distinguished expert in the field, will explore the intricate role of acetylcholine receptors (AChRs) in addiction and psychiatric disorders. Through her extensive research, Dr. Picciotto has made notable contributions to understanding the complex interplay between AChRs and other neurotransmitter systems, especially GABAergic system, revealing potential therapeutic targets for addiction (Zhou, 2022; Mineur, 2022; Fogaça, 2023). Her studies have elucidated the molecular mechanisms underlying substance dependence and provided insights into the neurobiology of addiction-related behaviors. Dr. Serge H. Ahmed, renowned for his work on the neurobiology of reward and motivation, will present groundbreaking findings on the mesolimbic dopamine system. His research has provided crucial insights into the mechanisms underlying drug-induced and sweet-induced reward, shedding light on the development and maintenance of addiction. Dr. Ahmed's studies have unraveled the neurochemical basis of reward processing and its dysregulation in addiction, offering new avenues for therapeutic interventions (Vandaele, 2021; Abarkan, 2023; Durand, 2022). His presentation will delve into the factors that influence drug choice and the neurobiological determinants of addictive behavior. Dr. Kazutaka Ikeda will discuss the reward system as a fundamental brain function, from its manifestations in Caenorhabditis elegans to its relevance in humans (Ide, 2022). Additionally, Dr. Ikeda will present his research findings on the G-protein-activated inwardly rectifying potassium (GIRK) channel, highlighting its potential as a therapeutic target for addiction. His studies have demonstrated the involvement of GIRK channels in preference to addictive substances and have explored the modulation of these channels as a strategy for addiction treatment (Kotajima-Murakami, 2022). This symposium aims to foster interdisciplinary discussions and facilitate the exchange of ideas among researchers and clinicians in the fields of neuropsychopharmacology and addiction. By showcasing the latest advancements and exploring future directions, we aspire to drive the development of innovative treatments for addiction, addressing the global burden imposed by addictive disorders. The symposium will provide a platform for researchers and clinicians to engage in meaningful discussions, collaborate on potential research endeavors, and promote advancements in addiction treatment. By integrating the collective expertise of the speakers, the symposium will offer a comprehensive overview of the neurobiological underpinnings of addiction and the identification of novel therapeutic targets. This multifaceted approach aims to unravel the complexity of addiction and pave the way for transformative interventions that can improve the lives of individuals affected by addiction. Through an in-depth exploration of the molecular and neurochemical mechanisms involved in addiction, attendees will gain valuable insights into the development of personalized and effective treatments. In summary, this symposium represents a significant opportunity for researchers, clinicians, and stakeholders in the field of addiction to come together and explore the latest advancements in targeting neurotransmitter systems for addiction treatment. We aim to accelerate the development of innovative interventions and ultimately alleviate the global burden of addiction-related disorders.
- Gain a comprehensive understanding of the neurobiological underpinnings of addiction and the intricate interplay between neurotransmitter systems involved in addictive behaviors.
- Explore the latest advancements in pharmacological modulation of neurotransmitter systems and their potential as therapeutic targets for addiction treatment.
- Discuss the future directions in addiction research, including innovative approaches and strategies that can be employed to develop personalized and effective treatments for addiction.
#ADDICTION #NEUROTRANSMITTER #REWARD SYSTEM #MOTIVATION #DEPENDENCE
Identifying and Fixing Dysfunctional Circuits in Depression: Leveraging Systems Neuroscience and Translational Approaches for Developing Novel Targets and Therapeutics.
Chair: Satoshi Kida (University of Tokyo)
Neural signatures of stress susceptibility and resilience in the amygdala-hippocampal network
Speaker: Mazen Kheirbek (UCSF)
Development of novel circuit based therapeutics for mood disorders
Speaker: Anatol Kreitzer (Maplight)
Emotional state regulation in the prelimbic cortex
Speaker: Gisella Vetere (ESPCI)
The past fifty years has seen significant progress in elucidating the brain regions that control emotional behavior, and how these circuits may be disrupted in depression. This work has implicated an extended network of interconnected brain regions, local circuit computations, and cell types that interact to generate the distinct behaviors that are disrupted in mood disorders. Recent technological breakthroughs in neuroscience, such as the ability to record and control large populations of genetically defined neuronal elements, have shed new light on how these behavioral dimensions are generated in the brain. This has led to a renewed efforts to translate these circuit-based findings to the clinic, using circuit and cell-type specific approaches for the development of novel therapeutics. In this symposium, we bring together 3 outstanding researchers at different stages of their careers that have approached these questions from different directions. Dr. Mazen Kheirbek, an associate professor at the University of California San Francisco, has a long-standing interest in the circuits that generate fear and anxiety-related behavior, recently having identified novel circuits and connections in the ventral hippocampus that control mood and anxiety-related behavior. He will discuss recent work describing a reverse translational approach in pre-clinical models to identify biomarkers in the hippocampal-amygdala circuit that can distinguish resiliency and susceptibility to chronic stress, and behavioral rescue through targeted circuit manipulation. The second speaker, Dr. Gisella Vetere is a professor at ESPCI in Paris and leader of the Cerebral Codes Circuits Connectivity team, whose work focuses on hippocampal-cortical connections in the control of emotional learning. She will present new work from her lab describing how distinct aversive states are represented in neurons of the medial prefrontal cortex. The last speaker will be Dr. Anatol Kreitzer of Maplight. Dr. Kreitzer ran a highly successful circuit neuroscience lab at the Gladstone Institute for many years, then decided to transition to industry as Chief Discovery Officer at Maplight, a company with the the goal of translating findings in circuit neuroscience to the clinic. He will discuss the latest programs at Maplight, including two programs in development of novel therapeutics for depression. The diverse expertise and background of the speakers will expose attendees to the wide range of questions, techniques and approaches employed for studying depression-relevant behaviors. By bringing together multiple viewpoints and approaches, attendees will leave this symposium with a more holistic understanding of the extended, cross scale interactions that generate depression-related behaviors. In addition, by bringing together investigators in academia and industry, the attendees will learn about how these two areas can work together to achieve the common goal of identifying new targets and developing novel therapeutics.
- Use of systems neuroscience approaches for identifying potential biomarkers for mood
- Understand the latest neuroscience techniques and analyses for probing mood circuits
- Understan how preclinical circuit-based approaches may inform drug development.
#systems neuroscience #neural circuits #depression
Sex Differences in Psychiatric Disorders: from Molecular Neurobiology to Therapeutic Strategies
Chair: Marin Veldic (Department of Psychiatry and Psychology, Mayo Clinic)
Ovarian Hormones and Early-life Stress Alter Transcriptional Regulation in the Nucleus Accumbens Resulting in Sex-specific Responses to Cocaine
Speaker: Marija Kundakovic (Department of Biological Sciences, Fordham University)
Sex Differences in Neural Mechanisms of Negative Cognitive Bias, a Cognitive Symptom of Depression
Speaker: Liisa Galea (Department of Psychiatry, University of Toronto/Centre for Addiction and Mental Health, Toronto)
Sex Differences in the Brain and Cognition in Schizophrenia
Speaker: Yoji Hirano (Department of Psychiatry, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki)
Sex differences are found across psychiatric disorders, although neither sex nor gender are currently taken into account in psychiatric practice. Understanding underlying biological mechanisms and neural substrates can lead to novel therapeutic strategies and facilitate precision medicine initiatives in psychiatry. This panel includes experts in neuroendocrinology, sex differences, and psychiatry and will address the topic of sex differences across species, levels of analyses, and psychiatric disorders. Dr. Kundakovic will discuss sex differences in cocaine use disorder. Women are reported to be more sensitive to cocaine than men, with early-life stress and ovarian hormones being contributing factors. To address underlying mechanisms, Dr. Kundakovic’s group used an early-life stress paradigm, tracking of the estrous cycle, and a 39,XO genetic mouse model. In the nucleus accumbens, they found changes in X-chromosome- and estrogen-signaling-related gene regulation, consistent with enhanced conditioning responses to cocaine seen after early-life stress and during the low-estrogenic state in females. During the low-estrogenic state, females respond to cocaine by increasing the accessibility of neuronal chromatin enriched for the binding sites of ΔFosB, a transcription factor implicated in cocaine addiction. Conversely, high-estrogenic females respond to cocaine by preferential chromatin closing, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. Estrogen withdrawal, early-life stress, and absence of the second X-chromosome all nullify the protective effect of high-estrogenic state on cocaine conditioning in females. This study highlights ovarian hormone-stress interaction, and reveals the molecular substrates through which female-specific factors can induce stronger and longer-lasting, sex-specific responses to cocaine. Dr. Galea will focus on sex differences in the major depressive disorder (MDD). Negative cognitive bias, a symptom of MDD, involves pattern separation, which relies on adult hippocampal neurogenesis and is impaired by inflammatory signalling. Dr. Galea’s group examined sex differences in the neural and molecular underpinnings of negative cognitive bias after chronic unpredictable stress (CUS) in rodents. Although CUS increased negative cognitive bias in both sexes, they found sex differences in underlying mechanisms. CUS sex-specifically increased cytokines in the basolateral amygdala (BLA) of females and increased the new neuron activation in the hippocampus in males; both outcomes were related to increased negative cognitive bias. These results suggest that stress-induced cognitive bias is driven by BLA inflammation in females and by hippocampal neurogenesis in males, highlighting that sex is a necessary factor in understanding the mechanisms of cognitive (dys)function. Dr. Hirano will discuss sex differences in schizophrenia. Early conceptualizations of schizophrenia highlighted sex disparities in epidemiology and clinical manifestations. There is now growing interest in the divergence in brain morphology between male and female patients. Despite methodological variations and limitations, there is evidence of sex differences in brain structure among patients with schizophrenia, greater reductions in the frontal and temporal lobes in men compared to women, and neurocognitive functioning, where men tend to present with more cognitive deficits than women. Overall, this panel will highlight sex differences across psychiatric disorders, ranging from molecular mechanisms to clinical endpoints. We will discuss current findings and future directions facilitating the development of sex-specific therapeutic strategies in psychiatry.
- Recognize sex differences in substance use disorders. Recognize the role of ovarian hormones and early-life stress in female-specific vulnerability to cocaine use disorder. Define epigenetic mechanisms and their sex-specific regulation in the brain reward system. Recognize how studies of hormonally- and stress-induced psychiatric risk can reveal sex-specific targets for treatment.
- Characterize different types of sex differences. Understand how “hidden” types of sex differences (mechanistic and latent) can help inform on major depressive disorder. Understand how studying cognitive dysfunction following chronic stress may inform on sex differences in major depressive disorder.
- Evidence of sex differences in the brain morphology and neurocognitive function in schizophrenia is presented. Further research is warranted to elucidate the intricate mechanisms underlying these sex differences and their potential clinical implications.
#sex differences #addiction #depression #schizophrenia
Predicting and Quantifying Treatment Response to Drugs for Psychosis and Symptom Severity in Schizophrenia Using Machine Learning
Chair: Søren Dinesen Østergaard (Aarhus University Hospital)
Predicting Treatment Outcomes in Trials of Drugs for Psychosis Using Symptom-level Data
Speaker: Fredrik Hieronymus (Sahlgrenska University Hospital)
Prediction of Clozapine Treatment Among Patients with Schizophrenia via Routinely Collected Data from Electronic Health Records
Speaker: Søren Dinesen Østergaard (Aarhus University Hospital)
Quantification of Schizophrenia Symptoms Using Natural Language Processing: Preliminary Results from a Large Conversational Corpus of Japanese Patients with Psychiatric Disorders
Speaker: Taishiro Kishimoto (Keio University School of Medicine)
Due to tremendous advances in computer performance and methods in recent years, machine learning (development and use of computer systems that can learn and adapt without following explicit instructions) has reached a level where it is becoming an increasingly appealing technology for the medical field – including psychiatry (Haug and Drazen, 2023). A subfield of machine learning called natural language processing (NLP), i.e., the application of computational techniques to the analysis and synthesis of both spoken and written language, may be particularly relevant for psychiatry due to the intimate relationship between language/speech and psychopathology – in particular in the context of schizophrenia (Rezaii et al., 2022). In this symposium, we will showcase three examples of how machine learning and NLP may inform the field of psychiatry and psychopharmacology – with emphasis on schizophrenia. First, Dr. Fredrik Hieronymus will present new unpublished results from a study using machine learning to identify predictors of response to drugs for psychosis based on data from randomized controlled trials (same data source as used in a recent study (Hieronymus et al., 2023)). Second, Dr. Søren Dinesen Østergaard will present new and unpublished results from a study aiming at identifying predictors of clozapine treatment, as a proxy for treatment-resistant schizophrenia, based on a large body of routinely collected data from electronic health records (Hansen et al., 2021). Notably, this study involves application of NLP on text (descriptions of symptoms etc.) from electronic health records. Third, Dr. Taishiro Kishimoto will introduce the rationale for- and preliminary results from the “Understanding psychiatric illness through natural language processing” (UNDERPIN) study, which aims at quantifying symptom severity of schizophrenia and related disorders by employing NLP on speech data (Kishimoto et al., 2022). Finally, an interactive Q&A session with the three speakers will conclude the symposium.
- To understand the concepts of machine learning and natural language processing and their relevance to psychiatry, psychopharmacology and personalized treatment.
- To learn that machine learning may aid in identifying clinical characteristics associated with good/suboptimal antipsychotic treatment response.
- To appreciate that natural language processing – analyzing speech or written text – may inform clinical practice (e.g., assessment of symptom severity) in the context of schizophrenia and related disorders.
#Schizophrenia #Drugs for Psychosis #Machine Learning #Natural Language Processing #Personalized Medicine
Dysfunction of Glutamate, Dopamine, and GABA Neurotransmission in Schizophrenia: Integrative View for Pathophysiologic Analysis and Innovative Treatment
Chair: Toru Nishikawa (Showa University School of Medicine/Kyoto Prefectural University of Medicine)
Interactions Among NMDA Receptor-D-serine System, Dopamine and GABA Neurotransmission in the Pathophysiology and Treatment Development in Schizophrenia
Speaker: Toru Nishikawa (Showa University School of Medicine/Kyoto Prefectural University of Medicine)
The Centrality of the Glutamatergic Synapse in the Pathophysiology of Schizophrenia
Speaker: Joseph T, Coyle (McLean Hospital and Harvard Medical School)
Neurocognition and NMDA Receptor Co-agonists Pathways in Individuals with Treatment Resistant First-episode Psychosis
Speaker: Kim Q. Do (Lausanne University)
Schizophrenia is a complex and common chronic brain disorder with an onset early in life leading to serious mental disability. This poor prognosis is primarily due to antipsychotic treatment-resistant negative and cognitive symptoms while positive symptoms are ameliorated by the pharmacotherapy. Molecular, pharmacological, anatomical, imaging and clinical studies provide compelling evidence that schizophrenia has a circuit pathophysiology that involves dopaminergic neuronal hyperactivity, hypoglutamatergic transmission via the N-methyl-D-aspartate receptor (NMDAR) and disturbed GABAergic transmission. However, the interrelationships among these neurotransmission abnormalities await clarification. The purpose of this symposium is to present an integrative scheme of the alterations in these neurotransmitter systems in schizophrenia to identify optimal targets for the development of improved treatments that address the antipsychotic-resistant and -responsive symptoms of schizophrenia. T. Nishikawa will describe his discovery of endogenous D-serine and its NMDAR-like distribution and metabolic processes in mammalian brains. Because of the coagonist nature of D-serine for the NMDAR, this discovery has revealed an unknown regulatory mechanism of the NMDAR, and provided a novel perspective on the NMDAR pathophysiology and the therapeutic strategies to restore the NMDAR function in schizophrenia. Thus, he will elucidate NMDAR coagonist-sensitive tonic inhibitory control by the NMDAR of dopamine transmission, and the regulation of the extracellular D-serine concentrations by the AMPA glutamate receptor (AMPAR), GABAAR and Asc-1 neutral amino acid transporter in the rodent prefrontal cortex. Moreover, he will discuss the significance of AMPAR antagonists as potential therapeutic agents for schizophrenia. J.T. Coyle will focus on Genome-Wide-Association-Studies showing that the proteins encoded by nearly thirty risk genes in schizophrenia are expressed in the glutamatergic synapse. To understand how they contribute to the schizophrenia phenotype, he silenced in mice the expression of serine racemase (SR), which synthesizes D-serine, to attenuate forebrain NMDAR function. The SR-/- mice exhibited pathology related to negative symptoms with cortical atrophy, ventricular enlargement, anhedonia and social deficits; cognitive symptoms with reduced dendritic spines, memory impairment and EEG gating deficits; increased striatal dopamine release, a biomarker for psychosis, and down regulation of cortical parvalbumin-positive-GABAergic neurons and oxidative stress. Many of these changes could be reversed in adulthood by restoring NMDAR function, suggesting an important target for treatment of schizophrenia. K.Q. Do will highlight the crucial role of the reciprocal interaction between NMDAR hypofunction and redox dysregulation/oxidative stress, leading to impairments of parvalbumin-GABAergic neurons circuitry, at the basis of cognitive deficits. In a prospective, observational, multimodal study in individuals with treatment-resistant in the early phases of psychosis, she will show that differential alterations in glutamatergic- and D-serine metabolic pathways between responders and treatment resistant individuals could be the underlying mechanisms of the observed early cognitive deficits and impaired functional outcome.These findings suggest a central role of dyscontrol of the cerebral NMDAR/D-serine system and associated redox in causing dopaminergic hyperactivity and GABAergic hypoactivity in schizophrenia. This viewpoint may open new avenues to develop innovative pharmacotherapy and biomarkers to overcome intractable symptoms of schizophrenia. All of the speakers’ investigations have been approved by the research ethics committees of their respective institutions.
- To learn the interrelationships among dysfunction of glutamate, dopamine and GABA neurotransmission and a crucial role of dysregulated NMDAR/D-serine/redox interaction in the pathophysiology and treatment development of schizophrenia
- To know discovery of endogenous NMDAR coagonist D-serine, and that deficit in D-serine induces NMDAR hypofunction and schizophrenia phenotype including negative and cognitive symptoms.
- To comprehend that NMDAR hypofunction produces dopaminergic hyperactivity by reducing GABAergic transmission, (2) blockade of the GABAAR or overactivation of the AMPAR results in diminished extracellular D-serine concentrations leading to NMDAR hypofunction, and (3) NMDAR hypofunction and redox dysregulation have mutual interaction.
#Schizophrenia #N-Methyl-D-aspartate receptor #D-serine #Dopamine #GABA
Late-Life Treatment Resistant Depression: Advances in Pharmacotherapy, Brain Stimulation, and Brain-based Mechanisms of Treatment Response Variability.
Chair: Jordan F. Karp (University of Arizona, College of Medicine)
The Old is New Again: Evidence-based Stepped Care Oral Pharmacotherapy and Ketamine for Late-life Treatment Resistant Depression.
Speaker: Jordan F. Karp (University of Arizona, College of Medicine)
Theta Burst Stimulation in Late-life Depression: Update on Outcomes, Biomarkers, and Mechanisms.
Speaker: Alisson P. Trevizol (CAMH, University of Toronto)
Brain-based Mechanisms of Treatment Response Variability in Late-life Depression
Speaker: Masaru Mimura (Center for Preventive Medicine, Keio University)
Late-life depression is common and treatable, affecting about 7% of older adults. Its association with comorbid physical illness, especially when chronic or treatment resistant, leads to increased 1) disability, 2) all-cause mortality, and 3) healthcare utilization. Addressing depression is vital for dementia prevention as it is a modifiable risk factor. Treatment-resistant depression (TRD) is typically defined as depression that does not remit despite two adequate trials of antidepressant medications; in older adults, treatment failure is associated with decreased psychological well-being, disability, and cognitive decline. A significant challenge is treatment-resistance to first-line therapies, with 55–81% of older adults with major depression failing to remit with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Advancing both 1) evidence-based clinical options for difficult to treat depression in late-life and 2) the mechanistic understanding of how depression and antidepressant interventions affect the aging brain should be an international priority in a shared effort to care for older adults and delay the incidence of dementia. This symposium, comprised of faculty from three different nations (including an early career investigator) will present cutting-edge research and advancements in three critical areas: pharmacotherapy, brain stimulation, and brain-based mechanisms of treatment response variability in late-life TRD. Consistent with the theme of CIPN2024, at least one of the presenters will address well-being as an outcome from a depression clinical trial. Professor Karp (USA) will describe the PCORI-funded OPTIMUM trial for late-life TRD recently published in NEJM. OPTIMUM tested benefits vs. risks of augmenting or switching antidepressants in older adults with TRD using a pragmatic trial. Dr. Karp will describe the study and observations that in older adults with TRD, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than switching to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. He will place these results in the context of the extant LL-TRD pharmacotherapy literature and then describe emerging evidence for using intranasal and intravenous ketamine in late-life TRD. Professor Trevisol (Canada; early career investigator) will describe the state of the science using brain stimulation, in particular transcranial magnetic stimulation (TMS) in late-life depression. Dr. Trevisol will describe advances in theta burst stimulation for late-life depression and the use of unilateral and bilateral repetitive TMS for late-life TRD. He will also describe biomarkers of treatment response and address the interaction between neurodegenerative diseases and treatment response to TMS in late-life depression. Professor Mimura (Japan) will present about brain-based potential mechanisms that may explain treatment response variability in late-life depression. He will provide an update on neuropsychological profiles, neuroimaging-modeled brain age, and subtypes of cognitive impairment and risk for and association with incident depression. He will also provide an update on the guidelines for diagnosis and treatment of depression in older adults from the Japanese Society of Mood Disorders.
- Appreciate the evidence supporting esketamine and IV ketamine in late-life treatment resistant depression.
- Understand advances in both repetitive transcranial magnetic stimulation and theta burst stimulation in late-life depression.
- Understand the mechanisms by which neurodegeneration is associated with late-life treatment response variability.
#late-life depression #treatment resistant depression #transcranial magnetic stimulation #biomarkers #ketamine
Multi-modal Approaches to Identify Novel Mitochondria-Based Strategies to the Diagnosis and Treatment Mood Disorders
Chair: Hilary P. Blumberg (Yale School of Medicine)
Novel Multi-modal Neuroimaging Approaches to Uncover Mitochondrial Mechanisms Underlying Brain Circuitry Dysfunction in Bipolar Disorder
Speaker: Hilary P. Blumberg (Yale School of Medicine)
Defining a Subtype of Bipolar Disorder with Mitochondrial Dysfunctions by Genomic Stratification Toward New Therapeutic Opportunities
Speaker: Masaki Nishioka (Juntendo University)
Unlocking the Potential of Mitochondrial Blood-based Patient Stratification for Bipolar Disorder and Depression: Towards Tailored Treatment Approaches
Speaker: Ana Andreazza (University of Toronto)
Mood Disorders are leading global causes of suffering, disability, and suicide; yet, there remains critical need to elucidate their underlying mechanisms and generate novel strategies to identify individuals at-risk and provide improved treatments. Especially given the major changes in physical energy levels that persons with mood disorders experience, mitochondrial mechanisms have long been implicated. The energy changes are often the first symptoms of episodes, suggesting they are linked to key pathophysiological mechanisms causing episodes and may be important targets for the early identification of episode initiation and prevention of progression to acute episodes. Mitochondrial involvement in mood disorders is supported by longstanding genetic, and serum and central nervous system lactate, findings. Recent advances in research methodologic approaches, including genomic, stem cell and neuroimaging, have now made possible far more detailed and multi-modal study of mitochondrial mechanisms in mood disorders that are revealing promising new targets for detection, patient stratification and personalized treatments. In this symposium, we will present these methodologies, new findings that have emerged from their use, and their novel clinical implications. Hilary Blumberg, MD, from Yale University, New Haven, USA, will present new data from individuals with bipolar disorder (BD) from use of novel multi-modal neuroimaging approaches to study regional brain function to energetic coupling, and of approaches to study mitochondrial morphology, mechanisms and functioning in stem cell derived brain organoids, and integration of these study approaches. Masaki Nishioka, MD, PhD, from Juntendo University, Tokyo, Japan, will present on a global collective effort to seek BD-associated rare variants, and findings of postzygotic mosaic variants arising in development as rare variants potentially associated with BD as a new kind of de novo variants. This will include presentation of data from deep exome sequencing revealing mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA genes in BD. This will include discussion of data supporting involvement of mitochondrial variants in tRNA genes, m.3243A>G heteroplasmic variants, the most major causative variants of mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), from recurrent detection in two independent patients with lower allelic fractions than MELAS. The m.3243A>G variants were also found in an independent sample postmortem brains from individuals with BD, adding additional support for the relevance of m.3243A>G variants. He will discuss genomic stratification of BD and a subtype of BD with mitochondrial dysfunctions toward detailed characterization of BD pathology and therapeutic opportunities. Ana Andreazza, PhD, from Toronto, Canada, will present a novel high-throughput mitochondrial-blood-based method of stratification for individuals with BD and major depressive disorder (MDD). She will also present on a new approach to determine the influence of mitochondrial-blood based biomarkers, disease progression, severity, or treatment resistance, using clinical datasets from patients with BD or MDD. This includes findings from the FACE-BD cohort FondaMental, France (n=1450) on relationships among elevations in lactate, lipid dysfunction, metabolic syndrome, and glucose and insulin dysregulation. These global multi-modal research collaborations can transform understanding of mitochondrial health, leading to better diagnoses, personalized treatments, and enhanced quality of life for persons with and at-risk for mood disorders.
- Understand brain imaging approaches to identify mitochondrial dysfunction
- Identify current findings of BD genomics, especially with regard to mitochondrial variants
- Understand how mitochondrial-blood based biomarkers may help patient stratification
#Bipolar Disorder #Mitochondria #Imaging #Biomarkers #Genomics
Multi-omics Approaches to Understand the Biological Mechanisms of Mood Disorders
Chair: Niamh Mullins (Icahn School of Medicine at Mount Sinai)
Statistical and Functional Fine-mapping of Genetic Risk Loci Informs the Biological Etiology of Bipolar Disorder
Speaker: Niamh Mullins (Icahn School of Medicine at Mount Sinai)
Single-cell Genomic Studies in Major Depressive Disorder
Speaker: Gustavo Turecki (McGill University)
Detection of Mitochondrial Dysfunction in Six Brain Regions Including the Paraventricular Thalamic Nucleus of Patients with Bipolar Disorder
Speaker: Mie Kubota-Sakashita (Juntendo University Graduate School of Medicine)
Mood disorders have substantial heritability and polygenic etiologies, requiring investigation across multiple molecular levels to elucidate their underlying mechanisms (Mokhtari et al., 2022). In this symposium, we present the latest multi-omics studies of major depressive disorder (MDD) and bipolar disorder (BD), and the novel insights gained into their biological etiologies. Symposium Chair Dr. Mullins will discuss statistical and functional fine-mapping of BD risk loci, identified by genome-wide association studies (Mullins et al., 2021). A suite of Bayesian fine-mapping tools was used to prioritize genes and SNPs with high probability of causality within 64 BD risk loci. These were validated computationally, by examining genomic annotations, overlap with functional features from brain tissues and cell-types, convergence with findings from rare variant sequencing studies of BD, and by testing the performance of fine-mapping-informed genetic risk predictors. To date, this work has prioritized >20 common variants with high likelihood of causality, implicating genes such as SCN2A, FKBP2, FURIN, SYNE1, THRA, and CACNA1B, many of which encode druggable proteins. Incorporating fine-mapping information improved the performance of genetic risk predictors for BD, with an increase of up to 2% in the variance explained in independent cohorts. We have developed this fine-mapping pipeline for release, as a rapid, scalable, and cost-effective strategy to prioritize genes and variants for experimental validation, along with insights into their likely functional consequences. Dr. Turecki will present recent technological advances in high-throughput single-cell genomics, and their application to study molecular and cellular changes in the prefrontal cortex in MDD. He will discuss single-nucleus transcriptomic studies (Nagy et al., 2020) and cell subtype changes observed in the depressed brain, based on studies of >160,000 nuclei from 71 female and male donors (Maitra et al., 2023). As significant sex-differences have been reported in brain molecular signatures associated with MDD, he will dissect differences and similarities between male and female findings. He will also share results of spatial transcriptomics and single-cell ATAC-seq, as well as their integration in MDD. Overall, this talk will provide a summary of single-cell genomic changes and adaptations associated with depression in the prefrontal cortex. Finally, clinical evidence suggests a relationship between BD and mitochondrial dysfunction (Kubota et al., 2010). Dr. Kubota-Sakashita will present an examination of postmortem brain samples of suicidal patients with BD and controls, via immunohistochemical staining of anti-cytochrome c oxidase (COX) and anti-succinate dehydrogenase (SDH) antibodies, where COX is encoded in mtDNA, and SDH is a nuclear-encoded mitochondrial protein. COX-negative neurons were detected in paraventricular thalamic nucleus (PVT) of patients with BD (Kasahara et al., 2016). To further characterize the mitochondrial dysfunction in the PVT, work is underway to analyze frozen brain samples using single nucleus RNAseq. The results will yield improved understanding of the relationship between mitochondrial dysfunction and BD.Together, these presentations encompass the latest approaches to understand causality and mechanisms underlying mood disorders, both computationally and experimentally, and at multiple molecular levels. We will each discuss opportunities and next steps to translate these findings into novel treatments and prevention strategies for BD and MDD.
- Provide an example of a gene likely to be causal for bipolar disorder and the supporting evidence.
- Describe the recent technological advances in single-cell genomics.
- Explain how mitochondrial dysfunction can be studied in frozen brain tissue.
#Mood disorders #Fine-mapping #Single-cell genomics #Postmortem brain #Mitochondria
Cognitive Inflexibility: Transdiagnostic Clinical Syndromes, Endophenotype, and Response to Neurostimulation and Pharmacological Treatment
Chair: Eric Hollander (Albert Einstein College of Medicine)
Cognitive Inflexibility; Diverse Health and Wellbeing Harms Indicate The Need For New Clinical and Public Health Approaches
Speaker: Naomi Fineberg (University of Hertfordshire)
Cognitive Inflexibility in Autism Spectrum Disorder and Related Developmental Disorders
Speaker: Casara J. Ferretti (Albert Einstein College of Medicine)
The role of cognitive flexibility in anxiety, mood disorders and posttraumatic stress disorder
Speaker: Michael Van Ameringen (McMaster University)
Cognitive inflexibility is a transdiagnostic endophenotype that presents across a range of disorders, including obsessive compulsive disorder (OCD), autism spectrum disorder (ASD), body dysmorphic disorder (BDD), and related conditions (Rosa-Alcazar et al, 2021; Grant and Chamberlain, 2023). Those with cognitive inflexibility, or inflexible thinking, are characterized as being cognitively rigid, and cannot easily transition from one thought or behavior to another, becoming stuck in ritualistic or repetitive patterns of behavior, which limits their ability to adapt to changes in routine and manage unpredictability. Individuals with OCD, BDD and ASD present with greater cognitive inflexibility than those without, and this construct is related to higher levels of anxiety, depression, and aggression and is predictive of emotional and behavioral difficulties across the lifespan. For example, post-pandemic and post-lockdown adjustment was poorer in those with OCPD traits and rigid behavioral styles (Fineberg et al, 2021). There are no known treatments for cognitive inflexibility, and it significantly contributes to the treatment-resistant nature of conditions like OCD, BDD and ASD. Immunomodulatory treatments, including Trichuris Suis Ova (TSO), may be a novel area of intervention, as they have shown promise in reducing cognitive rigidity, as measured by the Montefiore-Einstein Rigidity Scale-Revised (MERS-R; Taylor et al, 2022), and Restricted Behavior Scale-Revised (RBS-R) Sameness subscale (Hollander et al, 2020). Additionally, transcranial direct current stimulation (tDCS) is a promising treatment for the cognitive inflexibility present in OCD, with stimulation to the left orbitofrontal cortex (L-OFC) and supplementary motor area (SMA) resulting in improvements in Y-BOCS scores (Fineberg et al, 2023). There is a significant need to better understand this endophenotype, so that transdiagnostic treatment targets and subgroups can be identified and novel interventions developed. Dr. Fineberg will present on three new unpublished studies on ID/ED shift and cognitive inflexibility in OCD vs controls; on impact of transcranial direct current stimulation (tDCS) on cognitive flexibility in OCD; and on impact of cognitive inflexibility on vaccine hesitancy in the general population post covid-19. Dr. Fineberg and her team found that tDCS of both the orbitofrontal cortex (OFC) and the supplementary motor area (SMA) significantly improved cognitive inflexibility (ID/ED stage 8) compared to baseline (p<.05), whereas sham did not. Additionally, post-stimulation scores on the cognitive tasks were compared to those at baseline for each stimulation arm, and a pre-post effect size (within-group comparison) was calculated. Ms. Ferretti will present on cognitive inflexibility at both the family and individual level, and its relationship to metabolomic/lipidomic/immunome biomarkers in the ASD and Prader Willi Syndrome (PWS) population. We have found that immunome biomarkers were significantly correlated with cognitive inflexibility, as measured by the MERS-R, and irritability, as measured by the Aberrant Behavior Checklist (ABC). Dr. Van Ameringen will review the current evidence on the prevalence and impact of cognitive flexibility on symptom severity, functional impairment and potential treatment outcomes of generalized anxiety disorder, social anxiety disorder, major depressive disorder and posttraumatic stress disorder. Inflexible thinking has important public health implications, as it not only affects an individual’s ability to adapt to a constantly changing world, but also contributes to workplace and relationship difficulties, increased risk for suicide and even mass shootings.
- Attendees will describe how cognitive inflexibility presents across OCD, ASD, and internalizing disorders, and how to measure it with neurocognitive, caregiver, and clinician-rated measures.
- Attendees will describe how measures of cognitive inflexibility relate to metabolomic, lipidomic, and immunome biomarkers.
- Attendees will describe the effects of neurostimulation and pharmacological treatments on cognitive inflexibility.
#Transdiagnostic Endophenotype #Cognitive Inflexibility #Frontostriatal Circuitry #Clinical Biomarkers #Pharmacological Treatment