Reward Circuits and Apathy in Schizophrenia: Neuroimaging and Treatment Strategies

2017 ◽  
Vol 41 (S1) ◽  
pp. S58-S58
Author(s):  
A. Aleman
Keyword(s):  
Behavioral Treatment ◽  
Negative Symptoms ◽  
Meta Analysis ◽  
Critical Role ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Reward Processing ◽  
Motivated Behavior ◽  
Novel Treatment Strategies ◽  
Quantitative Integration

Approximately 50% of patients with schizophrenia shows deficits in motivation and initiation of goal-directed behavior, which are suggestive of reward system dysfunction. We conducted a meta-analysis of neuroimaging studies reporting on the neural correlates of reward processing and negative symptoms in schizophrenia. A significant mean weighted correlation was observerd, revealing deficits in activation of reward neurocircuitry. A more specific findings is comprised activation of the ventral striatum, involved in anticipation of reward, and structures that play a critical role in the ability to represent the value of outcomes and plans. In a study of VTA connectivity in the resting state in a large group of patients with schizophrenia, we found reduced connectivity with lateral prefrontal, temporal and parietal regions to be associated with higher degrees of apathy. Apathy belongs to the most debilitating symptoms of schizophrenia and represents a significant unmet need in its treatment. Quantitative integration of published findings suggests that treatment with noninvasive magnetic brain stimulation can improve negative symptoms. Previous PET-studies have shown that such stimulation may target circuits with dopaminergic innervation. A behavioral treatment approach that may also target reward-related circuits will also be discussed briefly. It can be concluded that recent results regarding reward and motivated behavior in schizophrenia have clinical implications and may help develop novel treatment strategies.Disclosure of interestAA received speaker fees from Lundbeck.

scholarly journals Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis

2019 ◽  
Vol 5 (12) ◽  
pp. eaay0370 ◽  
Author(s):  
David Izadi ◽  
Thomas B. Layton ◽  
Lynn Williams ◽  
Fiona McCann ◽  
Marisa Cabrita ◽  
...  
Keyword(s):  
Immune Cells ◽  
Single Cell Analysis ◽  
Unmet Need ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Low Grade ◽  
Interleukin 33 ◽  
Target Disease ◽  
Novel Treatment Strategies ◽  
Molecular Landscape

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren’s disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.

scholarly journals Human PD-1hiCD8+ T Cells Are a Cellular Source of IL-21 in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuhiko Higashioka ◽  
Motoki Yoshimura ◽  
Takahide Sakuragi ◽  
Masahiro Ayano ◽  
Yasutaka Kimoto ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Treatment Strategies ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Transcription Profiles ◽  
Cellular Source ◽  
Novel Treatment Strategies

BackgroundRheumatoid arthritis (RA) is a prototypical autoantibody-driven autoimmune disease in which T-B interactions play a critical role. Recent comprehensive analysis suggests that PD-1+CD8+ T cells as well as two distinct IL-21-producing PD-1+CD4+ T cell subsets, follicular helper T (Tfh) and peripheral helper T (Tph) cells, are involved in the pathogenesis of RA. Herein, we aimed to clarify a generation mechanism of IL-21-producing CD8+ T cells in humans, and to characterize this novel subset in patients with RA.MethodsCD8+ T cells in the peripheral blood (PB) and synovial fluid (SF) of healthy control (HC) and patients with RA were subject to the analysis of IL-21 mRNA and protein. We evaluated the surface marker, cytokine and transcription profiles of IL-21-producing CD8+ T cells in HCPB, RAPB and RASF.ResultsIL-21-producing CD8+ T cells were enriched in the CD45RA-(memory) PD-1+, especially PD-1hi subpopulation, and IL-12 and IL-21 synergistically induced IL-21 production by naïve CD8+ T cells. Memory PD-1hiCD8+ T cells in HCPB facilitated plasmablast differentiation and IgG production in an IL-21-dependent manner. In addition, PD-1hiCD8+ T cells in RASF and RAPB produced large amounts of IL-21 and were characterized by high levels of CD28, ICOS, CD69, HLA-DR, and CCR2 but not CXCR5. Furthermore, PD-1hiCD8+ T cells expressed high levels of transcripts of MAF and PRDM1, a feature observed in Tph cells.ConclusionsIdentification of IL-21-producing PD-1hiCD8+ T cells expands our knowledge of T cell subsets with B helper functions in RA. Selective targeting of these subsets could pave an avenue for the development of novel treatment strategies for this disease.

scholarly journals Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

2021 ◽  
Author(s):  
Robert A Bittner ◽  
Catherine V Barnes-Scheufler ◽  
Meike D Hettwer ◽  
Andreas Reif ◽  
Mishal Qubad
Keyword(s):  
Cognitive Impairment ◽  
Neural Plasticity ◽  
Clinical Symptoms ◽  
Therapeutic Potential ◽  
Cognitive Impairments ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Potential Effect ◽  
Current Evidence ◽  
Novel Treatment Strategies

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

Incentive salience: novel treatment strategies for major depression

CNS Spectrums ◽  
2013 ◽  
Vol 18 (6) ◽  
pp. 307-314 ◽  
Author(s):  
David P. Soskin ◽  
Daphne J. Holt ◽  
Garret R. Sacco ◽  
Maurizio Fava
Keyword(s):  
Positive Emotions ◽  
Drugs Of Abuse ◽  
Treatment Strategies ◽  
Reward Processing ◽  
Incentive Salience ◽  
Major Depressive ◽  
Dopaminergic Agents ◽  
Approach Behaviors ◽  
New Treatment ◽  
Novel Treatment Strategies

This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates “wanting,” or anticipatory reward, rather than “liking,” or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or “liking,” it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.

The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 846-859
Author(s):  
Mohd Saeed ◽  
Mohd Adnan Kausar ◽  
Rajeev Singh ◽  
Arif J. Siddiqui ◽  
Asma Akhter
Keyword(s):  
Protein Misfolding ◽  
Covalent Binding ◽  
Critical Role ◽  
Enzymatic Reaction ◽  
Treatment Strategies ◽  
Bioactive Molecules ◽  
Carbonyl Stress ◽  
Defense System ◽  
Pathological Conditions ◽  
Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

Neurobiological Reward-Related Abnormalities Across Mood Disorders

2019 ◽  
pp. 222-238
Author(s):  
Alexis E. Whitton ◽  
Michael T. Treadway ◽  
Manon L. Ironside ◽  
Diego A. Pizzagalli
Keyword(s):  
Decision Making ◽  
Mood Disorders ◽  
Treatment Strategies ◽  
Reward Processing ◽  
Reward Learning ◽  
Symptom Presentation ◽  
Psychiatric Symptomatology ◽  
Symptom Dimensions ◽  
Psychotherapeutic Interventions ◽  
Primary Focus

This chapter provides a critical review of recent behavioral and neuroimaging evidence of reward processing abnormalities in mood disorders. The primary focus is on the neural mechanisms underlying disruption in approach motivation, reward learning, and reward-based decision-making in major depression and bipolar disorder. Efforts focused on understanding how reward-related impairments contribute to psychiatric symptomatology have grown substantially in recent years. This has been driven by significant advances in the understanding of the neurobiology of reward processing and a growing recognition that disturbances in motivation and hedonic capacity are poorly targeted by current pharmacological and psychotherapeutic interventions. As a result, numerous studies have sought to test the presence of reward circuit dysfunction in psychiatric disorders that are marked by anhedonia, amotivation, mania, and impulsivity. Moreover, as the field has increasingly eschewed categorical diagnostic boundaries in favor of symptom dimensions, there has been a parallel rise in studies seeking to identify transdiagnostic neural markers of reward processing dysfunction that may transcend disorders. The thesis of this chapter is twofold: First, evidence indicates that specific subcomponents of reward processing map onto partially distinct neurobiological pathways. Second, specific subcomponents of reward processing, including reward learning and effort-based decision-making, are impaired across different mood disorder diagnoses and may point to dimensions in symptom presentation that possess more reliable behavioral and neural correlates. The potential for these findings to inform the development of prevention and treatment strategies is discussed.

scholarly journals Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

Children ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 482
Author(s):  
Irene Paraboschi ◽  
Laura Privitera ◽  
Gabriela Kramer-Marek ◽  
John Anderson ◽  
Stefano Giuliani
Keyword(s):  
Research Effort ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Treatment Protocols ◽  
Ongoing Research ◽  
Hematopoietic Stem ◽  
Novel Treatments ◽  
Therapeutic Modalities ◽  
High Risk Disease ◽  
Novel Treatment Strategies

Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, accounting for approximately 15% of all cancer-related deaths in the paediatric population1. It is characterised by heterogeneous clinical behaviour in neonates and often adverse outcomes in toddlers. The overall survival of children with high-risk disease is around 40–50% despite the aggressive treatment protocols consisting of intensive chemotherapy, surgery, radiation therapy and hematopoietic stem cell transplantation2,3. There is an ongoing research effort to increase NB’s cellular and molecular biology knowledge to translate essential findings into novel treatment strategies. This review aims to address new therapeutic modalities emerging from preclinical studies offering a unique translational opportunity for NB treatment.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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