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Asim M, Wang H, Waris A, Qianqian G, Chen X. Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease. Biofactors 2024; 50:1060-1075. [PMID: 38777339 PMCID: PMC11627476 DOI: 10.1002/biof.2081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
Cholecystokinin (CCK) plays a key role in various brain functions, including both health and disease states. Despite the extensive research conducted on CCK, there remain several important questions regarding its specific role in the brain. As a result, the existing body of literature on the subject is complex and sometimes conflicting. The primary objective of this review article is to provide a comprehensive overview of recent advancements in understanding the central nervous system role of CCK, with a specific emphasis on elucidating CCK's mechanisms for neuroplasticity, exploring its interactions with other neurotransmitters, and discussing its significant involvement in neurological disorders. Studies demonstrate that CCK mediates both inhibitory long-term potentiation (iLTP) and excitatory long-term potentiation (eLTP) in the brain. Activation of the GPR173 receptor could facilitate iLTP, while the Cholecystokinin B receptor (CCKBR) facilitates eLTP. CCK receptors' expression on different neurons regulates activity, neurotransmitter release, and plasticity, emphasizing CCK's role in modulating brain function. Furthermore, CCK plays a pivotal role in modulating emotional states, Alzheimer's disease, addiction, schizophrenia, and epileptic conditions. Targeting CCK cell types and circuits holds promise as a therapeutic strategy for alleviating these brain disorders.
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Affiliation(s)
- Muhammad Asim
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
- Department of Biomedical ScienceCity University of Hong KongKowloon TongHong Kong
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of SciencesPak Shek KokHong Kong
| | - Huajie Wang
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
| | - Abdul Waris
- Department of Biomedical ScienceCity University of Hong KongKowloon TongHong Kong
| | - Gao Qianqian
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
| | - Xi Chen
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
- Department of Biomedical ScienceCity University of Hong KongKowloon TongHong Kong
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of SciencesPak Shek KokHong Kong
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Gruenbaum BF, Schonwald A, Boyko M, Zlotnik A. The Role of Glutamate and Blood-Brain Barrier Disruption as a Mechanistic Link between Epilepsy and Depression. Cells 2024; 13:1228. [PMID: 39056809 PMCID: PMC11275034 DOI: 10.3390/cells13141228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/10/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Epilepsy is associated with substantial neuropsychiatric impairments that persist long after the onset of the condition, significantly impacting quality of life. The goal of this review was to uncover how the pathological consequences of epilepsy, such as excessive glutamate release and a disrupted blood-brain barrier (BBB), contribute to the emergence of neuropsychiatric disorders. We hypothesize that epilepsy induces a dysfunctional BBB through hyperexcitation, which then further amplifies post-ictal glutamate levels and, thus, triggers neurodegenerative and neuropsychiatric processes. This review identifies the determinants of glutamate concentration levels in the brain and explores potential therapeutic interventions that restore BBB integrity. Our focus on therapeutic BBB restoration is guided by the premise that it may improve glutamate regulation, consequently mitigating the neurotoxicity that contributes to the onset of neuropsychiatric symptoms.
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Affiliation(s)
- Benjamin F. Gruenbaum
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | - Matthew Boyko
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel; (M.B.); (A.Z.)
| | - Alexander Zlotnik
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel; (M.B.); (A.Z.)
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3
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Moraes ACN, Wijaya C, Freire R, Quagliato LA, Nardi AE, Kyriakoulis P. Neurochemical and genetic factors in panic disorder: a systematic review. Transl Psychiatry 2024; 14:294. [PMID: 39025836 PMCID: PMC11258274 DOI: 10.1038/s41398-024-02966-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 05/13/2024] [Accepted: 05/28/2024] [Indexed: 07/20/2024] Open
Abstract
This systematic review addresses the complex nature of Panic Disorder (PD), characterized by recurrent episodes of acute fear, with a focus on updating and consolidating knowledge regarding neurochemical, genetic, and epigenetic factors associated with PD. Utilizing the PRISMA methodology, 33 original peer-reviewed studies were identified, comprising 6 studies related to human neurochemicals, 10 related to human genetic or epigenetic alterations, and 17 animal studies. The review reveals patterns of altered expression in various biological systems, including neurotransmission, the Hypothalamic-Pituitary-Adrenal (HPA) axis, neuroplasticity, and genetic and epigenetic factors leading to neuroanatomical modifications. Noteworthy findings include lower receptor binding of GABAA and serotonin neurotransmitters in the amygdala. The involvement of orexin (ORX) neurons in the dorsomedial/perifornical region in triggering panic reactions is highlighted, with systemic ORX-1 receptor antagonists blocking panic responses. Elevated Interleukin 6 and leptin levels in PD patients suggest potential connections between stress-induced inflammatory changes and PD. Brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) signaling are implicated in panic-like responses, particularly in the dorsal periaqueductal gray (dPAG), where BDNF's panicolytic-like effects operate through GABAA-dependent mechanisms. GABAergic neurons' inhibitory influence on dorsomedial and posterior hypothalamus nuclei is identified, potentially reducing the excitability of neurons involved in panic-like responses. The dorsomedial hypothalamus (DMH) is highlighted as a specific hypothalamic nucleus relevant to the genesis and maintenance of panic disorder. Altered brain lactate and glutamate concentrations, along with identified genetic polymorphisms linked to PD, further contribute to the intricate neurochemical landscape associated with the disorder. The review underscores the potential impact of neurochemical, genetic, and epigenetic factors on the development and expression of PD. The comprehensive insights provided by this systematic review contribute to advancing our understanding of the multifaceted nature of Panic Disorder and pave the way for targeted therapeutic strategies.
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Affiliation(s)
| | - Clarissa Wijaya
- School of Psychology, Swinburne University, Melbourne, VIC, Australia
| | - Rafael Freire
- Department of Psychiatry and Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada
| | | | | | - Peter Kyriakoulis
- School of Psychology, Swinburne University, Melbourne, VIC, Australia
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Gruenbaum BF, Zlotnik A, Fleidervish I, Frenkel A, Boyko M. Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies. Int J Mol Sci 2022; 23:ijms23179628. [PMID: 36077024 PMCID: PMC9456007 DOI: 10.3390/ijms23179628] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients’ lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes to the development of neuropsychiatric conditions. We hypothesize that TBI causes long-term blood–brain barrier (BBB) dysfunction lasting many years and even decades. We propose that dysfunction in the BBB is the central factor that modulates increased glutamate after TBI and ultimately leads to neurodegenerative processes and subsequent manifestation of neuropsychiatric conditions. Here, we have identified factors that determine the upper and lower levels of glutamate concentration in the brain after TBI. Furthermore, we consider treatments of disruptions to BBB integrity, including repairing the BBB and controlling excess glutamate, as potential therapeutic modalities for the treatment of acute and chronic neuropsychiatric conditions and symptoms. By specifically focusing on the BBB, we hypothesize that restoring BBB integrity will alleviate neurotoxicity and related neurological sequelae.
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Affiliation(s)
- Benjamin F. Gruenbaum
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Alexander Zlotnik
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
| | - Ilya Fleidervish
- Department of Physiology and Cell Biology, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Amit Frenkel
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
| | - Matthew Boyko
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
- Correspondence:
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Cholecystokinin B receptor gene polymorphism (rs2941026) is associated with anxious personality and suicidal thoughts in a longitudinal study. Acta Neuropsychiatr 2022; 34:201-211. [PMID: 34924075 DOI: 10.1017/neu.2021.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVES Cholecystokinin is a neuropeptide with a role in the neurobiology of adaptive behaviour that is implicated in anxiety disorders, while the underlying mechanisms currently remain insufficiently explained. The rs2941026 variation in the cholecystokinin B receptor gene has previously been associated with trait anxiety. Our aim was to investigate associations between the CCKB receptor gene polymorphism rs2941026 with anxiety, personality, depressiveness and suicidality in a longitudinal study of late adolescence and early adulthood. METHODS We used reports on trait and state anxiety, depressiveness and suicidal thoughts, as well as Affective Neuroscience Personality Scales, from the two birth cohorts of the Estonian Children Personality, Behaviour and Health Study. We measured associations between the CCKBR gene rs2941026 and anxiety-related phenotypes both longitudinally and cross-sectionally at ages 15, 18, 25 and 33. RESULTS Homozygosity for both alleles of the CCKBR rs2941026 was associated with higher trait and state anxiety in the longitudinal analysis. Cross-sectional comparisons were statistically significant at ages 18 and 25 for trait anxiety and at ages 25 and 33 for state anxiety. Higher depressiveness and suicidal thoughts were associated with the A/A genotype at age 18. Additionally, homozygosity for the A-allele was related to higher FEAR and SADNESS in the Affective Neuroscience Personality Scales. The genotype effects were more apparent in females, who displayed higher levels of negative affect overall. CONCLUSIONS CCKBR genotype is persistently associated with negative affect in adolescence and young adulthood. The association of the CCKBR rs2941026 genotype with anxiety-related phenotypes is more pronounced in females.
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Lucido MJ, Bekhbat M, Goldsmith DR, Treadway MT, Haroon E, Felger JC, Miller AH. Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications. Pharmacol Rev 2021; 73:1084-1117. [PMID: 34285088 PMCID: PMC11060479 DOI: 10.1124/pharmrev.120.000043] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.
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Affiliation(s)
- Michael J Lucido
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
| | - Mandy Bekhbat
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
| | - David R Goldsmith
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
| | - Michael T Treadway
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
| | - Ebrahim Haroon
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
| | - Jennifer C Felger
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
| | - Andrew H Miller
- Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.)
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7
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Takaishi M, Asami T, Yoshida H, Nakamura R, Yoshimi A, Hirayasu Y. Smaller volume of right hippocampal CA2/3 in patients with panic disorder. Brain Imaging Behav 2021; 15:320-326. [PMID: 32125615 DOI: 10.1007/s11682-020-00259-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The hippocampus is thought to play an important role in conveying contextual information to the amygdala as the neural basis of panic disorder (PD). Previous studies have revealed functional abnormalities in the hippocampus in patients with PD compared with healthy control subjects (HC), but no study has reported volume abnormalities in the hippocampus or evaluated minute structural changes in the hippocampus in such patients. We thus investigated volume abnormalities in the subfields of the hippocampus to better understand the neurobiological basis of PD. The hippocampus was extracted from structural brain magnetic resonance images obtained from 38 patients with PD and 38 HC and then segmented into six subfields. The relative volume of each subfield was compared between the two groups. The severity of symptoms was assessed using the Panic Disorder Severity Scale (PDSS) and social functioning was assessed using the Global Assessment of Functioning (GAF) scale. Our results revealed that patients with PD had a significantly smaller volume of the right cornu ammonis (CA) 2/3 hippocampal subfield compared with HC. No significant associations were found between the volumes of the right CA 2/3 and the PDSS or GAF scores in correlation analyses. In conclusion, CA2/3 is thought to be related to contextual memory function, and our results suggest that this particular hippocampal subfield plays a role in the development of PD symptoms.
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Affiliation(s)
- Masao Takaishi
- Department of Psychiatry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan
| | - Takeshi Asami
- Department of Psychiatry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
| | - Haruhisa Yoshida
- Department of Psychiatry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan
| | - Ryota Nakamura
- Department of Psychiatry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan
| | - Asuka Yoshimi
- Department of Psychiatry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan
| | - Yoshio Hirayasu
- Department of Psychiatry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan
- Heian Hospital, Okinawa, Japan
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Batelaan NM, Seldenrijk A, van den Heuvel OA, van Balkom AJLM, Kaiser A, Reneman L, Tan HL. Anxiety, Mental Stress, and Sudden Cardiac Arrest: Epidemiology, Possible Mechanisms and Future Research. Front Psychiatry 2021; 12:813518. [PMID: 35185641 PMCID: PMC8850954 DOI: 10.3389/fpsyt.2021.813518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/29/2021] [Indexed: 12/26/2022] Open
Abstract
Sudden cardiac arrest (SCA) is a leading cause of mortality and morbidity in affluent societies, which underscores the need to identify persons at risk. The etiology of SCA is however complex, with predisposing and precipitating factors interacting. Although anxiety and mental stress have been linked to SCA for decades, their precise role and impact remain unclear and the biological underpinnings are insufficiently understood. In this paper, we systematically reviewed various types of observational studies (total n = 20) examining the association between anxiety or mental stress and SCA. Multiple methodological considerations challenged the summarizing and interpretation of the findings. For anxiety, the overall picture suggests that it predisposes for SCA in physically healthy populations (unadjusted OR = 2.44; 95% CI: 1.06-5.59; n = 3). However, in populations at risk for SCA (n = 4), associations were heterogeneous but not significant. Anxiety may partly predispose to SCA by contributing to other risk factors such as cardiovascular disease and diabetes mellitus via mechanisms such as unhealthy lifestyle and metabolic abnormalities. Mental stress appears to precipitate SCA, presumably by more directly impacting on the cardiac ion channels that control the heart's electrical properties. This may lead to ventricular fibrillation, the arrhythmia that underlies SCA. To advance this field of research, experimental studies that unravel the underlying biological mechanisms are deemed important, and most easily designed for mental stress as a precipitating factor because of the short timeframe. These proof-of-concept studies should examine the whole pathway from the brain to the autonomic nervous system, and eventually to cardiac ion channels. Ultimately, such studies may facilitate the identification of persons at risk and the development of novel preventive strategies.
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Affiliation(s)
- Neeltje M Batelaan
- Department of Psychiatry, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Amsterdam Public Health Research Institute, Amsterdam, Netherlands
| | - Adrie Seldenrijk
- Department of Psychiatry, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Amsterdam Public Health Research Institute, Amsterdam, Netherlands
| | - Odile A van den Heuvel
- Department of Psychiatry, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Amsterdam Neuroscience Research Institute, Amsterdam, Netherlands.,Department of Anatomy and Neuroscience, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Anton J L M van Balkom
- Department of Psychiatry, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Amsterdam Public Health Research Institute, Amsterdam, Netherlands
| | - Antonia Kaiser
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Department of Psychiatry, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Liesbeth Reneman
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Hanno L Tan
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Heart Institute, Utrecht, Netherlands
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Ballaz SJ, Bourin M. Cholecystokinin-Mediated Neuromodulation of Anxiety and Schizophrenia: A "Dimmer-Switch" Hypothesis. Curr Neuropharmacol 2021; 19:925-938. [PMID: 33185164 PMCID: PMC8686311 DOI: 10.2174/1570159x18666201113145143] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/08/2020] [Accepted: 11/10/2020] [Indexed: 11/22/2022] Open
Abstract
Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/ inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.
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Affiliation(s)
- Santiago J. Ballaz
- Address correspondence to this author at the School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador; Tel: 593 (06) 299 9100, ext. 2626; E-mail:
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10
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Milak MS, Rashid R, Dong Z, Kegeles LS, Grunebaum MF, Ogden RT, Lin X, Mulhern ST, Suckow RF, Cooper TB, Keilp JG, Mao X, Shungu DC, Mann JJ. Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial. JAMA Netw Open 2020; 3:e2013211. [PMID: 32785636 PMCID: PMC7424409 DOI: 10.1001/jamanetworkopen.2020.13211] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
IMPORTANCE A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. OBJECTIVE To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. DESIGN, SETTING, AND PARTICIPANTS This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. INTERVENTION Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. MAIN OUTCOMES AND MEASURES Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. RESULTS A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only (t5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. CONCLUSIONS AND RELEVANCE In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01558063.
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Affiliation(s)
- Matthew S. Milak
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
| | - Rain Rashid
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
| | - Zhengchao Dong
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
| | - Lawrence S. Kegeles
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
- Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Michael F. Grunebaum
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
| | - R. Todd Ogden
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York
| | - Xuejing Lin
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York
| | - Stephanie T. Mulhern
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
| | - Raymond F. Suckow
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
- Analytical Psychopharmacology Laboratory, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
| | - Thomas B. Cooper
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
- Analytical Psychopharmacology Laboratory, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
| | - John G. Keilp
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
| | - Xiangling Mao
- Department of Radiology, Weill Cornell Medicine, New York, New York
| | - Dikoma C. Shungu
- Department of Radiology, Weill Cornell Medicine, New York, New York
| | - J. John Mann
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
- Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
- Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, New York
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11
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Zhang F, Chen H, Zhang R, Liu Y, Kong N, Guo Y, Xu M. 5-Fluorouracil induced dysregulation of the microbiome-gut-brain axis manifesting as depressive like behaviors in rats. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165884. [PMID: 32574836 DOI: 10.1016/j.bbadis.2020.165884] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/08/2020] [Accepted: 06/17/2020] [Indexed: 02/08/2023]
Abstract
Disturbances of the gut microbiome have been widely suggested to be associated with 5-fluorouracil (5-Fu) induced digestive pathologies. Furthermore, it has been elucidated that the gut microbiome may play a key role in the pathogenesis of depressive disorders via the microbiota-gut-brain axis. Despite the speculation, there exists no direct evidence proving the causality between disturbances in the gut microbiome induced by 5-Fu and depressive mood dysregulation. Herein, behavioral testing was used to evaluate depressive-like behaviors in 5-Fu treated rats. Subsequently, the gut microbiota and prefrontal cortex (PFC) metabolic were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (1H NMR). To clarify the association between the gut microbiota and their role on depressive-like behaviors caused by 5-Fu, a fecal microbiota transplantation (FMT) experiment was carried out. The results suggested that 5-Fu could significantly alter the diversity and abundance of the gut microbiome, and induce PFC metabolic disorders, as well as depressive behaviors in rats. Transplantation of fecal microbiota from healthy control into 5-Fu treated rats significantly alleviated the PFC metabolic disorder and depressive-like behaviors. In conclusion, this study demonstrated that the gut microbiome was actively involved in the occurrence of 5-Fu induced depressive-like behaviors, and manipulation of specific gut microbiome parameters may serve as a promising novel target for side effects of 5-Fu treatment.
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Affiliation(s)
- Fan Zhang
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China
| | - Haitao Chen
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ruixin Zhang
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China
| | - Yu Liu
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Ning Kong
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yong Guo
- Department of Oncology, First Affiliated Hospital of Zhejiang Traditional Medical University, Hangzhou, Zhejiang 310003, China.
| | - Maosheng Xu
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China.
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12
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Chubar V, Van Leeuwen K, Bijttebier P, Van Assche E, Bosmans G, Van den Noortgate W, van Winkel R, Goossens L, Claes S. Gene-environment interaction: New insights into perceived parenting and social anxiety among adolescents. Eur Psychiatry 2020; 63:e64. [PMID: 32507125 PMCID: PMC7355173 DOI: 10.1192/j.eurpsy.2020.62] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background. Social anxiety symptoms (SAS) are among the most common mental health problems during adolescence, and it has been shown that parenting influences the adolescent’s level of social anxiety. In addition, it is now widely assumed that most mental health problems, including social anxiety, originate from a complex interplay between genes and environment. However, to date, gene–environment (G × E) interactions studies in the field of social anxiety remain limited. In this study, we have examined how 274 genes involved in different neurotransmission pathways interact with five aspects of perceived parenting as environmental exposure (i.e., support, proactive control, psychological control, punitive control, and harsh punitive control) to affect SAS during adolescence. Methods. We have applied an analytical technique that allows studying genetic information at the gene level, by aggregating data from multiple single-nucleotide-polymorphisms within the same gene and by taking into account the linkage disequilibrium structure of the gene. All participants were part of the STRATEGIES cohort of 948 Flemish adolescents (mean age = 13.7), a population-based study on the development of problem behaviors in adolescence. Relevant genes were preselected based on prior findings and neurotransmitter-related functional protein networks. Results. The results suggest that genes involved in glutamate (SLC1A1), glutathione neurotransmission (GSTZ1), and oxidative stress (CALCRL), in association with harsh punitive parenting, may contribute to social anxiety in adolescence. Isolated polymorphisms in these genes have been related to anxiety and related disorders in earlier work.Conclusions: Taken together, these findings provide new insights into possible biological pathways and environmental risk factors involved in the etiology of social anxiety symptoms’ development. Conclusions. Taken together, these findings provide new insights into possible biological pathways and environmental risk factors involved in the etiology of social anxiety symptoms’ development.
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Affiliation(s)
- Viktoria Chubar
- Mind-Body Research Group, Department of Neuroscience, KU Leuven, Leuven, Belgium
| | - Karla Van Leeuwen
- Parenting and Special Education Research Unit, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium
| | - Patricia Bijttebier
- School Psychology and Development in Context, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium
| | - Evelien Van Assche
- Mind-Body Research Group, Department of Neuroscience, KU Leuven, Leuven, Belgium.,University Psychiatric Center KU Leuven, Leuven, Belgium
| | - Guy Bosmans
- Clinical Psychology, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium
| | - Wim Van den Noortgate
- Department of Methodology of Educational Sciences, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium
| | - Ruud van Winkel
- University Psychiatric Center KU Leuven, Leuven, Belgium.,Center for Contextual Psychiatry, Department of Neuroscience, KU Leuven, Leuven, Belgium
| | - Luc Goossens
- School Psychology and Child and Adolescent Development Research Unit, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium
| | - Stephan Claes
- Mind-Body Research Group, Department of Neuroscience, KU Leuven, Leuven, Belgium.,University Psychiatric Center KU Leuven, Leuven, Belgium
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13
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Corcoran M, Hawkins EL, O'Hora D, Whalley HC, Hall J, Lawrie SM, Dauvermann MR. Are working memory and glutamate concentrations involved in early-life stress and severity of psychosis? Brain Behav 2020; 10:e01616. [PMID: 32385970 PMCID: PMC7303391 DOI: 10.1002/brb3.1616] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/18/2020] [Accepted: 03/10/2020] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Occurrences of early-life stress (ELS) are associated with the severity of psychotic symptoms and working memory (WM) deficits in patients with psychosis (PSY). This study investigated potential mediation roles of WM behavioral performance and glutamate concentrations in prefrontal brain regions on the association between ELS and psychotic symptom severity in PSY. METHOD Forty-seven patients with PSY (established schizophrenia, n = 30; bipolar disorder, n = 17) completed measures of psychotic symptom severity. In addition, data on ELS and WM performance were collected in both patients with PSY and healthy controls (HC; n = 41). Resting-state glutamate concentrations in the bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) were also assessed with proton magnetic resonance spectroscopy for both PSY and HC groups. t tests, analyses of variance, and regression analyses were utilized. RESULTS Participants with PSY reported significantly more ELS occurrences and showed poorer WM performance than HC. Furthermore, individuals with PSY displayed lower glutamate concentrations in the left DLPFC than HC. Neither ELS nor WM performance were predictive of severity of psychotic symptoms in participants with PSY. However, we found a significant negative correlation between glutamate concentrations in the left DLPFC and ELS occurrence in HC only. CONCLUSION In individuals with PSY, the current study found no evidence that the association between ELS and psychotic symptoms is mediated by WM performance or prefrontal glutamate concentrations. In HC, the association between ELS experience and glutamate concentrations may indicate a neurometabolite effect of ELS that is independent of an illness effect in psychosis.
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Affiliation(s)
- Mark Corcoran
- School of Psychology, National University of Ireland Galway, Galway, Ireland
| | - Emma L Hawkins
- Division of Psychiatry, University of Edinburgh, Edinburgh, UK
| | - Denis O'Hora
- School of Psychology, National University of Ireland Galway, Galway, Ireland
| | | | - Jeremy Hall
- Neuroscience and Mental Health Research Institute, Cardiff University School of Medicine, Cardiff, UK
| | | | - Maria R Dauvermann
- School of Psychology, National University of Ireland Galway, Galway, Ireland.,McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Psychiatry, University of Cambridge, Cambridge, UK
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14
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Yamasaki M, Makino T, Khor SS, Toyoda H, Miyagawa T, Liu X, Kuwabara H, Kano Y, Shimada T, Sugiyama T, Nishida H, Sugaya N, Tochigi M, Otowa T, Okazaki Y, Kaiya H, Kawamura Y, Miyashita A, Kuwano R, Kasai K, Tanii H, Sasaki T, Honda M, Tokunaga K. Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases. BMC Med Genomics 2020; 13:55. [PMID: 32223758 PMCID: PMC7104509 DOI: 10.1186/s12920-020-0699-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 02/24/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. METHODS Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. RESULTS Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. CONCLUSIONS This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.
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Affiliation(s)
- Maria Yamasaki
- Department of Health Data Science Research, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Medical Center, Tokyo, Japan
| | - Takashi Makino
- Laboratory of Evolutionary Genomics, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project (Toyama), National Center for for Global Health and Medicine, Tokyo, Japan
| | - Hiromi Toyoda
- Genome Medical Science Project (Toyama), National Center for for Global Health and Medicine, Tokyo, Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Taku Miyagawa
- Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Xiaoxi Liu
- RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Hitoshi Kuwabara
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yukiko Kano
- Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan
- Department of Child Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takafumi Shimada
- Division for Counseling and Support, The University of Tokyo, Tokyo, Japan
| | - Toshiro Sugiyama
- Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hisami Nishida
- Asunaro Hospital for Child and Adolescent Psychiatry, Mie, Japan
| | - Nagisa Sugaya
- Unit of Public Health and Preventive Medicine, School of Medicine, Yokohama City University, Kanagawa, Japan
| | - Mamoru Tochigi
- Department of Neuropsychiatry, Teikyo University Hospital, Tokyo, Japan
| | - Takeshi Otowa
- Department of Neuropsychiatry, NTT Medical Center Tokyo, Tokyo, Japan
| | - Yuji Okazaki
- Department of Psychiatry, Koseikai Michinoo Hospital, Nagasaki, Japan
| | - Hisanobu Kaiya
- Panic Disorder Research Center, Warakukai Med Corp, Tokyo, Japan
| | - Yoshiya Kawamura
- Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Akinori Miyashita
- Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan
| | - Ryozo Kuwano
- Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan
- Asahigawaso Research Institute, Asahigawaso Medical-Welfare Center, Okayama, Japan
| | - Kiyoto Kasai
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisashi Tanii
- Center for Physical and Mental Health, Mie University, Tsu, Mie Japan
| | - Tsukasa Sasaki
- Division of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan
| | - Makoto Honda
- Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project (Toyama), National Center for for Global Health and Medicine, Tokyo, Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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15
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Morgenroth E, Orlov N, Lythgoe DJ, Stone JM, Barker H, Munro J, Eysenck M, Allen P. Altered relationship between prefrontal glutamate and activation during cognitive control in people with high trait anxiety. Cortex 2019; 117:53-63. [PMID: 30928721 DOI: 10.1016/j.cortex.2019.02.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/06/2018] [Accepted: 02/22/2019] [Indexed: 01/08/2023]
Abstract
Trait anxiety can affect cognitive control resulting in ineffective and/or inefficient task performance. Moreover, previous functional Magnetic Resonance Imaging (fMRI) studies have reported altered dorsolateral prefrontal cortex (DLPFC) activity in anxious cohorts, particularly when executive control is required. Recently, it has been demonstrated that cortical glutamate levels can predict both functional activation during cognitive control, and anxiety levels. In the present study we sought to investigate the relationship between trait anxiety, prefrontal glutamate levels and functional activation in DLPFC during a cognitive control task. Thirty-nine participants assigned to either low trait anxiety (LTA) or high trait anxiety (HTA) groups underwent 1H-Magnetic Resonance Spectroscopy (1H-MRS) to measure levels of resting glutamate in the prefrontal cortex (PFC). Participants also completed fMRI during a Stroop task comprising congruent and incongruent colour word trials. The HTA group showed reduced task performance relative to the LTA group. In the LTA group, there was a positive association between PFC Glu levels and DLPFC activation during incongruent trials. This association was absent in the HTA group. Individual differences in trait anxiety affect the relationship between PFC glutamate levels and DLPFC activation, possibly contributing to ineffective task performance when cognitive control is required.
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Affiliation(s)
| | - Natasza Orlov
- Department of Psychology, University of Roehampton, London, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - David J Lythgoe
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - James M Stone
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Holly Barker
- Department of Psychology, University of Roehampton, London, UK
| | - James Munro
- Department of Psychology, University of Roehampton, London, UK; Department of Psychology, Edinburgh Napier University, Edinburgh, UK
| | - Michael Eysenck
- Department of Psychology, University of Roehampton, London, UK; Department of Psychology, Royal Holloway University of London, London, UK
| | - Paul Allen
- Department of Psychology, University of Roehampton, London, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Combined Universities Brain Imaging Centre, London, UK
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16
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Extrinsic and default mode networks in psychiatric conditions: Relationship to excitatory-inhibitory transmitter balance and early trauma. Neurosci Biobehav Rev 2019; 99:90-100. [PMID: 30769024 DOI: 10.1016/j.neubiorev.2019.02.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 01/30/2019] [Accepted: 02/07/2019] [Indexed: 02/08/2023]
Abstract
Over the last three decades there has been an accumulation of Magnetic Resonance Imaging (MRI) studies reporting that aberrant functional networks may underlie cognitive deficits and other symptoms across a range of psychiatric diagnoses. The use of pharmacological MRI and 1H-Magnetic Resonance Spectroscopy (1H-MRS) has allowed researchers to investigate how changes in network dynamics are related to perturbed excitatory and inhibitory neurotransmission in individuals with psychiatric conditions. More recently, changes in functional network dynamics and excitatory/inhibitory (E/I) neurotransmission have been linked to early childhood trauma, a major antecedents for psychiatric illness in adulthood. Here we review studies investigating whether perturbed network dynamics seen across psychiatric conditions are related to changes in E/I neurotransmission, and whether such changes could be linked to childhood trauma. Whilst there is currently a paucity of studies relating early traumatic experiences to altered E/I balance and network function, the research discussed here lead towards a plausible mechanistic hypothesis, linking early traumatic experiences to cognitive dysfunction and symptoms mediated by E/I neurotransmitter imbalances.
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17
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Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans. Neuropsychopharmacology 2018; 43:1498-1509. [PMID: 29511334 PMCID: PMC5983539 DOI: 10.1038/s41386-018-0027-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/19/2018] [Accepted: 02/01/2018] [Indexed: 12/11/2022]
Abstract
Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.
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18
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Sobanski T, Wagner G. Functional neuroanatomy in panic disorder: Status quo of the research. World J Psychiatry 2017; 7:12-33. [PMID: 28401046 PMCID: PMC5371170 DOI: 10.5498/wjp.v7.i1.12] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/16/2016] [Accepted: 01/11/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To provide an overview of the current research in the functional neuroanatomy of panic disorder. METHODS Panic disorder (PD) is a frequent psychiatric disease. Gorman et al (1989; 2000) proposed a comprehensive neuroanatomical model of PD, which suggested that fear- and anxiety-related responses are mediated by a so-called "fear network" which is centered in the amygdala and includes the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus coeruleus and other brainstem sites. We performed a systematic search by the electronic database PubMed. Thereby, the main focus was laid on recent neurofunctional, neurostructural, and neurochemical studies (from the period between January 2012 and April 2016). Within this frame, special attention was given to the emerging field of imaging genetics. RESULTS We noted that many neuroimaging studies have reinforced the role of the "fear network" regions in the pathophysiology of panic disorder. However, recent functional studies suggest abnormal activation mainly in an extended fear network comprising brainstem, anterior and midcingulate cortex (ACC and MCC), insula, and lateral as well as medial parts of the prefrontal cortex. Interestingly, differences in the amygdala activation were not as consistently reported as one would predict from the hypothesis of Gorman et al (2000). Indeed, amygdala hyperactivation seems to strongly depend on stimuli and experimental paradigms, sample heterogeneity and size, as well as on limitations of neuroimaging techniques. Advanced neurochemical studies have substantiated the major role of serotonergic, noradrenergic and glutamatergic neurotransmission in the pathophysiology of PD. However, alterations of GABAergic function in PD are still a matter of debate and also their specificity remains questionable. A promising new research approach is "imaging genetics". Imaging genetic studies are designed to evaluate the impact of genetic variations (polymorphisms) on cerebral function in regions critical for PD. Most recently, imaging genetic studies have not only confirmed the importance of serotonergic and noradrenergic transmission in the etiology of PD but also indicated the significance of neuropeptide S receptor, CRH receptor, human TransMEMbrane protein (TMEM123D), and amiloride-sensitive cation channel 2 (ACCN2) genes. CONCLUSION In light of these findings it is conceivable that in the near future this research will lead to the development of clinically useful tools like predictive biomarkers or novel treatment options.
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19
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Houtepen LC, Schür RR, Wijnen JP, Boer VO, Boks MPM, Kahn RS, Joëls M, Klomp DW, Vinkers CH. Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study. NEUROIMAGE-CLINICAL 2017; 14:195-200. [PMID: 28180078 PMCID: PMC5280001 DOI: 10.1016/j.nicl.2017.01.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 12/23/2016] [Accepted: 01/02/2017] [Indexed: 12/17/2022]
Abstract
There is ample evidence that the inhibitory GABA and the excitatory glutamate system are essential for an adequate response to stress. Both GABAergic and glutamatergic brain circuits modulate hypothalamus-pituitary-adrenal (HPA)-axis activity, and stress in turn affects glutamate and GABA levels in the rodent brain. However, studies examining stress-induced GABA and glutamate levels in the human brain are scarce. Therefore, we investigated the influence of acute psychosocial stress (using the Trier Social Stress Test) on glutamate and GABA levels in the medial prefrontal cortex of 29 healthy male individuals using 7 Tesla proton magnetic resonance spectroscopy. In vivo GABA and glutamate levels were measured before and 30 min after exposure to either the stress or the control condition. We found no associations between psychosocial stress or cortisol stress reactivity and changes over time in medial prefrontal glutamate and GABA levels. GABA and glutamate levels over time were significantly correlated in the control condition but not in the stress condition, suggesting that very subtle differential effects of stress on GABA and glutamate across individuals may occur. However, overall, acute psychosocial stress does not appear to affect in vivo medial prefrontal GABA and glutamate levels, at least this is not detectable with current practice 1H-MRS.
Psychosocial stress did not alter glutamate and GABA levels in the medial prefrontal cortex in healthy male individuals. Moreover, cortisol stress reactivity was not associated with medial prefrontal glutamate and GABA level change over time. Together, acute stress does not seem to affect in vivo medial prefrontal 7T MRI GABA and glutamate levels in humans.
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Affiliation(s)
- L C Houtepen
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - R R Schür
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - J P Wijnen
- Department of Radiology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - V O Boer
- Department of Radiology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - M P M Boks
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - R S Kahn
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - M Joëls
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - D W Klomp
- Department of Radiology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
| | - C H Vinkers
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
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Ruland T, Domschke K, Schütte V, Zavorotnyy M, Kugel H, Notzon S, Vennewald N, Ohrmann P, Arolt V, Pfleiderer B, Zwanzger P. Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic. Eur Neuropsychopharmacol 2015; 25:1677-82. [PMID: 26235955 DOI: 10.1016/j.euroneuro.2015.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/16/2015] [Accepted: 07/14/2015] [Indexed: 01/04/2023]
Abstract
An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.
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Affiliation(s)
- Tillmann Ruland
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Katharina Domschke
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Germany
| | - Valerie Schütte
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Maxim Zavorotnyy
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany; Department of Psychiatry and Psychotherapy, University of Marburg, Germany
| | - Harald Kugel
- Department of Clinical Radiology, University of Muenster, Germany
| | - Swantje Notzon
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Nadja Vennewald
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Patricia Ohrmann
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Volker Arolt
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | | | - Peter Zwanzger
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany.
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Meyer T, Chavanon ML, Herrrmann-Lingen C, Roggenthien M, Nolte K, Pieske B, Wachter R, Edelmann F. Elevated Plasma C-Terminal Endothelin-1 Precursor Fragment Concentrations Are Associated with Less Anxiety in Patients with Cardiovascular Risk Factors. Results from the Observational DIAST-CHF Study. PLoS One 2015; 10:e0136739. [PMID: 26322793 PMCID: PMC4556459 DOI: 10.1371/journal.pone.0136739] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 08/07/2015] [Indexed: 01/25/2023] Open
Abstract
Background The role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety. Methods Plasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2%) who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. Results Among the total study cohort (n = 1,410), there were 118 subjects (8.4%) with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013). In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β) = 0.247, 95%-confidence interval [95%-CI] = 0.067–0.914, p = 0.036). Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(β) = 0.114, 95%-CI = 0.023–0.566, p = 0.008). Conclusions Our data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.
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Affiliation(s)
- Thomas Meyer
- Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen, Göttingen, Germany
- German Centre for Cardiovascular Research, partner site Göttingen, Göttingen, Germany
| | - Mira-Lynn Chavanon
- Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen, Göttingen, Germany
- German Centre for Cardiovascular Research, partner site Göttingen, Göttingen, Germany
| | - Christoph Herrrmann-Lingen
- Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen, Göttingen, Germany
- German Centre for Cardiovascular Research, partner site Göttingen, Göttingen, Germany
| | - Maren Roggenthien
- Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen, Göttingen, Germany
| | - Kathleen Nolte
- Department of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Charité University Medicine, Berlin, Germany
- German Center for Cardiovascular Research, partner site Berlin, Berlin, Germany
| | - Rolf Wachter
- Department of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany
- German Center for Cardiovascular Research, partner site Berlin, Berlin, Germany
| | - Frank Edelmann
- Department of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany
- Department of Internal Medicine and Cardiology, Charité University Medicine, Berlin, Germany
- German Center for Cardiovascular Research, partner site Berlin, Berlin, Germany
- * E-mail:
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Romero-Perez GA, Takei S, Yao I. Imaging Mass Spectrometric Analysis of Neurotransmitters: A Review. Mass Spectrom (Tokyo) 2015; 3:S0049. [PMID: 26819893 PMCID: PMC4353836 DOI: 10.5702/massspectrometry.s0049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 01/22/2015] [Indexed: 01/19/2023] Open
Abstract
Imaging mass spectrometry (IMS) is a toolbox of versatile techniques that enable us to investigate analytes in samples at molecular level. In recent years, IMS, and especially matrix-assisted laser desorption/ionisation (MALDI), has been used to visualise a wide range of metabolites in biological samples. Simultaneous visualisation of the spatial distribution of metabolites in a single sample with little tissue disruption can be considered as one important advantage of MALDI over other techniques. However, several technical hurdles including low concentrations and rapid degradation rates of small molecule metabolites, matrix interference of signals and poor ionisation, need to be addressed before MALDI can be considered as a reliable tool for the analysis of metabolites such as neurotransmitters in brain tissues from different sources including humans. In the present review we will briefly describe current MALDI IMS techniques used to study neurotransmitters and discuss their current status, challenges, as well as future prospects.
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Affiliation(s)
| | | | - Ikuko Yao
- Hamamatsu University School of Medicine
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Abstract
The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.
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Affiliation(s)
- Oliver Howes
- Psychiatric Imaging, MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK Institute of Psychiatry, King's College London, London, UK
| | - Rob McCutcheon
- Psychiatric Imaging, MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK Institute of Psychiatry, King's College London, London, UK
| | - James Stone
- Psychiatric Imaging, MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK Institute of Psychiatry, King's College London, London, UK
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Modi S, Rana P, Kaur P, Rani N, Khushu S. Glutamate level in anterior cingulate predicts anxiety in healthy humans: a magnetic resonance spectroscopy study. Psychiatry Res 2014; 224:34-41. [PMID: 25156662 DOI: 10.1016/j.pscychresns.2014.03.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 01/28/2014] [Accepted: 03/07/2014] [Indexed: 11/25/2022]
Abstract
Anxiety, a personality dimension in healthy humans, has been found to be associated with many functional consequences such as increased distractibility and attentional bias in favour of threat-related information, along with morphological and microstructural changes in the brain. The associated metabolic/neurochemical alterations are sparsely studied. In the present magnetic resonance spectroscopy (MRS) study, we investigated the possible relationship between regional brain chemistry within anterior cingulate cortex (4-cm(3) voxel) and hippocampus (2.5-cm(3) voxel) and anxiety (measured by State-Trait Anxiety Inventory) in our subject group. In the anterior cingulate cortex, multivariate analysis of covariance showed an increase in myo-inositol and combined glutamate and glutamine levels in the high anxiety subject group as compared with the low anxiety group. In the partial correlation analysis between neurochemicals and anxiety, glutamate and combined glutamate and glutamine also showed a predictive value for anxiety. On analysing the trait anxiety sub-score separately, we found glutamate, inositol and combined glutamate and glutamine levels to be increased in the high trait anxiety group as compared with the low trait anxiety group. All three resonances also had a predictive value for trait anxiety. In the hippocampus, none of the neurochemicals showed significant difference between high and low anxiety groups. The study provides a first account of alterations in anterior cingulate cortex neurochemistry in relation to anxiety in healthy subjects. The study thus contributes to the limited literature available on altered metabolism and neural mechanisms underlying sub-clinical anxiety.
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Affiliation(s)
- Shilpi Modi
- NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Lucknow Road, Timarpur, Delhi 110054, India
| | - Poonam Rana
- NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Lucknow Road, Timarpur, Delhi 110054, India
| | - Prabhjot Kaur
- NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Lucknow Road, Timarpur, Delhi 110054, India
| | - Nisha Rani
- NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Lucknow Road, Timarpur, Delhi 110054, India
| | - Subash Khushu
- NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Lucknow Road, Timarpur, Delhi 110054, India.
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Zwanzger P, Yassouridis A, Pfleiderer B. 'Acute shift in glutamate-concentrations following experimentally induced panic with cholecystokinin-tetrapeptide-a 3T-MRS study in healthy subjects'-a reply to the letter to the editor. Neuropsychopharmacology 2014; 39:2707-8. [PMID: 24939760 PMCID: PMC4207332 DOI: 10.1038/npp.2014.104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Peter Zwanzger
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany,kbo-Inn-Salzach-Hospital, Wasserburg, Germany,Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany or kbo-Inn-Salzach-Hospital Wasserburg am Inn, Gabersee 7, Wasserburg, Germany, Tel: +49 8071 71 300, Fax: +49 8171 71 318, E-mail:
| | | | - Bettina Pfleiderer
- Department of Clinical Radiology, University of Muenster, Muenster, Germany
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Associations of regional GABA and glutamate with intrinsic and extrinsic neural activity in humans—a review of multimodal imaging studies. Neurosci Biobehav Rev 2014; 47:36-52. [PMID: 25066091 DOI: 10.1016/j.neubiorev.2014.07.016] [Citation(s) in RCA: 163] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 06/30/2014] [Accepted: 07/17/2014] [Indexed: 01/04/2023]
Abstract
The integration of multiple imaging modalities is becoming an increasingly well used research strategy for studying the human brain. The neurotransmitters glutamate and GABA particularly lend themselves towards such studies. This is because these transmitters are ubiquitous throughout the cortex, where they are the key constituents of the inhibition/excitation balance, and because they can be easily measured in vivo through magnetic resonance spectroscopy, as well as with select positron emission tomography approaches. How these transmitters underly functional responses measured with techniques such as fMRI and EEG remains unclear though, and was the target of this review. Consistently shown in the literature was a negative correlation between GABA concentrations and stimulus-induced activity within the measured region. Also consistently found was a positive correlation between glutamate concentrations and inter-regional activity relationships, both during tasks and rest. These findings are outlined along with results from populations with mental disorders to give an overview of what brain imaging has suggested to date about the biochemical underpinnings of functional activity in health and disease. We conclude that the combination of functional and biochemical imaging in humans is an increasingly informative approach that does however require a number of key methodological and interpretive issues be addressed before can meet its potential.
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Holm L, Liang W, Thorsell A, Hilke S. Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol. Pharmacol Biochem Behav 2014; 122:222-7. [PMID: 24732637 DOI: 10.1016/j.pbb.2014.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 03/30/2014] [Accepted: 04/05/2014] [Indexed: 01/03/2023]
Abstract
BACKGROUND The neuropeptide cholecystokinin (CCK) has been implicated in the neurobiology of anxiety and panic disorders, as well as in dopamine-related behaviours. Anxiety and panic-disorders are twice as common in females compared to males, but studies of females are rare, although increasing in number. Limited studies have found that CCK fluctuates in limbic regions during the estrous cycle, and that CCK and its receptors are sensitive to estrogen. AIM/PURPOSE The aim of the present work was to study the acute effects of 17β-estradiol on anxiety-like behaviour and on CCK-like immunoreactivity (LI) in the female rat brain (amygdala, hippocampus, nucleus accumbens, and cingulate cortex). METHODS Four groups of female Sprague-Dawley rats were used: ovariectomized, ovariectomized+17β-estradiol-replacement, sham, and sham+17β-estradiol-replacement. The effect of 17β-estradiol-replacement on anxiety-related behaviour was measured in all animals on the elevated plus maze 2-24 h after injection. CCK-LI concentration was measured in punch biopsies by means of radioimmunoassay. RESULTS 17β-estradiol decreased anxiety-like behaviour 2 h after administration in ovariectomized and sham-operated animals, as demonstrated by increased exploration of the open arms compared to respective sesame oil-treated controls. This effect was not present when testing occurred 24 h post-treatment. The rapid behavioural effect of 17β-estradiol was accompanied by changes in CCK-LI concentrations in regions of the limbic system including cingulate cortex, hippocampus, amygdala and nucleus accumbens. CONCLUSION Although the interpretation of these data requires caution since the data were collected from two different experiments, our results suggest that estrogen-induced anxiolytic effects may be associated with changes of the CCK-system in brain regions controlling anxiety-like behaviour.
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Affiliation(s)
- Lovisa Holm
- Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden
| | - Wen Liang
- TNO Metabolic Health Research, Leiden, Netherlands
| | - Annika Thorsell
- Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden
| | - Susanne Hilke
- Department of Clinical Chemistry, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
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The 5-HTTLPR genotype modulates heart rate variability and its adjustment by pharmacological panic challenge in healthy men. J Psychiatr Res 2014; 50:51-8. [PMID: 24342768 DOI: 10.1016/j.jpsychires.2013.11.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 11/25/2013] [Accepted: 11/29/2013] [Indexed: 01/01/2023]
Abstract
Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 μg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway.
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