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D'Addario C, Di Bartolomeo M. Epigenetic Control in Schizophrenia. Subcell Biochem 2025; 108:191-215. [PMID: 39820863 DOI: 10.1007/978-3-031-75980-2_5] [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] [Indexed: 01/19/2025]
Abstract
Schizophrenia is a severe and complex psychiatric condition ranking among the top 15 leading causes of disability worldwide. Despite the well-established heritability component, a complex interplay between genetic and environmental risk factors plays a key role in the development of schizophrenia and psychotic disorders in general. This chapter covers all the clinical evidence showing how the analysis of the epigenetic modulation in schizophrenia might be relevant to understand the pathogenesis of schizophrenia as well as potentially useful to develop new pharmacotherapies.
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Affiliation(s)
- Claudio D'Addario
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
| | - Martina Di Bartolomeo
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
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Douli E, Georgiou G, Konstantinopoulou E, Karampas A, Plakoutsis M, Sioka C, Aretouli E, Petrikis P. Neuropsychological performances and brain perfusion patterns in patients with first episode psychosis. J Psychiatr Res 2025; 181:237-244. [PMID: 39637714 DOI: 10.1016/j.jpsychires.2024.11.053] [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: 07/02/2024] [Revised: 11/16/2024] [Accepted: 11/22/2024] [Indexed: 12/07/2024]
Abstract
Abnormalities in cognition are a pronounced feature in primary psychotic disorders and may appear long before the manifestation of the first-episode psychosis (FEP). Although brain functional changes may precede structural alterations, brain perfusion patterns in FEP and most importantly their correlations with cognition remain poorly understood. In the present study we assessed neurocognitive functions and regional cerebral blood flow (rCBF) in 53 patients with a diagnosis of FEP. A special emphasis was placed on the assessment of basic executive functions. Cerebral perfusion patterns were measured by SPECT rCBF scintigraphy in cerebral lobes bilaterally and Brodmann Areas (BAs). Patients showed impairments in long-term verbal memory, processing speed/response latency and executive cognition. Pathological perfusion was prominent in the limbic lobes bilaterally. BAs with the largest hypoperfusion, were the subgenual area (BA25) and hippocampal areas (BA 28 and 36). The left temporal lobe was also hypoperfused, and specifically the inferior temporal gyrus (BA 20), the left middle (BA 21) and superior (BA 22) temporal gyrus, and the temporal pole (BA 38). Hypoperfusion was limited in the frontal regions, although specific BAs displayed pathological perfusion (i.e., BA 24). Cerebral lobe perfusion was not correlated with compromised cognitive abilities.
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Affiliation(s)
- Eleni Douli
- Lab of Cognitive Neuroscience, Department of Psychology, Aristotle University of Thessaloniki, Greece
| | - Georgios Georgiou
- Department of Psychiatry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece
| | - Eleni Konstantinopoulou
- Lab of Cognitive Neuroscience, Department of Psychology, Aristotle University of Thessaloniki, Greece
| | - Andreas Karampas
- Department of Psychiatry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece
| | - Marios Plakoutsis
- Department of Psychiatry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece
| | - Chrissa Sioka
- Department of Nuclear Medicine, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece
| | - Eleni Aretouli
- Department of Psychology, School of the Social Sciences, University of Ioannina, Greece
| | - Petros Petrikis
- Department of Psychiatry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece.
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3
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Lisoni J, Nibbio G, Baglioni A, Dini S, Manera B, Maccari A, Altieri L, Calzavara-Pinton I, Zucchetti A, Deste G, Barlati S, Vita A. Is It Possible to Combine Non-Invasive Brain Stimulation and Evidence-Based Psychosocial Interventions in Schizophrenia? A Critical Review. Brain Sci 2024; 14:1067. [PMID: 39595830 PMCID: PMC11591595 DOI: 10.3390/brainsci14111067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/24/2024] [Accepted: 10/26/2024] [Indexed: 11/28/2024] Open
Abstract
In schizophrenia, it was suggested that an integrated and multimodal approach, combining pharmacological and non-pharmacological interventions, could improve functional outcomes and clinical features in patients living with schizophrenia (PLWS). Among these alternatives, evidence-based psychosocial interventions (EBPIs) and Non-Invasive Brain Stimulation (NIBS) represent feasible treatment options targeting the clinical features that are unmet needs of PLWS (especially negative and cognitive symptoms). As no clear evidence is available on the combination of these non-pharmacological approaches, this review aimed to collect the available literature on the combination of EBPIs and NIBS in the treatment of PLWS. We demonstrated that the field of combining EBPIs and NIBS in schizophrenia is in its infancy, as only 11 studies were reviewed. In fact, only a few trials, with divergent results, combined these non-pharmacological modalities; while emerging evidence is available on the combination of cognitive remediation and rTMS/iTBS, inconclusive results were obtained. Conversely, albeit preliminary, more solid findings are available on the combination of HF-rTMS and family intervention. Moreover, despite the fact that cognitive activation could not be considered an EBPI, promising results are available in combination with tDCS to improve the working memory domain. To overcome these limitations, we considered several methodological issues to promote research in this field.
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Affiliation(s)
- Jacopo Lisoni
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, 25123 Brescia, Italy; (I.C.-P.); (A.Z.); (S.B.); (A.V.)
| | - Gabriele Nibbio
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Antonio Baglioni
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Simona Dini
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Bianca Manera
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Alessandra Maccari
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Luca Altieri
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Irene Calzavara-Pinton
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, 25123 Brescia, Italy; (I.C.-P.); (A.Z.); (S.B.); (A.V.)
| | - Andrea Zucchetti
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, 25123 Brescia, Italy; (I.C.-P.); (A.Z.); (S.B.); (A.V.)
| | - Giacomo Deste
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
- Department of Mental Health and Addiction Services, ASST Vallecamonica, 25040 Brescia, Italy
| | - Stefano Barlati
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, 25123 Brescia, Italy; (I.C.-P.); (A.Z.); (S.B.); (A.V.)
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
| | - Antonio Vita
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, 25123 Brescia, Italy; (I.C.-P.); (A.Z.); (S.B.); (A.V.)
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (G.N.); (A.B.); (S.D.); (B.M.); (A.M.); (L.A.); (G.D.)
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Pelegrino A, Guimaraes AL, Sena W, Emele N, Scoriels L, Panizzutti R. Dysregulated noradrenergic response is associated with symptom severity in individuals with schizophrenia. Front Psychiatry 2023; 14:1190329. [PMID: 38025452 PMCID: PMC10661901 DOI: 10.3389/fpsyt.2023.1190329] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction The locus coeruleus-noradrenaline (LC-NA) system is involved in a wide range of cognitive functions and may be altered in schizophrenia. A non-invasive method to indirectly measure LC activity is task-evoked pupillary response. Individuals with schizophrenia present reduced pupil dilation compared to healthy subjects, particularly when task demand increases. However, the extent to which alteration in LC activity contributes to schizophrenia symptomatology remains largely unexplored. We aimed to investigate the association between symptomatology, cognition, and noradrenergic response in individuals with schizophrenia. Methods We assessed task-evoked pupil dilation during a pro- and antisaccade task in 23 individuals with schizophrenia and 28 healthy subjects. Results Both groups showed similar preparatory pupil dilation during prosaccade trials, but individuals with schizophrenia showed significantly lower pupil dilation compared to healthy subjects in antisaccade trials. Importantly, reduced preparatory pupil dilation for antisaccade trials was associated with worse general symptomatology in individuals with schizophrenia. Discussion Our findings suggest that changes in LC-NA activity - measured by task-evoked pupil dilation - when task demand increases is associated with schizophrenia symptoms. Interventions targeting the modulation of noradrenergic responses may be suitable candidates to reduce schizophrenia symptomatology.
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Affiliation(s)
- Ana Pelegrino
- Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Anna Luiza Guimaraes
- Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Walter Sena
- Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nwabunwanne Emele
- Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Linda Scoriels
- Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Université Paris Cité, Institut de Psychiatrie et Neurosciences de Paris, Inserm, Paris, France
| | - Rogerio Panizzutti
- Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Goldwaser EL, Wang DJJ, Adhikari BM, Chiappelli J, Shao X, Yu J, Lu T, Chen S, Marshall W, Yuen A, Kvarta M, Ma Y, Du X, Gao S, Saeedi O, Bruce H, Donnelly P, O’Neill H, Shuldiner AR, Mitchell BD, Kochunov P, Hong LE. Evidence of Neurovascular Water Exchange and Endothelial Vascular Dysfunction in Schizophrenia: An Exploratory Study. Schizophr Bull 2023; 49:1325-1335. [PMID: 37078962 PMCID: PMC10483475 DOI: 10.1093/schbul/sbad057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
BACKGROUND AND HYPOTHESIS Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. STUDY DESIGN We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. STUDY RESULTS Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. CONCLUSIONS This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.
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Affiliation(s)
- Eric L Goldwaser
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Danny J J Wang
- Laboratory of FMRI Technology (LOFT), Mark & Mary Stevens Nueroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Bhim M Adhikari
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joshua Chiappelli
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xingfeng Shao
- Laboratory of FMRI Technology (LOFT), Mark & Mary Stevens Nueroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jiaao Yu
- Department of Mathematics, University of Maryland, College Park, MD, USA
| | - Tong Lu
- Department of Mathematics, University of Maryland, College Park, MD, USA
| | - Shuo Chen
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Mathematics, University of Maryland, College Park, MD, USA
| | - Wyatt Marshall
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alexa Yuen
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Mark Kvarta
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yizhou Ma
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xiaoming Du
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Si Gao
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Osamah Saeedi
- Department of Ophthalmology and Visual Sciences, University of Maryland Medical Center, Baltimore, MD, USA
| | - Heather Bruce
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Patrick Donnelly
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hugh O’Neill
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan R Shuldiner
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Braxton D Mitchell
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
| | - Peter Kochunov
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - L Elliot Hong
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
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Lisoni J, Baldacci G, Nibbio G, Zucchetti A, Butti Lemmi Gigli E, Savorelli A, Facchi M, Miotto P, Deste G, Barlati S, Vita A. Effects of bilateral, bipolar-nonbalanced, frontal transcranial Direct Current Stimulation (tDCS) on negative symptoms and neurocognition in a sample of patients living with schizophrenia: Results of a randomized double-blind sham-controlled trial. J Psychiatr Res 2022; 155:430-442. [PMID: 36182772 DOI: 10.1016/j.jpsychires.2022.09.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/20/2022] [Accepted: 09/12/2022] [Indexed: 10/31/2022]
Abstract
Negative symptoms (NS), conceived as Avolition-Apathy (AA) and Expressive Deficit (EXP) domains, and neurocognitive impairments represent unmet therapeutic needs for patients with schizophrenia. The present study investigated if bilateral bipolar-nonbalanced frontal transcranial Direct Current Stimulation (tDCS) could improve these psychopathological dimensions. This randomized, double-blind, sham-controlled study (active-tDCS versus sham-tDCS, both, n = 25) included 50 outpatients diagnosed with schizophrenia clinically stabilized. Patients received 20-min 2 mA active-tDCS or sham-tDCS (anode: left Dorsolateral Prefrontal Cortex; cathode: right orbitofrontal region). Primary outcomes included: PANSS-Negative subscale, Negative Factor (Neg-PANSS), AA and EXP domains; neurocognitive performance at Brief Assessment of Cognition in Schizophrenia. Secondary outcomes included: PANSS subscales and total score, Disorganized/Concrete (DiscC-PANSS) and Positive Factors, Clinical Global Impression (CGI) scores, clinical insight at Scale to Assess Unawareness of Mental Disorder (SUMD). Analysis of covariance (ANCOVA) was performed evaluating between-group changes over time. Significant improvements following active-tDCS were observed for all NS measures (all, p < 0.001; d > 0.8) and for working memory (p = 0.025, d = 0.31). Greater variations following to active treatment emerged also for PANSS-General Psychopathology subscale (p < 0.001; d = 0.54), PANSS total score (p < 0.001; d = 0.69), CGI indexes (all, p < 0.001; d > 0.6), DiscC-PANSS (p < 0.001; d = 0.80) and SUMD-general Unawareness index (p = 0.005; d = 0.15) but not for positive symptoms and others insight measures. Good safety/tolerability profiles were found. Bilateral bipolar-nonbalanced frontal-tDCS is a non-pharmacological approach in schizophrenia effectively improving NS, particularly the AA and EXP domains, probably acting by modulating dysfunctional cortical-subcortical networks. Preliminary results also suggest working memory improvements following tDCS. Further studies are needed to confirm the neurobiological basis of these results.
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Affiliation(s)
- Jacopo Lisoni
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy.
| | - Giulia Baldacci
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Gabriele Nibbio
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Andrea Zucchetti
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | | | - Arianna Savorelli
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Michele Facchi
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Paola Miotto
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Giacomo Deste
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Stefano Barlati
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Antonio Vita
- Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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Smucny J, Dienel SJ, Lewis DA, Carter CS. Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia. Neuropsychopharmacology 2022; 47:292-308. [PMID: 34285373 PMCID: PMC8617156 DOI: 10.1038/s41386-021-01089-0] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023]
Abstract
Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having "an orchestra without a conductor." Kraepelin further speculated that this "conductor" was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
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Affiliation(s)
- Jason Smucny
- Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, CA, USA
- Center for Neuroscience, University of California Davis, Davis, CA, USA
| | - Samuel J Dienel
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
| | - David A Lewis
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Cameron S Carter
- Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, CA, USA.
- Center for Neuroscience, University of California Davis, Davis, CA, USA.
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Fuentes-Claramonte P, Ramiro N, Torres L, Argila-Plaza I, Salgado-Pineda P, Soler-Vidal J, García-León MÁ, Albacete A, Bosque C, Panicalli F, Boix E, Munuera J, Tristany J, Sarró S, Bernardo M, Salvador R, McKenna PJ, Pomarol-Clotet E. Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect. NEUROIMAGE: CLINICAL 2022; 35:103119. [PMID: 35870381 PMCID: PMC9421442 DOI: 10.1016/j.nicl.2022.103119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 06/10/2022] [Accepted: 07/12/2022] [Indexed: 11/29/2022] Open
Abstract
Negative schizophrenic symptoms have been considered to reflect prefrontal cortex dysfunction. Functional imaging support for this theory is however weak, perhaps due to the tasks used. We examined negative symptom patients using a novel executive task measuring volitional behaviour. Comparison to patients without negative symptoms revealed prefrontal hypoactivation. Background The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. Method Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or ‘goal neglect’. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). Results On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. Conclusions This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region’s involvement in cognitive control, particularly the ‘regulative’ component of this.
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Affiliation(s)
- Paola Fuentes-Claramonte
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
| | - Núria Ramiro
- Psychiatry department, Hospital Sant Rafael, Barcelona, Spain
| | - Llanos Torres
- Hospital Mare de Dèu de la Mercé, Unitat Polivalent, Barcelona, Spain
| | | | - Pilar Salgado-Pineda
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
| | - Joan Soler-Vidal
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain; Benito Menni Complex Assistencial en Salut Mental, Sant Boi de Llobregat, Barcelona, Spain
| | - María Ángeles García-León
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
| | - Auria Albacete
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
| | - Clara Bosque
- Benito Menni Complex Assistencial en Salut Mental, Sant Boi de Llobregat, Barcelona, Spain
| | - Francesco Panicalli
- Benito Menni Complex Assistencial en Salut Mental, Sant Boi de Llobregat, Barcelona, Spain
| | - Ester Boix
- Mental Health Department, Hospital de Mataró, Mataró, Spain
| | - Josep Munuera
- Diagnostic Imaging Department, Hospital Sant Joan de Déu, Barcelona, Spain
| | | | - Salvador Sarró
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
| | - Miquel Bernardo
- CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain; Barcelona Clínic Schizophrenia Unit, Hospital Clínic of Barcelona, Institute of Neuroscience, Barcelona, Spain; Universitat de Barcelona, Barcelona, Spain; Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Raymond Salvador
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
| | - Peter J McKenna
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain.
| | - Edith Pomarol-Clotet
- FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain
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9
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Improvements of Frontotemporal Cerebral Blood Flow and Cognitive Functioning in Patients With First Episode of Schizophrenia Treated With Long-Acting Aripiprazole. J Clin Psychopharmacol 2021; 41:638-643. [PMID: 34459433 DOI: 10.1097/jcp.0000000000001477] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE/BACKGROUND Frontal and temporal cerebral blood flow (CBF) changes are the most common impairments of CBF described in patients with schizophrenia. Those impairments have also been associated with cognitive deficits, a hallmark of schizophrenia. In light of that fact, treatment interventions should target cognitive deficits to prevent chronic disability. However, specific therapies targeting cognitive symptoms are very few and far between. One of the treatment possibilities is aripiprazole, because several studies reported its potential procognitive effects. The objective of this study was to investigate whether use of aripiprazole in its long-acting injectable formulation (ALAI), during a 3-month treatment, has beneficial effects on CBF and cognitive functioning in patients with first episode of schizophrenia. METHODS/PROCEDURES Single-photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime was performed at 2 time points. Cognitive functions were assessed with a standardized test for cognitive functions, 5-KOG test, whereas severity of clinical symptoms was assessed with the Positive and Negative Syndrome Scale, both at the same 2 time points as single-photon emission computed tomography. Three-month treatment with ALAI was associated with improvement of several cognition indices and improvements of right-sided frontal and temporal CBF, as well as of clinical symptoms. FINDINGS/RESULTS Multivariate tests were used to test for the effects of ALAI treatment on cognitive functions, clinical presentation, and brain perfusion in a 3-month period. Multivariate model revealed statistical significance (F = 11.958, P < 0.001). Of 10 separate 5-KOG parameters, 3-month treatment with ALAI significantly influenced 4: undelayed recall, delayed recall, attention, and working memory-digit span forward. Finally, 3-month ALAI treatment significantly improved regional CBF in 2 of 4 investigated areas, both on the right side of the brain (frontally and temporally). IMPLICATIONS/CONCLUSIONS Results of this research showed that treatment with ALAI in patients with first episode of schizophrenia is associated with improved right-sided frontal and temporal CBF, as well as with improved symptoms, including cognition indices. Although we cannot confirm it directly, it is possible that improved frontotemporal CBF led to the improvement in cognition indices.
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10
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Jung HY, Jung S, Bang M, Choi TK, Park CI, Lee SH. White matter correlates of impulsivity in frontal lobe and their associations with treatment response in first-episode schizophrenia. Neurosci Lett 2021; 767:136309. [PMID: 34736723 DOI: 10.1016/j.neulet.2021.136309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND It is known that increased impulsivity in schizophrenia patients causes poor treatment outcomes by increasing cost, stigma, hospitalization, treatment challenge, and physical harm. Dysfunction in the prefrontal cortex appears to be involved in the impulsivity associated with schizophrenia; nonetheless, there is a dearth of research on specific white matter alterations in the prefrontal cortex related to impulsivity. METHODS We enrolled in the present study 119 first-episode schizophrenia patients. We measured their symptom severity at baseline and after eight weeks of treatment, using the positive and negative syndrome scale. We performed neuroimaging analysis using the Tract-Based Spatial Statistics program and by specifying the prefrontal white matter as a region of interest. RESULTS In voxel-wise correlational analysis, we observed white matter regions showing significant positive correlations with poor impulse control scores, in both the right dorsolateral prefrontal cortex and the right frontal pole region. The fractional anisotropy values of these areas correlated positively with symptom severity at baseline. Moreover, after eight weeks, treatment non responders showed significantly higher fractional anisotropy values in the same areas. CONCLUSIONS The results of the present study suggest that white matter tracts in the right dorsolateral prefrontal cortex and the right frontal pole may underlie dysfunctional impulse control and could be potential predictive markers for short-term treatment in patients with first-episode schizophrenia.
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Affiliation(s)
- Hye-Yeon Jung
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Department of Psychiatry, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea
| | - Sra Jung
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Department of Psychiatry, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea
| | - Minji Bang
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Department of Psychiatry, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea
| | - Tai Kiu Choi
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Department of Psychiatry, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea
| | - Chun Il Park
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Department of Psychiatry, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea.
| | - Sang-Hyuk Lee
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Department of Psychiatry, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea.
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11
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Increased Homotopic Connectivity in the Prefrontal Cortex Modulated by Olanzapine Predicts Therapeutic Efficacy in Patients with Schizophrenia. Neural Plast 2021; 2021:9954547. [PMID: 34512748 PMCID: PMC8429031 DOI: 10.1155/2021/9954547] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 08/08/2021] [Accepted: 08/18/2021] [Indexed: 11/18/2022] Open
Abstract
Background Previous studies have revealed the abnormalities in homotopic connectivity in schizophrenia. However, the relationship of these deficits to antipsychotic treatment in schizophrenia remains unclear. This study explored the effects of antipsychotic therapy on brain homotopic connectivity and whether the homotopic connectivity of these regions might predict individual treatment response in schizophrenic patients. Methods A total of 21 schizophrenic patients and 20 healthy controls were scanned by the resting-state functional magnetic resonance imaging. The patients received olanzapine treatment and were scanned at two time points. Voxel-mirrored homotopic connectivity (VMHC) and pattern classification techniques were applied to analyze the imaging data. Results Schizophrenic patients presented significantly decreased VMHC in the temporal and inferior frontal gyri, medial prefrontal cortex (MPFC), and motor and low-level sensory processing regions (including the fusiform gyrus and cerebellum lobule VI) relative to healthy controls. The VMHC in the superior/middle MPFC was significantly increased in the patients after eight weeks of treatment. Support vector regression (SVR) analyses revealed that VMHC in the superior/middle MPFC at baseline can predict the symptomatic improvement of the positive and negative syndrome scale after eight weeks of treatment. Conclusions This study demonstrated that olanzapine treatment may normalize decreased homotopic connectivity in the superior/middle MPFC in schizophrenic patients. The VMHC in the superior/middle MPFC may predict individual response for antipsychotic therapy. The findings of this study conduce to the comprehension of the therapy effects of antipsychotic medications on homotopic connectivity in schizophrenia.
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12
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Sonnweber M, Lau S, Kirchebner J. Violent and non-violent offending in patients with schizophrenia: Exploring influences and differences via machine learning. Compr Psychiatry 2021; 107:152238. [PMID: 33721584 DOI: 10.1016/j.comppsych.2021.152238] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 02/16/2021] [Accepted: 02/28/2021] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVES The link between schizophrenia and violent offending has long been the subject of research with significant impact on mental health policy, clinical practice and public perception of the dangerousness of people with psychiatric disorders. The present study attempts to identify factors that differentiate between violent and non-violent offenders based on a unique sample of 370 forensic offender patients with schizophrenia spectrum disorder by employing machine learning algorithms and an extensive set of variables. METHODS Using machine learning algorithms, 519 variables were explored in order to differentiate violent and non-violent offenders. To minimize the risk of overfitting, the dataset was split, employing variable filtering, machine learning model building and selection embedded in a nested resampling approach on one subset. The best model was then selected, and the most important variables applied on the second data subset. RESULTS Ten factors regarding criminal and psychiatric history as well as clinical, developmental, and social factors were identified to be most influential in differentiating between violent and non-violent offenders and are discussed in light of prior research on this topic. With an AUC of 0.76, a sensitivity of 72% and a specificity of 62%, a correct classification into violent and non-violent offences could be determined in almost three quarters of cases. CONCLUSIONS Our findings expand current research on the factors influencing violent offending in patients with SSD, which is crucial for the development of preventive and therapeutic strategies that could potentially reduce the prevalence of violence in this population. Limitations, clinical relevance and future directions are discussed.
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Affiliation(s)
- Martina Sonnweber
- Department of Forensic Psychiatry, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
| | - Steffen Lau
- Department of Forensic Psychiatry, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Johannes Kirchebner
- Department of Forensic Psychiatry, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
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13
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Suttkus S, Schumann A, de la Cruz F, Bär KJ. Working memory in schizophrenia: The role of the locus coeruleus and its relation to functional brain networks. Brain Behav 2021; 11:e02130. [PMID: 33784023 PMCID: PMC8119871 DOI: 10.1002/brb3.2130] [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: 10/26/2020] [Revised: 01/14/2021] [Accepted: 03/17/2021] [Indexed: 01/15/2023] Open
Abstract
Evidence suggests functional brain networks, especially the executive control network (ECN) and default mode network (DMN), to be abnormal in schizophrenia. Dysfunctions within the locus coeruleus (LC)-noradrenaline (NE) system, which is supposed to be pivotal to modulate neuronal network activation during executive control (e.g., working memory function), are also considered to play a vital role in the occurrence of positive (e.g., hallucinatory) or negative (e.g., inattentive) symptoms in these patients. In the present study, we sought to shed further light on the role of the LC-NE system in patients with schizophrenia. More specifically, we wanted to improve our understanding of the relationship and possible disturbances of the ECN and DMN during a working memory task in patients. A total of 58 healthy control subjects and 40 medicated patients with schizophrenia were investigated using a working memory 3-back task during functional magnetic resonance imaging. Main findings of our present study were differential dynamics of ECN and DMN blood oxygenation level-dependent (BOLD) activations with increasing task demands in both patients and controls. Moreover, we found increased BOLD activation in the LC in patients compared to controls in the interaction contrast between groups and conditions. LC BOLD activation significantly correlated with both, the main hub of the ECN, that is, the dorsolateral prefrontal cortex, and of the DMN, that is, the posterior cingulate cortex. Thus, the LC-NE system seems to be crucial in modulating neuronal network activity in a 3-back working memory task and might significantly contribute to cognitive impairments in schizophrenia.
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Affiliation(s)
- Stefanie Suttkus
- Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, University Hospital Jena, Germany
| | - Andy Schumann
- Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, University Hospital Jena, Germany
| | - Feliberto de la Cruz
- Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, University Hospital Jena, Germany
| | - Karl-Jürgen Bär
- Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, University Hospital Jena, Germany
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14
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Perez SM, Lodge DJ. Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia. Int J Neuropsychopharmacol 2021; 24:344-353. [PMID: 33587746 PMCID: PMC8059491 DOI: 10.1093/ijnp/pyaa080] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/13/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity. METHODS Here we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats). RESULTS Aberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats. CONCLUSION Taken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.
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Affiliation(s)
- Stephanie M Perez
- Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA
| | - Daniel J Lodge
- Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA
- South Texas Veterans Health Care System, Audie L. Murphy Division, USA
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15
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Shan X, Liao R, Ou Y, Pan P, Ding Y, Liu F, Chen J, Zhao J, Guo W, He Y. Increased regional homogeneity modulated by metacognitive training predicts therapeutic efficacy in patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci 2021; 271:783-798. [PMID: 32215727 PMCID: PMC8119286 DOI: 10.1007/s00406-020-01119-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
Previous studies have demonstrated the efficacy of metacognitive training (MCT) in schizophrenia. However, the underlying mechanisms related to therapeutic effect of MCT remain unknown. The present study explored the treatment effects of MCT on brain regional neural activity using regional homogeneity (ReHo) and whether these regions' activities could predict individual treatment response in schizophrenia. Forty-one patients with schizophrenia and 20 healthy controls were scanned using resting-state functional magnetic resonance imaging. Patients were randomly divided into drug therapy (DT) and drug plus psychotherapy (DPP) groups. The DT group received only olanzapine treatment, whereas the DPP group received olanzapine and MCT for 8 weeks. The results revealed that ReHo in the right precuneus, left superior medial prefrontal cortex (MPFC), right parahippocampal gyrus and left rectus was significantly increased in the DPP group after 8 weeks of treatment. Patients in the DT group showed significantly increased ReHo in the left ventral MPFC/anterior cingulate cortex (ACC), left superior MPFC/middle frontal gyrus (MFG), left precuneus, right rectus and left MFG, and significantly decreased ReHo in the bilateral cerebellum VIII and left inferior occipital gyrus (IOG) after treatment. Support vector regression analyses showed that high ReHo levels at baseline in the right precuneus and left superior MPFC could predict symptomatic improvement of Positive and Negative Syndrome Scale (PANSS) after 8 weeks of DPP treatment. Moreover, high ReHo levels at baseline and alterations of ReHo in the left ventral MPFC/ACC could predict symptomatic improvement of PANSS after 8 weeks of DT treatment. This study suggests that MCT is associated with the modulation of ReHo in schizophrenia. ReHo in the right precuneus and left superior MPFC may predict individual therapeutic response for MCT in patients with schizophrenia.
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Affiliation(s)
- Xiaoxiao Shan
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,National Clinical Research Center on Mental Disorders, Changsha, 410011 Hunan China
| | - Rongyuan Liao
- grid.412990.70000 0004 1808 322XThe Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan China
| | - Yangpan Ou
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,National Clinical Research Center on Mental Disorders, Changsha, 410011 Hunan China
| | - Pan Pan
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,National Clinical Research Center on Mental Disorders, Changsha, 410011 Hunan China
| | - Yudan Ding
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,National Clinical Research Center on Mental Disorders, Changsha, 410011 Hunan China
| | - Feng Liu
- grid.412645.00000 0004 1757 9434Department of Radiology, Tianjin Medical University General Hospital, Tianjin, 300000 China
| | - Jindong Chen
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,National Clinical Research Center on Mental Disorders, Changsha, 410011 Hunan China
| | - Jingping Zhao
- grid.452708.c0000 0004 1803 0208Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,National Clinical Research Center on Mental Disorders, Changsha, 410011 Hunan China
| | - Wenbin Guo
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China. .,National Clinical Research Center on Mental Disorders, Changsha, 410011, Hunan, China.
| | - Yiqun He
- The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
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16
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Egerton A, Grace AA, Stone J, Bossong MG, Sand M, McGuire P. Glutamate in schizophrenia: Neurodevelopmental perspectives and drug development. Schizophr Res 2020; 223:59-70. [PMID: 33071070 DOI: 10.1016/j.schres.2020.09.013] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 08/12/2020] [Accepted: 09/20/2020] [Indexed: 12/14/2022]
Abstract
Research into the neurobiological processes that may lead to the onset of schizophrenia places growing emphasis on the glutamatergic system and brain development. Preclinical studies have shown that neurodevelopmental, genetic, and environmental factors contribute to glutamatergic dysfunction and schizophrenia-related phenotypes. Clinical research has suggested that altered brain glutamate levels may be present before the onset of psychosis and relate to outcome in those at clinical high risk. After psychosis onset, glutamate dysfunction may also relate to the degree of antipsychotic response and clinical outcome. These findings support ongoing efforts to develop pharmacological interventions that target the glutamate system and could suggest that glutamatergic compounds may be more effective in specific patient subgroups or illness stages. In this review, we consider the updated glutamate hypothesis of schizophrenia, from a neurodevelopmental perspective, by reviewing recent preclinical and clinical evidence, and discuss the potential implications for novel therapeutics.
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Affiliation(s)
- Alice Egerton
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Anthony A Grace
- Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA
| | - James Stone
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Matthijs G Bossong
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Michael Sand
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
| | - Philip McGuire
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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17
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Wang Q, She S, Luo L, Li H, Ning Y, Ren J, Wu Z, Huang R, Zheng Y. Abnormal Contingent Negative Variation Drifts During Facial Expression Judgment in Schizophrenia Patients. Front Hum Neurosci 2020; 14:274. [PMID: 32760264 PMCID: PMC7371930 DOI: 10.3389/fnhum.2020.00274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/18/2020] [Indexed: 02/05/2023] Open
Abstract
Schizophrenia patients often show impaired facial expression recognition, which leads to difficulties in adaptation to daily life. However, it remains unclear whether the deficit is at the perceptual or higher cognitive level of facial emotion processing. Recent studies have shown that earlier face-evoked event-related potential (ERP) components such as N170 and P100 can effectively distinguish schizophrenia patients from healthy controls; however, findings for later waveforms are ambiguous. To clarify this point, in this study we compared electroencephalographic signals in schizophrenia patients and control subjects during a facial expression judgment task. We found that group effects of the occipital N170 and frontal lobe contingent negative variation (CNV) were both significant. The effect sizes (ESs) of N170 and CNV amplitudes were generally medium or small, whereas that of CNV slope for an upright face was large (>0.8). Moreover, N170 amplitude and CNV slope but not CNV amplitude was correlated with Personal and Social Performance (PSP) Scale score. These results suggest that the slope of CNV drift during facial expression processing has a potential clinical value for schizophrenia.
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Affiliation(s)
- Qian Wang
- Department of Clinical Psychology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Shenglin She
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Lu Luo
- School of Psychological and Cognitive Sciences, Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China
| | - Haijing Li
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Yuping Ning
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Jianjuan Ren
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Zhangying Wu
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Rongcheng Huang
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Yingjun Zheng
- Department of General Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
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18
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Spironelli C, Maffei A, Romeo Z, Piazzon G, Padovan G, Magnolfi G, Pasini I, Gomez Homen F, Concari G, Angrilli A. Evidence of language-related left hypofrontality in Major Depression: An EEG Beta band study. Sci Rep 2020; 10:8166. [PMID: 32424130 PMCID: PMC7235005 DOI: 10.1038/s41598-020-65168-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 04/23/2020] [Indexed: 02/05/2023] Open
Abstract
Major depression (MDD) has been associated with an altered EEG frontal asymmetry measured in resting state; nevertheless, this association has showed a weak consistency across studies. In the present study, which starts from an evolutionistic view of psychiatric disorders, we investigated frontal asymmetry in MDD, using language as a probe to test the integrity of large inter- and intra-hemispheric networks and processes. Thirty MDD patients (22 women) and 32 matched controls (HC) were recruited for an EEG recording in resting state and during two linguistic tasks, phonological and semantic. Normalized alpha and beta EEG spectral bands were measured across all three conditions in the two groups. EEG alpha amplitude showed no hemispheric asymmetry, regardless of group, both at rest and during linguistic tasks. During resting state, analysis of EEG beta revealed a lack of hemispheric asymmetry in both groups, but during linguistic tasks, HC exhibited the typical greater left frontal beta activation, whereas MDD patients showed a lack of frontal asymmetry and a significantly lower activation of left frontal sites. In depressed patients, positive affect was negatively correlated with depression levels and positively correlated with left frontal EEG beta amplitude. Language represents the human process that requires the largest level of integration between and within the hemispheres; thus, language asymmetry was a valid probe to test the left frontal alteration encompassing highly impairing psychiatric disorders, such as schizophrenia and MDD. Indeed, these severe diseases are marked by delusions, ruminations, thought disorders, and hallucinations, all of which have a clear linguistic or metalinguistic basis.
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Affiliation(s)
- Chiara Spironelli
- Department of General Psychology, University of Padova, Padova, Italy. .,Padova Neuroscience Center, University of Padova, Padova, Italy.
| | - Antonio Maffei
- Department of General Psychology, University of Padova, Padova, Italy
| | | | - Giulia Piazzon
- Psychiatric Clinic, Neuroscience Department, University of Padova, Padova, Italy
| | - Giordano Padovan
- Psychiatric Clinic, Neuroscience Department, University of Padova, Padova, Italy
| | - Gianna Magnolfi
- Psychiatric Clinic, Neuroscience Department, University of Padova, Padova, Italy
| | - Ilenia Pasini
- Department of General Psychology, University of Padova, Padova, Italy
| | | | | | - Alessandro Angrilli
- Department of General Psychology, University of Padova, Padova, Italy.,Padova Neuroscience Center, University of Padova, Padova, Italy.,CNR Institute of Neuroscience, Padova, Italy
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19
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Wake R, Miyaoka T, Kawakami K, Tsuchie K, Inagaki T, Horiguchi J, Yamamoto Y, Hayashi T, Kitagaki H. Characteristic brain hypoperfusion by 99mTc-ECD single photon emission computed tomography (SPECT) in patients with the first-episode schizophrenia. Eur Psychiatry 2020; 25:361-5. [DOI: 10.1016/j.eurpsy.2009.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Revised: 12/14/2009] [Accepted: 12/14/2009] [Indexed: 11/29/2022] Open
Abstract
AbstractObjectiveIn this study, we evaluated brain perfusion in patients with first-episode medicated schizophrenia using the new analytical method, statistical parametric mapping (SPM) applied to single photon emission computed tomography (SPECT).MethodWe performed SPECT with 99-Tc-ethyl cysteinate dimer (99mTc-ECD) of the brain and magnetic resonance imaging (MRI) in patients with schizophrenia (n = 30) and control subjects matched for age and gender (n = 37). A voxel-by-voxel group analysis was performed using SPM2 (Z > 3.0, P < 0.001, uncorrected for multiple comparisons).ResultIn comparison with control subjects, the volumes of the bilateral frontal areas were found to be decreased on MRI. Blood flow was found to be reduced in the bilateral temporal areas in the patients with schizophrenia on SPECT.ConclusionIn this study, patients with first-episode schizophrenia appeared to have significant bilateral temporal hypoperfusion, although temporal volumes were not significantly decreased in comparison with control subjects. Abnormality of temporal lobe blood flow in schizophrenia may show that functional changes occur earlier than structural changes, and may assist in the diagnosis of schizophrenia.
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Pedapati EV, Mooney LN, Wu SW, Erickson CA, Sweeney JA, Shaffer RC, Horn PS, Wink LK, Gilbert DL. Motor cortex facilitation: a marker of attention deficit hyperactivity disorder co-occurrence in autism spectrum disorder. Transl Psychiatry 2019; 9:298. [PMID: 31723120 PMCID: PMC6853984 DOI: 10.1038/s41398-019-0614-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 09/23/2019] [Accepted: 10/15/2019] [Indexed: 01/06/2023] Open
Abstract
The neural correlates distinguishing youth with Autism Spectrum Disorder (ASD-) and ASD with co-occurring Attention Deficit Hyperactivity Disorder (ASD+) are poorly understood despite significant phenotypic and prognostic differences. Paired-pulse transcranial magnetic stimulation (TMS) measures, including intracortical facilitation (ICF), short interval cortical inhibition (SICI), and cortical silent period (CSP) were measured in an age matched cohort of youth with ASD- (n = 20), ASD + (n = 29), and controls (TDC) (n = 24). ASD- and ASD+ groups did not differ by IQ or social functioning; however, ASD+ had significantly higher inattention and hyperactivity ratings. ICF (higher ratio indicates greater facilitation) in ASD+ (Mean 1.0, SD 0.19) was less than ASD- (Mean 1.3, SD 0.36) or TDC (Mean 1.2, SD 0.24) (F2,68 = 6.5, p = 0.003; post-hoc tests, ASD+ vs either TDC or ASD-, p ≤ 0.05). No differences were found between groups for SICI or age corrected active/resting motor threshold (AMT/RMT). Across all ASD youth (ASD- and ASD+), ICF was inversely correlated with worse inattention (Conners-3 Inattention (r = -0.41; p < 0.01) and ADHDRS-IV Inattention percentile (r = -0.422, p < 0.01) scores. ICF remains intact in ASD- but is impaired in ASD+. Lack of ICF is associated with inattention and executive function across ASD. Taken with the present findings, ADHD may have a distinct electrophysiological "signature" in ASD youth. ICF may constitute an emerging biomarker to study the physiology of ADHD in ASD, which may align with disease prognosis or treatment response.
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Affiliation(s)
- Ernest V. Pedapati
- 0000 0000 9025 8099grid.239573.9Divisions of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA ,0000 0000 9025 8099grid.239573.9Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Lindsey N. Mooney
- 0000 0000 9025 8099grid.239573.9Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA ,0000 0004 1936 9684grid.27860.3bDepartment of Psychology, University of California, Davis, CA USA
| | - Steve W. Wu
- 0000 0000 9025 8099grid.239573.9Divisions of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Craig A. Erickson
- 0000 0000 9025 8099grid.239573.9Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - John A. Sweeney
- 0000 0001 2179 9593grid.24827.3bDepartment of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH USA
| | - Rebecca C. Shaffer
- 0000 0000 9025 8099grid.239573.9Developmental and Behavioral Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Paul S. Horn
- 0000 0000 9025 8099grid.239573.9Divisions of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA ,0000 0000 9025 8099grid.239573.9Divisions of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Logan K. Wink
- 0000 0000 9025 8099grid.239573.9Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Donald L. Gilbert
- 0000 0000 9025 8099grid.239573.9Divisions of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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21
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Matsuda Y, Makinodan M, Morimoto T, Kishimoto T. Neural changes following cognitive remediation therapy for schizophrenia. Psychiatry Clin Neurosci 2019; 73:676-684. [PMID: 31278805 DOI: 10.1111/pcn.12912] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/13/2019] [Accepted: 07/01/2019] [Indexed: 01/15/2023]
Abstract
Patients with schizophrenia experience cognitive impairments that relate to poorer social functioning even after amelioration of positive symptoms. Pharmacological treatment and cognitive remediation are the two important therapeutic approaches for cognitive impairment in schizophrenia. Cognitive remediation therapy (CRT) for schizophrenia improves cognitive functioning and induces neuroplasticity, but different approaches and durations of CRT and different neuroimaging devices have led to varying results in meta-analyses. The objective of this review was to explore the impact of CRT on neurobiology. Several studies have provided evidence of increased activation in the frontal brain regions, such as the prefrontal cortex, anterior cingulate cortex, and parietal and occipital regions during working memory or executive function tasks after CRT. Two studies have shown alterations in resting-state connectivity between the prefrontal cortex and temporal regions. Two studies have reported that CRT induces changes in gray matter volume in the hippocampus. Further, one study observed that patients who had received CRT had elevated fractional anisotropy in the basal ganglia. We conclude that neuroimaging studies assessing CRT in patients with schizophrenia showed functional, structural, and connectivity changes that were positively correlated with cognitive improvements despite heterogeneous CRT approaches. Future studies that combine multiple modalities are required to address the differences, effects of intrinsic motivation, and pharmacological augmentation of CRT. Further understanding of the biological basis might lead to predictions of the CRT response in patients with schizophrenia and contribute to identification of schizophrenia patients for future interventions.
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Affiliation(s)
- Yasuhiro Matsuda
- Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Nara, Japan
| | - Manabu Makinodan
- Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Nara, Japan
| | - Tsubasa Morimoto
- Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Nara, Japan
| | - Toshifumi Kishimoto
- Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Nara, Japan
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22
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Emmons EB, Kennedy M, Kim Y, Narayanan NS. Corticostriatal stimulation compensates for medial frontal inactivation during interval timing. Sci Rep 2019; 9:14371. [PMID: 31591426 PMCID: PMC6779764 DOI: 10.1038/s41598-019-50975-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/20/2019] [Indexed: 11/09/2022] Open
Abstract
Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.
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Affiliation(s)
- Eric B Emmons
- Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Morgan Kennedy
- Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Youngcho Kim
- Department of Neurology, University of Iowa, Iowa City, IA, USA
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23
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Yamazaki M, Yamamoto N, Yarimizu J, Okabe M, Moriyama A, Furutani M, Marcus MM, Svensson TH, Harada K. Functional mechanism of ASP5736, a selective serotonin 5-HT 5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia. Eur Neuropsychopharmacol 2018; 28:620-629. [PMID: 29571967 DOI: 10.1016/j.euroneuro.2018.03.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 02/17/2018] [Accepted: 03/02/2018] [Indexed: 10/17/2022]
Abstract
The 5-HT5A receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT5A receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT5A receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT5A receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT5A receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.
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Affiliation(s)
- Mayako Yamazaki
- Department of Neuroscience, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
| | - Noriyuki Yamamoto
- Department of Neuroscience, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Junko Yarimizu
- Department of Neuroscience, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Mayuko Okabe
- Department of Neuroscience, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Ai Moriyama
- Analysis & Pharmacokinetics Research, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Masako Furutani
- Analysis & Pharmacokinetics Research, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Monica M Marcus
- Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Torgny H Svensson
- Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Katsuya Harada
- Department of Neuroscience, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
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24
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Abstract
The high prevalence of nicotine dependence contributes to excess mortality in schizophrenia. Cue reactivity, or the encounter of drug-related cues or contexts, triggers craving, drug-seeking, and relapse. Prior functional magnetic resonance imaging (fMRI) research indicates that individuals with schizophrenia have blunted neural responses to rewarding stimuli in association with more severe negative symptoms. The objectives of this study are to determine if smokers with schizophrenia have altered neural reactivity to smoking cues compared with non-psychiatrically ill smokers and to evaluate the influence of negative symptoms on cue reactivity. Twenty smokers with schizophrenia and 19 control smokers underwent fMRI while viewing smoking-related and neutral cues. The primary analysis was group comparison of Smoking-Neutral contrast using whole-brain analysis (Pcorrected < .05). Smokers with schizophrenia had significantly greater baseline carbon monoxide levels and longer duration of smoking, suggesting more nicotine use. While both groups had greater brain reactivity to smoking vs neutral cues, smokers with schizophrenia had significantly decreased cue reactivity (Smoking-Neutral) compared to controls in bilateral frontal midline regions. There were significant negative correlations between negative symptoms and frontal midline reactivity. Despite greater nicotine use, smokers with schizophrenia exhibited decreased smoking cue-induced neural reactivity in frontal midline regions, suggesting that increased smoking and low cessation rates in schizophrenia are not primarily driven by responses to smoking-related cues. The finding of negative correlations between cue reactivity and negative symptoms is consistent with previous research demonstrating decreased neural responses to rewarding cues, particularly in patients with negative symptoms.
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Affiliation(s)
- Lauren V Moran
- Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA,To whom correspondence should be addressed; McLean Hospital, 115 Mill Street, AB3S, Belmont, MA 02478, US; tel: 617-855-3395; fax: 617-855-2895; e-mail:
| | - Jennifer M Betts
- Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA
| | - Dost Ongur
- Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA
| | - Amy C Janes
- Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA
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25
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Ward G, Allport A. Planning and Problem solving Using the Five disc Tower of London Task. ACTA ACUST UNITED AC 2018. [DOI: 10.1080/713755681] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
This paper investigates the planning and problem-solving abilities of normal adult subjects using a complex version of Shallice's (1982, 1988) Tower of London (TOL) task. Subjects were required to plan a fluent solution to a range of 5-disc TOL puzzles and then execute their formulated plans as fast as possible. The number of errors and the times taken to prepare the most efficient solutions increased monotonically with the number of chunks of subgoal moves. A subgoal move is a move that is essential for the solution of the puzzle, but which does not place a disc into its goal position. A subgoal chunk is a consecutive series of subgoal moves that all transfer discs to and from the same pegs. Furthermore, preparation time was found to be sensitive to a manipulation that increased the number of competing alternative choices, at critical steps in move selection. When subjects planned their action sequences “on-line”, analyses of individual moves and individual move latencies suggested that planning TOL solutions was limited by the difficulty in evaluating and selecting one action (or one subgoal chunk) from the set of competing potential actions at each step in the course of problem solving.
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Affiliation(s)
- Geoff Ward
- Department of Psychology, University of Essex, Colchester, Essex, U.K
| | - Alan Allport
- Department of Psychology, University of Essex, Colchester, Essex, U.K
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26
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İnce E, Üçok A. Relationship Between Persistent Negative Symptoms and Findings of Neurocognition and Neuroimaging in Schizophrenia. Clin EEG Neurosci 2018; 49:27-35. [PMID: 29243526 DOI: 10.1177/1550059417746213] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Negative symptoms are defined as loss or reduction of otherwise present behaviors or functions in illness situation, and they have constituted an important aspect of schizophrenia. Although negative symptoms have usually been considered as a single entity, neurobiological investigations yielded discrepant results. To overcome challenges that derive from this discrepancy, researchers have proposed several approaches to structure negative symptoms into more homogenous constructs. Concept of persistent negative symptoms (PNS) is one of the proposed approaches, and includes both primary and secondary negative symptoms that persist after adequate treatment. PNS is relatively easy to assess, and by definition, more inclusive; yet it represents an unmet therapeutic need. Therefore, it is a target of several neurobiological and pharmacological studies. There are several structural and functional brain alterations associated with negative symptoms. On the other hand, neurocognitive investigations in patients with schizophrenia have revealed deficits in several domains that showed correlations with negative symptoms. There are several shared features between negative symptoms and neurocognitive deficits in schizophrenia such as prevalence rates, course through the illness, prognostic importance, and impact on social functioning. However, exact mechanisms behind the neurobiology of PNS and how it interacts with neurocognition remain to be explained. Earlier reviews on neuroimaging and neurocognitive correlates of PNS have been focused on studies with broadly defined negative symptoms that were selected by methodological closeness to PNS. In this review, we focus on neural correlates and neurocognitive associations of PNS, and we discuss PNS findings available to date.
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Affiliation(s)
- Ezgi İnce
- 1 Department of Psychiatry, Faculty of Medicine, Istanbul University, Çapa, Istanbul, Turkey
| | - Alp Üçok
- 1 Department of Psychiatry, Faculty of Medicine, Istanbul University, Çapa, Istanbul, Turkey
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27
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Liemburg EJ, van Es F, Knegtering H, Aleman A. Effects of aripiprazole versus risperidone on brain activation during planning and social-emotional evaluation in schizophrenia: A single-blind randomized exploratory study. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:112-119. [PMID: 28558941 DOI: 10.1016/j.pnpbp.2017.05.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/28/2017] [Accepted: 05/26/2017] [Indexed: 12/28/2022]
Abstract
Impaired function of prefrontal brain networks may be the source of both negative symptoms and neurocognitive problems in psychotic disorders. Whereas most antipsychotics may decrease prefrontal activation, the partial dopamine D2-receptor agonist aripiprazole is hypothesized to improve prefrontal function. This study investigated whether patients with a psychotic disorder would show stronger activation of prefrontal areas and associated regions after treatment with aripiprazole compared to risperidone treatment. In this exploratory pharmacological neuroimaging study, 24 patients were randomly assigned to either aripiprazole or risperidone. At baseline and after nine weeks treatment they underwent an interview and MRI session. Here we report on brain activation (measured with arterial spin labeling) during performance of two tasks, the Tower of London and the Wall of Faces. Aripiprazole treatment decreased activation of the middle frontal, superior frontal and occipital gyrus (ToL) and medial temporal and inferior frontal gyrus, putamen and cuneus (WoF), while activation increased after risperidone. Activation increased in the ventral anterior cingulate and posterior insula (ToL), and superior frontal, superior temporal and precentral gyrus (WoF) after aripiprazole treatment and decreased after risperidone. Both treatment groups had increased ventral insula activation (ToL) and middle temporal gyrus (WoF), and decreased occipital cortex, precuneus and caudate head activation (ToL) activation. In conclusion, patients treated with aripiprazole may need less frontal resources for planning performance and may show increased frontotemporal and frontostriatal reactivity to emotional stimuli. More research is needed to corroborate and extend these preliminary findings.
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Affiliation(s)
- Edith J Liemburg
- BCN Neuroimaging Center, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Rob Giel Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Frank van Es
- Rob Giel Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; University Center Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Henderikus Knegtering
- BCN Neuroimaging Center, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Rob Giel Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Lentis Research, Center for Mental Health, Groningen, The Netherlands.
| | - André Aleman
- BCN Neuroimaging Center, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Psychology, University of Groningen, Groningen, The Netherlands.
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28
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Guo W, Liu F, Chen J, Wu R, Li L, Zhang Z, Chen H, Zhao J. Olanzapine modulates the default-mode network homogeneity in recurrent drug-free schizophrenia at rest. Aust N Z J Psychiatry 2017; 51:1000-1009. [PMID: 28605934 DOI: 10.1177/0004867417714952] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Previous studies on brain function alterations associated with antipsychotic treatment for schizophrenia have produced conflicting results because they used short treatment periods and different designs. METHODS Resting-state functional magnetic resonance imaging scans were obtained from 17 drug-free patients with recurrent schizophrenia and 24 healthy controls. The patients were treated with olanzapine for 6 months and were scanned at three time points (baseline, 6 weeks of treatment and 6 months of treatment). Network homogeneity was used to analyze the imaging data to examine default-mode network homogeneity alterations associated with antipsychotic treatment. RESULTS Compared with the controls, the patients at baseline showed increased network homogeneity in the bilateral precuneus and decreased network homogeneity in the bilateral middle temporal gyrus. Network homogeneity values in the bilateral precuneus decreased, and network homogeneity values in the left superior medial prefrontal cortex and the right middle temporal gyrus increased in patients administered olanzapine as antipsychotic treatment. By contrast, network homogeneity values in the left middle temporal gyrus remained unchanged in patients after treatment. CONCLUSION This study provides evidence that antipsychotic treatment with olanzapine modulates the default-mode network homogeneity in schizophrenia. These findings contribute to the understanding of antipsychotic treatment effects on brain functions.
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Affiliation(s)
- Wenbin Guo
- 1 Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, China.,2 Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, China.,3 National Clinical Research Center on Mental Disorders, Changsha, China.,4 National Technology Institute on Mental Disorders, Changsha, China.,5 Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China
| | - Feng Liu
- 6 Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Jindong Chen
- 1 Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, China.,2 Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, China.,3 National Clinical Research Center on Mental Disorders, Changsha, China.,4 National Technology Institute on Mental Disorders, Changsha, China.,5 Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China
| | - Renrong Wu
- 1 Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, China.,2 Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, China.,3 National Clinical Research Center on Mental Disorders, Changsha, China.,4 National Technology Institute on Mental Disorders, Changsha, China.,5 Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China
| | - Lehua Li
- 1 Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, China.,2 Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, China.,3 National Clinical Research Center on Mental Disorders, Changsha, China.,4 National Technology Institute on Mental Disorders, Changsha, China.,5 Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China
| | - Zhikun Zhang
- 7 Mental Health Center, the First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Huafu Chen
- 6 Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Jingping Zhao
- 1 Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, China.,2 Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, China.,3 National Clinical Research Center on Mental Disorders, Changsha, China.,4 National Technology Institute on Mental Disorders, Changsha, China.,5 Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China
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29
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Zuccoli GS, Saia-Cereda VM, Nascimento JM, Martins-de-Souza D. The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence. Front Neurosci 2017; 11:493. [PMID: 28936160 PMCID: PMC5594406 DOI: 10.3389/fnins.2017.00493] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 08/22/2017] [Indexed: 12/27/2022] Open
Abstract
Psychiatric disorders represent a great medical and social challenge and people suffering from these conditions face many impairments regarding personal and professional life. In addition, a mental disorder will manifest itself in approximately one quarter of the world's population at some period of their life. Dysfunction in energy metabolism is one of the most consistent scientific findings associated with these disorders. With this is mind, this review compiled data on disturbances in energy metabolism found by proteomic analyses of postmortem brains collected from patients affected by the most prevalent psychiatric disorders: schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). We searched in the PubMed database to gather the studies and compiled all the differentially expressed proteins reported in each work. SCZ studies revealed 92 differentially expressed proteins related to energy metabolism, while 95 proteins were discovered in BPD, and 41 proteins in MDD. With the compiled data, it was possible to determine which proteins related to energy metabolism were found to be altered in all the disorders as well as which ones were altered exclusively in one of them. In conclusion, the information gathered in this work could contribute to a better understanding of the impaired metabolic mechanisms and hopefully bring insights into the underlying neuropathology of psychiatric disorders.
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Affiliation(s)
- Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
| | - Verônica M Saia-Cereda
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
| | - Juliana M Nascimento
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
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30
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Penadés R, González-Rodríguez A, Catalán R, Segura B, Bernardo M, Junqué C. Neuroimaging studies of cognitive remediation in schizophrenia: A systematic and critical review. World J Psychiatry 2017; 7:34-43. [PMID: 28401047 PMCID: PMC5371171 DOI: 10.5498/wjp.v7.i1.34] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/14/2016] [Accepted: 12/14/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To examine the effects of cognitive remediation therapies on brain functioning through neuroimaging procedures in patients with schizophrenia.
METHODS A systematic, computerised literature search was conducted in the PubMed/Medline and PsychInfo databases. The search was performed through February 2016 without any restrictions on language or publication date. The search was performed using the following search terms: [(“cogniti*” and “remediation” or “training” or “enhancement”) and (“fMRI” or “MRI” or “PET” or “SPECT”) and (schizophrenia or schiz*)]. The search was accompanied by a manual online search and a review of the references from each of the papers selected, and those papers fulfilling our inclusion criteria were also included.
RESULTS A total of 101 studies were found, but only 18 of them fulfilled the inclusion criteria. These studies indicated that cognitive remediation improves brain activation in neuroimaging studies. The most commonly reported changes were those that involved the prefrontal and thalamic regions. Those findings are in agreement with the hypofrontality hypothesis, which proposes that frontal hypoactivation is the underlying mechanism of cognitive impairments in schizophrenia. Nonetheless, great heterogeneity among the studies was found. They presented different hypotheses, different results and different findings. The results of more recent studies interpreted cognitive recovery within broader frameworks, namely, as amelioration of the efficiency of different networks. Furthermore, advances in neuroimaging methodologies, such as the use of whole-brain analysis, tractography, graph analysis, and other sophisticated methodologies of data processing, might be conditioning the interpretation of results and generating new theoretical frameworks. Additionally, structural changes were described in both the grey and white matter, suggesting a neuroprotective effect of cognitive remediation. Cognitive, functional and structural improvements tended to be positively correlated.
CONCLUSION Neuroimaging studies of cognitive remediation in patients with schizophrenia suggest a positive effect on brain functioning in terms of the functional reorganisation of neural networks.
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Pan E, Ates MA, Algul A, Aytekin A, Basoglu C, Ebrinc S, Cetin M, Kose S. Fractional Anisotropic Changes of Corpus Callosum Associated with Antipsychotic Treatment in First-Episode Antipsychotic Drug-Naive Patients with Schizophrenia. ACTA ACUST UNITED AC 2017. [DOI: 10.5455/bcp.20160319021659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Erdal Pan
- Department of Psychiatry, Eskisehir Military Hospital, Eskisehir—Turkey
| | - Mehmet Alpay Ates
- Department of Psychiatry, Gulhane Military Medical Academy Haydarpasa Research and Training Hospital, Istanbul - Turkey
| | - Ayhan Algul
- Department of Psychiatry, Gulhane Military Medical Academy Haydarpasa Research and Training Hospital, Istanbul - Turkey
| | - Aykut Aytekin
- Department of Radiology, Balikesir Military Hospital, Balıkesir - Turkey
| | - Cengiz Basoglu
- Department of Psychiatry, Gulhane Military Medical Academy Haydarpasa Research and Training Hospital, Istanbul - Turkey
| | - Servet Ebrinc
- Department of Psychiatry, Gulhane Military Medical Academy Haydarpasa Research and Training Hospital, Istanbul - Turkey
| | - Mesut Cetin
- Department of Psychiatry, Gulhane Military Medical Academy Haydarpasa Research and Training Hospital, Istanbul - Turkey
| | - Samet Kose
- H. Kalyoncu University, Department of Psychology, Gaziantep - Turkey
- University of Texas Medical School of Houston, TX, USA and Center for Neurobehavioral Research on Addictions, Houston, TX, USA
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Neuregulin-1 mutant mice indicate motor and sensory deficits, indeed few references for schizophrenia endophenotype model. Behav Brain Res 2017; 322:177-185. [PMID: 28089851 DOI: 10.1016/j.bbr.2017.01.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 01/05/2017] [Accepted: 01/10/2017] [Indexed: 11/23/2022]
Abstract
Neuregulins (Nrg) are a gene family that binds to tyrosine kinase receptors of the ErbB family. The protein of Nrg1 is to be involved in heart formation, migration of neurons, axonal pathfinding and synaptic function. A relation between Nrg1 and schizophrenia is assumed. Chronic impairment in schizophrenia is characterized by different positive and negative symptoms. Detectable markers of this disease in human and in animal models are activity, social behavior and sensory processing. In this study we compared heterozygous Nrg1 mutant mice in behavior and quantification of dopaminergic and serotoninergic neurons with wild type-like littermates. In the Nrg1 mutant mice the epidermal growth factor-like domain is replaced by the neomycin resistance gene. We found significant differences in locomotor and pain perception behavior. No differences were found in specific schizophrenia social interaction and prepulse inhibition behavior. The number of dopaminergic and serotoninergic neurons did not differ in the investigated regions ventral tegmental area, substantia nigra, periaqueductal grey and raphe nuclei. In conclusion, this analyzed Nrg1 mutant mice model did not serve as a complete schizophrenia model. Particular aspects of schizophrenia disease in locomotor and sensory behavior deficits could represent in this Nrg1 mutant mice. Beside several different models could Nrg1 deficiency represent an endophenotype of schizophrenia disease.
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MacKay M, Cetin M, Baker G, Dursun S. Modulation of Central Nitric Oxide as a Therapeutic Strategy for Schizophrenia. ACTA ACUST UNITED AC 2016. [DOI: 10.1080/10177833.2010.11790644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Marnie MacKay
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada, Centre for Psychiatric Assessment and Therapeutics, Alberta Hospital Edmonton, Alberta Health Services, Edmonton, Canada
| | - Mesut Cetin
- GATA Haydarpasa Training Hospital, Department of Psychiatry, Istanbul-Turkey
| | - Glen Baker
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada, Centre for Psychiatric Assessment and Therapeutics, Alberta Hospital Edmonton, Alberta Health Services, Edmonton, Canada
| | - Serdar Dursun
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada, Centre for Psychiatric Assessment and Therapeutics, Alberta Hospital Edmonton, Alberta Health Services, Edmonton, Canada
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Opacic T, Paefgen V, Lammers T, Kiessling F. Status and trends in the development of clinical diagnostic agents. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2016; 9. [DOI: 10.1002/wnan.1441] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/02/2016] [Accepted: 09/15/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Tatjana Opacic
- Department of Experimental Molecular Imaging; RWTH Aachen University; Aachen Germany
| | - Vera Paefgen
- Department of Experimental Molecular Imaging; RWTH Aachen University; Aachen Germany
| | - Twan Lammers
- Department of Experimental Molecular Imaging; RWTH Aachen University; Aachen Germany
- Department of Pharmaceutics; Utrecht University; Utrecht The Netherlands
- Department of Targeted Therapeutics; University of Twente; Enschede The Netherlands
| | - Fabian Kiessling
- Department of Experimental Molecular Imaging; RWTH Aachen University; Aachen Germany
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Demeter G, Szendi I, Domján N, Juhász M, Greminger N, Szőllősi Á, Racsmány M. Preserved Intention Maintenance and Impaired Execution of Prospective Memory Responses in Schizophrenia: Evidence from an Event-based Prospective Memory Study. Front Psychol 2016; 7:593. [PMID: 27199827 PMCID: PMC4848737 DOI: 10.3389/fpsyg.2016.00593] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 04/11/2016] [Indexed: 11/17/2022] Open
Abstract
Executive system dysfunction and impaired prospective memory (PM) are widely documented in schizophrenia. However, it is not yet clarified which components of PM function are impaired in this disorder. Two plausible target components are the maintenance of delayed intentions and the execution of PM responses. Furthermore, it is debated whether the impaired performance on frequently used executive tasks is associated with deficit in PM functions. The aim of our study was twofold. First, we aimed to investigate the specific processes involved in event-based PM function, mainly focusing on difference between maintenance of intention and execution of PM responses. Second, we aimed to unfold the possible connections between executive functions, clinical symptoms, and PM performance. An event-based PM paradigm was applied with three main conditions: baseline (with no expectation of PM stimuli, and without PM stimuli), expectation condition (participants were told that PM stimuli might occur, though none actually did), and execution condition (participants were told that PM stimuli might occur, and PM stimuli did occur). This procedure allowed us to separately investigate performances associated with intention maintenance and execution of PM responses. We assessed working memory and set-shifting executive functions by memory span tasks and by the Wisconsin Card Sorting Test (WCST), respectively. Twenty patients diagnosed with schizophrenia and 20 healthy control subjects (matched according to age and education) took part in the study. It was hypothesized that patients would manifest different levels of performance in the expectation and execution conditions of the PM task. Our results confirmed that the difference between baseline performance and performance in the execution condition (execution cost) was significantly larger for participants diagnosed with schizophrenia in comparison with matched healthy control group. However, this difference was not observed in the expectation condition. The PM performance in the execution condition was correlated with impaired executive functions in schizophrenia. Specifically, the size of execution cost positively correlated with percent of perseverative errors committed on WCST by the patient group. Our results suggest that maintenance of delayed intentions is unimpaired in schizophrenia, whereas the impairment in execution of PM responses is associated with set-shifting deficit.
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Affiliation(s)
- Gyula Demeter
- Frontostriatal System Research Group, Hungarian Academy of SciencesBudapest, Hungary; Department of Cognitive Science, Budapest University of Technology and EconomicsBudapest, Hungary
| | - István Szendi
- Department of Psychiatry, University of Szeged Szeged, Hungary
| | - Nóra Domján
- Department of Psychiatry, University of Szeged Szeged, Hungary
| | - Marianna Juhász
- Department of Psychiatry, University of Szeged Szeged, Hungary
| | - Nóra Greminger
- Department of Psychiatry, University of Szeged Szeged, Hungary
| | - Ágnes Szőllősi
- Department of Cognitive Science, Budapest University of Technology and Economics Budapest, Hungary
| | - Mihály Racsmány
- Frontostriatal System Research Group, Hungarian Academy of SciencesBudapest, Hungary; Department of Cognitive Science, Budapest University of Technology and EconomicsBudapest, Hungary
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The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patients with schizophrenia. Schizophr Res 2016; 172:114-22. [PMID: 26830318 DOI: 10.1016/j.schres.2016.01.045] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/23/2016] [Accepted: 01/25/2016] [Indexed: 11/23/2022]
Abstract
Schizophrenia-associated cognitive deficits are resistant to treatment and thus pose a lifelong burden. The Brief Assessment of Cognition in Schizophrenia (BACS) provides reliable and valid assessments across cognitive domains. However, because the prefrontal functional abnormalities specifically associated with the level of cognitive deficits in schizophrenia have not been examined, we explored this relationship. Patients with schizophrenia (N=87) and matched healthy controls (N=50) participated in the study. Using near-infrared spectroscopy (NIRS), we measured the hemodynamic responses in the prefrontal and superior temporal cortical surface areas during a working memory task. Correlation analyses revealed a relationship between the hemodynamics and the BACS composite and domain scores. Hemodynamic responses of the left dorsolateral prefrontal cortex (DLPFC) and left frontopolar cortex (FPC) in the higher-level-of-cognitive-function schizophrenia group were weaker than the responses of the controls but similar to those of the lower-level-of-cognitive-function schizophrenia group. However, hemodynamic responses in the right DLPFC, bilateral ventrolateral PFC (VLPFC), and right temporal regions decreased with increasing cognitive deficits. In addition, the hemodynamic response correlated positively with the level of cognitive function (BACS composite scores) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions in schizophrenia. The correlation was driven by all BACS domains. Our results suggest that the linked functional deficits in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions may be related to BACS-measured cognitive impairments in schizophrenia and show that linking the neurocognitive deficits and brain abnormalities can increase our understanding of schizophrenia pathophysiology.
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Renes RA, Vink M, van der Weiden A, Prikken M, Koevoets MGJC, Kahn RS, Aarts H, van Haren NEM. Impaired frontal processing during agency inferences in schizophrenia. Psychiatry Res Neuroimaging 2016; 248:134-141. [PMID: 26776080 DOI: 10.1016/j.pscychresns.2015.12.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 11/24/2015] [Accepted: 12/22/2015] [Indexed: 11/30/2022]
Abstract
People generally experience themselves as the cause of outcomes following from their own actions. Such agency inferences occur fluently and are essential to social interaction. However, schizophrenia patients often experience difficulties in distinguishing their own actions from those of others. Building on recent research into the neural substrates underlying agency inferences in healthy individuals, the present study investigates how these inferences are represented on a neural level in patients with schizophrenia. Thirty-one schizophrenia patients and 31 healthy controls performed an agency inference task while functional magnetic resonance images were obtained. Participants were presented with a task wherein the relationship between their actions and the subsequent outcomes was ambiguous. They received instructions to cause specific outcomes to occur by pressing a key, but the task was designed to match or mismatch the color outcome with the participants' goal. Both groups experienced stronger agency when their goal matched (vs. mismatched) the outcome. However, region of interest analyses revealed that only controls showed the expected involvement of the medial prefrontal cortex and superior frontal gyrus, whereas in patients the agency experience was not related to brain activation. These findings are discussed in light of a hypofrontality model of schizophrenia.
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Affiliation(s)
- Robert A Renes
- Department of Psychology, Utrecht University, Utrecht, The Netherlands.
| | - Matthijs Vink
- Department of Psychiatry of the Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Anouk van der Weiden
- Department of Psychiatry of the Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Merel Prikken
- Department of Psychiatry of the Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Martijn G J C Koevoets
- Department of Psychiatry of the Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - René S Kahn
- Department of Psychiatry of the Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Henk Aarts
- Department of Psychology, Utrecht University, Utrecht, The Netherlands
| | - Neeltje E M van Haren
- Department of Psychiatry of the Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
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Bryden DW, Burton AC, Barnett BR, Cohen VJ, Hearn TN, Jones EA, Kariyil RJ, Kunin A, In Kwak S, Lee J, Lubinski BL, Rao GK, Zhan A, Roesch MR. Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex. Neuropsychopharmacology 2016; 41:716-25. [PMID: 26189451 PMCID: PMC4707818 DOI: 10.1038/npp.2015.197] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 05/26/2015] [Accepted: 05/27/2015] [Indexed: 01/06/2023]
Abstract
Prenatal nicotine exposure (PNE) is linked to numerous psychiatric disorders including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex. Yet, it is unclear how neural activity in the medial prefrontal cortex (mPFC) is modulated during tasks that assess response inhibition or if these neural correlates, along with behavior, are affected by PNE. To address this issue, we recorded from single mPFC neurons in control and PNE rats as they performed a stop-signal task. We found that PNE rats were faster for all trial-types, made more premature responses, and were less likely to inhibit behavior on 'STOP' trials during which rats had to inhibit an already initiated response. Activity in mPFC was modulated by response direction and was positively correlated with accuracy and movement time in control but not PNE rats. Although the number of single neurons correlated with response direction was significantly reduced by PNE, neural activity observed on general STOP trials was largely unaffected. However, dramatic behavioral deficits on STOP trials immediately following non-conflicting (GO) trials in the PNE group appear to be mediated by the loss of conflict monitoring signals in mPFC. We conclude that prenatal nicotine exposure makes rats impulsive and disrupts firing of mPFC neurons that carry signals related to response direction and conflict monitoring.
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Affiliation(s)
- Daniel W Bryden
- Department of Psychology, University of Maryland, College Park, MD, USA,Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD, USA,Department of Psychology and Program in Neuroscience and Cognitive Science, University of Maryland, Bio-psyc Building, College Park, MD 20742, USA, Tel: 301 405 2274, Fax: 301 314 9566, E-mail: or
| | - Amanda C Burton
- Department of Psychology, University of Maryland, College Park, MD, USA,Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD, USA
| | - Brian R Barnett
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Valerie J Cohen
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Taylor N Hearn
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Emily A Jones
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Reshma J Kariyil
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Alice Kunin
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Sae In Kwak
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Jessica Lee
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Brooke L Lubinski
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Gautam K Rao
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Ashley Zhan
- Gemstone Honors Program, University of Maryland, College Park, MD, USA
| | - Matthew R Roesch
- Department of Psychology, University of Maryland, College Park, MD, USA,Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD, USA,Department of Psychology and Program in Neuroscience and Cognitive Science, University of Maryland, Bio-psyc Building, College Park, MD 20742, USA, Tel: 301 405 2274, Fax: 301 314 9566, E-mail: or
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Frankle WG, Cho RY, Prasad KM, Mason NS, Paris J, Himes ML, Walker C, Lewis DA, Narendran R. In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients. Am J Psychiatry 2015; 172:1148-59. [PMID: 26133962 PMCID: PMC5070491 DOI: 10.1176/appi.ajp.2015.14081031] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. METHOD The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). RESULTS [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. CONCLUSIONS This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.
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McAllister KAL, Mar AC, Theobald DE, Saksida LM, Bussey TJ. Comparing the effects of subchronic phencyclidine and medial prefrontal cortex dysfunction on cognitive tests relevant to schizophrenia. Psychopharmacology (Berl) 2015. [PMID: 26194915 DOI: 10.1007/s00213-015-4018-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
RATIONALE It is becoming increasingly clear that the development of treatments for cognitive symptoms of schizophrenia requires urgent attention, and that valid animal models of relevant impairments are required. With subchronic psychotomimetic agent phencyclidine (scPCP), a putative model of such impairment, the extent to which changes following scPCP do or do not resemble those following dysfunction of the prefrontal cortex is of importance. OBJECTIVES The present study carried out a comparison of the most common scPCP dosing regimen with excitotoxin-induced medial prefrontal cortex (mPFC) dysfunction in rats, across several cognitive tests relevant to schizophrenia. METHODS ScPCP subjects were dosed intraperitoneal with 5 mg/kg PCP or vehicle twice daily for 1 week followed by 1 week washout prior to behavioural testing. mPFC dysfunction was induced via fibre-sparing excitotoxin infused into the pre-limbic and infralimbic cortex. Subjects were tested on spontaneous novel object recognition, touchscreen object-location paired-associates learning and touchscreen reversal learning. RESULTS A double-dissociation was observed between object-location paired-associates learning and object recognition: mPFC dysfunction impaired acquisition of the object-location task but not spontaneous novel object recognition, while scPCP impaired spontaneous novel object recognition but not object-location associative learning. Both scPCP and mPFC dysfunction resulted in a similar facilitation of reversal learning. CONCLUSIONS The pattern of impairment following scPCP raises questions around its efficacy as a model of cognitive impairment in schizophrenia, particularly if importance is placed on faithfully replicating the effects of mPFC dysfunction.
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Affiliation(s)
- K A L McAllister
- University of Cambridge Department of Psychology, Downing Street, Cambridge, CB2 3EB, UK. .,MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK. .,, 20 Manchester Sq., London, W1U 3PZ, UK.
| | - A C Mar
- University of Cambridge Department of Psychology, Downing Street, Cambridge, CB2 3EB, UK.,MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK
| | - D E Theobald
- University of Cambridge Department of Psychology, Downing Street, Cambridge, CB2 3EB, UK.,MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK
| | - L M Saksida
- University of Cambridge Department of Psychology, Downing Street, Cambridge, CB2 3EB, UK.,MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK
| | - T J Bussey
- University of Cambridge Department of Psychology, Downing Street, Cambridge, CB2 3EB, UK.,MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK
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Galderisi S, Merlotti E, Mucci A. Neurobiological background of negative symptoms. Eur Arch Psychiatry Clin Neurosci 2015; 265:543-58. [PMID: 25797499 DOI: 10.1007/s00406-015-0590-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Accepted: 03/15/2015] [Indexed: 01/29/2023]
Abstract
Studies investigating neurobiological bases of negative symptoms of schizophrenia failed to provide consistent findings, possibly due to the heterogeneity of this psychopathological construct. We tried to review the findings published to date investigating neurobiological abnormalities after reducing the heterogeneity of the negative symptoms construct. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, genetics and neurobiology of schizophrenia. We searched PubMed with the keywords "negative symptoms," "deficit schizophrenia," "persistent negative symptoms," "neurotransmissions," "neuroimaging" and "genetic." Additional articles were identified by manually checking the reference lists of the relevant publications. Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included. Structural and functional imaging studies addressed the issue of neurobiological background of negative symptoms from several perspectives (considering them as a unitary construct, focusing on primary and/or persistent negative symptoms and, more recently, clustering them into factors), but produced discrepant findings. The examined studies provided evidence suggesting that even primary and persistent negative symptoms include different psychopathological constructs, probably reflecting the dysfunction of different neurobiological substrates. Furthermore, they suggest that complex alterations in multiple neurotransmitter systems and genetic variants might influence the expression of negative symptoms in schizophrenia. On the whole, the reviewed findings, representing the distillation of a large body of disparate data, suggest that further deconstruction of negative symptomatology into more elementary components is needed to gain insight into underlying neurobiological mechanisms.
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Affiliation(s)
- Silvana Galderisi
- Department of Psychiatry, Second University of Naples (SUN), L.go Madonna delle Grazie, 1, 80138, Naples, Italy.
| | - Eleonora Merlotti
- Department of Psychiatry, Second University of Naples (SUN), L.go Madonna delle Grazie, 1, 80138, Naples, Italy
| | - Armida Mucci
- Department of Psychiatry, Second University of Naples (SUN), L.go Madonna delle Grazie, 1, 80138, Naples, Italy
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"Hyperfrontality" as seen on FDG PET in unmedicated schizophrenia patients with positive symptoms. Clin Nucl Med 2015; 39:694-7. [PMID: 24978342 DOI: 10.1097/rlu.0000000000000502] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Decreased frontal activity has been reported widely in unmedicated schizophrenic patients with predominantly negative symptoms. Not many studies have assessed the frontal lobe status in unmedicated patients with positive symptoms. PATIENTS AND METHODS Fifty-one patients with schizophrenia (all unmedicated, 38 never medicated) and 12 healthy age-matched controls were evaluated with FDG PET CT. The patients met ICD-10 and DSM-IV criteria for schizophrenia, and all reported psychotic, "positive" symptoms when tested. RESULTS Schizophrenic patients with positive symptoms had a hypermetabolic frontal metabolic pattern on quantification by region to occipital ratio comparison. Associated statistically significant differences were also found when comparing ratios of occipital to thalamic, striatal and temporal cortex in schizophrenic patients. CONCLUSION The finding of a hyperfrontality in unmedicated and never medicated psychotic schizophrenic patients is observed when there is a predominance of positive symptoms. There could be a possible disruption of cortico-striato-thalamic feedback loops causing hyperfrontality as seen in experimentally induced models of psychosis .
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Abstract
Dopamine, a prominent neuromodulator, is implicated in many neuropsychiatric disorders. It has wide-ranging effects on both cortical and subcortical brain regions and on many types of cognitive tasks that rely on a variety of different learning and memory systems. As neuroscience and behavioral evidence for the existence of multiple memory systems and their corresponding neural networks accumulated, so did the notion that dopamine's role is markedly different depending on which memory system is engaged. As a result, dopamine-directed treatments will have different effects on different types of cognitive behaviors. To predict what these effects will be, it is critical to understand: which memory system is mediating the behavior; the neural basis of the mediating memory system; the nature of the dopamine projections into that system; and the time course of dopamine after its release into the relevant brain regions. Consideration of these questions leads to different predictions for how changes in brain dopamine levels will affect automatic behaviors and behaviors mediated by declarative, procedural, and perceptual representation memory systems.
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Affiliation(s)
- F Gregory Ashby
- Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA, USA
| | - Vivian V Valentin
- Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA, USA
| | - Stella S von Meer
- Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA, USA
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Spironelli C, Angrilli A. Language-related gamma EEG frontal reduction is associated with positive symptoms in schizophrenia patients. Schizophr Res 2015; 165:22-9. [PMID: 25913900 DOI: 10.1016/j.schres.2015.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 02/27/2015] [Accepted: 04/05/2015] [Indexed: 10/23/2022]
Abstract
OBJECTIVES Frontal hypoactivation has been consistently found in schizophrenia. We hypothesized that patients' deficit is asymmetrical, i.e., centred over the left frontal locations, associated with loss of language-related asymmetry, and correlated with positive symptoms. METHOD The amplitude of EEG gamma band (36-48Hz) was measured during the processing of three linguistic (Phonological vs. Semantic vs. Visuo-perceptual) tasks and used as index of activation/connectivity in 18 schizophrenia patients and 18 healthy participants. RESULTS Healthy controls showed higher gamma in frontal sites, revealing a significantly greater left vs. right asymmetry in all linguistic tasks, whereas patients exhibited decreased and bilateral gamma amplitude (i.e., reduced activation/connectivity) in frontal regions. The patients' left hypofrontality during phonological processing was positively correlated with higher levels of Delusions (P1) and Hallucination (P3) PANSS subscales. A significantly greater left posterior gamma amplitude was found in patients compared with controls. CONCLUSION Results suggest, in schizophrenia patients, a functional deficit of left frontal regions including Broca's area, a key site playing a fundamental hierarchical role between and within hemispheres which integrates many basic processes in linguistic and conceptual organization. The significant correlation between lack of the left anterior asymmetry and increased positive symptoms is in line with Crow's hypothesis postulating the aetiological role of disrupted linguistic frontal asymmetry on the onset of the key symptoms of schizophrenia.
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Affiliation(s)
- Chiara Spironelli
- Department of General Psychology, University of Padova, via Venezia 8, 35131 Padova, Italy; CCN, Center for Cognitive Neuroscience, via Venezia 8, 35131 Padova, Italy.
| | - Alessandro Angrilli
- Department of General Psychology, University of Padova, via Venezia 8, 35131 Padova, Italy; CCN, Center for Cognitive Neuroscience, via Venezia 8, 35131 Padova, Italy; CNR Neuroscience Institute, Padova Section, via G. Colombo 3, 35121 Padova, Italy
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45
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Hippocampal Pruning as a New Theory of Schizophrenia Etiopathogenesis. Mol Neurobiol 2015; 53:2065-2081. [PMID: 25902861 DOI: 10.1007/s12035-015-9174-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 04/13/2015] [Indexed: 12/20/2022]
Abstract
Pruning in neurons has been suggested to be strongly involved in Schizophrenia's (SKZ) etiopathogenesis in recent biological, imaging, and genetic studies. We investigated the impact of protein-coding genes known to be involved in pruning, collected by a systematic literature research, in shaping the risk for SKZ in a case-control sample of 9,490 subjects (Psychiatric Genomics Consortium). Moreover, their modifications through evolution (humans, chimpanzees, and rats) and subcellular localization (as indicative of their biological function) were also investigated. We also performed a biological pathways (Gene Ontology) analysis. Genetics analyses found four genes (DLG1, NOS1, THBS4, and FADS1) and 17 pathways strongly involved in pruning and SKZ in previous literature findings to be significantly associated with the sample under analysis. The analysis of the subcellular localization found that secreted genes, and so regulatory ones, are the least conserved through evolution and also the most associated with SKZ. Their cell line and regional brain expression analysis found that their areas of primary expression are neuropil and the hippocampus, respectively. At the best of our knowledge, for the first time, we were able to describe the SKZ neurodevelopmental hypothesis starting from a single biological process. We can also hypothesize how alterations in pruning fine regulation and orchestration, strongly related with the evolutionary newest (and so more sensitive) secreted proteins, may be of particular relevance in the hippocampus. This early alteration may lead to a mis-structuration of neural connectivity, resulting in the different brain alteration that characterizes SKZ patients.
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Baskak B, Baran Z, Ozguven HD, Karaboga I, Oner O, Ozel Kizil ET, Hosgoren Y. Prefrontal activity measured by functional near infrared spectroscopy during probabilistic inference in subjects with persecutory delusions. Schizophr Res 2015; 161:237-43. [PMID: 25439391 DOI: 10.1016/j.schres.2014.11.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 10/27/2014] [Accepted: 11/03/2014] [Indexed: 10/24/2022]
Abstract
Jumping to conclusions (JTC) is a probabilistic reasoning bias and is thought to contribute to delusion formation. Neurobiological correlates of the JTC bias are not known. We aimed to examine the rostral prefrontal cortex (rPFC) activity with functional near ınfrared spectroscopy during a modified version of the Beads in a Jar Task (BIJT) in subjects with persecutory delusions (N=25). In BIJT participants are presented beads either drawn from one of the two jars with opposite probability ratios (PRs) of colored beads and are required to decide from which jar beads are being drawn. We administered the BIJT with 90/10 and 55/45 PRs. Compared to healthy controls (N=20), patients reached a decision earlier in both conditions. While the medial rPFC regions were more active in the 90/10 condition in controls compared to patients, lateral rPFC activation was higher in the 55/45 condition in patients than controls. Only in the control group, there was a marked decline in the lateral rPFC activation in the 55/45 condition compared to the 90/10 condition. The activity in the lateral rPFC was negatively correlated with the amount of beads drawn in healthy controls but not in subjects with persecutory delusions. Our results suggest that during the BIJT, rPFC does not function as a single unit and rather consists of functional subunits that are organized differently in patients and controls. The failure to deactivate the lateral rPFC may be associated with earlier decisions in subjects with persecutory delusions.
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Affiliation(s)
- Bora Baskak
- Ankara University School of Medicine Psychiatry Department, Ankara University Brain Research Center, TR06590, Dikimevi, Ankara, Turkey.
| | - Zeynel Baran
- Hacettepe Universitesi Psikoloji Bölümü, Deneysel Psikoloji Laboratuarı, Beytepe, Ankara, Turkey.
| | - Halise Devrimci Ozguven
- Ankara University School of Medicine Psychiatry Department, Ankara University Brain Research Center, TR06590, Dikimevi, Ankara, Turkey.
| | - Isil Karaboga
- Ankara University School of Medicine Psychiatry Department, Ankara University Brain Research Center, TR06590, Dikimevi, Ankara, Turkey.
| | - Ozgur Oner
- Ankara Universitesi, Tip Fakultesi, Cebeci Hastanesi, Çocuk Ruh Sağlığı ve Hastalıkları Anabilim Dali, TR06590, Dikimevi, Ankara, Turkey.
| | - Erguvan Tugba Ozel Kizil
- Ankara University School of Medicine Psychiatry Department, Ankara University Brain Research Center, TR06590, Dikimevi, Ankara, Turkey.
| | - Yasemin Hosgoren
- Ankara University School of Medicine Psychiatry Department, Ankara University Brain Research Center, TR06590, Dikimevi, Ankara, Turkey.
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47
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Liemburg EJ, Dlabac-De Lange JJLAS, Bais L, Knegtering H, van Osch MJP, Renken RJ, Aleman A. Neural correlates of planning performance in patients with schizophrenia--relationship with apathy. Schizophr Res 2015; 161:367-75. [PMID: 25497221 DOI: 10.1016/j.schres.2014.11.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 11/06/2014] [Accepted: 11/22/2014] [Indexed: 11/15/2022]
Abstract
Patients with schizophrenia often suffer from apathy: a quantitative reduction of voluntary, goal-directed behaviors that impairs daily functioning. We hypothesized that schizophrenia patients with high levels of apathy would show decreased activation in brain regions involved in planning and goal-directed behavior. Patients with schizophrenia or psychotic spectrum disorder (n=47) and healthy controls (n=20) performed the Tower of London (ToL) task during fMRI scanning using arterial spin labeling. To investigate the relationship between apathy and planning in patients, a proxy measure of apathy based on the Positive and Negative syndrome Scale was regressed against the task-related brain activation. Brain activation was also compared between patients and healthy controls. Higher levels of apathy were associated with less task-related activation within the inferior parietal lobule precuneus and thalamus. Compared to controls, patients showed lower activation in lateral prefrontal regions, parietal and motor areas, and a higher activation of medial frontal areas. Apathy was related to abnormal activation in thalamus and parietal regions during the ToL task. This supports the hypothesis that impaired function of brain regions involved in planning and goal-directed behavior may underlie apathy in schizophrenia. Moreover, impaired lateral prefrontal activation in schizophrenia patients compared to controls is consistent with the hypofrontality model of schizophrenia. In contrast, stronger medial frontal activation in patients may be related to increased effort to perform a task with conflicting task solutions.
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Affiliation(s)
- Edith J Liemburg
- Department of Neuroscience, and BCN Neuroimaging Center, University of Groningen, University Medical Center Groningen, FA32, Antonius Deusinglaan 2, 9713 AW Groningen, The Netherlands; Rob Giel Research Centrum, University of Groningen, University Medical Center Groningen, CC72, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
| | - Jozarni J L A S Dlabac-De Lange
- Department of Neuroscience, and BCN Neuroimaging Center, University of Groningen, University Medical Center Groningen, FA32, Antonius Deusinglaan 2, 9713 AW Groningen, The Netherlands.
| | - Leonie Bais
- Department of Neuroscience, and BCN Neuroimaging Center, University of Groningen, University Medical Center Groningen, FA32, Antonius Deusinglaan 2, 9713 AW Groningen, The Netherlands; Lentis Research, Center for Mental Health, Hereweg 80, 9725 AG Groningen, The Netherlands.
| | - Henderikus Knegtering
- Department of Neuroscience, and BCN Neuroimaging Center, University of Groningen, University Medical Center Groningen, FA32, Antonius Deusinglaan 2, 9713 AW Groningen, The Netherlands; Rob Giel Research Centrum, University of Groningen, University Medical Center Groningen, CC72, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
| | - Matthias J P van Osch
- Department of Radiology, Leiden University Medical Center, Postzone C2S, Postbox 9600, 2300 RC, Leiden, The Netherlands.
| | - Remco J Renken
- Department of Neuroscience, and BCN Neuroimaging Center, University of Groningen, University Medical Center Groningen, FA32, Antonius Deusinglaan 2, 9713 AW Groningen, The Netherlands.
| | - André Aleman
- Department of Neuroscience, and BCN Neuroimaging Center, University of Groningen, University Medical Center Groningen, FA32, Antonius Deusinglaan 2, 9713 AW Groningen, The Netherlands; Department of Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS Groningen, The Netherlands.
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48
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Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr 2014; 19 Suppl 1:38-52; quiz 35-7, 53. [PMID: 25403863 DOI: 10.1017/s1092852914000601] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Since currently available antipsychotic medications predominantly treat hallucinations, delusions, disorganized thoughts and behavior, and related agitation/aggression, attention has traditionally been focused on managing positive symptoms. However, prominent negative symptoms and clinically relevant cognitive impairment affect approximately 40% and 80% of people with schizophrenia, respectively. Moreover, negative and cognitive symptoms are closely related to functional outcomes, and contribute substantially to the overall illness burden. Therefore, approaches to describe, measure, and manage these symptom domains are relevant. This article summarizes the phenomenology, prevalence, assessment, and treatment of negative and cognitive symptoms in patients with schizophrenia, including pharmacologic and nonpharmacologic management strategies that can be used in clinical care now, as well as pharmacologic approaches that are being tested. Currently, no approved treatments targeting negative or cognitive symptomatology in schizophrenia are available. It is hoped that progress in the understanding of the neurobiology of these important symptom domains of schizophrenia will help develop effective treatment strategies in the future. However, until this goal is achieved, clinicians should avoid therapeutic nihilism. Rather, the severity and impact of negative and cognitive symptoms should be determined, quantified, and monitored. Further, psychosocial treatments have shown therapeutic benefits. Thus, cognitive behavioral therapy, cognitive remediation, social skills training, and computer-assisted training programs should be offered in conjunction with antipsychotic treatment. Several non-antipsychotic augmentation strategies can be tried off-label. Treatment plans that incorporate currently available management options for negative and cognitive symptomatology in patients with schizophrenia should be adapted over time and based on the individual's needs, with the aim to enhance overall outcomes.
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Hornig T, Valerius G, Feige B, Bubl E, Olbrich HM, van Elst LT. Neuropsychological and cerebral morphometric aspects of negative symptoms in schizophrenia: negative symptomatology is associated with specific mnestic deficits in schizophrenic patients. BMC Psychiatry 2014; 14:326. [PMID: 25420531 PMCID: PMC4247219 DOI: 10.1186/s12888-014-0326-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 11/10/2014] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The prevalence of negative symptoms in schizophrenic patients seems to be an important indicator for treatment response and prognosis. Although negative symptoms have often been attributed to frontal lobe anomalies, neuropsychological and anatomical findings do not explicitly support this assumption. Since knowledge about the cerebral correlate of negative symptoms in schizophrenia might have a strong impact on therapeutic and psychopharmacological interventions, we aimed to answer this question by investigating the relationship between negative symptoms, neuropsychological functioning and cerebral volumes in schizophrenic patients. METHODS Twenty schizophrenic patients and 32 healthy controls were examined using a neuropsychological test battery for the assessment of temporal (mnestic) and frontal (executive) faculties. Volumetric measurements of temporal (hippocampus and amygdala) and frontal (orbitofrontal, dorsolateral prefrontal, and anterior cingulate area) brain areas were performed. Negative symptoms were assessed using the Scale for the Assessment of Negative Symptoms (SANS). RESULTS Schizophrenic patients performed worse than healthy controls in tests assessing verbal and visuospatial learning and memory functions and on the Stroop interference task. After dividing the schizophrenic group in patients with high and low SANS scores almost all of these deficits were restricted to the former group. There were no overall group differences regarding cerebral subarea volumes. Overall negative symptoms were significantly correlated with verbal memory functions but not with frontal lobe faculties. CONCLUSIONS Negative symptoms in schizophrenia could specifically associated with verbal memory deficits.
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Affiliation(s)
- Tobias Hornig
- Department for Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, Freiburg, 79104, Germany.
| | - Gabi Valerius
- Department for Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, Freiburg, 79104, Germany.
| | - Bernd Feige
- Department for Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, Freiburg, 79104, Germany.
| | - Emanuel Bubl
- Department for Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, Freiburg, 79104, Germany.
| | - Hans M Olbrich
- Department for Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, Freiburg, 79104, Germany.
| | - Ludger Tebartz van Elst
- Department for Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, Freiburg, 79104, Germany.
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50
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Cassaday HJ, Nelson AJD, Pezze MA. From attention to memory along the dorsal-ventral axis of the medial prefrontal cortex: some methodological considerations. Front Syst Neurosci 2014; 8:160. [PMID: 25249948 PMCID: PMC4157611 DOI: 10.3389/fnsys.2014.00160] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 08/15/2014] [Indexed: 12/16/2022] Open
Abstract
Distinctions along the dorsal-ventral axis of medial prefrontal cortex (mPFC), between anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) sub-regions, have been proposed on a variety of neuroanatomical and neurophysiological grounds. Conventional lesion approaches (as well as some electrophysiological studies) have shown that these distinctions relate to function in that a number behavioral dissociations have been demonstrated, particularly using rodent models of attention, learning, and memory. For example, there is evidence to suggest that AC has a relatively greater role in attention, whereas IL is more involved in executive function. However, the well-established methods of behavioral neuroscience have the limitation that neuromodulation is not addressed. The neurotoxin 6-hydroxydopamine has been used to deplete dopamine (DA) in mPFC sub-regions, but these lesions are not selective anatomically and noradrenalin is typically also depleted. Microinfusion of drugs through indwelling cannulae provides an alternative approach, to address the role of neuromodulation and moreover that of specific receptor subtypes within mPFC sub-regions, but the effects of such treatments cannot be assumed to be anatomically restricted either. New methodological approaches to the functional delineation of the role of mPFC in attention, learning and memory will also be considered. Taken in isolation, the conventional lesion methods which have been a first line of approach may suggest that a particular mPFC sub-region is not necessary for a particular aspect of function. However, this does not exclude a neuromodulatory role and more neuropsychopharmacological approaches are needed to explain some of the apparent inconsistencies in the results.
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Affiliation(s)
| | - Andrew J D Nelson
- School of Psychology, University of Nottingham Nottingham, UK ; School of Psychology, Cardiff University Cardiff, UK
| | - Marie A Pezze
- School of Psychology, University of Nottingham Nottingham, UK
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