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Teles M, Maximo JO, Lahti AC, Kraguljac NV. Topological Perturbations in the Functional Connectome Support the Deficit/Non-deficit Distinction in Antipsychotic Medication-Naïve First Episode Psychosis Patients. Schizophr Bull 2024; 50:839-847. [PMID: 38666705 PMCID: PMC11283198 DOI: 10.1093/schbul/sbae054] [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: 06/11/2024]
Abstract
BACKGROUND Heterogeneity in the etiology, pathophysiology, and clinical features of schizophrenia challenges clinicians and researchers. A helpful approach could be stratifying patients according to the presence or absence of clinical features of the deficit syndrome (DS). DS is characterized by enduring and primary negative symptoms, a clinically less heterogeneous subtype of the illness, and patients with features of DS are thought to present abnormal brain network characteristics, however, this idea has received limited attention. We investigated functional brain network topology in patients displaying deficit features and those who do not. DESIGN We applied graph theory analytics to resting-state functional magnetic resonance imaging data of 61 antipsychotic medication-naïve first episode psychosis patients, 18 DS and 43 non-deficit schizophrenia (NDS), and 72 healthy controls (HC). We quantified small-worldness, global and nodal efficiency measures, shortest path length, nodal local efficiency, and synchronization and contrasted them among the 3 groups. RESULTS DS presented decreased network integration and segregation compared to HC and NDS. DS showed lower global efficiency, longer global path lengths, and lower global local efficiency. Nodal efficiency was lower and the shortest path length was longer in DS in default mode, ventral attention, dorsal attention, frontoparietal, limbic, somatomotor, and visual networks compared to HC. Compared to NDS, DS showed lower efficiency and longer shortest path length in default mode, limbic, somatomotor, and visual networks. CONCLUSIONS Our data supports increasing evidence, based on topological perturbations of the functional connectome, that deficit syndrome may be a distinct form of the illness.
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Affiliation(s)
- Matheus Teles
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jose Omar Maximo
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Adrienne Carol Lahti
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nina Vanessa Kraguljac
- Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA
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Perez-Rando M, Penades-Gomiz C, Martinez-Marin P, García-Martí G, Aguilar EJ, Escarti MJ, Grasa E, Corripio I, Sanjuan J, Nacher J. Volume alterations of the hippocampus and amygdala in patients with schizophrenia and persistent auditory hallucinations. REVISTA DE PSIQUIATRIA Y SALUD MENTAL 2023:S1888-9891(23)00014-9. [PMID: 37495479 DOI: 10.1016/j.rpsm.2023.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/05/2022] [Accepted: 05/24/2023] [Indexed: 07/28/2023]
Abstract
INTRODUCTION Auditory hallucinations (AH) are one of the most prevalent symptoms of schizophrenia. They might cause several brain alterations, especially changes in the volumes of hippocampus and amygdala, regions related to the relay and processing of auditory cues and emotional memories. MATERIAL AND METHODS We have recruited 41 patients with schizophrenia and persistent AH, 35 patients without AH, and 55 healthy controls. Using their MRIs, we have performed semiautomatic segmentations of the hippocampus and amygdala using Freesurfer. We have also performed bilateral correlations between the total PSYRATS score and the volumes of affected subregions and nuclei. RESULTS In the hippocampus, we found bilateral increases in the volume of its hippocampal fissure and decreases in the right fimbria in patients with and without AH. The volume of the right hippocampal tail and left head of the granule cell layer from the dentate gyrus were decreased in patients with AH. In the amygdala, we found its left total volume was shrunk, and there was a decrease of its left accessory basal nucleus in patients with AH. CONCLUSIONS We have detected volume alterations of different limbic structures likely due to the presence of AH. The volumes of the right hippocampal tail and left head of the granule cell layer from the dentate gyrus, and total volume of the amygdala and its accessory basal nucleus, were only affected in patients with AH. Bilateral volume alterations in the hippocampal fissure and right fimbria seem inherent of schizophrenia and due to traits not contemplated in our research.
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Affiliation(s)
- Marta Perez-Rando
- Institute of Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Burjassot, Spain; Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Institute of Research of the Clinic Hospital from Valencia (INCLIVA), Valencia, Spain.
| | - Carlota Penades-Gomiz
- Institute of Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Pablo Martinez-Marin
- Institute of Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Gracián García-Martí
- Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Quironsalud Hospital, Valencia, Spain
| | - Eduardo J Aguilar
- Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Psychiatry Unit, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Maria J Escarti
- Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Institute of Research of the Clinic Hospital from Valencia (INCLIVA), Valencia, Spain; Psychiatry Unit, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Eva Grasa
- Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Mental Health, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Iluminada Corripio
- Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Mental Health, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain; Mental Health and Psychiatry Department, Vic Hospital Consortium, Catalonia, Spain
| | - Julio Sanjuan
- Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Psychiatry Unit, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Juan Nacher
- Institute of Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Burjassot, Spain; Spanish National Network for Research in Mental Health (CIBERSAM), Madrid, Spain; Institute of Research of the Clinic Hospital from Valencia (INCLIVA), Valencia, Spain.
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Li J, Zhang X, Yang H, Yang M, Sun H. Lack of correlation between hippocampal substructure atrophy and attention dysfunction in deficit schizophrenia. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2023; 9:24. [PMID: 37080983 PMCID: PMC10119300 DOI: 10.1038/s41537-023-00354-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 04/08/2023] [Indexed: 04/22/2023]
Abstract
Hippocampal abnormalities are an established finding in the neuroimaging study of schizophrenia. However, no studies have examined the possibility of regional hippocampal abnormalities specific to deficit schizophrenia (DS) and associations with the unique symptoms of this schizophrenia subtype. This study compared 33 DS and 39 non-deficit schizophrenia (NDS) patients and 38 healthy subjects for hippocampal subfield volumetry. Clinical symptoms were assessed by PANSS, cognition by the neurocognitive battery on the day of the MRI scan. The automatic hippocampal segmentation were preprocesses use FreeSurfer 7.2.0. Unfortunately, the associations between neurocognitive scores and hippocampal subfield volumes in the DS group were not significant after the Bonferroni correction. Our results did not support a causal relationship between hippocampal subregional atrophy and cognitive deficits in DS.
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Affiliation(s)
- Jin Li
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, 11 Guangqian Road, Suzhou, 215137, Jiangsu, China
| | - Xiaobin Zhang
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, 11 Guangqian Road, Suzhou, 215137, Jiangsu, China
| | - Haidong Yang
- Department of Psychiatry, The Fourth People's Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University, Lianyungang, 222003, PR China
| | - Man Yang
- Department of Psychiatry, The Fourth People's Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University, Lianyungang, 222003, PR China
| | - Hongyan Sun
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, 11 Guangqian Road, Suzhou, 215137, Jiangsu, China.
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King VL, Lahti AC, Maximo JO, ver Hoef LW, John S, Kraguljac NV. Contrasting Frontoparietal Network Connectivity in Antipsychotic Medication-Naive First-Episode Psychosis Patients Who Do and Do Not Display Features of the Deficit Syndrome. Schizophr Bull 2022; 48:1344-1353. [PMID: 35869578 PMCID: PMC9673254 DOI: 10.1093/schbul/sbac081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The deficit syndrome is a clinical subtype of schizophrenia that is characterized by enduring negative symptoms. Several lines of evidence point to frontoparietal involvement, but the frontoparietal control network (FPCN) and its subsystems (FPCNA and FPCNB) proposed by Yeo et al. have not been systematically characterized at rest in patients with the deficit syndrome. METHODS We used resting-state fMRI to investigate the FPCN and its subnetworks in 72 healthy controls and 65 antipsychotic medication-naive, first-episode psychosis patients (22 displayed deficit syndrome features, 43 did not). To assess whole-brain FPCN connectivity, we used the right posterior parietal cortex as the seed region. We then performed region of interest analyses in FPCN subsystems. RESULTS We found that patterns of FPCN dysconnectivity to the whole brain differed in patients who displayed deficit syndrome features compared with those who did not. Examining the FPCN on a more granular level revealed reduced within-FPCN(A) connectivity only in patients displaying deficit features. FPCNB connectivity did not differ between patient groups. DISCUSSION Here, we describe a neurobiological signature of aberrant FPCN connectivity in antipsychotic-naive, first-episode patients who display clinical features of the deficit syndrome. Importantly, frontoparietal subnetwork connectivity differentiated subgroups, where the FPCNA is selectively involved in patients with deficit features. Our findings add to the growing body of literature supporting a neurobiological distinction between two clinical subtypes of schizophrenia, which has the potential to be leveraged for patient stratification in clinical trials and the development of novel treatments.
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Affiliation(s)
- Victoria L King
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Adrienne C Lahti
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jose O Maximo
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lawrence W ver Hoef
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sooraj John
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nina V Kraguljac
- To whom correspondence should be addressed; Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, SC 501, 1720 7th Ave S, Birmingham, AL 35294-0017, USA; tel: 205-996-7171, e-mail:
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Hepdurgun C, Karakoc G, Polat I, Ozalay O, Eroglu S, Erdogan Y, Kitis O, Gonul AS. A longitudinal study of lateral ventricle volumes in deficit and non-deficit schizophrenia. Psychiatry Res Neuroimaging 2021; 313:111311. [PMID: 34052603 DOI: 10.1016/j.pscychresns.2021.111311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/01/2021] [Accepted: 05/11/2021] [Indexed: 10/21/2022]
Abstract
Although it is generally accepted that negative symptoms of schizophrenia are associated with larger lateral ventricles, this general assumption could not be validated in patients with primary negative symptoms. To elucidate this issue, we conducted a five-year longitudinal study, including deficit (n = 13) and non-deficit (n = 26) schizophrenia patients with healthy controls (n = 18). Analysis with linear mixed effects modeling showed that both the left and the right lateral ventricles of the deficit patients enlarged more than the non-deficit patients. Our results suggest that structural alterations in deficit patients might follow a different trajectory than those in non-deficit patients.
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Affiliation(s)
- Cenan Hepdurgun
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey
| | - Gulser Karakoc
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey
| | - Irmak Polat
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey; Department of Psychiatry, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Ozgun Ozalay
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Seda Eroglu
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey; Department of Psychology, Faculty of Letters, Dokuz Eylul University, Izmir, Turkey
| | - Yigit Erdogan
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey; Department of Drug Abuse, BATI Institute, Ege University, Izmir, Turkey
| | - Omer Kitis
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey; Department of Neuroradiology, School of Medicine Ege University, Izmir, Turkey
| | - Ali Saffet Gonul
- SoCAT Lab, Department of Psychiatry, School of Medicine, Ege University, Izmir, Turkey; Mercer University, School of Medicine, Department of Psychiatry and Behavioral Sciences Macon, GA, United States.
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Gerbaldo H, Georgi K, Pieschl D. The deficit syndrome in first-admission patients with psychotic and non-psychotic disorders. Eur Psychiatry 2020; 12:53-7. [DOI: 10.1016/s0924-9338(97)89642-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/1996] [Accepted: 12/04/1996] [Indexed: 11/16/2022] Open
Abstract
SummaryThe authors study the frequency of primary enduring negative symptoms in first-admission patients with schizophrenic and non-schizophrenic disorders. Carpenter's criteria for distinguishing the primary, enduring negative symptoms from the more transient negative symptoms (secondary to different factors) were applied. Furthermore, they compare negative symptom complexes between first-admission patients and patients with recurrent hospitalizations (within 5 years after first admission). There was a trend for patients with recurrent admissions to show more frequently a deficit syndrome than first-admission patients. Nevertheless, this difference was not significant (χ2 = 0.90). First-admission patients with deficit syndrome had significantly higher affective blunting (P < 0.05) and anhedonia (P < 0.001) than those with recurrent admissions. First-admission subjects with psychotic disorders had significantly higher frequency of deficit syndrome than those first-admission patients with non-psychotic disorders (P < 0.05). These results show that negative symptoms observed in first-admitted non-schizophrenic patients can also be enduring and primary. Thereby this work does not contribute to support the specificity of primary enduring negative symptoms for schizophrenia. Moreover, data suggest, that primary anhedonia and affective blunting can decrease within the first 5 years after discharge.
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Ahmed-Leitao F, Rosenstein D, Marx M, Young S, Korte K, Seedat S. Posttraumatic stress disorder, social anxiety disorder and childhood trauma: Differences in hippocampal subfield volume. Psychiatry Res Neuroimaging 2019; 284:45-52. [PMID: 30684895 DOI: 10.1016/j.pscychresns.2018.12.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 12/14/2018] [Accepted: 12/29/2018] [Indexed: 12/22/2022]
Abstract
Volume-based hippocampal findings in Social Anxiety Disorder (SAD) and Posttraumatic Stress Disorder (PTSD) have been inconsistent, with very little investigation of hippocampal subfields. We assessed the effects of early childhood trauma on hippocampal subfields in participants with SAD with and without early childhood trauma and PTSD, compared to healthy controls. The sample comprised 26 participants SAD with early childhood trauma, 22 participants with SAD without early childhood trauma, 17 with PTSD secondary to early childhood trauma and 25 control participants. We used Freesurfer version 6 to determine hippocampal subfield volumes. Findings included significant reduction in right parasubiculum volume between the PTSD group secondary to early childhood trauma and the SAD group without early childhood trauma, as well as a significant reduction in left HATA (Hippocampal Amygdala Transition Area) volume between PTSD with early childhood trauma compared to controls, as well as compared to SAD with early childhood trauma. These findings did withstand correction for multiple resting using the false discovery rate. Our findings of an association of reduced volumes in the parasubiculum and HATA regions with PTSD secondary to childhood trauma are interesting. Further work should investigate whether parasubiculum and HATA regional volume reductions in PTSD are a specific effect of early childhood trauma or a specific manifestation of PTSD pathology. Further work should also be undertaken to determine if hippocampal subfield atrophy is associated with SAD in the setting of early childhood maltreatment.
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Affiliation(s)
- Fatima Ahmed-Leitao
- South African Research Chairs Initiative (SARChI) in Posttraumatic Stress Disorder, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Tygerberg 8000, South Africa.
| | - David Rosenstein
- South African Research Chairs Initiative (SARChI) in Posttraumatic Stress Disorder, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Tygerberg 8000, South Africa
| | - Melanie Marx
- South African Research Chairs Initiative (SARChI) in Posttraumatic Stress Disorder, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Tygerberg 8000, South Africa
| | - Susanne Young
- South African Research Chairs Initiative (SARChI) in Posttraumatic Stress Disorder, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Tygerberg 8000, South Africa
| | - Kristina Korte
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, United States
| | - Soraya Seedat
- South African Research Chairs Initiative (SARChI) in Posttraumatic Stress Disorder, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Tygerberg 8000, South Africa
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Viviano JD, Buchanan RW, Calarco N, Gold JM, Foussias G, Bhagwat N, Stefanik L, Hawco C, DeRosse P, Argyelan M, Turner J, Chavez S, Kochunov P, Kingsley P, Zhou X, Malhotra AK, Voineskos AN. Resting-State Connectivity Biomarkers of Cognitive Performance and Social Function in Individuals With Schizophrenia Spectrum Disorder and Healthy Control Subjects. Biol Psychiatry 2018; 84:665-674. [PMID: 29779671 PMCID: PMC6177285 DOI: 10.1016/j.biopsych.2018.03.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 03/12/2018] [Accepted: 03/31/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Deficits in neurocognition and social cognition are drivers of reduced functioning in schizophrenia spectrum disorders, with potentially shared neurobiological underpinnings. Many studies have sought to identify brain-based biomarkers of these clinical variables using a priori dichotomies (e.g., good vs. poor cognition, deficit vs. nondeficit syndrome). METHODS We evaluated a fully data-driven approach to do the same by building and validating a brain connectivity-based biomarker of social cognitive and neurocognitive performance in a sample using resting-state and task-based functional magnetic resonance imaging (n = 74 healthy control participants, n = 114 persons with schizophrenia spectrum disorder, 188 total). We used canonical correlation analysis followed by clustering to identify a functional connectivity signature of normal and poor social cognitive and neurocognitive performance. RESULTS Persons with poor social cognitive and neurocognitive performance were differentiated from those with normal performance by greater resting-state connectivity in the mirror neuron and mentalizing systems. We validated our findings by showing that poor performers also scored lower on functional outcome measures not included in the original analysis and by demonstrating neuroanatomical differences between the normal and poorly performing groups. We used a support vector machine classifier to demonstrate that functional connectivity alone is enough to distinguish normal and poorly performing participants, and we replicated our findings in an independent sample (n = 75). CONCLUSIONS A brief functional magnetic resonance imaging scan may ultimately be useful in future studies aimed at characterizing long-term illness trajectories and treatments that target specific brain circuitry in those with impaired cognition and function.
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Affiliation(s)
- Joseph D Viviano
- Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario
| | - Robert W Buchanan
- Department of Psychiatry, Maryland Psychiatric Research Center, Catonsville, Maryland
| | - Navona Calarco
- Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario
| | - James M Gold
- Department of Psychiatry, Maryland Psychiatric Research Center, Catonsville, Maryland
| | - George Foussias
- Department of Psychiatry, University of Toronto, Toronto, Ontario
| | - Nikhil Bhagwat
- Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario; Computational Brain Anatomy Laboratory, Brain Imaging Center, Douglas Mental Health University Institute, Verdun, Quebec, Canada
| | - Laura Stefanik
- Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario
| | - Colin Hawco
- Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario; Department of Psychiatry, University of Toronto, Toronto, Ontario
| | - Pamela DeRosse
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, Manhasset; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, New York
| | - Miklos Argyelan
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, Manhasset; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, New York
| | - Jessica Turner
- Department of Psychology, Georgia State University, Atlanta, Georgia
| | - Sofia Chavez
- Department of Psychiatry, University of Toronto, Toronto, Ontario; MRI Unit, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario
| | - Peter Kochunov
- Department of Psychiatry, Maryland Psychiatric Research Center, Catonsville, Maryland
| | - Peter Kingsley
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, Manhasset; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, New York
| | - Xiangzhi Zhou
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, Manhasset; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, New York
| | - Anil K Malhotra
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, Manhasset; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, New York
| | - Aristotle N Voineskos
- Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario; Department of Psychiatry, University of Toronto, Toronto, Ontario.
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Moser DA, Doucet GE, Lee WH, Rasgon A, Krinsky H, Leibu E, Ing A, Schumann G, Rasgon N, Frangou S. Multivariate Associations Among Behavioral, Clinical, and Multimodal Imaging Phenotypes in Patients With Psychosis. JAMA Psychiatry 2018; 75. [PMID: 29516092 PMCID: PMC5875357 DOI: 10.1001/jamapsychiatry.2017.4741] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
IMPORTANCE Alterations in multiple neuroimaging phenotypes have been reported in psychotic disorders. However, neuroimaging measures can be influenced by factors that are not directly related to psychosis and may confound the interpretation of case-control differences. Therefore, a detailed characterization of the contribution of these factors to neuroimaging phenotypes in psychosis is warranted. OBJECTIVE To quantify the association between neuroimaging measures and behavioral, health, and demographic variables in psychosis using an integrated multivariate approach. DESIGN, SETTING, AND PARTICIPANTS This imaging study was conducted at a university research hospital from June 26, 2014, to March 9, 2017. High-resolution multimodal magnetic resonance imaging data were obtained from 100 patients with schizophrenia, 40 patients with bipolar disorder, and 50 healthy volunteers; computed were cortical thickness, subcortical volumes, white matter fractional anisotropy, task-related brain activation (during working memory and emotional recognition), and resting-state functional connectivity. Ascertained in all participants were nonimaging measures pertaining to clinical features, cognition, substance use, psychological trauma, physical activity, and body mass index. The association between imaging and nonimaging measures was modeled using sparse canonical correlation analysis with robust reliability testing. MAIN OUTCOMES AND MEASURES Multivariate patterns of the association between nonimaging and neuroimaging measures in patients with psychosis and healthy volunteers. RESULTS The analyses were performed in 92 patients with schizophrenia (23 female [25.0%]; mean [SD] age, 27.0 [7.6] years), 37 patients with bipolar disorder (12 female [32.4%]; mean [SD] age, 27.5 [8.1] years), and 48 healthy volunteers (20 female [41.7%]; mean [SD] age, 29.8 [8.5] years). The imaging and nonimaging data sets showed significant covariation (r = 0.63, P < .001), which was independent of diagnosis. Among the nonimaging variables examined, age (r = -0.53), IQ (r = 0.36), and body mass index (r = -0.25) were associated with multiple imaging phenotypes; cannabis use (r = 0.23) and other substance use (r = 0.33) were associated with subcortical volumes, and alcohol use was associated with white matter integrity (r = -0.15). Within the multivariate models, positive symptoms retained associations with the global neuroimaging (r = -0.13), the cortical thickness (r = -0.22), and the task-related activation variates (r = -0.18); negative symptoms were mostly associated with measures of subcortical volume (r = 0.23), and depression/anxiety was associated with measures of white matter integrity (r = 0.12). CONCLUSIONS AND RELEVANCE Multivariate analyses provide a more accurate characterization of the association between brain alterations and psychosis because they enable the modeling of other key factors that influence neuroimaging phenotypes.
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Affiliation(s)
- Dominik A. Moser
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gaelle E. Doucet
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Won Hee Lee
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alexander Rasgon
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hannah Krinsky
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Evan Leibu
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alex Ing
- Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
| | - Gunter Schumann
- Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
| | - Natalie Rasgon
- Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California,Center for Neuroscience in Women’s Health, Stanford University, Palo Alto, California
| | - Sophia Frangou
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
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Fujimaki K, Toki S, Yamashita H, Oyamada T, Yamawaki S. Predictors of negative symptoms in the chronic phase of schizophrenia: A cross-sectional study. Psychiatry Res 2018; 262:600-608. [PMID: 28965809 DOI: 10.1016/j.psychres.2017.09.051] [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: 04/29/2017] [Revised: 09/19/2017] [Accepted: 09/22/2017] [Indexed: 11/15/2022]
Abstract
This study was designed to investigate the relationship between negative symptoms and key indicators for long-term hospital stays among inpatients with schizophrenia. A further aim was to elucidate the clinical determinants of negative symptoms. The following were used as index factors: age, duration of illness, duration of hospitalization, age at onset, years of education, smoking status, body mass index, concentrations of serum triglycerides, total cholesterol, uric acid, QTc interval duration from electrocardiography, dose equivalents of antipsychotic and anticholinergic agents, neurocognitive function, drug-induced extrapyramidal symptoms, involuntary movements, and psychiatric symptoms. Spearman's rank correlation coefficients were calculated and regression analyses were performed to examine associations between these factors and negative symptoms. Positive symptoms correlated positively with negative symptoms as rated on the Brief Psychiatric Rating Scale. Age at onset correlated negatively with negative symptoms. Multiple regression analysis showed that dose equivalents of atypical antipsychotics and positive symptoms predicted negative symptoms. Increasing our understanding of these predictors as key indicators of the severity of negative symptoms may aid in the reconsideration of therapeutic programs for chronic schizophrenia.
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Affiliation(s)
- Koichiro Fujimaki
- Faculty of Health and Welfare, Prefectural University of Hiroshima, Mihara, Japan.
| | | | - Hidehisa Yamashita
- Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Shigeto Yamawaki
- Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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11
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Grey matter reduction in the caudate nucleus in patients with persistent negative symptoms: An ALE meta-analysis. Schizophr Res 2018; 192:9-15. [PMID: 28390850 DOI: 10.1016/j.schres.2017.04.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 03/20/2017] [Accepted: 04/01/2017] [Indexed: 10/19/2022]
Abstract
OBJECTIVES In the present study, we used Activation Likelihood Estimation (ALE) meta-analysis to quantitatively examine brain grey matter reduction in schizophrenia patients with persistent negative symptoms (PNS). METHOD A total of 12 voxel-based morphometry (VBM) studies were included in ALE meta-analysis using more stringent criterion of PNS. RESULTS Significant grey matter reduction in the PNS group relative to controls was observed in the left caudate nucleus, the left precentral region, the left middle frontal region, the bilateral parahippocampal region, the left anterior cingulate region, the bilateral medial frontal gyrus, the thalamus and the insula. CONCLUSION Our results suggest that brain regions in the reward network may be specifically related to PNS, especially the left caudate nucleus. It is possible that abnormality in reward processing may constitute the neural basis of PNS.
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12
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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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13
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Yu M, Dai Z, Tang X, Wang X, Zhang X, Sha W, Yao S, Shu N, Wang X, Yang J, Zhang X, Zhang X, He Y, Zhang Z. Convergence and Divergence of Brain Network Dysfunction in Deficit and Non-deficit Schizophrenia. Schizophr Bull 2017; 43:1315-1328. [PMID: 29036672 PMCID: PMC5737538 DOI: 10.1093/schbul/sbx014] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Deficit schizophrenia (DS), characterized by primary and enduring negative symptoms, has been considered as a pathophysiologically distinct schizophrenic subgroup. Neuroimaging characteristics of DS, especially functional brain network architecture, remain largely unknown. Resting-state functional magnetic resonance imaging and graph theory approaches were employed to investigate the topological organization of whole-brain functional networks of 114 male participants including 33 DS, 41 non-deficit schizophrenia (NDS) and 40 healthy controls (HCs). At the whole-brain level, both the NDS and DS group exhibited lower local efficiency (Eloc) than the HC group, implying the reduction of local specialization of brain information processing (reduced functional segregation). The DS, but not NDS group, exhibited enhanced parallel information transfer (enhanced functional integration) as determined by smaller characteristic path length (Lp) and higher global efficiency (Eglob). The Lp and Eglob presented significant correlations with Brief Psychiatric Rating Scale (BPRS) total score in the DS group. At the nodal level, both the NDS and DS groups showed higher functional connectivity in the inferior frontal gyrus and hippocampus, and lower connectivity in the visual areas and striatum than the controls. The DS group exhibited higher nodal connectivity in the right inferior temporal gyrus than the NDS and HC group. The diminished expression of Scale for the Assessment of Negative Symptoms (SANS) subfactors negatively correlated with nodal connectivity of right putamen, while asociality/amotivation positively correlated with right hippocampus across whole patients. We highlighted the convergence and divergence of brain functional network dysfunctions in patients with DS and NDS, which provides crucial insights into pathophysiological mechanisms of the 2 schizophrenic subtypes.
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Affiliation(s)
- Miao Yu
- Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhengjia Dai
- Department of Psychology, Sun Yat-sen University, Guangzhou, China,State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
| | - Xiaowei Tang
- Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, China
| | - Xiang Wang
- Medical Psychological Institute of the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaobin Zhang
- Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, China
| | - Weiwei Sha
- Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, China
| | - Shuqiao Yao
- Medical Psychological Institute of the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ni Shu
- State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
| | - Xindi Wang
- State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
| | - Jiaying Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, China
| | - Xiangyang Zhang
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX
| | - Xiangrong Zhang
- Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China,Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China,To whom correspondence should be addressed; Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, No.87 DingJiaQiao Road, Nanjing 210009, China; tel: 0086-25-822906586, fax:0086-25-83719457, e-mail:
| | - Yong He
- State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
| | - Zhijun Zhang
- Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China,Beijing Institute for Brain Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
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14
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Linking persistent negative symptoms to amygdala-hippocampus structure in first-episode psychosis. Transl Psychiatry 2017; 7:e1195. [PMID: 28786981 PMCID: PMC5611735 DOI: 10.1038/tp.2017.168] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/12/2017] [Accepted: 05/15/2017] [Indexed: 01/07/2023] Open
Abstract
Early persistent negative symptoms (PNS) following a first episode of psychosis (FEP) are linked to poor functional outcome. Reports of reduced amygdalar and hippocampal volumes in early psychosis have not accounted for heterogeneity of symptoms. Age is also seldom considered in this population, a factor that has the potential to uncover symptom-specific maturational biomarkers pertaining to volume and shape changes within the hippocampus and amygdala. T1-weighted volumes were acquired for early (N=21), secondary (N=30), non-(N=44) PNS patients with a FEP, and controls (N=44). Amygdalar-hippocampal volumes and surface area (SA) metrics were extracted with the Multiple Automatically Generated Templates (MAGeT)-Brain algorithm. Linear mixed models were applied to test for a main effect of group and age × group interactions. Early PNS patients had significantly reduced left amygdalar and right hippocampal volumes, as well as similarly lateralized negative age × group interactions compared to secondary PNS patients (P<0.017, corrected). Morphometry revealed decreased SA in early PNS compared with other patient groups in left central amygdala, and in a posterior region when compared with controls. Early and secondary PNS patients had significantly decreased SA as a function of age compared with patients without such symptoms within the right hippocampal tail (P<0.05, corrected). Significant amygdalar-hippocampal changes with age are linked to PNS after a FEP, with converging results from volumetric and morphometric analyses. Differential age trajectories suggest an aberrant maturational process within FEP patients presenting with PNS, which could represent dynamic endophenotypes setting these patients apart from their non-symptomatic peers. Studies are encouraged to parse apart such symptom constructs when examining neuroanatomical changes emerging after a FEP.
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15
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Mucci A, Merlotti E, Üçok A, Aleman A, Galderisi S. Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases. Schizophr Res 2017; 186:19-28. [PMID: 27242069 DOI: 10.1016/j.schres.2016.05.014] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 05/10/2016] [Accepted: 05/17/2016] [Indexed: 02/01/2023]
Abstract
Primary and persistent negative symptoms (PPNS) represent an unmet need in the care of people with schizophrenia. They have an unfavourable impact on real-life functioning and do not respond to available treatments. Underlying etiopathogenetic mechanisms of PPNS are still unknown. The presence of primary and enduring negative symptoms characterizes deficit schizophrenia (DS), proposed as a separate disease entity with respect to non-deficit schizophrenia (NDS). More recently, to reduce the heterogeneity of negative symptoms by using criteria easily applicable in the context of clinical trials, the concept of persistent negative symptoms (PNS) was developed. Both PNS and DS constructs include enduring negative symptoms (at least 6months for PNS and 12months for DS) that do not respond to available treatments. PNS exclude secondary negative symptoms based on a cross-sectional evaluation of severity thresholds on commonly used rating scales for positive symptoms, depression and extrapyramidal side effects; the DS diagnosis, instead, excludes all potential sources of secondary negative symptoms based on a clinical longitudinal assessment. In this paper we review the evolution of concepts and assessment modalities relevant to PPNS, data on prevalence of DS and PNS, as well as studies on clinical, neuropsychological, brain imaging electrophysiological and psychosocial functioning aspects of DS and PNS.
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Affiliation(s)
- Armida Mucci
- Department of Psychiatry, University of Naples SUN, Naples, Italy.
| | | | - Alp Üçok
- Department of Psychiatry, Psychotic Disorders Research Program, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - André Aleman
- University of Groningen, University Medical Center Groningen, Department of Neuroscience and Department of Psychology, Groningen, The Netherlands
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16
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Waltzman D, Knowlton BJ, Cohen JR, Bookheimer SY, Bilder RM, Asarnow RF. DTI microstructural abnormalities in adolescent siblings of patients with childhood-onset schizophrenia. Psychiatry Res Neuroimaging 2016; 258:23-29. [PMID: 27829189 DOI: 10.1016/j.pscychresns.2016.10.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 10/25/2016] [Accepted: 10/28/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Dana Waltzman
- War Related Illness and Injury Study Center, Veterans Affairs Palo Alto Health Care System (VAPAHCS), United States; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States.
| | | | - Jessica Rachel Cohen
- Department of Psychology and Neurosciences, University of North Carolina at Chapel Hill, United States
| | - Susan Yost Bookheimer
- David Geffen School of Medicine at University of California Los Angeles, United States
| | - Robert Martin Bilder
- David Geffen School of Medicine at University of California Los Angeles, United States
| | - Robert Franklin Asarnow
- Department of Psychology, University of California Los Angeles, United States; David Geffen School of Medicine at University of California Los Angeles, United States
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17
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De Rossi P, Dacquino C, Piras F, Caltagirone C, Spalletta G. Left nucleus accumbens atrophy in deficit schizophrenia: A preliminary study. Psychiatry Res Neuroimaging 2016; 254:48-55. [PMID: 27322868 DOI: 10.1016/j.pscychresns.2016.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 06/02/2016] [Accepted: 06/04/2016] [Indexed: 01/21/2023]
Abstract
A question that remains to be answered is whether schizophrenia can be characterized by a single etiopathophysiology or whether separate sub-syndromes should be differentiated to define specific mechanisms for each sub-type. Individuals affected by the deficit subtype of schizophrenia (DSZ) display avolitional/amotivational features that respond poorly to conventional treatments. Characterizing DSZ from a neuroanatomical point of view may help clarify this issue and develop new treatment strategies. To determine if DSZ is associated with structural alterations in specific deep grey matter structures linked to its key clinical features, 22 DSZ patients, 22 non-deficit schizophrenia (NDSZ) patients and 22 healthy controls (HC) were recruited for a case-control cross-sectional study. High-resolution magnetic resonance imaging was performed in all subjects and volumes of deep grey matter structures were measured using FreeSurfer. DSZ patients displayed smaller left accumbens volumes compared to both NDSZ patients and HC. Moreover, age and duration of illness were significantly associated with lower volume of the left accumbens in DSZ but not in NDSZ. Findings indicate that DSZ is associated with lower volume of the nucleus accumbens in the dominant hemisphere. This is consistent with the psychopathological features and functional impairments present in DSZ and thus indicates a potential mechanism.
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Affiliation(s)
- Pietro De Rossi
- Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy; Department NESMOS, Faculty of Medicine and Psychology, University "Sapienza" of Rome, Rome, Italy; Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
| | - Claudia Dacquino
- Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy; Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Italy
| | - Fabrizio Piras
- Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy
| | - Carlo Caltagirone
- Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy; Department of Neuroscience, "Tor Vergata" University, 00173, Rome, Italy
| | - Gianfranco Spalletta
- Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy; Beth K. and Stuart C. Yudofsky Division of Neuropsychiatry, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
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18
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Neurocognitive impairment in the deficit subtype of schizophrenia. Eur Arch Psychiatry Clin Neurosci 2016; 266:397-407. [PMID: 26260899 DOI: 10.1007/s00406-015-0629-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 08/03/2015] [Indexed: 12/26/2022]
Abstract
Schizophrenia is a heterogeneous disorder characterized by numerous diverse signs and symptoms. Individuals with prominent, persistent, and idiopathic negative symptoms are thought to encompass a distinct subtype of schizophrenia. Previous work, including studies involving neuropsychological evaluations, has supported this position. The present study sought to further examine whether deficit patients are cognitively distinct from non-deficit patients with schizophrenia. A comprehensive neurocognitive battery including tests of verbal memory, vigilance, processing speed, reasoning, and working memory was administered to 657 patients with schizophrenia. Of these, 144 (22 %) patients were classified as deficit patients using a proxy identification method based on severity, persistence over time, and possible secondary sources (e.g., depression) of negative symptoms. Deficit patients with schizophrenia performed worse on all tests of cognition relative to non-deficit patients. These patients were characterized by a generalized cognitive impairment on the order of about 0.4 standard deviations below that of non-deficit patients. However, when comparing deficit patients to non-deficit patients who also present with negative symptoms, albeit not enduring or primary, no group differences in cognitive performance were found. Furthermore, a discriminant function analysis classifying patients into deficit/non-deficit groups based on cognitive scores demonstrated only 62.3 % accuracy, meaning over one-third of individuals were misclassified. The deficit subtype of schizophrenia is not markedly distinct from non-deficit schizophrenia in terms of neurocognitive performance. While deficit patients tend to have poorer performance on cognitive tests, the magnitude of this effect is relatively modest, translating to over 70 % overlap in scores between groups.
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19
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Moustafa AA, Phillips J, Kéri S, Misiak B, Frydecka D. On the Complexity of Brain Disorders: A Symptom-Based Approach. Front Comput Neurosci 2016; 10:16. [PMID: 26941635 PMCID: PMC4763073 DOI: 10.3389/fncom.2016.00016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 02/05/2016] [Indexed: 12/27/2022] Open
Abstract
Mounting evidence shows that brain disorders involve multiple and different neural dysfunctions, including regional brain damage, change to cell structure, chemical imbalance, and/or connectivity loss among different brain regions. Understanding the complexity of brain disorders can help us map these neural dysfunctions to different symptom clusters as well as understand subcategories of different brain disorders. Here, we discuss data on the mapping of symptom clusters to different neural dysfunctions using examples from brain disorders such as major depressive disorder (MDD), Parkinson’s disease (PD), schizophrenia, posttraumatic stress disorder (PTSD) and Alzheimer’s disease (AD). In addition, we discuss data on the similarities of symptoms in different disorders. Importantly, computational modeling work may be able to shed light on plausible links between various symptoms and neural damage in brain disorders.
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Affiliation(s)
- Ahmed A Moustafa
- School of Social Sciences and Psychology, Western Sydney UniversitySydney, NSW, Australia; Marcs Institute for Brain and Behavior, Western Sydney UniversitySydney, NSW, Australia
| | - Joseph Phillips
- School of Social Sciences and Psychology, Western Sydney University Sydney, NSW, Australia
| | - Szabolcs Kéri
- Nyírö Gyula Hospital, National Institute of Psychiatry and Addictions Budapest, Hungary
| | - Blazej Misiak
- Department and Clinic of Psychiatry, Wroclaw Medical UniversityWroclaw, Poland; Department of Genetics, Wroclaw Medical UniversityWroclaw, Poland
| | - Dorota Frydecka
- Department and Clinic of Psychiatry, Wroclaw Medical University Wroclaw, Poland
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20
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Sarkar S, Hillner K, Velligan DI. Conceptualization and treatment of negative symptoms in schizophrenia. World J Psychiatry 2015; 5:352-361. [PMID: 26740926 PMCID: PMC4694548 DOI: 10.5498/wjp.v5.i4.352] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/07/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
Negative symptoms of schizophrenia including social withdrawal, diminished affective response, lack of interest, poor social drive, and decreased sense of purpose or goal directed activity predict poor functional outcomes for patients with schizophrenia. They may develop and be maintained as a result of structural and functional brain abnormalities, particularly associated with dopamine reward pathways and by environmental and psychosocial factors such as self-defeating cognitions and the relief from overstimulation that accompanies withdrawal from social and role functioning. Negative symptoms are more difficult to treat than the positive symptoms of schizophrenia and represent an unmet therapeutic need for large numbers of patients with schizophrenia. While antipsychotic medications to treat the symptoms of schizophrenia have been around for decades, they have done little to address the significant functional impairments in the disorder that are associated with negative symptoms. Negative symptoms and the resulting loss in productivity are responsible for much of the world-wide personal and economic burden of schizophrenia. Pharmacologic treatments may be somewhat successful in treating secondary causes of negative symptoms, such as antipsychotic side effects and depression. However, in the United States there are no currently approved treatments for severe and persistent negative symptoms (PNS) that are not responsive to treatments for secondary causes. Pharmacotherapy and psychosocial treatments are currently being developed and tested with severe and PNS as their primary targets. Academia, clinicians, the pharmaceutical industry, research funders, payers and regulators will need to work together to pursue novel treatments to address this major public health issue.
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21
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Khalil R, Abo Elfetoh N, Moftah MZ, Khedr EM. Acquired equivalence associative learning in GTC epileptic patients: experimental and computational study. Front Cell Neurosci 2015; 9:418. [PMID: 26578883 PMCID: PMC4621864 DOI: 10.3389/fncel.2015.00418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 10/02/2015] [Indexed: 12/24/2022] Open
Abstract
Previous cognitive behavioral studies based on Acquired Equivalence Associative learning Task (AEALT) showed a strong relation between hippocampus and basal ganglia in associative learning. However, experimental behavioral studies of patients with Generalized Tonic Clonic (GTC) epilepsy remained sparse. The aim of the present study is to integrate a classical behavioral cognitive analysis with a computational model approach to investigate cognitive associative learning impairments in patients with GTC epilepsy. We measured the accuracy of associative learning response performance in five GTC epileptic patients and five control subjects by using AEALT, all subjects were matched in age and gender. We ran the task using E-Prime, a neuropsychological software program, and SPSS for data statistical analysis. We tested whether GTC epileptic patients would have different learning performance than normal subjects, based on the degree and the location of impairment either in basal ganglia and/or hippocampus. With the number of patients that was available, our behavioral analysis showed no remarkable differences in learning performance of GTC patients as compared to their control subjects, both in the transfer and acquisition phases. In parallel, our simulation results confirmed strong connection and interaction between hippocampus and basal ganglia in our GTC and their control subjects. Nevertheless, the differences in neural firing rate of the connectionist model and weight update of basal ganglia were not significantly different between GTC and control subjects. Therefore, the behavioral analysis and the simulation data provided the same result, thus indicating that the computational model is likely to predict cognitive outcomes.
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Affiliation(s)
- Radwa Khalil
- Department of Cognitive Biology, Otto-von-Guericke Universität Magdeburg, Germany ; Department of Developmental Physiology, Institute of Physiology, Otto-von-Guericke Universität Magdeburg, Germany ; IMN - Institut des Maladies Neurodégénératives, University of Bordeaux Bordeaux, France
| | - Noha Abo Elfetoh
- Department of Neurology, Faculty of Medicine, Assiut University Assiut, Egypt
| | - Marie Z Moftah
- Department of Zoology, Faculty of Science, Alexandria University Alexandria, Egypt
| | - Eman M Khedr
- Department of Neurology, Faculty of Medicine, Assiut University Assiut, Egypt
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22
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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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23
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Yu M, Tang X, Wang X, Zhang X, Zhang X, Sha W, Yao S, Shu N, Zhang X, Zhang Z. Neurocognitive Impairments in Deficit and Non-Deficit Schizophrenia and Their Relationships with Symptom Dimensions and Other Clinical Variables. PLoS One 2015; 10:e0138357. [PMID: 26381645 PMCID: PMC4575183 DOI: 10.1371/journal.pone.0138357] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 08/28/2015] [Indexed: 11/18/2022] Open
Abstract
Background Deficit schizophrenia (DS) has been proposed as a pathophysiologically distinct subgroup within schizophrenia. Earlier studies focusing on neurocognitive function of DS patients have yielded inconsistent findings ranging from substantial deficits to no significant difference relative to non-deficit schizophrenia patients (NDS). The present study investigated the severity and characteristic patterns of neurocognitive impairments in DS and NDS patients and their relationships with clinical variables. Methods Attention, ideation fluency, cognitive flexibility and visuospatial memory function were assessed in 40 DS patients, 57 NDS patients, and 52 healthy controls by a comprehensive neuropsychological battery. Results Both schizophrenia subgroups had overall more severe cognitive impairments than controls while DS performed worse on every neuropsychological measure except the Stroop interference than the NDS patients with age and education as the covariates. Profile analysis found significantly different patterns of cognitive profiles between two patients group mainly due to their differences in attention and cognitive flexibility functions. Age, education, illness duration and negative symptoms were found to have the correlations with cognitive impairments in the NDS group, while only age and the negative symptoms were correlated with the cognitive impairments in the DS group. Multiple regression analyses revealed that sustained attention and cognitive flexibility were the core impaired cognitive domains mediating other cognitive functions in DS and NDS patients respectively. Conclusions DS patients exemplified worse in almost all cognitive domains than NDS patients. Sustained attention and cognitive flexibility might be the key impaired cognitive domains for DS and NDS patients respectively. The present study suggested the DS as a specific subgroup of schizophrenia.
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Affiliation(s)
- Miao Yu
- Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - XiaoWei Tang
- Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, Jiangsu, China
| | - Xiang Wang
- Medical Psychological Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - XiangRong Zhang
- Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
- Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
- * E-mail: (XRZ); (ZJZ)
| | - XiaoBin Zhang
- Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, Jiangsu, China
| | - WeiWei Sha
- Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, Jiangsu, China
| | - ShuQiao Yao
- Medical Psychological Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ni Shu
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China
| | - XiangYang Zhang
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, United States of America
| | - ZhiJun Zhang
- Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
- * E-mail: (XRZ); (ZJZ)
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Schizophrenia and bipolar disorder: The road from similarities and clinical heterogeneity to neurobiological types. Clin Chim Acta 2015; 449:49-59. [DOI: 10.1016/j.cca.2015.02.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 02/13/2015] [Indexed: 01/06/2023]
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25
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Lei W, Li N, Deng W, Li M, Huang C, Ma X, Wang Q, Guo W, Li Y, Jiang L, Zhou Y, Hu X, McAlonan GM, Li T. White matter alterations in first episode treatment-naïve patients with deficit schizophrenia: a combined VBM and DTI study. Sci Rep 2015; 5:12994. [PMID: 26257373 PMCID: PMC4530339 DOI: 10.1038/srep12994] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 07/06/2015] [Indexed: 02/05/2023] Open
Abstract
Categorizing ‘deficit schizophrenia’ (DS) as distinct from ‘non-deficit’ schizophrenia (NDS) may help reduce heterogeneity within schizophrenia. However, it is unknown if DS has a discrete white matter signature. Here we used MRI to compare white matter volume (voxel-based morphometry) and microstructural integrity (fractional anisotropy, FA) in first-episode treatment-naïve patients with DS and NDS and their unaffected relatives to control groups of similar age. We found that white matter disruption was prominent in DS compared to controls; the DS group had lower volumes in the cerebellum, bilateral extra-nuclear and bilateral frontoparietal regions, and lower FA in the body of corpus callosum, posterior superior longitudinal fasciculus and uncinate fasciculus. The DS group also had lower volume in bilateral extra-nuclear regions compared to NDS, and the volume of these clusters was negatively correlated with deficit symptom ratings. NDS patients however, had no significant volume alterations and limited disruption of microstructural integrity compared to controls. Finally, first-degree relatives of those with DS shared volume abnormalities in right extra-nuclear white matter. Thus, white matter pathology in schizophrenia is most evident in the deficit condition, and lower extra-nuclear white matter volumes in both DS patients and their relatives may represent a brain structural ‘endophenotype’ for DS.
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Affiliation(s)
- Wei Lei
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Na Li
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Wei Deng
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Mingli Li
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Chaohua Huang
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Xiaohong Ma
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Qiang Wang
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Wanjun Guo
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Yinfei Li
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Lijun Jiang
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Yi Zhou
- Department of Radiology, Hospital of Chengdu Office of People's Government of Tibetan autonomous Region, Branch Hospital of West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Xun Hu
- Huaxi Biobank, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
| | - Grainne Mary McAlonan
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK
| | - Tao Li
- The Mental Health Center &Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China
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26
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White matter alterations in first episode treatment-naïve patients with deficit schizophrenia: a combined VBM and DTI study. Sci Rep 2015. [PMID: 26257373 DOI: 10.1038/srep12994.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Categorizing 'deficit schizophrenia' (DS) as distinct from 'non-deficit' schizophrenia (NDS) may help reduce heterogeneity within schizophrenia. However, it is unknown if DS has a discrete white matter signature. Here we used MRI to compare white matter volume (voxel-based morphometry) and microstructural integrity (fractional anisotropy, FA) in first-episode treatment-naïve patients with DS and NDS and their unaffected relatives to control groups of similar age. We found that white matter disruption was prominent in DS compared to controls; the DS group had lower volumes in the cerebellum, bilateral extra-nuclear and bilateral frontoparietal regions, and lower FA in the body of corpus callosum, posterior superior longitudinal fasciculus and uncinate fasciculus. The DS group also had lower volume in bilateral extra-nuclear regions compared to NDS, and the volume of these clusters was negatively correlated with deficit symptom ratings. NDS patients however, had no significant volume alterations and limited disruption of microstructural integrity compared to controls. Finally, first-degree relatives of those with DS shared volume abnormalities in right extra-nuclear white matter. Thus, white matter pathology in schizophrenia is most evident in the deficit condition, and lower extra-nuclear white matter volumes in both DS patients and their relatives may represent a brain structural 'endophenotype' for DS.
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27
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Mørch-Johnsen L, Nesvåg R, Faerden A, Haukvik UK, Jørgensen KN, Lange EH, Andreassen OA, Melle I, Agartz I. Brain structure abnormalities in first-episode psychosis patients with persistent apathy. Schizophr Res 2015; 164:59-64. [PMID: 25818626 DOI: 10.1016/j.schres.2015.03.001] [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: 05/08/2014] [Revised: 03/02/2015] [Accepted: 03/02/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Apathy is an enduring and debilitating feature related to poor outcome in patients with first-episode psychosis (FEP). The biological underpinnings of apathy are unknown. We tested if FEP patients with persistent apathy (PA) differed from FEP patients without persistent apathy (NPA) in specific brain structure measures in the early phase of illness. METHODS A total of 70 Norwegian FEP patients were recruited within 1 year of first adequate treatment. They were defined as having PA (N=18) or NPA (N=52) based on Apathy Evaluation Scale score at baseline and 1 year later. MRI measures of cortical thickness and subcortical structure volumes were compared between the PA and NPA groups. RESULTS The PA group had significantly thinner left orbitofrontal cortex and left anterior cingulate cortex. The results remained significant after controlling for depressive symptoms and antipsychotic medication. DISCUSSION FEP patients with persistent apathy in the early phase of their illness show brain structural changes compared to FEP patients without persistent apathy. The changes are confined to regions associated with motivation, occur early in the disease course and appear selectively in PA patients when both groups are compared to healthy controls.
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Affiliation(s)
- Lynn Mørch-Johnsen
- Department of Psychiatric Research, Diakonhjemmet Hospital, 0319 Oslo, Norway; NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway.
| | - Ragnar Nesvåg
- Norwegian Institute of Public Health, 0403 Oslo, Norway
| | - Ann Faerden
- Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway
| | - Unn K Haukvik
- Department of Psychiatric Research, Diakonhjemmet Hospital, 0319 Oslo, Norway; NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
| | - Kjetil N Jørgensen
- Department of Psychiatric Research, Diakonhjemmet Hospital, 0319 Oslo, Norway; NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
| | - Elisabeth H Lange
- Department of Psychiatric Research, Diakonhjemmet Hospital, 0319 Oslo, Norway; NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
| | - Ole A Andreassen
- NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway
| | - Ingrid Melle
- NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway
| | - Ingrid Agartz
- Department of Psychiatric Research, Diakonhjemmet Hospital, 0319 Oslo, Norway; NORMENT and K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
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Spalletta G, De Rossi P, Piras F, Iorio M, Dacquino C, Scanu F, Girardi P, Caltagirone C, Kirkpatrick B, Chiapponi C. Brain white matter microstructure in deficit and non-deficit subtypes of schizophrenia. Psychiatry Res 2015; 231:252-261. [PMID: 25649975 DOI: 10.1016/j.pscychresns.2014.12.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/05/2014] [Accepted: 12/23/2014] [Indexed: 01/20/2023]
Abstract
Dividing schizophrenia into its deficit (SZD) and nondeficit (SZND) subtypes may help to identify specific and more homogeneous pathophysiological characteristics. Our aim was to define a whole brain voxelwise map specifically characterizing white matter tracts of schizophrenia patients with and without the deficit syndrome. We compared microstructural diffusion-related parameters as measured by diffusion tensor imaging in 21 SZD patients, 21 SZND patients, and 21 healthy controls, age- and gender-matched. Results showed that fractional anisotropy was reduced in the right precentral area in SZND patients, and in the left corona radiata of the schizophrenia group as a whole. Axial diffusivity was reduced in the left postcentral area of SZD patients and in the left cerebellum of the whole schizophrenia group. Radial diffusivity was increased in the left forceps minor of SZD patients, in the left internal capsule of SZND patients, and in the right inferior fronto-occipital fasciculus in the whole schizophrenia group. Mean diffusivity was increased from healthy controls to SZD patients to SZND patients in the right occipital lobe. In conclusion, SZD patients are not simply at the extreme end of a severity continuum of white matter disruption. Rather, the SZD and SZND subtypes are associated with distinct and specific brain microstructural anomalies that are consistent with their peculiar psychopathological dimensions.
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Affiliation(s)
- Gianfranco Spalletta
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
| | - Pietro De Rossi
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; NESMOS Department, Faculty of Medicine and Psychology, "Sapienza" University of Rome, Rome, Italy
| | - Fabrizio Piras
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Mariangela Iorio
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Claudia Dacquino
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Francesca Scanu
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Neurology and Psychiatry, Faculty of Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Paolo Girardi
- NESMOS Department, Faculty of Medicine and Psychology, "Sapienza" University of Rome, Rome, Italy
| | - Carlo Caltagirone
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Neuroscience, "Tor Vergata" University, Rome, Italy
| | - Brian Kirkpatrick
- Department of Psychiatry and Behavioral Science, University of Nevada School of Medicine, Reno, NV, USA
| | - Chiara Chiapponi
- Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy
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Wagshal D, Knowlton BJ, Cohen JR, Bookheimer SY, Bilder RM, Fernandez VG, Asarnow RF. Cognitive correlates of gray matter abnormalities in adolescent siblings of patients with childhood-onset schizophrenia. Schizophr Res 2015; 161:345-50. [PMID: 25541139 PMCID: PMC4405249 DOI: 10.1016/j.schres.2014.12.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 12/03/2014] [Accepted: 12/05/2014] [Indexed: 01/04/2023]
Abstract
Patients with childhood onset schizophrenia (COS) display widespread gray matter (GM) structural brain abnormalities. Healthy siblings of COS patients share some of these structural abnormalities, suggesting that GM abnormalities are endophenotypes for schizophrenia. Another possible endophenotype for schizophrenia that has been relatively unexplored is corticostriatal dysfunction. The corticostriatal system plays an important role in skill learning. Our previous studies have demonstrated corticostriatal dysfunction in COS siblings with a profound skill learning deficit and abnormal pattern of brain activation during skill learning. This study investigated whether structural abnormalities measured using volumetric brain morphometry (VBM) were present in siblings of COS patients and whether these were related to deficits in cognitive skill learning. Results revealed smaller GM volume in COS siblings relative to controls in a number of regions, including occipital, parietal, and subcortical regions including the striatum, and greater GM volume relative to controls in several subcortical regions. Volume in the right superior frontal gyrus and cerebellum were related to performance differences between groups on the weather prediction task, a measure of cognitive skill learning. Our results support the idea that corticostriatal and cerebellar impairment in unaffected siblings of COS patients are behaviorally relevant and may reflect genetic risk for schizophrenia.
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Affiliation(s)
- Dana Wagshal
- University of California San Francisco, United States.
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30
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Wagshal D, Knowlton BJ, Suthana NA, Cohen JR, Poldrack RA, Bookheimer SY, Bilder RM, Asarnow RF. Evidence for corticostriatal dysfunction during cognitive skill learning in adolescent siblings of patients with childhood-onset schizophrenia. Schizophr Bull 2014; 40:1030-9. [PMID: 24162516 PMCID: PMC4133665 DOI: 10.1093/schbul/sbt147] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Patients with schizophrenia perform poorly on cognitive skill learning tasks. This study is the first to investigate the neural basis of impairment in cognitive skill learning in first-degree adolescent relatives of patients with schizophrenia. We used functional magnetic resonance imaging to compare activation in 16 adolescent siblings of patients with childhood-onset schizophrenia (COS) and 45 adolescent controls to determine whether impaired cognitive skill learning in individuals with genetic risk for schizophrenia was associated with specific patterns of neural activation. The siblings of patients with COS were severely impaired on the Weather Prediction Task (WPT) and showed a relative deactivation in frontal regions and in the striatum after extensive training on the WPT compared with controls. These differences were not accounted for by performance differences in the 2 groups. The results suggest that corticostriatal dysfunction may be part of the liability for schizophrenia.
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Affiliation(s)
- Dana Wagshal
- Department of Neurology, University of California San Francisco, San Francisco, CA;
| | | | | | | | - Russel Alan Poldrack
- Departments of Psychology and Neurobiology, Imaging Research Center, University of Texas at Austin, Austin, TX
| | - Susan Yost Bookheimer
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA
| | - Robert Martin Bilder
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA
| | - Robert Franklin Asarnow
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA
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31
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Hirjak D, Wolf RC, Koch SC, Mehl L, Kelbel JK, Kubera KM, Traeger T, Fuchs T, Thomann PA. Neurological abnormalities in recent-onset schizophrenia and asperger-syndrome. Front Psychiatry 2014; 5:91. [PMID: 25147527 PMCID: PMC4123603 DOI: 10.3389/fpsyt.2014.00091] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 07/14/2014] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Neurological abnormalities including a variety of subtle deficits such as discrete impairments in sensory integration, motor coordination (MOCO), and sequencing of complex motor acts are frequently found in patients with schizophrenia (SZ) and commonly referred to as neurological soft signs (NSS). Asperger-syndrome (AS) is characterized by sensory-motor difficulties as well. However, the question whether the two disorders share a common or a disease-specific pattern of NSS remains unresolved. METHOD A total of 78 age- and education-matched participants [26 patients with recent-onset SZ, 26 individuals with AS, and 26 healthy controls (HC)] were recruited for the study. Analyses of covariance (ANCOVAs), with age, years of education, and medication included as covariates, were used to examine group differences on total NSS and the five subscale scores. Discriminant analyses were employed to identify the NSS subscales that maximally discriminate between the three groups. RESULTS Significant differences among the three groups were found in NSS total score and on the five NSS subscales. The clinical groups differed significantly in the NSS subscale MOCO. The correct discriminant rate between patients with SZ and individuals with AS was 61.5%. The correct discriminant rate was 92.3% between individuals with AS and HC, and 80.8% between SZ patients and HC, respectively. CONCLUSION Our findings provide new evidence for the presence of NSS in AS and lend further support to previously reported difficulties in movement control in this disorder. According to the present results, SZ and AS seem to be characterized by both quantitative and qualitative NSS expression.
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Affiliation(s)
- Dusan Hirjak
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
| | - Robert Christian Wolf
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
- Department of Psychiatry, Psychotherapy and Psychosomatics, Saarland University, Homburg, Germany
| | - Sabine C. Koch
- Department of Dance Movement Therapy, Faculty of Therapeutic Sciences, SRH University Heidelberg, Heidelberg, Germany
| | - Laura Mehl
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
| | - Janna K. Kelbel
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
| | - Katharina Maria Kubera
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
| | - Tanja Traeger
- Personality, Psychological Assessment, and Psychological Methods, Department of Psychology, University of Koblenz Landau, Landau, Germany
| | - Thomas Fuchs
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
| | - Philipp Arthur Thomann
- Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
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Motor Abnormalities and Basal Ganglia in Schizophrenia: Evidence from Structural Magnetic Resonance Imaging. Brain Topogr 2014; 28:135-52. [DOI: 10.1007/s10548-014-0377-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 05/10/2014] [Indexed: 12/13/2022]
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33
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Hovington CL, Lepage M. Neurocognition and neuroimaging of persistent negative symptoms of schizophrenia. Expert Rev Neurother 2014; 12:53-69. [DOI: 10.1586/ern.11.173] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Gruber O, Chadha Santuccione A, Aach H. Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system. Front Psychiatry 2014; 5:32. [PMID: 24765078 PMCID: PMC3982059 DOI: 10.3389/fpsyt.2014.00032] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 03/14/2014] [Indexed: 01/27/2023] Open
Abstract
Schizophrenia is characterized by positive, negative, and cognitive symptoms. While positive symptoms occur periodically during psychotic exacerbations, negative and cognitive symptoms often emerge before the first psychotic episode and persist with low functional outcome and poor prognosis. This review article outlines the importance of modern functional magnetic resonance imaging techniques for developing a stratified therapy of schizophrenic disorders. Functional neuroimaging evidence on the neural correlates of positive and particularly negative symptoms and cognitive deficits in schizophrenic disorders is briefly reviewed. Acute dysregulation of dopaminergic neurotransmission is crucially involved in the occurrence of psychotic symptoms. However, increasing evidence also implicates glutamatergic pathomechanisms, in particular N-methyl-d-aspartate (NMDA) receptor dysfunction in the pathogenesis of schizophrenia and in the appearance of negative symptoms and cognitive dysfunctions. In line with this notion, several gene variants affecting the NMDA receptor's pathway have been reported to increase susceptibility for schizophrenia, and have been investigated using the imaging genetics approach. In recent years, several attempts have been made to develop medications modulating the glutamatergic pathway with modest evidences for efficacy. The most successful approaches were those that aimed at influencing this pathway using compounds that enhance NMDA receptor function. More recently, the selective glycine reuptake inhibitor bitopertin has been shown to improve NMDA receptor hypofunction by increasing glycine concentrations in the synaptic cleft. Further research is required to test whether pharmacological agents with effects on the glutamatergic system can help to improve the treatment of negative symptoms in schizophrenic disorders.
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Affiliation(s)
- Oliver Gruber
- Center for Translational Research in Systems Neuroscience and Psychiatry, Clinic for Psychiatry and Psychotherapy, University Medical Center Göttingen , Göttingen , Germany
| | | | - Helmut Aach
- Medical Affairs - Psychiatry, Roche Pharma AG , Grenzach-Wyhlen , Germany
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Fervaha G, Remington G. Neuroimaging findings in schizotypal personality disorder: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43:96-107. [PMID: 23220094 DOI: 10.1016/j.pnpbp.2012.11.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Revised: 11/10/2012] [Accepted: 11/28/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND Schizotypal personality disorder is the prototypical schizophrenia-spectrum condition, sharing similar phenomenological, cognitive, genetic, physiological, neurochemical, neuroanatomical and neurofunctional abnormalities with schizophrenia. Investigations into SPD circumvent many confounds inherent to schizophrenia such as medication and institutionalization. Hence, SPD offers a unique vantage point from which to study schizophrenia-spectrum conditions. METHODS We systematically reviewed the neuroimaging literature in SPD to establish: (1) whether there are concordant findings in SPD and schizophrenia, possibly reflective of core pathology between the two conditions and (2) whether there are discordant findings in SPD and schizophrenia, possibly reflecting protective factors in the former. The findings are synthesized across structural and functional neuroimaging domains. RESULTS A total of 54 studies were identified. Medial temporal lobe structures seem to be compromised in both SPD and schizophrenia. In schizophrenia prefrontal structures are further compromised, whereas in SPD these seem to be larger-than-normal, possibly reflecting a compensatory mechanism. Additional pathology is discussed, including evidence of aberrant subcortical dopaminergic functioning. CONCLUSIONS SPD is a schizophrenia-spectrum condition that shares pathology with schizophrenia, but is distinct in showing unique neural findings. Future studies are needed to confirm and localize regions of common and disparate pathology between SPD and schizophrenia.
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Affiliation(s)
- Gagan Fervaha
- Schizophrenia Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
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Li Z, Zheng B, Deng W, Liu X, Zheng Z, Li T. Multi-components of evoked-brain potentials in deficit and nondeficit schizophrenia. Asia Pac Psychiatry 2013; 5:69-79. [PMID: 23857807 DOI: 10.1111/appy.12030] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 12/02/2012] [Indexed: 02/05/2023]
Abstract
INTRODUCTION The present study aims to detect the specific and common impairment index relative to evoked brain potentials (EBPS ) in deficit schizophrenia (DS) and nondeficit schizophrenia (NDS), and investigates the relationship between EBPs and clinical variables. METHODS The study used EBPs in 21 patients with DS, 38 patients with NDS, and 50 healthy controls (HCs) to investigate P300 waves, mismatch negative (MMN), sensory gating (SG) P50 and contingent negative variation (CNV). A comparison of three groups and the relationship between EBPs and clinical variables were performed using general linear model analyses and partial correlation, respectively. RESULTS Compared with HCs, both groups of patients showed delayed N1 , N2 , and P3a latency, and reduced N1 and N2 amplitude. The MMN showed delayed latency. The P50 ratios and the inhibited ratios were impaired, whereas SG loss ratios increased. CNV amplitude was reduced. Compared with HCs, NDS showed delayed latency of S2'-C in CNV, whereas DS showed shortened latency. Only NDS, when compared with HCs, showed delayed latency of P3b , Also, only DS, when compared with HCs, showed delayed latency of point A in CNV. Latency of point A in CNV of DS, correlated with a poorer Global Assessment of Functioning Scale (6 weeks) and was independent of clinical characteristics. DISCUSSION Schizophrenia represents a clinical syndrome with shared impairments in brain function, whereas DS is a relatively homogeneous subgroup of schizophrenia with unique pathophysiological changes.
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Affiliation(s)
- Zhe Li
- Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Orbitofrontal cortex abnormality and deficit schizophrenia. Schizophr Res 2013; 143:246-52. [PMID: 23228712 DOI: 10.1016/j.schres.2012.11.015] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 11/02/2012] [Accepted: 11/16/2012] [Indexed: 11/20/2022]
Abstract
Deficit syndrome, which is characterized by primary and enduring negative symptoms, is a homogeneous subtype within schizophrenia. Negative symptoms in schizophrenia are currently considered to be closely linked with frontal lobe impairment. However, the etiology in the frontal lobe of people with deficit syndrome is not fully understood. We measured regional cerebral blood flow (rCBF) with single photon emission computed tomography (SPECT) in 33 patients with deficit syndrome, 40 patients with nondeficit syndrome, and 45 healthy controls, and we compared groups using the voxel-wise method. Schizophrenia combined group, the deficit syndrome and the nondeficit syndrome presented hypoperfusion in mainly the medial and lateral prefrontal cortices. The deficit syndrome group showed a significant decrease in rCBF in the right orbitofrontal cortex (OFC) compared to the nondeficit group. These results demonstrated that at-rest hypofrontality was a common feature within the disease group and suggested that the OFC might play an important role in the development of severe negative symptoms in people with deficit syndrome.
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Wagshal D, Knowlton BJ, Cohen JR, Poldrack RA, Bookheimer SY, Bilder RM, Fernandez VG, Asarnow RF. Deficits in probabilistic classification learning and liability for schizophrenia. Psychiatry Res 2012; 200:167-72. [PMID: 22763090 PMCID: PMC5332149 DOI: 10.1016/j.psychres.2012.06.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 06/08/2012] [Accepted: 06/10/2012] [Indexed: 10/28/2022]
Abstract
Patients with schizophrenia show deficits in skill learning. We tested the hypothesis that impaired skill learning is associated with liability for schizophrenia by determining if it is present in non-affected siblings of patients. This study examined cognitive skill learning in adolescent siblings of patients with childhood onset schizophrenia (COS), who are at high genetic risk for the disorder, and age-matched controls. A probabilistic classification task was used to assess cognitive skill learning, which has been shown to be impaired in patients with striatal dysfunction or schizophrenia. Differences between the groups emerged within the first 50 trials of training: the controls showed significant learning while the COS siblings did not. Furthermore, after extended training over 800 additional trials the siblings of COS probands reached a lower level of asymptotic performance than controls. These results suggest that a behavioral impairment in probabilistic classification learning in healthy, unaffected siblings mirrors the deficits seen in patients and thus may reflect genetic liability for the disease.
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Affiliation(s)
- Dana Wagshal
- University of California Los Angeles, CA 90095, United States.
| | | | | | - Russell Alan Poldrack
- Imaging Research Center and Departments of Psychology and Neurobiology at University of Texas at Austin, United States
| | - Susan Yost Bookheimer
- David Geffen School of Medicine at University of California Los Angeles, United States
| | - Robert Martin Bilder
- David Geffen School of Medicine at University of California Los Angeles, United States
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Dorsolateral prefrontal cortex volume in patients with deficit or nondeficit schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2012; 37:264-9. [PMID: 22349577 DOI: 10.1016/j.pnpbp.2012.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Revised: 01/30/2012] [Accepted: 02/05/2012] [Indexed: 12/28/2022]
Abstract
Deficit schizophrenia (DS) represents a promising putative clinical subtype of schizophrenia and is characterized by the presence of primary and enduring negative symptoms. Previous studies have often reported a reduced amount of gray matter within prefrontal and temporal cortices in schizophrenia subjects with prevailing negative symptoms; however, the evidence concerning brain structural abnormalities in patients with DS remains controversial. The aim of the present study was to investigate whether patients with DS differed from those with nondeficit schizophrenia (NDS) with respect to the volume of the dorsolateral prefrontal cortex (DLPFC) and hippocampus, two brain areas considered as key regions in the pathogenesis of schizophrenia. In the present study a 3D-T1w MR imaging procedure and an extensive clinical assessment was carried out in 18 patients with schizophrenia, (10 DS and 8 NDS). 3D MPRAGE images were preprocessed with SPM software and two regions of interest (hippocampus and DLPFC) were manually traced to obtain their gray matter volumes. We found a significant reduction of DLPFC in the entire schizophrenia group, with respect to healthy subjects. Although the subgroup of patients with DS had a more severe clinical picture and more impaired social functioning, the DLPFC volume reduction was greater in NDS than in DS patients. In conclusion, according to our structural neuroimaging findings, DS patients, although characterized by a more severe clinical picture and a worse outcome, show less neurobiological abnormalities.
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Fischer BA, Keller WR, Arango C, Pearlson G, McMahon RP, Meyer WA, Francis A, Kirkpatrick B, Carpenter WT, Buchanan RW. Cortical structural abnormalities in deficit versus nondeficit schizophrenia. Schizophr Res 2012; 136:51-4. [PMID: 22336954 PMCID: PMC3298625 DOI: 10.1016/j.schres.2012.01.030] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 01/23/2012] [Accepted: 01/25/2012] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To examine the structural integrity of the dorsolateral prefrontal-basal ganglia-thalamocortical circuit in people with the deficit form of schizophrenia. METHOD A three-dimensional structural MRI sequence was used to conduct morphometric assessments of cortical and subcortical regions in deficit and nondeficit outpatients with schizophrenia and healthy controls. RESULTS The superior prefrontal and superior and middle temporal gyral gray matter volumes were significantly smaller in the deficit versus the nondeficit group and normal control groups. There were no significant group differences in examined subcortical structures. CONCLUSION People with deficit schizophrenia are characterized by selective reductions in the prefrontal and temporal cortex.
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Affiliation(s)
- Bernard A. Fischer
- Veterans Affairs Capital Network (VISN 5) Mental Illness Research, Education, and Clinical Center (MIRECC), Baltimore, Maryland, USA.,Maryland Psychiatric Research Center, University Of Maryland School of Medicine, Baltimore, Maryland, USA
| | - William R. Keller
- Maryland Psychiatric Research Center, University Of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Celso Arango
- Departmento de Psiquiatria, Hospital General Universitario Gregorio Marañón, CIBERSAM, Madrid, Spain
| | - Godfrey Pearlson
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
| | - Robert P. McMahon
- Maryland Psychiatric Research Center, University Of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Walter A. Meyer
- Maryland Psychiatric Research Center, University Of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Alan Francis
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Brian Kirkpatrick
- Department of Psychiatry and Behavioral Science, Texas A&M Health Science Center-College of Medicine, Temple, Texas, USA
| | - William T. Carpenter
- Veterans Affairs Capital Network (VISN 5) Mental Illness Research, Education, and Clinical Center (MIRECC), Baltimore, Maryland, USA.,Maryland Psychiatric Research Center, University Of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Robert W. Buchanan
- Maryland Psychiatric Research Center, University Of Maryland School of Medicine, Baltimore, Maryland, USA.,Corresponding Author Address: Robert W. Buchanan, M.D., Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228, , phone: 410.402.7876, fax: 410.402.7198
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Benoit A, Bodnar M, Malla AK, Joober R, Lepage M. The structural neural substrates of persistent negative symptoms in first-episode of non-affective psychosis: a voxel-based morphometry study. Front Psychiatry 2012; 3:42. [PMID: 22586412 PMCID: PMC3346965 DOI: 10.3389/fpsyt.2012.00042] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 04/19/2012] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVES An important subset of patients with schizophrenia present clinically significant persistent negative symptoms (PNS). Identifying the neural substrates of PNS could help improve our understanding and treatment of these symptoms. METHODS This study included 64 non-affective first-episode of psychosis (FEP) patients and 60 healthy controls; 16 patients displayed PNS (i.e., at least one primary negative symptom at moderate or worse severity sustained for at least six consecutive months). Using voxel-based morphometry (VBM), we explored for gray matter differences between PNS and non-PNS patients; patient groups were also compared to controls. All comparisons were performed at p < 0.05, corrected for multiple comparisons. RESULTS PNS patients had smaller gray matter in the right frontal medial-orbital gyrus (extending into the inferior frontal gyrus) and right parahippocampal gyrus (extending into the fusiform gyrus) compared to non-PNS patients. Compared to controls, PNS patients had smaller gray matter in the right parahippocampal gyrus (extending into the fusiform gyrus and superior temporal gyrus); non-PNS patients showed no significant differences to controls. CONCLUSION Neural substrates of PNS are evident in FEP patients. A better understanding of the neural etiology of PNS may encourage the search for new medications and/or alternative treatments to better help those affected.
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Affiliation(s)
- Audrey Benoit
- Brain Imaging Group, Douglas Mental Health University Institute Verdun, QC, Canada
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Optimized voxel brain morphometry: association between brain volumes and the response to atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci 2011; 261:407-16. [PMID: 21191610 DOI: 10.1007/s00406-010-0182-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Accepted: 12/15/2010] [Indexed: 01/18/2023]
Abstract
To date, few studies have addressed the relationship between brain structure alterations and responses to atypical antipsychotics in schizophrenia. To this end, in this study, magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to assess the relationship between the brain volumes of gray (GM) and white (WM) matters and the clinical response to risperidone or olanzapine in 30 schizophrenia patients. In comparison with healthy controls, the patients in this study showed a bilateral decrease in the anteromedial cerebellar hemispheres, the rectal gyrus and the insula, together with bilateral increases in GM in the basal ganglia. Both patient groups had a significantly smaller volume of WM in a region encompassing the internal and external capsules as compared to the controls. We found an inverse association between striatal size and the degree of clinical improvement, and a direct association between the degree of insular volume deficit and its improvement. The non-responder patient group showed a significant decrease in their left rectal gyrus as compared with the responder group. This study reveals a pattern of structural alterations in schizophrenia associated with the response to risperidone or olanzapine.
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Keller WR, Fischer BA, Carpenter WT. Revisiting the diagnosis of schizophrenia: where have we been and where are we going? CNS Neurosci Ther 2011; 17:83-8. [PMID: 21199450 PMCID: PMC6493851 DOI: 10.1111/j.1755-5949.2010.00229.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Appropriate and reliable classification of mental illness is crucial for advancing the field of psychiatry as agreement on diagnosis has broad implications for treatment of mental disorders and research into the etiopathophysiology of mental disorders. Since schizophrenia was first recognized by Kraepelin (as dementia praecox), there has been much discussion about what does and does not diagnostically constitute the disorder. The importance placed upon different symptoms and course types associated with schizophrenia has been as heterogeneous as the disorder itself. This article focuses upon the classification of schizophrenia over the last 100 years, the current diagnosis of schizophrenia, changes for schizophrenia planned in the upcoming DSM 5, future directions for improving the diagnosis of schizophrenia, and the implications of a new diagnostic paradigm for the illness.
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Affiliation(s)
- William R Keller
- Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Moustafa AA, Gluck MA. Computational cognitive models of prefrontal-striatal-hippocampal interactions in Parkinson's disease and schizophrenia. Neural Netw 2011; 24:575-91. [PMID: 21411277 DOI: 10.1016/j.neunet.2011.02.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Revised: 01/22/2011] [Accepted: 02/17/2011] [Indexed: 11/29/2022]
Abstract
Disruption to different components of the prefrontal cortex, basal ganglia, and hippocampal circuits leads to various psychiatric and neurological disorders including Parkinson's disease (PD) and schizophrenia. Medications used to treat these disorders (such as levodopa, dopamine agonists, antipsychotics, among others) affect the prefrontal-striatal-hippocampal circuits in a complex fashion. We have built models of prefrontal-striatal and striatal-hippocampal interactions which simulate cognitive dysfunction in PD and schizophrenia. In these models, we argue that the basal ganglia is key for stimulus-response learning, the hippocampus for stimulus-stimulus representational learning, and the prefrontal cortex for stimulus selection during learning about multidimensional stimuli. In our models, PD is associated with reduced dopamine levels in the basal ganglia and prefrontal cortex. In contrast, the cognitive deficits in schizophrenia are associated primarily with hippocampal dysfunction, while the occurrence of negative symptoms is associated with frontostriatal deficits in a subset of patients. In this paper, we review our past models and provide new simulation results for both PD and schizophrenia. We also describe an extended model that includes simulation of the different functional role of D1 and D2 dopamine receptors in the basal ganglia and prefrontal cortex, a dissociation we argue is essential for understanding the non-uniform effects of levodopa, dopamine agonists, and antipsychotics on cognition. Motivated by clinical and physiological data, we discuss model limitations and challenges to be addressed in future models of these brain disorders.
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Affiliation(s)
- Ahmed A Moustafa
- Center for Molecular and Behavioral Neuroscience, Rutgers University-Newark, Newark, New Jersey 07102, USA.
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Cascella NG, Fieldstone SC, Rao VA, Pearlson GD, Sawa A, Schretlen DJ. Gray-matter abnormalities in deficit schizophrenia. Schizophr Res 2010; 120:63-70. [PMID: 20452187 DOI: 10.1016/j.schres.2010.03.039] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 03/28/2010] [Accepted: 03/30/2010] [Indexed: 11/24/2022]
Abstract
Deficit schizophrenia (D-SZ) has been proposed as a putative disease subtype defined by prominent, primary negative symptoms that endure as trait-like features during periods of clinical stability. In this study, we acquired magnetic resonance images of the whole brain using a 1.5 T scanner in 19 outpatients with D-SZ, 31 with non-deficit schizophrenia (ND-SZ), and 90 healthy adults. Voxel-based morphometry was used to investigate differences in regional gray-matter volume (GMV) between outpatients with D-SZ and ND-SZ, and between the combined patient subgroups and healthy adults. Compared to healthy adults outpatients with schizophrenia showed GMV reductions, especially in left frontal and temporal cortices and in the left insula. The D-SZ subgroup showed reduced GMV in the insula bilaterally and in the left superior frontal, middle temporal and occipital gyri. Regions in which GMV reductions best distinguished D-SZ from ND-SZ patients included the superior frontal gyrus (Brodmann area 8) and superior temporal gyrus (Brodmann areas 22, 38) bilaterally, the left supplementary motor area (Brodmann area 6), left anterior cingulate, left cuneus and right putamen. These results suggest that patients with deficit schizophrenia have brain abnormalities that differ from those of patients with non-deficit schizophrenia. Further, the neuroanatomic differences between these two putative subtypes of schizophrenia involve brain regions that appear to be associated with the negative symptoms that define the deficit syndrome of schizophrenia.
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Affiliation(s)
- Nicola G Cascella
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Kaspárek T, Prikryl R, Schwarz D, Tronerová S, Cesková E, Mikl M, Vanícek J. Movement sequencing abilities and basal ganglia morphology in first-episode schizophrenia. World J Biol Psychiatry 2010; 10:752-62. [PMID: 18609414 DOI: 10.1080/15622970701882433] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Studies of brain morphology suggest a link between movement sequencing ability and basal ganglia dysfunction. Unfortunately, relevant studies have provided inconsistent data, which may be the result of differences in the methods of brain morphology assessment, statistical analysis or heterogeneity of the populations studied. AIM To test the hypothesis of a link between the dysfunction of movement sequencing and basal ganglia morphology in a homogenous sample of first-episode schizophrenia patients. METHOD Thirty-seven first-episode schizophrenia patients underwent an assessment of movement sequencing abilities using the NES scale and basal ganglia morphology from MR images. The data were compared with a group of 19 age- and sex-matched healthy controls. RESULTS The group of first-episode patients had a higher concentration of gray matter than healthy controls in the putamen and pallidum in both hemispheres. Patients with abnormal sequencing of movements had lower gray matter concentration than patients without such abnormalities in the left putamen, and no differences were found between the symptomatic group and healthy controls. SUMMARY AND CONCLUSION Our study suggests the involvement of the left putamen in the movement sequencing abnormalities in schizophrenia. Because of the potential confounding effect of medication, the lack of support from external evidence and the low power to perform the whole-brain analysis the results should be considered as preliminary. Further studies, especially with antipsychotic-naive first-episode schizophrenia patients are needed to solve these issues.
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Affiliation(s)
- Tomás Kaspárek
- Department of Psychiatry, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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Abstract
Increasingly, it is recognized that first-episode schizophrenia represents a critical stage of illness during which the effectiveness of therapeutic interventions can affect long-term outcome. In this regard, the advent of clozapine and subsequent atypical antipsychotic drugs held promise for improved outcomes in patients with first-episode schizophrenia, given the expectation of improved therapeutic efficacy and a more benign side effect burden compared with typical antipsychotic drugs. A growing number of large clinical trials have evaluated the merits of atypical antipsychotic drugs in the early stages of psychosis. A number of conclusions can be drawn from studies completed to date, with the caveat that data are either limited or unavailable for the antipsychotic drugs most recently approved by the US FDA. Studies of atypical antipsychotic drugs support data obtained with typical agents indicating that positive symptoms of psychosis are very treatment responsive and generally at lower doses than in chronic illness. It also appears that first-episode patients tend to stay on atypical antipsychotic drugs longer than on typical agents when all-cause discontinuation criteria are considered as the primary outcome measure. However, there are few differential advantages of clinical efficacy among the individual atypical antipsychotic drugs and there is little evidence to support distinct therapeutic advantages for negative symptoms or cognitive symptoms for atypical agents. Furthermore, while new-onset psychosis patients are particularly susceptible to extrapyramidal symptoms, they are also prone to gain weight and related metabolic adverse effects associated with many, but not all, atypical antipsychotic drugs. Recent data indicating that certain atypical antipsychotic drugs may have a sparing effect on cortical grey matter loss in first-episode schizophrenia is intriguing, given the potential long-term benefits. In summary, atypical antipsychotic drugs represent an incremental advance for patients in first-episode schizophrenia, especially in the area of neurological tolerability. However, metabolic concerns associated with many atypical agents along with limited benefits in cognition and negative symptom domains highlight the persistent therapeutic needs of these patients.
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Affiliation(s)
- Kayvon Salimi
- Department of Psychiatry, University of North Carolina at Chapel Hill, USA
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Galderisi S, Maj M. Deficit schizophrenia: an overview of clinical, biological and treatment aspects. Eur Psychiatry 2009; 24:493-500. [PMID: 19553087 DOI: 10.1016/j.eurpsy.2009.03.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2008] [Revised: 03/18/2009] [Accepted: 03/19/2009] [Indexed: 10/20/2022] Open
Abstract
The concept of deficit schizophrenia is regarded as one of the most promising attempts to reduce heterogeneity within schizophrenia. This paper summarizes the clinical, neurocognitive, brain imaging and electrophysiological correlates of this subtype of schizophrenia. Attempts to identify genetic and non-genetic risk factors are reviewed. Methodological limitations of studies supporting the efficacy of atypical antipsychotics in the treatment of the syndrome are highlighted. Two decades of research on deficit schizophrenia have failed to prove that it represents the extreme end of a severity continuum in schizophrenia, while some findings support the claim that it may be a separate disease entity.
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Affiliation(s)
- S Galderisi
- Department of Psychiatry, Medical School, University of Naples SUN, Largo Madonna delle Grazie, Naples, Italy.
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Rowland LM, Spieker EA, Francis A, Barker PB, Carpenter WT, Buchanan RW. White matter alterations in deficit schizophrenia. Neuropsychopharmacology 2009; 34:1514-22. [PMID: 19052539 PMCID: PMC2669692 DOI: 10.1038/npp.2008.207] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Schizophrenia can be classified into two separate syndromes: deficit and nondeficit. Primary, enduring negative symptoms are used to define the deficit form of the illness, which is believed to have a unique neurobiological substrate. Previous research suggests that an aberrant prefrontal-thalamic-parietal network underlies deficit schizophrenia. In this study we conducted diffusion tensor imaging (DTI) fiber tracking to assess the integrity of the superior longitudinal fasciculus (SLF), the major white matter tract that connects prefrontal and parietal cortical regions, in deficit and nondeficit people with schizophrenia. We also used proton magnetic resonance spectroscopy (1H-MRS) to assess neurochemistry in the left middle prefrontal and left inferior parietal cortical regions. A total of 20 subjects with schizophrenia (10 deficit and 10 nondeficit) and 11 healthy subjects participated in this study. Results revealed reduced fractional anisotropy (FA), an index of white matter integrity, in the right hemisphere SLF and frontal white matter in the deficit subjects. There were no differences in MRS metabolite concentrations among groups. To our knowledge, this is the first DTI study to show compromised integrity of the major white matter tract that connects frontal and parietal regions in deficit schizophrenia. These findings provide further support for altered frontal-parietal network in deficit schizophrenia.
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Affiliation(s)
- Laura M. Rowland
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore MD, USA,Corresponding Author: Laura M. Rowland, Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228, , Phone: 410-402-6803, Fax: 410-402-6077
| | - Elena A. Spieker
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore MD, USA
| | - Alan Francis
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore MD, USA
| | - Peter B. Barker
- Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore MD, USA,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore MD, USA
| | - William T. Carpenter
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore MD, USA
| | - Robert W. Buchanan
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore MD, USA
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Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG. Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008; 60:358-403. [PMID: 18922967 PMCID: PMC4821196 DOI: 10.1124/pr.107.00107] [Citation(s) in RCA: 176] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.
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Affiliation(s)
- Jeffrey A Lieberman
- Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, 1051 Riverside Dr., Unit 4, New York, NY 10032, USA.
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