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Short-term Medication Effects on Brain Functional Activity and Network Architecture in First-Episode psychosis: a longitudinal fMRI study. Brain Imaging Behav 2023; 17:137-148. [PMID: 36646973 DOI: 10.1007/s11682-022-00704-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/17/2022] [Accepted: 07/04/2022] [Indexed: 01/18/2023]
Abstract
The effect of antipsychotic medications is critical for the long-term outcome of symptoms and functions during first-episode psychosis (FEP). However, how brain functions respond to the antipsychotic treatment in the early stage of psychosis and its underlying neural mechanisms remain unclear. In this study, we explored the cross-sectional and longitudinal changes of regional homogeneity (ReHo), whole-brain functional connectivity, and network topological properties via resting-state functional magnetic resonance images. Thirty-two drug-naïve FEP patients and 30 matched healthy volunteers (HV) were included, where 23 patients were re-visited with effective responses after two months of antipsychotic treatment. Compared to HV, drug-naive patients demonstrated significantly different patterns of functional connectivity involving the right thalamus. These functional alterations mainly involved decreased ReHo, increased nodal efficiency in the right thalamus, and increased thalamic-sensorimotor-frontoparietal connectivity. In the follow-up analysis, patients after treatment showed reduced ReHo and nodal clustering in visual networks, as well as disturbances of visual-somatomotor and hippocampus-superior frontal gyrus connectivity. The longitudinal changes of ReHo in the visual cortex were associated with an improvement in general psychotic symptoms. This study provides new evidence regarding alterations in brain function linked to schizophrenia onset and affected by antipsychotic medications. Moreover, our results demonstrated that the functional alterations at baseline were not fully modulated by antipsychotic medications, suggesting that antipsychotic medications may reduce psychotic symptoms but limit the effects in regions involved in disease pathophysiology.
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Subcortical Structures in Demented Schizophrenia Patients: A Comparative Study. Biomedicines 2023; 11:biomedicines11010233. [PMID: 36672741 PMCID: PMC9855401 DOI: 10.3390/biomedicines11010233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/09/2023] [Accepted: 01/09/2023] [Indexed: 01/19/2023] Open
Abstract
There are few studies on dementia and schizophrenia in older patients looking for structural differences. This paper aims to describe relation between cognitive performance and brain volumes in older schizophrenia patients. Twenty schizophrenic outpatients -10 without-dementia (SND), 10 with dementia (SD)- and fifteen healthy individuals -as the control group (CG)-, older than 50, were selected. Neuropsychological tests were used to examine cognitive domains. Brain volumes were calculated with magnetic resonance images. Cognitive performance was significantly better in CG than in schizophrenics. Cognitive performance was worst in SD than SND, except in semantic memory and visual attention. Hippocampal volumes showed significant differences between SD and CG, with predominance on the right side. Left thalamic volume was smaller in SD group than in SND. Structural differences were found in the hippocampus, amygdala, and thalamus; more evident in the amygdala and thalamus, which were mainly related to dementia. In conclusion, cognitive performance and structural changes allowed us to differentiate between schizophrenia patients and CG, with changes being more pronounced in SD than in SND. When comparing SND with SD, the functional alterations largely coincide, although sometimes in the opposite direction. Moreover, volume lost in the hippocampus, amygdala, and thalamus may be related to the possibility to develop dementia in schizophrenic patients.
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Balamurugan VP, Chew QH, Sim K. Relationship between volume reductions of hippocampal subfields and thalamus and duration of untreated psychosis in schizophrenia. Asian J Psychiatr 2022; 71:103082. [PMID: 35299141 DOI: 10.1016/j.ajp.2022.103082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/09/2022] [Indexed: 11/15/2022]
Affiliation(s)
| | - Qian Hui Chew
- Institute of Mental Health, Research Division, Singapore
| | - Kang Sim
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Mental Health, West Region, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Huang AS, Rogers BP, Sheffield JM, Vandekar S, Anticevic A, Woodward ND. Characterizing effects of age, sex and psychosis symptoms on thalamocortical functional connectivity in youth. Neuroimage 2021; 243:118562. [PMID: 34506914 PMCID: PMC10021021 DOI: 10.1016/j.neuroimage.2021.118562] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/29/2021] [Accepted: 09/06/2021] [Indexed: 01/09/2023] Open
Abstract
The thalamus is composed of multiple nuclei densely connected with the cortex in an organized manner, forming parallel thalamocortical networks critical to sensory, motor, and cognitive functioning. Thalamocortical circuit dysfunction has been implicated in multiple neurodevelopmental disorders, including schizophrenia, which also often exhibit sex differences in prevalence, clinical characteristics, and neuropathology. However, very little is known about developmental and sex effects on thalamocortical networks in youth. The present study characterized the effects of age, sex and psychosis symptomatology in anatomically constrained thalamocortical networks in a large community sample of youth (n = 1100, aged 8-21) from the Philadelphia Neurodevelopmental Cohort (PNC). Cortical functional connectivity of seven anatomically defined thalamic nuclear groups were examined: anterior, mediodorsal, ventral lateral, ventral posterolateral, pulvinar, medial and lateral geniculate nuclear groups. Age and sex effects were characterized using complementary thalamic region-of-interest (ROI) to cortical ROI and voxel-wise analyses. Effects of clinical symptomatology were analyzed by separating youth into three groups based on their clinical symptoms; typically developing youth (n = 298), psychosis spectrum youth (n = 320), and youth with other psychopathologies (n = 482). As an exploratory analysis, association with PRIME scores were used as a dimensional measure of psychopathology. Age effects were broadly characterized by decreasing connectivity with sensory/motor cortical areas, and increasing connectivity with heteromodal prefrontal and parietal cortical areas. This pattern was most pronounced for thalamic motor and sensory nuclei. Females showed greater connectivity between multiple thalamic nuclear groups and the visual cortex compared to males, while males showed greater connectivity with the inferior frontal and orbitofrontal cortices. Youth with psychosis spectrum symptoms showed a subtle decrease in thalamic connectivity with the premotor and prefrontal cortices. Across all youth, greater PRIME scores were associated with lower connectivity between the prefrontal cortex and mediodorsal thalamus. By characterizing typical development in anatomically constrained thalamocortical networks, this study provides an anchor for conceptualizing disruptions to the integrity of these networks observed in neurodevelopmental disorders.
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Affiliation(s)
- Anna S Huang
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
| | - Baxter P Rogers
- Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Julia M Sheffield
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Simon Vandekar
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Alan Anticevic
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Neil D Woodward
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
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Mapping thalamocortical functional connectivity with large-scale brain networks in patients with first-episode psychosis. Sci Rep 2021; 11:19815. [PMID: 34615924 PMCID: PMC8494789 DOI: 10.1038/s41598-021-99170-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/16/2021] [Indexed: 11/09/2022] Open
Abstract
Abnormal thalamocortical networks involving specific thalamic nuclei have been implicated in schizophrenia pathophysiology. While comparable topography of anatomical and functional connectivity abnormalities has been reported in patients across illness stages, previous functional studies have been confined to anatomical pathways of thalamocortical networks. To address this issue, we incorporated large-scale brain network dynamics into examining thalamocortical functional connectivity. Forty patients with first-episode psychosis and forty healthy controls underwent T1-weighted and resting-state functional magnetic resonance imaging. Independent component analysis of voxelwise thalamic functional connectivity maps parcellated the cortex into thalamus-related networks, and thalamic subdivisions associated with these networks were delineated. Functional connectivity of (1) networks with the thalamus and (2) thalamic subdivision seeds were examined. In patients, functional connectivity of the salience network with the thalamus was decreased and localized to the ventrolateral (VL) and ventroposterior (VP) thalamus, while that of a network comprising the cerebellum, temporal and parietal regions was increased and localized to the mediodorsal (MD) thalamus. In patients, thalamic subdivision encompassing the VL and VP thalamus demonstrated hypoconnectivity and that encompassing the MD and pulvinar regions demonstrated hyperconnectivity. Our results extend the implications of disrupted thalamocortical networks involving specific thalamic nuclei to dysfunctional large-scale brain network dynamics in schizophrenia pathophysiology.
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Perez SM, Lodge DJ. Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia. Int J Neuropsychopharmacol 2021; 24:344-353. [PMID: 33587746 PMCID: PMC8059491 DOI: 10.1093/ijnp/pyaa080] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/13/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity. METHODS Here we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats). RESULTS Aberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats. CONCLUSION Taken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.
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Affiliation(s)
- Stephanie M Perez
- Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA
| | - Daniel J Lodge
- Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA
- South Texas Veterans Health Care System, Audie L. Murphy Division, USA
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Huang AS, Rogers BP, Sheffield JM, Jalbrzikowski ME, Anticevic A, Blackford JU, Heckers S, Woodward ND. Thalamic Nuclei Volumes in Psychotic Disorders and in Youths With Psychosis Spectrum Symptoms. Am J Psychiatry 2020; 177:1159-1167. [PMID: 32911995 PMCID: PMC7708443 DOI: 10.1176/appi.ajp.2020.19101099] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Thalamus models of psychosis implicate association nuclei in the pathogenesis of psychosis and mechanisms of cognitive impairment. Studies to date have provided conflicting findings for structural deficits specific to these nuclei. The authors sought to characterize thalamic structural abnormalities in psychosis and a neurodevelopmental cohort, and to determine whether nuclear volumes were associated with cognitive function. METHODS Thalamic nuclei volumes were tested in a cross-sectional sample of 472 adults (293 with psychosis) and the Philadelphia Neurodevelopmental Cohort (PNC), consisting of 1,393 youths (398 with psychosis spectrum symptoms and 609 with other psychopathologies), using a recently developed, validated method for segmenting thalamic nuclei and complementary voxel-based morphometry. Cognitive function was measured with the Screen for Cognitive Impairment in Psychiatry in the psychosis cohort and the Penn Computerized Neurocognitive Battery in the PNC. RESULTS The psychosis group had smaller pulvinar, mediodorsal, and, to a lesser extent, ventrolateral nuclei volumes compared with the healthy control group. Youths with psychosis spectrum symptoms also had smaller pulvinar volumes, compared with both typically developing youths and youths with other psychopathologies. Pulvinar volumes were positively correlated with general cognitive function. CONCLUSIONS The study findings demonstrate that smaller thalamic association nuclei represent a neurodevelopmental abnormality associated with psychosis, risk for psychosis in youths, and cognitive impairment. Identifying specific thalamic nuclei abnormalities in psychosis has implications for early detection of psychosis risk and treatment of cognitive impairment in psychosis.
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Affiliation(s)
- Anna S. Huang
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center
| | | | - Julia M. Sheffield
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center
| | | | - Alan Anticevic
- Department of Psychiatry, Yale University School of Medicine
| | - Jennifer Urbano Blackford
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center
- Research Health Scientist, Research and Development, Department of Veterans Affairs Medical Center, Nashville, TN
| | - Stephan Heckers
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center
| | - Neil D. Woodward
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center
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Tan AS, Chew QH, Sim K. Cerebral white matter changes in deficit and non-deficit subtypes of schizophrenia. J Neural Transm (Vienna) 2020; 127:1073-1079. [PMID: 32435900 DOI: 10.1007/s00702-020-02207-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 05/08/2020] [Indexed: 01/01/2023]
Abstract
The considerable clinical heterogeneity in schizophrenia makes elucidation of its neurobiology challenging. Subtyping the disorder is one way to reduce this heterogeneity and deficit status is one such categorization based on the prominence of negative symptoms. We aimed to utilize diffusion tensor imaging (DTI) to identify unique white matter cerebral changes in deficit schizophrenia (DS) compared with non-deficit schizophrenia (NDS) and healthy controls (HC) in an Asian sample. A total of 289 subjects (111 HC, 133 NDS and 45 DS) underwent DTI and completed rating scales which assessed the severity of psychopathology, psychosocial functioning and premorbid intelligence.We found that DS patients had fractional anisotropy (FA) reductions in the Body of the Corpus Callosum (BCC) and right Posterior Thalamic Radiation (PTR) regions relative to HCs, and FA reductions in the right PTR relative to NDS patients. NDS patients had FA reductions of the BCC and right PTR relative to HCs. Binomial logistic regression analyses revealed that FA reductions of the right PTR FA was an independent predictor of deficit status. The identified brain white matter changes especially in the PTR relate to deficits of cognitive control and emotional awareness, which may underlie psychopathology associated with deficit status like inattention and affective blunting. These potential biomarkers of DS warrant further examination to determine their utility for monitoring illness progression and intervention response in schizophrenia.
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Affiliation(s)
- An Sen Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Qian Hui Chew
- Institute of Mental Health, 10, Buangkok View, Singapore, Republic of Singapore
| | - Kang Sim
- Institute of Mental Health, 10, Buangkok View, Singapore, Republic of Singapore.
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Wang J, Jiang Y, Tang Y, Xia M, Curtin A, Li J, Sheng J, Zhang T, Li C, Hui L, Zhu H, Biswal BB, Jia Q, Luo C, Wang J. Altered functional connectivity of the thalamus induced by modified electroconvulsive therapy for schizophrenia. Schizophr Res 2020; 218:209-218. [PMID: 31956007 DOI: 10.1016/j.schres.2019.12.044] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 12/29/2019] [Accepted: 12/31/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Electroconvulsive therapy (ECT) has been shown to be effective in schizophrenia (SZ), particularly in drug-refractory cases or when rapid symptom relief is needed. However, its precise mechanisms of action remain largely unclear. To clarify the mechanisms underlying modified electroconvulsive therapy (mECT) for SZ, we conducted a longitudinal cohort study evaluating functional connectivity of the thalamus before and after mECT treatment using sub-regions of thalamus as regions of interest (ROIs). METHODS Twenty-one SZ individuals taking only antipsychotics (DSZ group) for 4 weeks and 21 SZ patients receiving a regular course of mECT combining with antipsychotics (MSZ group) were observed in parallel. All patients underwent magnetic resonance imaging scans at baseline (t1) and follow-up (t2, ~4 weeks) time points. Data were compared to a matched healthy control group (HC group) consisting of 23 persons who were only scanned at baseline. Group differences in changes of thalamic functional connectivity between two SZ groups over time, as well as in functional connectivity among two SZ groups and HC group were assessed. RESULTS Significant interaction of group by time was found in functional connectivity of the right thalamus to right putamen during the course of about 4-week treatment. Post-hoc analysis showed a significantly enhanced functional connectivity of the right thalamus to right putamen in the MSZ group contrasting to the DSZ group. In addition, a decreased and an increased functional connectivity of the thalamus to sensory cortex were observed within the MSZ and DSZ group after 4-week treatment trial, respectively. CONCLUSION Our findings suggest that changes in functional connectivity of the thalamus may be associated with the brain mechanisms of mECT for schizophrenia.
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Affiliation(s)
- Junjie Wang
- Institute of Mental Health, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu 215137, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China
| | - Yuchao Jiang
- Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Yingying Tang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China.
| | - Mengqing Xia
- Institute of Mental Health, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu 215137, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China
| | - Adrian Curtin
- School of Biomedical Engineering & Health Sciences, Drexel University, Philadelphia, PA 19104, USA; Med-X Institute, Shanghai Jiaotong University, Shanghai 200300, China
| | - Jin Li
- Institute of Mental Health, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu 215137, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China
| | - Jianhua Sheng
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China
| | - Tianhong Zhang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China
| | - Chunbo Li
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China; CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, China; Brain Science and Technology Research Center, Shanghai Jiaotong University, Shanghai 200030, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiaotong University, Shanghai 200030, China
| | - Li Hui
- Institute of Mental Health, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu 215137, China
| | - Hongliang Zhu
- Institute of Mental Health, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu 215137, China
| | - Bharat B Biswal
- Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA
| | - Qiufang Jia
- Institute of Mental Health, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu 215137, China.
| | - Cheng Luo
- Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.
| | - Jijun Wang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China; CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, China; Brain Science and Technology Research Center, Shanghai Jiaotong University, Shanghai 200030, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiaotong University, Shanghai 200030, China
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Tu PC, Bai YM, Li CT, Chen MH, Lin WC, Chang WC, Su TP. Identification of Common Thalamocortical Dysconnectivity in Four Major Psychiatric Disorders. Schizophr Bull 2019; 45:1143-1151. [PMID: 30500946 PMCID: PMC6737486 DOI: 10.1093/schbul/sby166] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent genetic and imaging analyses of large datasets suggested that common biological substrates exist across psychiatric diagnoses. Functional connectivity (FC) abnormalities of thalamocortical circuits were consistently found in patients with schizophrenia but have been less studied in other major psychiatric disorders. This study aimed to examine thalamocortical FC in 4 major psychiatric disorders to identify the common connectivity abnormalities across major psychiatric disorders. METHODS This study recruited 100 patients with schizophrenia, 100 patients with bipolar I disorder, 88 patients with bipolar II disorder, 100 patients with major depressive disorder, and 160 healthy controls (HCs). Each participant underwent resting functional magnetic resonance imaging. The thalamus was used to derive FC maps, and group comparisons were made between each patient group and HCs using an independent-sample t test. Conjunction analysis was used to identify the common thalamocortical abnormalities among these 4 psychiatric disorders. RESULTS The 4 groups of patients shared a similar pattern of thalamocortical dysconnectivity characterized by a decrease in thalamocortical FC with the dorsal anterior cingulate, anterior prefrontal cortex and inferior parietal cortex. The groups also showed an increase in FC with the postcentral gyrus, precentral gyrus, superior temporal cortex, and lateral occipital areas. Further network analysis demonstrated that the frontoparietal regions showing hypoconnectivity belonged to the salience network. CONCLUSION Our findings provide FC evidence that supports the common network hypothesis by identifying common thalamocortical dysconnectivities across 4 major psychiatric disorders. The network analysis also supports the cardinal role of salience network abnormalities in major psychiatric disorders.
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Affiliation(s)
- Pei-Chi Tu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Institute of Philosophy of Mind and Cognition, School of Humanities and Social Sciences, National Yang-Ming University, Taipei, Taiwan,Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ya Mei Bai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Ta Li
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan,Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wei-Chen Lin
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wan-Chen Chang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tung-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan,Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan,Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan,To whom correspondence should be addressed; Tung-Ping Su, Department of Psychiatry, Cheng-Hsin General Hospital, No.45, Cheng Hsin St., Taipei 112, Taiwan; tel: +886-2-28264400 ext. 3502, fax: +886-2-28742421, e-mail:
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11
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Thalamic connectivity measured with fMRI is associated with a polygenic index predicting thalamo-prefrontal gene co-expression. Brain Struct Funct 2019; 224:1331-1344. [DOI: 10.1007/s00429-019-01843-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 01/31/2019] [Indexed: 01/11/2023]
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12
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Yamamoto M, Kushima I, Suzuki R, Branko A, Kawano N, Inada T, Iidaka T, Ozaki N. Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia. Psychiatry Res Neuroimaging 2018; 278:35-41. [PMID: 29981940 DOI: 10.1016/j.pscychresns.2018.06.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/13/2018] [Accepted: 06/15/2018] [Indexed: 11/20/2022]
Abstract
Resting-state (rs) functional magnetic resonance imaging (fMRI) studies have revealed dysfunctional thalamocortical functional connectivity (FC) in schizophrenia. However, the relationship between thalamocortical FC and cognitive impairment has not been thoroughly investigated. We hypothesized that aberrant thalamocortical FC is related to attention deficits in schizophrenia. Thirty-eight patients with schizophrenia and 38 matched healthy controls underwent rs-fMRI and task fMRI while performing a Flanker task. We observed decreased left thalamic activation in patients with schizophrenia using task fMRI to determine the thalamic seed. A seed-based analysis using this seed was performed in the whole brain to assess differences in thalamocortical FC between the groups. Significantly worse performance was observed in the patient group. The rs-fMRI analysis revealed significantly increased FC between the left thalamus seed and the occipital cortices/postcentral gyri in patients when compared to controls. In the patient group, significant positive correlations were observed between the degree of FC from the left thalamus to the bilateral occipital gyri, which correspond to the visual cortex, and the Flanker effect. No significant correlation was detected in the control group. These results indicate that aberrant FC between the left thalamus and the visual cortex is related to attention deficits in schizophrenia.
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Affiliation(s)
- Maeri Yamamoto
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
| | - Itaru Kushima
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan; Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan
| | - Ryohei Suzuki
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
| | - Aleksic Branko
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
| | - Naoko Kawano
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan; Institutes of Innovation for Future Society, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan
| | - Toshiya Inada
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
| | - Tetsuya Iidaka
- Department of Physical and Occupational Therapy, Nagoya University, Graduate School of Medicine, 1-1-20, Daiko-minami, Higashi, Nagoya, Aichi 461-8673, Japan.
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
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Wolf R, Dobrowolny H, Nullmeier S, Bogerts B, Schwegler H. Effects of neonatal excitotoxic lesions in ventral thalamus on social interaction in the rat. Eur Arch Psychiatry Clin Neurosci 2018; 268:461-470. [PMID: 28361258 DOI: 10.1007/s00406-017-0781-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 03/06/2017] [Indexed: 12/31/2022]
Abstract
The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia.
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Affiliation(s)
- Rainer Wolf
- Department of Psychiatry, Ruhr-University Bochum, Alexandrinenstr. 1, 44791, Bochum, Germany.
- Department of Psychiatry, Otto-von-Guericke University, Magdeburg, Germany.
| | - Henrik Dobrowolny
- Department of Psychiatry, Otto-von-Guericke University, Magdeburg, Germany
| | - Sven Nullmeier
- Institute of Anatomy, Otto-von-Guericke University, Magdeburg, Germany
| | - Bernhard Bogerts
- Department of Psychiatry, Otto-von-Guericke University, Magdeburg, Germany
| | - Herbert Schwegler
- Institute of Anatomy, Otto-von-Guericke University, Magdeburg, Germany
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Penner J, Osuch EA, Schaefer B, Théberge J, Neufeld RWJ, Menon RS, Rajakumar N, Bourne JA, Williamson PC. Higher order thalamic nuclei resting network connectivity in early schizophrenia and major depressive disorder. Psychiatry Res Neuroimaging 2018; 272:7-16. [PMID: 29247717 DOI: 10.1016/j.pscychresns.2017.12.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 12/05/2017] [Accepted: 12/06/2017] [Indexed: 12/21/2022]
Abstract
The pulvinar and the mediodorsal (MDN) nuclei of the thalamus are higher order nuclei which have been implicated in directed effort and corollary discharge systems. We used seed-based resting fMRI to examine functional connectivity to bilateral pulvinar and MDN in 24 schizophrenic patients (SZ), 24 major depressive disorder patients (MDD), and 24 age-matched healthy controls. SZ had less connectivity than controls between the left pulvinar and precuneus, left ventral-lateral prefrontal cortex (vlPFC), and superior and medial-frontal regions, between the right pulvinar and right frontal pole, and greater connectivity between the right MDN and left dorsolateral prefrontal cortex (dlPFC). SZ had less connectivity than MDD between the left pulvinar and ventral anterior cingulate (vACC), left vlPFC, anterior insula, posterior cingulate cortex (PCC), and right hippocampus, between the right pulvinar and right PCC, and between the right MDN and right dorsal anterior cingulate (dACC). This is the first study to measure the functional connectivity to the higher order nuclei of the thalamus in both SZ and MDD. We observed less connectivity in SZ than MDD between pulvinar and emotional encoding regions, a directed effort region, and a region involved in representation and salience, and between MDN and a directed effort region.
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Affiliation(s)
- Jacob Penner
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Imaging Division, Lawson Health Research Institute, London, Ontario, Canada; First Episode Mood & Anxiety Program (FEMAP), London Health Sciences Centre, London, Ontario, Canada.
| | - Elizabeth A Osuch
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; First Episode Mood & Anxiety Program (FEMAP), London Health Sciences Centre, London, Ontario, Canada
| | - Betsy Schaefer
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada
| | - Jean Théberge
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; Imaging Division, Lawson Health Research Institute, London, Ontario, Canada
| | - Richard W J Neufeld
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Department of Psychology, University of Western Ontario, London, Ontario, Canada; Department of Neuroscience Program, University of Western Ontario, London, Ontario, Canada
| | - Ravi S Menon
- Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; Centre for Functional and Metabolic Mapping, Robarts Research Institute, London, Ontario, Canada; Imaging Division, Lawson Health Research Institute, London, Ontario, Canada
| | - Nagalingam Rajakumar
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
| | - James A Bourne
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
| | - Peter C Williamson
- Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; Imaging Division, Lawson Health Research Institute, London, Ontario, Canada
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Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype. Eur Arch Psychiatry Clin Neurosci 2017; 267:213-224. [PMID: 27565806 DOI: 10.1007/s00406-016-0725-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 08/16/2016] [Indexed: 12/22/2022]
Abstract
Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12-15 Hz) and slow (9-12 Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.
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A Neurophysiological Perspective on a Preventive Treatment against Schizophrenia Using Transcranial Electric Stimulation of the Corticothalamic Pathway. Brain Sci 2017; 7:brainsci7040034. [PMID: 28350371 PMCID: PMC5406691 DOI: 10.3390/brainsci7040034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/11/2017] [Accepted: 03/24/2017] [Indexed: 12/16/2022] Open
Abstract
Schizophrenia patients are waiting for a treatment free of detrimental effects. Psychotic disorders are devastating mental illnesses associated with dysfunctional brain networks. Ongoing brain network gamma frequency (30–80 Hz) oscillations, naturally implicated in integrative function, are excessively amplified during hallucinations, in at-risk mental states for psychosis and first-episode psychosis. So, gamma oscillations represent a bioelectrical marker for cerebral network disorders with prognostic and therapeutic potential. They accompany sensorimotor and cognitive deficits already present in prodromal schizophrenia. Abnormally amplified gamma oscillations are reproduced in the corticothalamic systems of healthy humans and rodents after a single systemic administration, at a psychotomimetic dose, of the glutamate N-methyl-d-aspartate receptor antagonist ketamine. These translational ketamine models of prodromal schizophrenia are thus promising to work out a preventive noninvasive treatment against first-episode psychosis and chronic schizophrenia. In the present essay, transcranial electric stimulation (TES) is considered an appropriate preventive therapeutic modality because it can influence cognitive performance and neural oscillations. Here, I highlight clinical and experimental findings showing that, together, the corticothalamic pathway, the thalamus, and the glutamatergic synaptic transmission form an etiopathophysiological backbone for schizophrenia and represent a potential therapeutic target for preventive TES of dysfunctional brain networks in at-risk mental state patients against psychotic disorders.
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Giraldo-Chica M, Woodward ND. Review of thalamocortical resting-state fMRI studies in schizophrenia. Schizophr Res 2017; 180:58-63. [PMID: 27531067 PMCID: PMC5297399 DOI: 10.1016/j.schres.2016.08.005] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 08/03/2016] [Accepted: 08/06/2016] [Indexed: 12/19/2022]
Abstract
Brain circuitry underlying cognition, emotion, and perception is abnormal in schizophrenia. There is considerable evidence that the neuropathology of schizophrenia includes the thalamus, a key hub of cortical-subcortical circuitry and an important regulator of cortical activity. However, the thalamus is a heterogeneous structure composed of several nuclei with distinct inputs and cortical connections. Limitations of conventional neuroimaging methods and conflicting findings from post-mortem investigations have made it difficult to determine if thalamic pathology in schizophrenia is widespread or limited to specific thalamocortical circuits. Resting-state fMRI has proven invaluable for understanding the large-scale functional organization of the brain and investigating neural circuitry relevant to psychiatric disorders. This article summarizes resting-state fMRI investigations of thalamocortical functional connectivity in schizophrenia. Particular attention is paid to the course, diagnostic specificity, and clinical correlates of thalamocortical network dysfunction.
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Woodward ND, Heckers S. Mapping Thalamocortical Functional Connectivity in Chronic and Early Stages of Psychotic Disorders. Biol Psychiatry 2016; 79:1016-25. [PMID: 26248537 PMCID: PMC4698230 DOI: 10.1016/j.biopsych.2015.06.026] [Citation(s) in RCA: 205] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 05/21/2015] [Accepted: 06/18/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND There is considerable evidence that the thalamus is abnormal in psychotic disorders. Resting-state functional magnetic resonance imaging has revealed an intriguing pattern of thalamic dysconnectivity in psychosis characterized by reduced prefrontal cortex (PFC) connectivity and increased somatomotor-thalamic connectivity. However, critical knowledge gaps remain with respect to the onset, anatomical specificity, and clinical correlates of thalamic dysconnectivity in psychosis. METHODS Resting-state functional magnetic resonance imaging was collected on 105 healthy subjects and 148 individuals with psychosis, including 53 early-stage psychosis patients. Using all 253 subjects, the thalamus was parceled into functional regions of interest (ROIs) on the basis of connectivity with six a priori defined cortical ROIs covering most of the cortical mantle. Functional connectivity between each cortical ROI and its corresponding thalamic ROI was quantified and compared across groups. Significant differences in the ROI-to-ROI analysis were followed up with voxelwise seed-based analyses to further localize thalamic dysconnectivity. RESULTS ROI analysis revealed reduced PFC-thalamic connectivity and increased somatomotor-thalamic connectivity in both chronic and early-stage psychosis patients. PFC hypoconnectivity and motor cortex hyperconnectivity correlated in patients, suggesting that they result from a common pathophysiological mechanism. Seed-based analyses revealed thalamic hypoconnectivity in psychosis localized to dorsolateral PFC, medial PFC, and cerebellar areas of the well-described executive control network. Across all subjects, thalamic connectivity with areas of the fronto-parietal network correlated with cognitive functioning, including verbal learning and memory. CONCLUSIONS Thalamocortical dysconnectivity is present in both chronic and early stages of psychosis, includes reduced thalamic connectivity with the executive control network, and is related to cognitive impairment.
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Walter C, Oertel BG, Felden L, Kell CA, Nöth U, Vermehren J, Kaiser J, Deichmann R, Lötsch J. Brain Mapping-Based Model of Δ(9)-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix. Neuropsychopharmacology 2016; 41:1659-69. [PMID: 26514581 PMCID: PMC4832029 DOI: 10.1038/npp.2015.336] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 10/09/2015] [Accepted: 10/10/2015] [Indexed: 01/08/2023]
Abstract
Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.
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Affiliation(s)
- Carmen Walter
- Institute of Clinical Pharmacology, Goethe University, Frankfurt am Main, Germany
| | - Bruno G Oertel
- Institute of Clinical Pharmacology, Goethe University, Frankfurt am Main, Germany
| | - Lisa Felden
- Institute of Clinical Pharmacology, Goethe University, Frankfurt am Main, Germany
| | - Christian A Kell
- Brain Imaging Center, Goethe University, Frankfurt am Main, Germany,Department of Neurology, Goethe University, Frankfurt am Main, Germany
| | - Ulrike Nöth
- Brain Imaging Center, Goethe University, Frankfurt am Main, Germany
| | - Johannes Vermehren
- Institute of Clinical Pharmacology, Goethe University, Frankfurt am Main, Germany
| | - Jochen Kaiser
- Institute of Medical Psychology, Goethe University, Frankfurt am Main, Germany
| | - Ralf Deichmann
- Brain Imaging Center, Goethe University, Frankfurt am Main, Germany
| | - Jörn Lötsch
- Institute of Clinical Pharmacology, Goethe University, Frankfurt am Main, Germany,Institute of Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany, Tel: +49 69 6301 4589, Fax: +49 69 6301 4354, E-mail:
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20
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Balleine BW, Morris RW, Leung BK. Thalamocortical integration of instrumental learning and performance and their disintegration in addiction. Brain Res 2015; 1628:104-16. [DOI: 10.1016/j.brainres.2014.12.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 12/03/2014] [Accepted: 12/06/2014] [Indexed: 01/01/2023]
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21
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Tu PC, Lee YC, Chen YS, Hsu JW, Li CT, Su TP. Network-specific cortico-thalamic dysconnection in schizophrenia revealed by intrinsic functional connectivity analyses. Schizophr Res 2015; 166:137-43. [PMID: 26081977 DOI: 10.1016/j.schres.2015.05.023] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 04/15/2015] [Accepted: 05/01/2015] [Indexed: 11/29/2022]
Abstract
BACKGROUND Cortico-thalamic connections are thought to be abnormal in schizophrenia due to their important roles in sensory relay and higher cognitive control, both of which are affected by this devastating illness. This study tested the cortico-thalamic dysconnection hypothesis in schizophrenia and further explored cortico-thalamic network properties using functional connectivity MRI (fcMRI). METHODS Forty-eight participants with schizophrenia and 48 healthy controls underwent resting fMRI scans and clinical evaluations. Six a priori cortical regions of interests (ROIs) were used to derive the six networks: dorsal default mode network (dDMN), fronto-parietal network (FPN), cingulo-opercular network (CON), primary sensorimotor network (SM1), primary auditory network (A1) and primary visual network (V1). The cortico-thalamic connectivity for each network was calculated for each participant and then compared between groups. RESULTS A repeated measures analysis of variance (ANOVA) showed significant group×network interactions (F(5, 90)=9.5, P<0.001), which were driven by a significant increase in FC within the SM1 (t(94)=4.1, P<0.001) and A1 (t(94)=4.2, P<0.001) networks in schizophrenics, as well as a significant decrease within the CON (t(94)=-2.8, P=0.04). The cortico-thalamic dysconnection did not correlate with symptom severity, representing a state independent abnormality. CONCLUSION The network analysis indicates that cortico-thalamic dysconnection in schizophrenia involves multiple networks and shows network specific changes. The findings provide support for dysfunctional thalamus-related networks in schizophrenia and further elaborate their network properties.
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Affiliation(s)
- Pei-Chi Tu
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan; Institute of Philosophy of Mind and Cognition, National Yang-Ming University, Taipei, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ying-Chiao Lee
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ying-Shiue Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ju-Wei Hsu
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Ta Li
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Tung-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
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The role of the thalamus in schizophrenia from a neuroimaging perspective. Neurosci Biobehav Rev 2015; 54:57-75. [DOI: 10.1016/j.neubiorev.2015.01.013] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 12/19/2014] [Accepted: 01/12/2015] [Indexed: 02/06/2023]
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Abstract
PURPOSE OF REVIEW The neural connections, interconnections and organized networks of the central nervous system (CNS), which represent the human connectome, are critical for intact brain function. Consequently, disturbances at any level or juncture of these networks may alter behaviour and/or lead to brain dysfunction. In this review, we focus on highlighting recent work using advanced imaging methods to address alterations in the structural and functional connectome in patients with schizophrenia. RECENT FINDINGS Using structural, diffusion, resting-state and task-related functional imaging and advanced computational analysis methods such as graph theory, more than 200 publications have addressed different aspects of structural and/or functional connectivity in schizophrenia over the last year. These studies have focused on determining how brain networks differ from those in controls, interact with symptom profiles within and across diagnoses, interface with disease-related cognitive impairments and confer genetic risk for the disorder. SUMMARY Much existing evidence supports the view that schizophrenia is a disorder of altered brain connectivity. Recent and continued characterization of the structural and functional connectome in schizophrenia patients have advanced our understanding of the neurobiology underlying clinical symptoms and cognitive impairments in a particular patient, their overlaps with other neuropsychiatric disorders sharing common features as well as the contributions of genetic risk factors. Although the clinical utility of the schizophrenia connectome remains to be realized, recent findings provide further promise that research in this area may lead to improved diagnosis, treatments and clinical outcomes.
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Höflich A, Hahn A, Küblböck M, Kranz GS, Vanicek T, Windischberger C, Saria A, Kasper S, Winkler D, Lanzenberger R. Ketamine-Induced Modulation of the Thalamo-Cortical Network in Healthy Volunteers As a Model for Schizophrenia. Int J Neuropsychopharmacol 2015; 18:pyv040. [PMID: 25896256 PMCID: PMC4576520 DOI: 10.1093/ijnp/pyv040] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 04/03/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Schizophrenia has been associated with disturbances of thalamic functioning. In light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether modulation of the glutamatergic system via blockage of the N-methyl-D-aspartate (NMDA)-receptor might lead to changes of thalamic functional connectivity. METHODS Based on the ketamine model of psychosis, we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55-minute resting-state scan. Thirty healthy volunteers were measured with pharmacological functional magnetic resonance imaging using a double-blind, randomized, placebo-controlled, crossover design. RESULTS Functional connectivity analysis revealed significant ketamine-specific changes within the thalamus hub network, more precisely, an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex. CONCLUSIONS Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behavior during the application of NMDA-receptor antagonists.
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Affiliation(s)
- Anna Höflich
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Andreas Hahn
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Martin Küblböck
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Georg S Kranz
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Thomas Vanicek
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Christian Windischberger
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Alois Saria
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Siegfried Kasper
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Dietmar Winkler
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria)
| | - Rupert Lanzenberger
- Department of Psychiatry and Psychotherapy (Drs Höflich, Hahn, Kranz, Vanicek, Kasper, Winkler, and Lanzenberger), and MR Center of Excellence and Center for Biomedical Engineering and Physics (Mr Küblböck and Dr Windischberger), Medical University of Vienna, Vienna, Austria; Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria (Dr Saria).
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Poh JS, Li Y, Ratnarajah N, Fortier MV, Chong YS, Kwek K, Saw SM, Gluckman PD, Meaney MJ, Qiu A. Developmental synchrony of thalamocortical circuits in the neonatal brain. Neuroimage 2015; 116:168-76. [PMID: 25812713 DOI: 10.1016/j.neuroimage.2015.03.039] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 02/17/2015] [Accepted: 03/14/2015] [Indexed: 11/15/2022] Open
Abstract
The thalamus is a deep gray matter structure and consists of axonal fibers projecting to the entire cortex, which provide the anatomical support for its sensorimotor and higher-level cognitive functions. There is limited in vivo evidence on the normal thalamocortical development, especially in early life. In this study, we aimed to investigate the developmental patterns of the cerebral cortex, the thalamic substructures, and their connectivity with the cortex in the first few weeks of the postnatal brain. We hypothesized that there is developmental synchrony of the thalamus, its cortical projections, and corresponding target cortical structures. We employed diffusion tensor imaging (DTI) and divided the thalamus into five substructures respectively connecting to the frontal, precentral, postcentral, temporal, and parietal and occipital cortex. T2-weighted magnetic resonance imaging (MRI) was used to measure cortical thickness. We found age-related increases in cortical thickness of bilateral frontal cortex and left temporal cortex in the early postnatal brain. We also found that the development of the thalamic substructures was synchronized with that of their respective thalamocortical connectivity in the first few weeks of the postnatal life. In particular, the right thalamo-frontal substructure had the fastest growth in the early postnatal brain. Our study suggests that the distinct growth patterns of the thalamic substructures are in synchrony with those of the cortex in early life, which may be critical for the development of the cortical and subcortical functional specialization.
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Affiliation(s)
- Joann S Poh
- Department of Biomedical Engineering, National University of Singapore, Singapore; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore
| | - Yue Li
- Department of Biomedical Engineering, National University of Singapore, Singapore
| | - Nagulan Ratnarajah
- Department of Biomedical Engineering, National University of Singapore, Singapore
| | - Marielle V Fortier
- Department of Diagnostic and Interventional Imaging, KK Women's and Children's Hospital, Singapore
| | - Yap-Seng Chong
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore; Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore
| | - Kenneth Kwek
- Department of Maternal Fetal Medicine, KK Women's and Children's Hospital, Singapore
| | - Seang-Mei Saw
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Peter D Gluckman
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore; Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Michael J Meaney
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore; Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Canada; Sackler Program for Epigenetics and Psychobiology, McGill University, Canada
| | - Anqi Qiu
- Department of Biomedical Engineering, National University of Singapore, Singapore; Clinical Imaging Research Centre, National University of Singapore, Singapore; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore.
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Sepede G, Spano MC, Lorusso M, Berardis DD, Salerno RM, Giannantonio MD, Gambi F. Sustained attention in psychosis: Neuroimaging findings. World J Radiol 2014; 6:261-273. [PMID: 24976929 PMCID: PMC4072813 DOI: 10.4329/wjr.v6.i6.261] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 02/07/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
To provide a systematic review of scientific literature on functional magnetic resonance imaging (fMRI) studies on sustained attention in psychosis. We searched PubMed to identify fMRI studies pertaining sustained attention in both affective and non-affective psychosis. Only studies conducted on adult patients using a sustained attention task during fMRI scanning were included in the final review. The search was conducted on September 10th, 2013. 15 fMRI studies met our inclusion criteria: 12 studies were focused on Schizophrenia and 3 on Bipolar Disorder Type I (BDI). Only half of the Schizophrenia studies and two of the BDI studies reported behavioral abnormalities, but all of them evidenced significant functional differences in brain regions related to the sustained attention system. Altered functioning of the insula was found in both Schizophrenia and BDI, and therefore proposed as a candidate trait marker for psychosis in general. On the other hand, other brain regions were differently impaired in affective and non-affective psychosis: alterations of cingulate cortex and thalamus seemed to be more common in Schizophrenia and amygdala dysfunctions in BDI. Neural correlates of sustained attention seem to be of great interest in the study of psychosis, highlighting differences and similarities between Schizophrenia and BDI.
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Takebayashi H, Yamamoto N, Umino A, Nishikawa T. Identification of developmentally regulated PCP-responsive non-coding RNA, prt6, in the rat thalamus. PLoS One 2014; 9:e97955. [PMID: 24886782 PMCID: PMC4041572 DOI: 10.1371/journal.pone.0097955] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Accepted: 04/26/2014] [Indexed: 12/19/2022] Open
Abstract
Schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, usually develop after adolescence. Moreover, adult-type behavioral disturbance following NMDA receptor antagonist application in rodents is observed after a critical period at around 3 postnatal weeks. These observations suggest that the schizophrenic symptoms caused by and psychotomimetic effects of NMDA antagonists require the maturation of certain brain neuron circuits and molecular networks, which differentially respond to NMDA receptor antagonists across adolescence and the critical period. From this viewpoint, we have identified a novel developmentally regulated phencyclidine-responsive transcript from the rat thalamus, designated as prt6, as a candidate molecule involved in the above schizophrenia-related systems using a DNA microarray technique. The transcript is a non-coding RNA that includes sequences of at least two microRNAs, miR132 and miR212, and is expressed strongly in the brain and testis, with trace or non-detectable levels in the spleen, heart, liver, kidney, lung and skeletal muscle, as revealed by Northern blot analysis. The systemic administration of PCP (7.5 mg/kg, subcutaneously (s.c.)) significantly elevated the expression of prt6 mRNA in the thalamus at postnatal days (PD) 32 and 50, but not at PD 8, 13, 20, or 24 as compared to saline-treated controls. At PD 50, another NMDA receptor antagonist, dizocilpine (0.5 mg/kg, s.c.), and a schizophrenomimetic dopamine agonist, methamphetamine (4.8 mg/kg, s.c.), mimicked a significant increase in the levels of thalamic prt6 mRNAs, while a D2 dopmamine receptor antagonist, haloperidol, partly inhibited the increasing influence of PCP on thalamic prt6 expression without its own effects. These data indicate that prt6 may be involved in the pathophysiology of the onset of drug-induced schizophrenia-like symptoms and schizophrenia through the possible dysregulation of target genes of the long non-coding RNA or microRNAs in the transcript.
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Affiliation(s)
- Hironao Takebayashi
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Naoki Yamamoto
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Asami Umino
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Toru Nishikawa
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- * E-mail:
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Gardner RJ, Kersanté F, Jones MW, Bartsch U. Neural oscillations during non-rapid eye movement sleep as biomarkers of circuit dysfunction in schizophrenia. Eur J Neurosci 2014; 39:1091-106. [DOI: 10.1111/ejn.12533] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 01/06/2014] [Accepted: 01/29/2014] [Indexed: 12/25/2022]
Affiliation(s)
- Richard J. Gardner
- School of Physiology and Pharmacology; University of Bristol; Medical Sciences Building University Walk Bristol BS8 1TD UK
| | - Flavie Kersanté
- School of Physiology and Pharmacology; University of Bristol; Medical Sciences Building University Walk Bristol BS8 1TD UK
| | - Matthew W. Jones
- School of Physiology and Pharmacology; University of Bristol; Medical Sciences Building University Walk Bristol BS8 1TD UK
| | - Ullrich Bartsch
- School of Physiology and Pharmacology; University of Bristol; Medical Sciences Building University Walk Bristol BS8 1TD UK
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Zhang Y, Su TP, Liu B, Zhou Y, Chou KH, Lo CY, Hung CC, Chen WL, Jiang T, Lin CP. Disrupted thalamo-cortical connectivity in schizophrenia: a morphometric correlation analysis. Schizophr Res 2014; 153:129-35. [PMID: 24529363 DOI: 10.1016/j.schres.2014.01.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 01/03/2014] [Accepted: 01/22/2014] [Indexed: 10/25/2022]
Abstract
Increasing studies have implicated the thalamus in schizophrenia, supporting the view that this structure has an important role in this disorder. Given that extensive reciprocal connections exist between the thalamus and the cerebral cortex, it is believed that disruptions of the thalamo-cortical connections may underlie the multiplicity of schizophrenic symptoms. Therefore, assessing the relationship between the thalamus and the neocortex may provide new insights into the pathophysiology of schizophrenia. We analyzed magnetic resonance images from a sample of 101 schizophrenic patients and 101 healthy controls. By assessing the correlation between the thalamic volume and cortical thickness at each vertex on the cortical surface, a thalamo-cortical network was obtained for each group. We compared the patterns of thalamo-cortical connectivity between the two groups. Compared with healthy controls, less distributed cortical regions were identified in the thalamo-cortical network in patients with schizophrenia. Vertex-wise comparison revealed decreased thalamo-cortical connectivity in bilateral inferior frontal gyrus, the left superior temporal gyrus and the right parieto-occipital region in schizophrenia. The observed disruptions in thalamo-cortical connectivity might be the substrate underlying the wide range of schizophrenic symptoms and provide further evidence to support the notion of schizophrenia as a disorder of brain dysconnectivity.
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Affiliation(s)
- Yuanchao Zhang
- School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China; National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, PR China
| | - Tung-Ping Su
- Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei 11221, Taiwan
| | - Bing Liu
- National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, PR China
| | - Yuan Zhou
- Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, PR China; Magnetic Resonance Imaging Research Center, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Kun-Hsien Chou
- Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan
| | - Chun-Yi Lo
- Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan
| | - Chia-Chun Hung
- Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei 11221, Taiwan; Department of Psychiatry, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Wei-Ling Chen
- Department of Psychiatry, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Tianzi Jiang
- School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China; National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, PR China.
| | - Ching-Po Lin
- Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei 11221, Taiwan.
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Thong JYJ, Qiu A, Sum MY, Kuswanto CN, Tuan TA, Donohoe G, Sitoh YY, Sim K. Effects of the neurogranin variant rs12807809 on thalamocortical morphology in schizophrenia. PLoS One 2013; 8:e85603. [PMID: 24386483 PMCID: PMC3875583 DOI: 10.1371/journal.pone.0085603] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 11/28/2013] [Indexed: 12/31/2022] Open
Abstract
Although the genome wide supported psychosis susceptibility neurogranin (NRGN) gene is expressed in human brains, it is unclear how it impacts brain morphology in schizophrenia. We investigated the influence of NRGN rs12807809 on cortical thickness, subcortical volumes and shapes in patients with schizophrenia. One hundred and fifty six subjects (91 patients with schizophrenia and 65 healthy controls) underwent structural MRI scans and their blood samples were genotyped. A brain mapping algorithm, large deformation diffeomorphic metric mapping, was used to perform group analysis of subcortical shapes and cortical thickness. Patients with risk TT genotype were associated with widespread cortical thinning involving frontal, parietal and temporal cortices compared with controls with TT genotype. No volumetric difference in subcortical structures (hippocampus, thalamus, amygdala, basal ganglia) was observed between risk TT genotype in patients and controls. However, patients with risk TT genotype were associated with thalamic shape abnormalities involving regions related to pulvinar and medial dorsal nuclei. Our results revealed the influence of the NRGN gene on thalamocortical morphology in schizophrenia involving widespread cortical thinning and thalamic shape abnormalities. These findings help to clarify underlying NRGN mediated pathophysiological mechanisms involving cortical-subcortical brain networks in schizophrenia.
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Affiliation(s)
- Jamie Yu Jin Thong
- Department of Bioengineering, National University of Singapore, Singapore
| | - Anqi Qiu
- Department of Bioengineering, National University of Singapore, Singapore
- Clinical Imaging Research Center, National University of Singapore, Singapore
- Singapore Institute for Clinical Sciences, the Agency for Science, Technology and Research, Singapore
- * E-mail:
| | - Min Yi Sum
- Research Division, Institute of Mental Health, Singapore
| | | | - Ta Ahn Tuan
- Department of Bioengineering, National University of Singapore, Singapore
| | - Gary Donohoe
- Department of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Republic of Ireland
| | - Yih Yian Sitoh
- Department of Neuroradiology, National Neuroscience Institute, Singapore
| | - Kang Sim
- Research Division, Institute of Mental Health, Singapore
- Department of General Psychiatry, Institute of Mental Health, Singapore
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Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice. Brain Struct Funct 2013; 220:71-83. [DOI: 10.1007/s00429-013-0638-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 09/10/2013] [Indexed: 10/26/2022]
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Bai J, Abdul-Rahman MF, Rifkin-Graboi A, Chong YS, Kwek K, Saw SM, Godfrey KM, Gluckman PD, Fortier MV, Meaney MJ, Qiu A. Population differences in brain morphology and microstructure among Chinese, Malay, and Indian neonates. PLoS One 2012; 7:e47816. [PMID: 23112850 PMCID: PMC3480429 DOI: 10.1371/journal.pone.0047816] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 09/17/2012] [Indexed: 11/18/2022] Open
Abstract
We studied a sample of 75 Chinese, 73 Malay, and 29 Indian healthy neonates taking part in a cohort study to examine potential differences in neonatal brain morphology and white matter microstructure as a function of ethnicity using both structural T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). We first examined the differences in global size and morphology of the brain among the three groups. We then constructed the T2-weighted MRI and DTI atlases and employed voxel-based analysis to investigate ethnic differences in morphological shape of the brain from the T2-weighted MRI, and white matter microstructure measured by fractional anisotropy derived from DTI. Compared with Malay neonates, the brains of Indian neonates' tended to be more elongated in anterior and posterior axis relative to the superior-inferior axis of the brain even though the total brain volume was similar among the three groups. Although most anatomical regions of the brain were similar among Chinese, Malay, and Indian neonates, there were anatomical variations in the spinal-cerebellar and cortical-striatal-thalamic neural circuits among the three populations. The population-related brain regions highlighted in our study are key anatomical substrates associated with sensorimotor functions.
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Affiliation(s)
- Jordan Bai
- Department of Bioengineering, National University of Singapore, Singapore, Singapore
| | | | - Anne Rifkin-Graboi
- Singapore Institute for Clinical Sciences, the Agency for Science, Technology and Research, Singapore, Singapore
| | - Yap-Seng Chong
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
| | - Kenneth Kwek
- Department of Maternal Fetal Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Seang-Mei Saw
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Keith M. Godfrey
- Medical Research Council Lifecourse Epidemiology Unit (University of Southampton) and Southampton NIHR Nutrition Biomedical Research Centre, Southampton, United Kingdom
| | | | - Marielle V. Fortier
- Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Michael J. Meaney
- Singapore Institute for Clinical Sciences, the Agency for Science, Technology and Research, Singapore, Singapore
- Departments of Psychiatry and Neurology & Neurosurgery, McGill University, Montreal, Canada
| | - Anqi Qiu
- Department of Bioengineering, National University of Singapore, Singapore, Singapore
- Singapore Institute for Clinical Sciences, the Agency for Science, Technology and Research, Singapore, Singapore
- Clinical Imaging Research Centre, National University of Singapore, Singapore, Singapore
- * E-mail:
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Abstract
OBJECTIVE The thalamus and cerebral cortex are connected via topographically organized, reciprocal connections. Previous studies have revealed thalamic abnormalities in schizophrenia; however, it is not known whether thalamocortical networks are differentially affected in the disorder. To explore this possibility, the authors examined functional connectivity in intrinsic low-frequency blood-oxygen-level-dependent (BOLD) signal fluctuations between major divisions of the cortex and thalamus using resting-state functional MRI (fMRI). METHOD Seventy-seven healthy subjects and 62 patients with schizophrenia underwent resting-state fMRI. To identify functional subdivisions of the thalamus, the authors parceled the cortex into six regions of interest: the prefrontal cortex, motor cortex/supplementary motor area, somatosensory cortex, temporal lobe, posterior parietal cortex, and occipital lobe. Mean BOLD time series were extracted for each region of interest and entered into a seed-based functional connectivity analysis. RESULTS Consistent with previous reports, activity in distinct cortical areas correlated with specific, largely nonoverlapping regions of the thalamus in both healthy comparison subjects and schizophrenia patients. Direct comparison between groups revealed reduced prefrontal-thalamic connectivity and increased motor/somatosensory-thalamic connectivity in schizophrenia. The changes in connectivity were unrelated to local gray matter content within the thalamus and to antipsychotic medication dosage. No differences were observed in temporal, posterior parietal, or occipital cortex connectivity with the thalamus. CONCLUSIONS These findings establish differential abnormalities of thalamocortical networks in schizophrenia. The etiology of schizophrenia may disrupt the development of prefrontal-thalamic connectivity and refinement of somatomotor connectivity with the thalamus that occurs during brain maturation.
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Welch KA, Stanfield AC, McIntosh AM, Whalley HC, Job DE, Moorhead TW, Owens DGC, Lawrie SM, Johnstone EC. Impact of cannabis use on thalamic volume in people at familial high risk of schizophrenia. Br J Psychiatry 2011; 199:386-90. [PMID: 21903664 DOI: 10.1192/bjp.bp.110.090175] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND No longitudinal study has yet examined the association between substance use and brain volume changes in a population at high risk of schizophrenia. AIMS To examine the effects of cannabis on longitudinal thalamus and amygdala-hippocampal complex volumes within a population at high risk of schizophrenia. METHOD Magnetic resonance imaging scans were obtained from individuals at high genetic risk of schizophrenia at the point of entry to the Edinburgh High-Risk Study (EHRS) and approximately 2 years later. Differential thalamic and amygdala-hippocampal complex volume change in high-risk individuals exposed (n = 25) and not exposed (n = 32) to cannabis in the intervening period was investigated using repeated-measures analysis of variance. RESULTS Cannabis exposure was associated with bilateral thalamic volume loss. This effect was significant on the left (F = 4.47, P = 0.04) and highly significant on the right (F= 7.66, P= 0.008). These results remained significant when individuals using other illicit drugs were removed from the analysis. CONCLUSIONS These are the first longitudinal data to demonstrate an association between thalamic volume loss and exposure to cannabis in currently unaffected people at familial high risk of developing schizophrenia. This observation may be important in understanding the link between cannabis exposure and the subsequent development of schizophrenia.
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Affiliation(s)
- Killian A Welch
- Robert Ferguson Unit, Astley Ainslee Hospital, Edinburgh and Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.
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Kurnianingsih YA, Kuswanto CN, McIntyre RS, Qiu A, Ho BC, Sim K. Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. J Neural Transm (Vienna) 2011; 118:1621-39. [DOI: 10.1007/s00702-011-0672-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 06/05/2011] [Indexed: 04/08/2023]
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Smith MJ, Wang L, Cronenwett W, Mamah D, Barch DM, Csernansky JG. Thalamic morphology in schizophrenia and schizoaffective disorder. J Psychiatr Res 2011; 45:378-85. [PMID: 20797731 PMCID: PMC2996474 DOI: 10.1016/j.jpsychires.2010.08.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Revised: 07/28/2010] [Accepted: 08/03/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND Biomarkers are needed that can distinguish between schizophrenia and schizoaffective disorder to inform the ongoing debate over the diagnostic boundary between these two disorders. Neuromorphometric abnormalities of the thalamus have been reported in individuals with schizophrenia and linked to core features of the disorder, but have not been similarly investigated in individuals with schizoaffective disorder. In this study, we examine whether individuals with schizoaffective disorder have a pattern of thalamic deformation that is similar or different to the pattern found in individuals with schizophrenia. METHOD T1-weighted magnetic resonance images were collected from individuals with schizophrenia (n = 47), individuals with schizoaffective disorder (n = 15), and controls (n = 42). Large-deformation, high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. Multiple analyses of variance were used to test for group differences in volume and measures of surface shape. RESULTS Individuals with schizophrenia or schizoaffective disorder have similar thalamic volumes. Thalamic surface shape deformation associated with schizophrenia suggests selective involvement of the anterior and posterior thalamus, while deformations in mediodorsal and ventrolateral regions were observed in both groups. Schizoaffective disorder had distinct deformations in medial and lateral thalamic regions. CONCLUSIONS Abnormalities distinct to schizoaffective disorder suggest involvement of the central and ventroposterior medial thalamus which may be involved in mood circuitry, dorsolateral nucleus which is involved in recall processing, and the lateral geniculate nucleus which is involved in visual processing.
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Affiliation(s)
- Matthew J. Smith
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Lei Wang
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
,Department of Radiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Will Cronenwett
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Daniel Mamah
- Department of Psychiatry, Washington University, St. Louis, Missouri
| | - Deanna M. Barch
- Department of Psychiatry, Washington University, St. Louis, Missouri
,Department of Psychology, Washington University, St. Louis, Missouri
,Department of Anatomy & Neurobiology, Washington University, St. Louis, Missouri
| | - John G. Csernansky
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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37
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Dwyer ND, Manning DK, Moran JL, Mudbhary R, Fleming MS, Favero CB, Vock VM, O'Leary DDM, Walsh CA, Beier DR. A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype. Neural Dev 2011; 6:3. [PMID: 21214893 PMCID: PMC3024922 DOI: 10.1186/1749-8104-6-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Accepted: 01/07/2011] [Indexed: 12/02/2022] Open
Abstract
Background The dorsal thalamus acts as a gateway and modulator for information going to and from the cerebral cortex. This activity requires the formation of reciprocal topographic axon connections between thalamus and cortex. The axons grow along a complex multistep pathway, making sharp turns, crossing expression boundaries, and encountering intermediate targets. However, the cellular and molecular components mediating these steps remain poorly understood. Results To further elucidate the development of the thalamocortical system, we first created a thalamocortical axon reporter line to use as a genetic tool for sensitive analysis of mutant mouse phenotypes. The TCA-tau-lacZ reporter mouse shows specific, robust, and reproducible labeling of thalamocortical axons (TCAs), but not the overlapping corticothalamic axons, during development. Moreover, it readily reveals TCA pathfinding abnormalities in known cortical mutants such as reeler. Next, we performed an unbiased screen for genes involved in thalamocortical development using random mutagenesis with the TCA reporter. Six independent mutant lines show aberrant TCA phenotypes at different steps of the pathway. These include ventral misrouting, overfasciculation, stalling at the corticostriatal boundary, and invasion of ectopic cortical cell clusters. An outcross breeding strategy coupled with a genomic panel of single nucleotide polymorphisms facilitated genetic mapping with small numbers of mutant mice. We mapped a ventral misrouting mutant to the Emx2 gene, and discovered that some TCAs extend to the olfactory bulbs in this mutant. Mapping data suggest that other lines carry mutations in genes not previously known for roles in thalamocortical development. Conclusions These data demonstrate the feasibility of a forward genetic approach to understanding mammalian brain morphogenesis and wiring. A robust axonal reporter enabled sensitive analysis of a specific axon tract inside the mouse brain, identifying mutant phenotypes at multiple steps of the pathway, and revealing a new aspect of the Emx2 mutant. The phenotypes highlight vulnerable choice points and latent tendencies of TCAs, and will lead to a refined understanding of the elements and interactions required to form the thalamocortical system. See Commentary: http://www.biomedcentral.com/1741-7007/9/1
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Affiliation(s)
- Noelle D Dwyer
- Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
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Spoletini I, Cherubini A, Banfi G, Rubino IA, Peran P, Caltagirone C, Spalletta G. Hippocampi, thalami, and accumbens microstructural damage in schizophrenia: a volumetry, diffusivity, and neuropsychological study. Schizophr Bull 2011; 37:118-30. [PMID: 19542526 PMCID: PMC3004185 DOI: 10.1093/schbul/sbp058] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Volumetric abnormalities in the subcortical structures have been described in schizophrenia. However, it still has to be clarified if subtle microstructural damage is also present. Thus, we aimed to detect subcortical volume and mean diffusivity (MD) alterations in 45 patients with diagnosis of schizophrenia compared with 45 age-, gender-, and educational attainment-matched healthy comparison (HC) participants, by using a combined volumetry and diffusion tensor imaging (DTI) method. A secondary aim was to identify the neuropsychological correlates of subcortical abnormalities in the schizophrenic group. We found thalami and hippocampi bilaterally and left accumbens to show MD increase in the schizophrenic group. No volumetric decrease was found. Moreover, significant correlations between the MD values in subcortical structures (right thalamus and hippocampus and left accumbens) and working memory performance were found. Thus, subcortical microstructural alterations are present in schizophrenia even in absence of volumetric abnormalities. Furthermore, microstructural damage in subcortical areas is linked to working memory, suggesting the presence of a subtle microstructural subcortical dysfunction in the pathoetiological mechanism underlying high cognitive load performances in schizophrenia. Finally, our findings indicate that MD is a more sensitive marker of brain tissue deficits than signal intensity variations measured in T1-weighted imaging data, consistently with previous reports. Thus, DTI appears to be an invaluable tool to investigate subcortical pathology in schizophrenia, greatly enhancing the ability to detect subtle brain changes in this complex disorder.
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Affiliation(s)
- Ilaria Spoletini
- Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy
| | - Andrea Cherubini
- Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy
| | - Giulia Banfi
- Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy
| | - Ivo Alex Rubino
- Department of Neuroscience, Tor Vergata University, Rome, Italy
| | - Patrice Peran
- Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy
| | - Carlo Caltagirone
- Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy,Department of Neuroscience, Tor Vergata University, Rome, Italy
| | - Gianfranco Spalletta
- Department of Neuroscience, Tor Vergata University, Rome, Italy,To whom correspondence should be addressed; Laboratory of Clinical and Behavioural Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Via Ardeatina 306. 00179 Rome, Italy; tel: +39-06-51501575, fax: +39-06-51501575, e-mail:
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Rao NP, Kalmady S, Arasappa R, Venkatasubramanian G. Clinical correlates of thalamus volume deficits in anti-psychotic-naïve schizophrenia patients: A 3-Tesla MRI study. Indian J Psychiatry 2010; 52:229-35. [PMID: 21180407 PMCID: PMC2990822 DOI: 10.4103/0019-5545.70975] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Thalamus, the sensory and motor gateway to the cortex, plays an important role in cognitive and perceptual disturbances in schizophrenia. Studies examining the volume of the thalamus in schizophrenia have reported conflicting findings due to the presence of potential confounding factors such as low-resolution imaging and anti-psychotics. The thalamus volume in anti-psychotic-naïve patients determined using high-resolution 3-Tesla magnetic resonance imaging (MRI) has not yet been examined. MATERIALS AND METHODS Using 3-Tesla MRI, this study for the first time examined anti-psychotic-naïve schizophrenia patients (n=18; M:F:11:7) in comparison with healthy controls (n=19;M:F:9:10) group-matched for age, sex, handedness, education, and socioeconomic status. The volume of the thalamus was measured using a three-dimensional, interactive, semi-automated analysis with good inter-rater and intra-rater reliability. Psychopathology was assessed using the Scale for Assessment of Negative Symptoms (SANS) and the Scale for Assessment of Positive Symptoms (SAPS). RESULTS Right, left, and total thalamus volumes of patients were significantly smaller than those of controls after controlling for the potential confounding effect of intracranial volume. Thalamus volumes had significant positive correlation with positive symptoms score (SAPS) and significant negative correlation with negative symptoms score (SANS). CONCLUSIONS Thalamus volume deficits in anti-psychotic-naïve schizophrenia patients support a neurodevelopmental pathogenesis. The contrasting correlation of thalamus volume deficits with psychopathology scores suggests that contrasting pruning aberrations underlie symptom genesis in schizophrenia.
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Affiliation(s)
- Naren P. Rao
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029, India
| | - Sunil Kalmady
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029, India
| | - Rashmi Arasappa
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029, India
| | - Ganesan Venkatasubramanian
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029, India
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40
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Leube DT, Knoblich G, Erb M, Schlotterbeck P, Kircher TTJ. The neural basis of disturbed efference copy mechanism in patients with schizophrenia. Cogn Neurosci 2010; 1:111-7. [PMID: 24168277 DOI: 10.1080/17588921003646156] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Core psychopathological symptoms in patients with schizophrenia suggest that their sense of self may be disturbed. A disturbance in predictive motor mechanisms may be the cause of such symptoms. Ten patients with schizophrenia and ten healthy right-handed control subjects opened and closed their hand. This movement was filmed with an MRI compatible video camera and projected online onto a monitor. BOLD contrast was measured with fMRI. The temporal delay between movement and feedback was parametrically varied. Participants judged whether or not there was a delay. Patients were less sensitive to these delays than a matched control group. Comparing neural activation between the two groups showed a reduced attenuation of movement-sensitive perceptual areas in patients with increasing delay and a higher activation in the putamen in controls. The results provide further evidence that impaired efference copy mechanisms may contribute to the pathogenesis of schizophrenia and its first rank symptoms.
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Abstract
The thalamus plays a critical role in the coordination of information as it passes from region to region within the brain. A disruption of that information flow may give rise to some of the cardinal symptoms of schizophrenia. In support of this hypothesis, schizophrenia-like syndromes emerge when illnesses, such as stroke, selectively damage the thalamus while sparing the rest of the brain. Evidence from many sources has implicated thalamic dysfunction in schizophrenia. In postmortem studies, several subregions of the thalamus, including the mediodorsal nucleus and the pulvinar, have been shown to have fewer neurons in schizophrenia. Neurochemical disturbances are also seen, with changes in both the glutamate and dopamine systems; thalamic glutamate receptor expression is altered in schizophrenia, and dopamine appears to be elevated in thalamic subregions, while evidence exists of an imbalance between dopamine and other neurotransmitters. In vivo studies using magnetic resonance imaging have demonstrated smaller thalamic volumes in schizophrenia, as well as shape deformations suggesting changes in those thalamic regions that are most densely connected to the portions of the brain responsible for executive function and sensory integration. These changes seem to be correlated with clinical symptoms. The thalamus is a starting point for several parallel, overlapping networks that extend from thalamic nuclei to the cortex. Evidence is emerging that changes in the thalamic nodes of these networks are echoed by changes at other points along the chain; this suggests that schizophrenia might be a disease of disrupted thalamocortical neural networks. This model distributes the pathology throughout the network, but also concentrates attention on the thalamus as a critical structure, especially because of its role in coordinating the flow of information within and between neural networks.
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Affiliation(s)
- Will J Cronenwett
- Psychiatry and Behavioral Sciences, Northwestern University, 446 E. Ontario, Suite 7-200, Chicago, IL 60611, USA.
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Pakkenberg B, Scheel-Krüger J, Kristiansen LV. Schizophrenia; from structure to function with special focus on the mediodorsal thalamic prefrontal loop. Acta Psychiatr Scand 2009; 120:345-54. [PMID: 19807715 DOI: 10.1111/j.1600-0447.2009.01447.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To describe structural and biochemical evidence from postmortem brains that implicates the reciprocal connections between the mediodorsal thalamic nucleus and the prefrontal cortex in cognitive symptoms of schizophrenia. METHOD The estimation of the regional volumes and cell numbers was obtained using stereological methods. The biochemical analyses of molecular expression in postmortem brain involve quantitative measurement of transcripts and proteins by in-situ (RNA) or Western blot/autoradiography in brains from patients with schizophrenia and comparison subjects. RESULTS Stereological studies in postmortem brain from patients with schizophrenia have reported divergent and often opposing findings in the total number of neurons and volume of the mediodorsal (MD) thalamic nucleus, and to a lesser degree in its reciprocally associated areas of the prefrontal cortex. Similarly, quantitative molecular postmortem studies have found large inter-subject and between-study variance at both the transcript and protein levels for receptors and their interacting molecules of several neurotransmitter systems in these interconnected anatomical regions. Combined, large variation in stereological and molecular studies indicates a complex and heterogeneous involvement of the MD thalamic-prefrontal loop in schizophrenia. CONCLUSION Based on a considerable heterogeneity in patients suffering from schizophrenia, large variation in postmortem studies, including stereological and molecular postmortem studies of the MD thalamus and frontal cortex, might be expected and may in fact partly help to explain the variable endophenotypic traits associated with this severe psychiatric illness.
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Affiliation(s)
- B Pakkenberg
- Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, Copenhagen, Denmark.
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Qiu A, Zhong J, Graham S, Chia MY, Sim K. Combined analyses of thalamic volume, shape and white matter integrity in first-episode schizophrenia. Neuroimage 2009; 47:1163-71. [DOI: 10.1016/j.neuroimage.2009.04.027] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2009] [Revised: 03/26/2009] [Accepted: 04/08/2009] [Indexed: 11/15/2022] Open
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Takebayashi H, Yamamoto N, Umino A, Nishikawa T. Developmentally regulated and thalamus-selective induction of leiomodin2 gene by a schizophrenomimetic, phencyclidine, in the rat. Int J Neuropsychopharmacol 2009; 12:1111-26. [PMID: 19254430 DOI: 10.1017/s1461145709009997] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The onset of schizophrenia and the schizophrenomimetic effects of an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, rarely occur during infancy and childhood, suggesting that schizophrenia-related neuron circuits and molecules in the brain might show an age-related response to an NMDA receptor antagonist. By using a DNA microarray technique, we have identified the developmentally regulated PCP-inducible gene leiomodin2 (Lmod2) that encodes a tropomyosin-binding actin-capping protein enriched in the cardiac and skeletal muscles. PCP caused an increase in the thalamic amounts of Lmod2 transcripts at postnatal days (PD) 32 and 50 without affecting them at PD 8, 13, 20 and 24, while the NMDA antagonist failed to produce a significant change in the gene expression in the adult heart. In-situ hybridization analysis revealed that the basal and PCP-induced expression of the Lmod2 gene is almost confined to the lateral and anterior nuclei of the thalamus among the brain regions at PD 50. The PCP-induced up-regulation of Lmod2 mRNAs in the adult thalamus was mimicked totally (also up-regulated) by another NMDA antagonist, dizocilpine, and partly by the indirect dopamine agonist, methamphetamine. Moreover, pretreatment with a D(2)-preferring dopamine receptor antagonist, haloperidol, partially antagonizes the increasing effects of PCP on thalamic Lmod2 gene expression. These findings suggest that Lmod2 might be involved in the pathophysiology of the age-dependent onset of drug-induced schizophrenia-like psychosis and schizophrenia and that the limited thalamic nuclei expressing the Lmod2 gene could compose the neuron circuits that are specifically disturbed in these mental disorders.
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Affiliation(s)
- Hironao Takebayashi
- Section of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
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45
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Sepede G, Ferretti A, Perrucci MG, Gambi F, Di Donato F, Nuccetelli F, Del Gratta C, Tartaro A, Salerno RM, Ferro FM, Romani GL. Altered brain response without behavioral attention deficits in healthy siblings of schizophrenic patients: an event-related fMRI study. Neuroimage 2009; 49:1080-90. [PMID: 19646537 DOI: 10.1016/j.neuroimage.2009.07.053] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2009] [Revised: 07/10/2009] [Accepted: 07/21/2009] [Indexed: 01/03/2023] Open
Abstract
Attention deficits are common in schizophrenics and sometimes reported in their healthy relatives. The aim of this study was to analyse the behavioural performance and the brain activation of healthy siblings of schizophrenic patients during a sustained-attention task. Eleven healthy siblings of schizophrenic patients and eleven matched controls performed a Continuous Performance Test (CPT), during 1.5 T fMRI. The stimuli were presented at three difficulty-levels, using different degrees of degradation (0, 25 and 40%). There were no significant differences in CPT performance (mean reaction time and percentage of errors) between the two groups. Performance worsened with increasing degradation in both groups. Differences were found when comparing the BOLD signal change in the medial frontal gyrus/dorsal anterior cingulate, right precentral gyrus, bilateral posterior cingulate and bilateral insula. The most evident between group differences were observed in the left insula/inferior frontal gyrus: siblings showed a larger activation during wrong responses and a reduced activation during correct responses in the degraded runs. In conclusion, healthy siblings of schizophrenic patients showed differences in brain function in several brain regions previously reported in schizophrenic subjects, in the absence of behavioral attention deficits. The differences were greater in the two more difficult levels of attention demand and might be expressions of altered and/or compensatory mechanisms in subjects at increased risk for schizophrenia.
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Affiliation(s)
- Gianna Sepede
- Department of Clinical Sciences and Bio-imaging, G. D'Annunzio University of Chieti, Via dei Vestini 33, Chieti Scalo (CH), Italy.
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Arikan MK, Kütükcü A, Karay A, Ozmen M. A case of psychosis associated with left thalamic lacunar infarcts. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:729-30. [PMID: 19303042 DOI: 10.1016/j.pnpbp.2009.02.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2009] [Revised: 02/26/2009] [Accepted: 02/27/2009] [Indexed: 11/30/2022]
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Sim K, Yang GL, Loh D, Poon LY, Sitoh YY, Verma S, Keefe R, Collinson S, Chong SA, Heckers S, Nowinski W, Pantelis C. White matter abnormalities and neurocognitive deficits associated with the passivity phenomenon in schizophrenia: a diffusion tensor imaging study. Psychiatry Res 2009; 172:121-7. [PMID: 19297135 DOI: 10.1016/j.pscychresns.2009.02.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2008] [Revised: 02/04/2009] [Accepted: 02/10/2009] [Indexed: 11/19/2022]
Abstract
The passivity phenomenon is a distressing Schneiderian first rank symptom in patients with schizophrenia. Based on extant data of functional and structural cerebral changes underlying passivity, we sought to examine cerebral white matter integrity in our subjects. We hypothesised that the passivity phenomenon would be associated with white matter changes in specific cortical (frontal, parietal cortices, and cingulate gyrus) and subcortical regions (thalamus and basal ganglia) and correlated with relevant neurocognitive deficits, compared with characteristics in those without the passivity phenomenon. Thirty-six subjects (11 with passivity and 25 without passivity) with schizophrenia were compared with 32 age-, gender- and handedness-matched healthy controls using diffusion tensor imaging. Neuropsychological testing was administered. Patients with passivity were associated with increased fractional anisotropy within the frontal cortex, cingulate gyrus, and basal ganglia and decreased fractional anisotropy within the thalamus when compared with patients without passivity. Within patients with passivity, fractional anisotropy in the frontal cortex correlated with the age of onset of illness and neurocognitive deficits related to attention and executive functioning. The findings suggest distributed involvement of cortical and subcortical regions underlying passivity and support the notion of neural network models underlying specific psychiatric symptoms such as passivity.
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Affiliation(s)
- Kang Sim
- Department of General Psychiatry, Woodbridge Hospital, Institute of Mental Health, 10, Buangkok View, 539747 Singapore.
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Chan WY, Chia MY, Yang GL, Woon PS, Sitoh YY, Collinson SL, Nowinski WL, Sim K. Duration of Illness, Regional Brain Morphology and Neurocognitive Correlates in Schizophrenia. ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2009. [DOI: 10.47102/annals-acadmedsg.v38n5p388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Introduction: Previous studies examining brain effects of duration of illness in schizophrenia have focused on either cortical or subcortical structures. Hence this study sought to elucidate the regional grey matter changes (both cortical and subcortical) and neurocognitive correlates with increased duration of illness in a large sample of patients with schizophrenia using voxel-based morphometry.
Materials and Methods: Ninety patients (72 males and 18 females) with DSM-IV diagnosis of schizophrenia were recruited and assessed using magnetic resonance imaging and a battery of neuropsychological tests.
Results: A longer duration of illness was associated with smaller grey matter volumes in the left superior frontal gyrus, bilateral putamen, right superior temporal gyrus, right superior occipital gyrus as well as the right thalamus. No region showed increased grey matter volume above threshold with longer duration of illness. Longer duration of illness was correlated with poorer attention.
Conclusions: The grey matter reductions in different brain regions highlighted that a distributed network of cortical and subcortical regions was associated with duration of illness. This is consistent with neural models that implicate involvement of thalamo-cortical circuitry as the disruption in these neural pathways can result in specific deficits such as poorer attention. The results have implications for the understanding of brain changes in schizophrenia, and with further studies, may guide better tailored and targeted clinical management in terms of reducing the impact of duration of illness on neural substrates in schizophrenia in the future.
Key words: Duration of Illness, Grey Matter, Magnetic resonance imaging, Voxel-based Morphometry
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Affiliation(s)
| | | | | | | | | | | | | | - Kang Sim
- Woodbridge Hospital/ Institute of Mental Health, Singapore
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Abstract
While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.
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Byne W, Hazlett EA, Buchsbaum MS, Kemether E. The thalamus and schizophrenia: current status of research. Acta Neuropathol 2009; 117:347-68. [PMID: 18604544 DOI: 10.1007/s00401-008-0404-0] [Citation(s) in RCA: 167] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2008] [Revised: 06/09/2008] [Accepted: 06/10/2008] [Indexed: 12/21/2022]
Abstract
The thalamus provides a nodal link for multiple functional circuits that are impaired in schizophrenia (SZ). Despite inconsistencies in the literature, a meta analysis suggests that the volume of the thalamus relative to that of the brain is decreased in SZ. Morphometric neuroimaging studies employing deformation, voxel-based and region of interest methodologies suggest that the volume deficit preferentially affects the thalamic regions containing the anterior and mediodorsal nuclei, and the pulvinar. Postmortem design-based stereological studies have produced mixed results regarding volume and neuronal deficits in these nuclei. This review examines those aspects of thalamic circuitry and function that suggest salience to SZ. Evidence for anomalies of thalamic structure and function obtained from postmortem and neuroimaging studies is then examined and directions for further research proposed.
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Affiliation(s)
- William Byne
- Department of Psychiatry, James J Peters VA Medical Center, Research Bldg. Room 2F39, Bronx, NY 10468, USA.
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