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Schwefel MK, Kaufmann C, Gutmann G, Henze R, Fydrich T, Rapp MA, Ströhle A, Heissel A, Heinzel S. Effect of physical exercise training on neural activity during working memory in major depressive disorder. J Affect Disord 2025; 372:269-278. [PMID: 39638060 DOI: 10.1016/j.jad.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 11/28/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Deficits in working memory (WM) are common in patients with Major Depression Disorder (MDD). Previous research mainly in healthy adults indicated that physical exercise training may improve cognitive functions by stimulating neuronal plasticity particularly in hippocampal structures. Thus, the goal of this functional Magnetic Resonance Imaging (fMRI) study was to examine alterations in neuronal activity during a WM task and to investigate changes in brain volume and functioning following a physical exercise training in patients with MDD with a specific focus on hippocampal structures. METHODS 86 (39 female) MDD outpatients (average age 37.3), diagnosed by clinical psychologists, were randomly assigned to one of three groups for a 12-week intervention: High intensity exercise training (HEX), low intensity exercise training (LEX) or waiting list control group (WL). An n-back task (with WM loads of 0, 1, 2, and 3) during fMRI was conducted before and after interventions/waiting period. RESULTS Both exercise groups showed better performance and shorter reaction times at higher WM loads after 12-weeks of physical exercise training. Specifically in the HEX, we found an improvement in physical fitness and an increase in neural activation in the left hippocampus as compared to the WL following the exercise training. Training-related structural volume changes in gray matter or hippocampus were not detected. CONCLUSIONS Our results partly support the hypothesis that physical exercise training positively affects WM functions by improving neuronal plasticity in hippocampal regions. Exercise training seems to be a promising intervention to improve deficient WM performance in patients with MDD. CLINICAL TRIALS REGISTRATION NAME Neurobiological correlates and mechanisms of the augmentation of psychotherapy with endurance exercise in mild to moderate depression - SPeED, http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00008869, DRKS00008869.
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Affiliation(s)
- M K Schwefel
- Clinical Psychology and Psychotherapy, Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany.
| | - C Kaufmann
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - G Gutmann
- Clinical Psychology and Psychotherapy, Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany
| | - R Henze
- Clinical Psychology and Psychotherapy, Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - T Fydrich
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - M A Rapp
- Social and Preventive Medicine, University of Potsdam, Potsdam, Germany
| | - A Ströhle
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - A Heissel
- Social and Preventive Medicine, University of Potsdam, Potsdam, Germany
| | - S Heinzel
- Clinical Psychology and Psychotherapy, Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany; Institute of Psychology, Department of Educational Sciences and Psychology, TU Dortmund University, Dortmund, Germany
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Khalil MH, Steemers K. Housing Environmental Enrichment, Lifestyles, and Public Health Indicators of Neurogenesis in Humans: A Pilot Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2024; 21:1553. [PMID: 39767394 PMCID: PMC11675618 DOI: 10.3390/ijerph21121553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/18/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND In response to the rising mental health concerns and cognitive decline associated with the human brain's neurogenesis, which continues until the tenth decade of life but declines with age and is suppressed by poor environments, this pilot study investigates how physical environments may influence public health proxy measures of neurogenesis in humans. This pilot study focuses on the residential environment where people spend most of their time and age in place, exploring the dependency of depression, anxiety, and cognitive impairment variations on spatial and lifestyle variables. METHODS A total of 142 healthy adults in England completed a survey consisting of PHQ-8, GAD-7, and CFI questionnaires and other questions developed to capture the variance in spatial and lifestyle factors such as time spent at home, house type layout complexity, spaciousness, physical activity, routine and spatial novelty, and perceived loneliness. RESULTS Extensive time spent at home has adverse effects on all measures, while multi-storey houses perform better than single-story houses with positive correlations with physical activity and spatial novelty. Separate regression models on the variance in depression, as the most salient dependent variable and reliably associated with neurogenesis, reveal that getting out of the house explains 20.5% of the variance in depression symptoms. At the scale of the house, multi-storey houses explain 16.5% of the variance. Both percentages are closer to the effect of loneliness, which we found to explain 26.6% of the variance in depression. CONCLUSIONS The built environment appears to be significantly associated with changes in cognitive function and mental health symptoms associated with neurogenesis. This pilot study shows the equally important effect of physical and social enrichment, offering critically needed insights for neuroarchitecture and brain health research that is interested in public health.
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Khalil MH. Environmental Affordance for Physical Activity, Neurosustainability, and Brain Health: Quantifying the Built Environment's Ability to Sustain BDNF Release by Reaching Metabolic Equivalents (METs). Brain Sci 2024; 14:1133. [PMID: 39595896 PMCID: PMC11592236 DOI: 10.3390/brainsci14111133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/08/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Unlike enriched environments for rodents, human-built environments often hinder neuroplasticity through sedentary lifestyles, to which exercise can merely overcome its adverse effects. This paper introduces "environmental affordance for physical activity" to quantify the potential of spatial layout designs to stimulate activity and sustain neuroplasticity, mainly hippocampal neurogenesis. Methods: A novel framework links metabolic equivalents (METs) that can be afforded by the spatial layout of the built environment to its role in increasing the brain-derived neurotrophic factor (BDNF)-a biomarker that promotes and sustains adult hippocampal neurogenesis and synaptic plasticity. Equations are developed to assess the built environment's affordance for physical activity through BDNF changes measurable after brief exposure to the built environment for 20-35 min. Results: The developed equations are evidenced to be feasible to cause BDNF release through low- to moderate-intensity physical activity. This model provides a feasible assessment tool to test the built environment's effectiveness towards neurosustainability. Conclusions: By sustaining neurogenesis, the environmental affordance for physical activity holds promise for improving mental health and preventing cognitive decline.
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Verma R, Ganesh R, Narnoli S, Sharma P, Shrivastava NP, Dhyani I, Singhal S, Karna S. Evaluating prefrontal changes in depression using functional near-infrared spectroscopy utilizing Stroop test: A comparison with healthy controls. Indian J Psychiatry 2024; 66:1014-1023. [PMID: 39790352 PMCID: PMC11708974 DOI: 10.4103/indianjpsychiatry.indianjpsychiatry_602_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/07/2024] [Accepted: 10/25/2024] [Indexed: 01/12/2025] Open
Abstract
Background Functional near-infrared spectroscopy (fNIRS) is being increasingly utilized to visualize the brain areas involved in cognitive activity to understand the human brain better. Its portability and easy setup give it an advantage over other functional brain imaging tools. The current study utilizes fNIRS while performing a Stroop test, which is commonly used to assess the impairment of information selection in depression. Aim To compare cortical activation during the Stroop test in depressed individuals to healthy controls. Methods This cross-sectional study compared oxyhemoglobin (OxyHb) concentration changes in 39 individuals with depression to 40 healthy individuals. The Stroop test was construed in an event-related design with an intertrial interval of 2 seconds with jitter. A continuous wave fNIRS system was used for recording the cortical activity at 17 locations. Analysis of fNIRS data was done using statistical parametric mapping (SPM) for estimating general linear model (GLM) coefficients. Further analysis of the mean change of OxyHb concentrations during the 2 seconds after the presentation of congruent and incongruent stimuli was done between the groups using Mann-Whitney U test corrected for multiple comparisons with Bonferroni correction. Results While the number of errors and correct responses were similar between the groups, the reaction time for correct responses was more in the depression group in comparison to healthy individuals (t = -2.39, P = 0.01). For both healthy and depressive individuals in incongruent versus congruent task contrast, deactivation was seen in the region between the left middle frontal sulcus and frontopolar area of the brain (t = 0.41 and t = 0.21, respectively, P < 0.05). The depressed group had a higher mean change in OxyHb concentration following incongruent stimuli in comparison to the HCs (mean rank: HC = 32.63, depression = 47.56). Conclusion Our findings indicate that individuals with depression exhibited prolonged reaction times and distinct activation patterns of the frontal cortex compared to healthy individuals. The observed pattern of brain activation for congruent and incongruent tasks among both healthy and depressed individuals aligns with the findings of the prior studies, emphasizing the utility of fNIRS as a valuable instrument for assessing brain activity.
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Affiliation(s)
- Rohit Verma
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Ragul Ganesh
- Department of Psychiatry, JIPMER, Puducherry, India
| | - Shubham Narnoli
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Panna Sharma
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Neha P. Shrivastava
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Ishita Dhyani
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Sonali Singhal
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - Stuti Karna
- Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
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Yang H, Chen Y, Tao Q, Shi W, Tian Y, Wei Y, Li S, Zhang Y, Han S, Cheng J. Integrative molecular and structural neuroimaging analyses of the interaction between depression and age of onset: A multimodal magnetic resonance imaging study. Prog Neuropsychopharmacol Biol Psychiatry 2024; 134:111052. [PMID: 38871019 DOI: 10.1016/j.pnpbp.2024.111052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/30/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024]
Abstract
Depression is a neurodevelopmental disorder that exhibits progressive gray matter volume (GMV) atrophy. Research indicates that brain development is influential in depression-induced GMV alterations. However, the interaction between depression and age of onset is not well understood by the underlying molecular and neuropathological mechanisms. Thus, 152 first-episode depression individuals and matched 130 healthy controls (HCs) were recruited to undergo T1-weighted high-resolution magnetic resonance imaging for this study. By two-way ANOVA, age and diagnosis were used as factors when analyzing the interaction of GMV in the participants. Then, spatial correlations between neurotransmitter maps and factor-related volume maps are established. Results illustrate a pronounced antagonistic interaction between depression and age of onset in the right insula, superior temporal gyrus, anterior cingulate gyrus, and orbitofrontal gyrus. Depression-caused reductions in GMV are mainly distributed in thalamic-limbic-cortical regions, regardless of age. For the main effect of age, adults exhibit brain atrophy in frontal, cerebellum, parietal, and temporal lobe structures. Cross-modal correlations showed that GMV changes in the interactive regions were linked with the serotonergic system and dopaminergic systems. Summarily, our results reveal the interaction between depression and age of onset in neurobiological mechanisms, which provide hints for future treatment of different ages of depression.
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Affiliation(s)
- Huiting Yang
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China
| | - Yuan Chen
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China
| | - Qiuying Tao
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China
| | - Wenqing Shi
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China
| | - Ya Tian
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China
| | - Yarui Wei
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China
| | - Shuying Li
- Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Zhang
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China.
| | - Shaoqiang Han
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China.
| | - Jingliang Cheng
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of brain function and cognitive magnetic resonance imaging, Zhengzhou, China; Henan Engineering Technology Research Center for detection and application of brain function, Zhengzhou, China; Henan Engineering Research Center of medical imaging intelligent diagnosis and treatment, Zhengzhou, China; Henan key laboratory of imaging intelligence research, Zhengzhou, China; Henan Engineering Research Center of Brain Function Development and Application, Zhengzhou, China.
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Jindal M, Chhetri A, Ludhiadch A, Singh P, Peer S, Singh J, Brar RS, Munshi A. Neuroimaging Genomics a Predictor of Major Depressive Disorder (MDD). Mol Neurobiol 2024; 61:3427-3440. [PMID: 37989980 DOI: 10.1007/s12035-023-03775-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 11/05/2023] [Indexed: 11/23/2023]
Abstract
Depression is a complex psychiatric disorder influenced by various genetic and environmental factors. Strong evidence has established the contribution of genetic factors in depression through twin studies and the heritability rate for depression has been reported to be 37%. Genetic studies have identified genetic variations associated with an increased risk of developing depression. Imaging genetics is an integrated approach where imaging measures are combined with genetic information to explore how specific genetic variants contribute to brain abnormalities. Neuroimaging studies allow us to examine both structural and functional abnormalities in individuals with depression. This review has been designed to study the correlation of the significant genetic variants with different regions of neural activity, connectivity, and structural alteration in the brain as detected by imaging techniques to understand the scope of biomarkers in depression. This might help in developing novel therapeutic interventions targeting specific genetic pathways or brain circuits and the underlying pathophysiology of depression based on this integrated approach can be established at length.
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Affiliation(s)
- Manav Jindal
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Bathinda, India
| | - Aakash Chhetri
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | - Abhilash Ludhiadch
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | - Paramdeep Singh
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Bathinda, India
| | - Sameer Peer
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Bathinda, India
| | - Jawahar Singh
- Department of Psychiatry, All India Institute of Medical Sciences, Bathinda, India
| | - Rahatdeep Singh Brar
- Department of Diagnostic and Interventional Radiology, Homi Bhabha Cancer Hospital & Research Center, Mohali, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India.
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Stoyanov D, Paunova R, Dichev J, Kandilarova S, Khorev V, Kurkin S. Functional magnetic resonance imaging study of group independent components underpinning item responses to paranoid-depressive scale. World J Clin Cases 2023; 11:8458-8474. [PMID: 38188204 PMCID: PMC10768520 DOI: 10.12998/wjcc.v11.i36.8458] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/10/2023] [Accepted: 12/05/2023] [Indexed: 12/22/2023] Open
Abstract
BACKGROUND Our study expand upon a large body of evidence in the field of neuropsychiatric imaging with cognitive, affective and behavioral tasks, adapted for the functional magnetic resonance imaging (MRI) (fMRI) experimental environment. There is sufficient evidence that common networks underpin activations in task-based fMRI across different mental disorders. AIM To investigate whether there exist specific neural circuits which underpin differential item responses to depressive, paranoid and neutral items (DN) in patients respectively with schizophrenia (SCZ) and major depressive disorder (MDD). METHODS 60 patients were recruited with SCZ and MDD. All patients have been scanned on 3T magnetic resonance tomography platform with functional MRI paradigm, comprised of block design, including blocks with items from diagnostic paranoid (DP), depression specific (DS) and DN from general interest scale. We performed a two-sample t-test between the two groups-SCZ patients and depressive patients. Our purpose was to observe different brain networks which were activated during a specific condition of the task, respectively DS, DP, DN. RESULTS Several significant results are demonstrated in the comparison between SCZ and depressive groups while performing this task. We identified one component that is task-related and independent of condition (shared between all three conditions), composed by regions within the temporal (right superior and middle temporal gyri), frontal (left middle and inferior frontal gyri) and limbic/salience system (right anterior insula). Another component is related to both diagnostic specific conditions (DS and DP) e.g. It is shared between DEP and SCZ, and includes frontal motor/language and parietal areas. One specific component is modulated preferentially by to the DP condition, and is related mainly to prefrontal regions, whereas other two components are significantly modulated with the DS condition and include clusters within the default mode network such as posterior cingulate and precuneus, several occipital areas, including lingual and fusiform gyrus, as well as parahippocampal gyrus. Finally, component 12 appeared to be unique for the neutral condition. In addition, there have been determined circuits across components, which are either common, or distinct in the preferential processing of the sub-scales of the task. CONCLUSION This study has delivers further evidence in support of the model of trans-disciplinary cross-validation in psychiatry.
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Affiliation(s)
- Drozdstoy Stoyanov
- Department of Psychiatry, Medical University Plovdiv, Plovdiv 4000, Bulgaria
| | - Rositsa Paunova
- Research Institute, Medical University, Plovdiv 4002, Bulgaria
| | - Julian Dichev
- Faculty of Medicine, Medical University, Plovdiv 4002, Bulgaria
| | - Sevdalina Kandilarova
- Department of Psychiatry and Medical Psychology, Medical University, Plovdiv 4002, Bulgaria
| | - Vladimir Khorev
- Baltic Center for Artificial Intelligence and Neurotechnology, Immanuel Kant Baltic Federal University, Kaliningrad 236041, Russia
| | - Semen Kurkin
- Baltic Center for Artificial Intelligence and Neurotechnology, Immanuel Kant Baltic Federal University, Kaliningrad 236041, Russia
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Liang J, Yu Q, Liu Y, Qiu Y, Tang R, Yan L, Zhou P. Gray matter abnormalities in patients with major depressive disorder and social anxiety disorder: a voxel-based meta-analysis. Brain Imaging Behav 2023; 17:749-763. [PMID: 37725323 PMCID: PMC10733224 DOI: 10.1007/s11682-023-00797-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND Major depressive and social anxiety disorders have a high comorbidity rate and similar cognitive patterns. However, their unique and shared neuroanatomical characteristics have not been fully identified. METHODS Voxel-based morphometric studies comparing gray matter volume between patients with major depressive disorder/social anxiety disorder and healthy controls were searched using 4 electronic databases from the inception to March 2022. Stereotactic data were extracted and subsequently tested for convergence and differences using activation likelihood estimation. In addition, based on the result of the meta-analysis, behavioral analysis was performed to assess the functional roles of the regions affected by major depressive disorder and/or social anxiety disorder. RESULTS In total, 34 studies on major depressive disorder with 2873 participants, and 10 studies on social anxiety disorder with 1004 subjects were included. Gray matter volume conjunction analysis showed that the right parahippocampal gyrus region, especially the amygdala, was smaller in patients compared to healthy controls. The contrast analysis of major depressive disorder and social anxiety disorder revealed lower gray matter volume in the right lentiform nucleus and medial frontal gyrus in social anxiety disorder and lower gray matter volume in the left parahippocampal gyrus in major depressive disorder. Behavioral analysis showed that regions with lower gray matter volume in social anxiety disorder are strongly associated with negative emotional processes. CONCLUSIONS The shared and unique patterns of gray matter volume abnormalities in patients with major depressive and social anxiety disorder may be linked to the underlying neuropathogenesis of these mental illnesses and provide potential biomarkers. PROSPERO registration number: CRD42021277546.
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Affiliation(s)
- Junquan Liang
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical Medical School of Guangzhou University of Chinese Medicine, Shenzhen, 518101, Guangdong, China
- The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qiaoyun Yu
- Jingzhou Traditional Chinese Medicine Hospital, Jingzhou, Hubei, China
| | - Yuchen Liu
- Shenzhen Luohu District Hospital of TCM, Shenzhen, Guangdong, China
| | - Yidan Qiu
- Centre for the Study of Applied Psychology, Guangdong Key Laboratory of Mental Health and Cognitive Science, School of Psychology, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong, China
| | - Rundong Tang
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical Medical School of Guangzhou University of Chinese Medicine, Shenzhen, 518101, Guangdong, China
| | - Luda Yan
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical Medical School of Guangzhou University of Chinese Medicine, Shenzhen, 518101, Guangdong, China
| | - Peng Zhou
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical Medical School of Guangzhou University of Chinese Medicine, Shenzhen, 518101, Guangdong, China.
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Zavaliangos-Petropulu A, McClintock SM, Joshi SH, Taraku B, Al-Sharif NB, Espinoza RT, Narr KL. Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment. Front Psychiatry 2023; 14:1227879. [PMID: 37876623 PMCID: PMC10590913 DOI: 10.3389/fpsyt.2023.1227879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/11/2023] [Indexed: 10/26/2023] Open
Abstract
Introduction Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Methods Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Results Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). Discussion These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.
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Affiliation(s)
- Artemis Zavaliangos-Petropulu
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
| | - Shawn M. McClintock
- Division of Psychology, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States
| | - Shantanu H. Joshi
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
| | - Brandon Taraku
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
| | - Noor B. Al-Sharif
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
| | - Randall T. Espinoza
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
| | - Katherine L. Narr
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States
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10
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Coutens B, Lejards C, Bouisset G, Verret L, Rampon C, Guiard BP. Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice. Transl Psychiatry 2023; 13:227. [PMID: 37365183 DOI: 10.1038/s41398-023-02519-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/04/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect.
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Affiliation(s)
- Basile Coutens
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Université de Toulouse, Toulouse, France
| | - Camille Lejards
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Université de Toulouse, Toulouse, France
| | - Guillaume Bouisset
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Université de Toulouse, Toulouse, France
| | - Laure Verret
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Université de Toulouse, Toulouse, France
| | - Claire Rampon
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Université de Toulouse, Toulouse, France.
| | - Bruno P Guiard
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Université de Toulouse, Toulouse, France.
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11
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Dehdar K, Salimi M, Tabasi F, Dehghan S, Sumiyoshi A, Garousi M, Jamaati H, Javan M, Reza Raoufy M. Allergen induces depression-like behavior in association with altered prefrontal-hippocampal circuit in male rats. Neuroscience 2023:S0306-4522(23)00254-3. [PMID: 37286161 DOI: 10.1016/j.neuroscience.2023.05.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 05/27/2023] [Accepted: 05/30/2023] [Indexed: 06/09/2023]
Abstract
Allergic asthma is a common chronic inflammatory condition associated with psychiatric comorbidities. Notably depression, correlated with adverse outcomes in asthmatic patients. Peripheral inflammation's role in depression has been shown previously. However, evidence regarding the effects of allergic asthma on the medial prefrontal cortex (mPFC)-ventral hippocampus (vHipp) interactions, an important neurocircuitry in affective regulation, is yet to be demonstrated. Herein, we investigated the effects of allergen exposure in sensitized rats on the immunoreactivity of glial cells, depression-like behavior, brain regions volume, as well as activity and connectivity of the mPFC-vHipp circuit. We found that allergen-induced depressive-like behavior was associated with more activated microglia and astrocytes in mPFC and vHipp, as well as reduced hippocampus volume. Intriguingly, depressive-like behavior was negatively correlated with mPFC and hippocampus volumes in the allergen-exposed group. Moreover, mPFC and vHipp activity were altered in asthmatic animals. Allergen disrupted the strength and direction of functional connectivity in the mPFC-vHipp circuit so that, unlike normal conditions, mPFC causes and modulates vHipp activity. Our results provide new insight into the underlying mechanism of allergic inflammation-induced psychiatric disorders, aiming to develop new interventions and therapeutic approaches for improving asthma complications.
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Affiliation(s)
- Kolsoum Dehdar
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Morteza Salimi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Farhad Tabasi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain Sciences and Cognition, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Samaneh Dehghan
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran; Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Akira Sumiyoshi
- Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Japan; National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
| | - Mani Garousi
- Department of Electrical and Engineering, Tarbiat Modares University, Tehran, Iran
| | - Hamidreza Jamaati
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javan
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain Sciences and Cognition, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Reza Raoufy
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain Sciences and Cognition, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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12
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Yoon S, Iqbal H, Kim SM, Jin M. Phytochemicals That Act on Synaptic Plasticity as Potential Prophylaxis against Stress-Induced Depressive Disorder. Biomol Ther (Seoul) 2023; 31:148-160. [PMID: 36694423 PMCID: PMC9970837 DOI: 10.4062/biomolther.2022.116] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023] Open
Abstract
Depression is a neuropsychiatric disorder associated with persistent stress and disruption of neuronal function. Persistent stress causes neuronal atrophy, including loss of synapses and reduced size of the hippocampus and prefrontal cortex. These alterations are associated with neural dysfunction, including mood disturbances, cognitive impairment, and behavioral changes. Synaptic plasticity is the fundamental function of neural networks in response to various stimuli and acts by reorganizing neuronal structure, function, and connections from the molecular to the behavioral level. In this review, we describe the alterations in synaptic plasticity as underlying pathological mechanisms for depression in animal models and humans. We further elaborate on the significance of phytochemicals as bioactive agents that can positively modulate stress-induced, aberrant synaptic activity. Bioactive agents, including flavonoids, terpenes, saponins, and lignans, have been reported to upregulate brain-derived neurotrophic factor expression and release, suppress neuronal loss, and activate the relevant signaling pathways, including TrkB, ERK, Akt, and mTOR pathways, resulting in increased spine maturation and synaptic numbers in the neuronal cells and in the brains of stressed animals. In clinical trials, phytochemical usage is regarded as safe and well-tolerated for suppressing stress-related parameters in patients with depression. Thus, intake of phytochemicals with safe and active effects on synaptic plasticity may be a strategy for preventing neuronal damage and alleviating depression in a stressful life.
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Affiliation(s)
- Soojung Yoon
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
| | - Hamid Iqbal
- Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sun Mi Kim
- Department of Psychiatry, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea,Department of Psychiatry, Chung-Ang University Hospital, Seoul 06973, Republic of Korea
| | - Mirim Jin
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea,Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea,Corresponding Author E-mail: , Tel: +82-32-899-6080, Fax: +82-32-899-6029
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13
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Stopyra MA, Simon JJ, Rheude C, Nikendei C. Pathophysiological aspects of complex PTSD - a neurobiological account in comparison to classic posttraumatic stress disorder and borderline personality disorder. Rev Neurosci 2023; 34:103-128. [PMID: 35938987 DOI: 10.1515/revneuro-2022-0014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 06/25/2022] [Indexed: 01/11/2023]
Abstract
Despite a great diagnostic overlap, complex posttraumatic stress disorder (CPTSD) has been recognised by the ICD-11 as a new, discrete entity and recent empirical evidence points towards a distinction from simple posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD). The development and maintenance of these disorders is sustained by neurobiological alterations and studies using functional magnetic resonance imaging (fMRI) may further contribute to a clear differentiation of CPTSD, PTSD and BPD. However, there are no existing fMRI studies directly comparing CPTSD, PTSD and BPD. In addition to a summarization of diagnostic differences and similarities, the current review aims to provide a qualitative comparison of neuroimaging findings on affective, attentional and memory processing in CPTSD, PTSD and BPD. Our narrative review alludes to an imbalance in limbic-frontal brain networks, which may be partially trans-diagnostically linked to the degree of trauma symptoms and their expression. Thus, CPTSD, PTSD and BPD may underlie a continuum where similar brain regions are involved but the direction of activation may constitute its distinct symptom expression. The neuronal alterations across these disorders may conceivably be better understood along a symptom-based continuum underlying CPTSD, PTSD and BPD. Further research is needed to amend for the heterogeneity in experimental paradigms and sample criteria.
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Affiliation(s)
- Marion A Stopyra
- Department of General Internal Medicine and Psychosomatics, Centre for Psychosocial Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Joe J Simon
- Department of General Internal Medicine and Psychosomatics, Centre for Psychosocial Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Christiane Rheude
- Department of General Internal Medicine and Psychosomatics, Centre for Psychosocial Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Christoph Nikendei
- Department of General Internal Medicine and Psychosomatics, Centre for Psychosocial Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
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14
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Watanabe K, Okamoto N, Ueda I, Tesen H, Fujii R, Ikenouchi A, Yoshimura R, Kakeda S. Disturbed hippocampal intra-network in first-episode of drug-naïve major depressive disorder. Brain Commun 2023; 5:fcac323. [PMID: 36601619 PMCID: PMC9798279 DOI: 10.1093/braincomms/fcac323] [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: 03/14/2022] [Revised: 09/27/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Complex networks inside the hippocampus could provide new insights into hippocampal abnormalities in various psychiatric disorders and dementia. However, evaluating intra-networks in the hippocampus using MRI is challenging. Here, we employed a high spatial resolution of conventional structural imaging and independent component analysis to investigate intra-networks structural covariance in the hippocampus. We extracted the intra-networks based on the intrinsic connectivity of each 0.9 mm isotropic voxel to every other voxel using a data-driven approach. With a total volume of 3 cc, the hippocampus contains 4115 voxels for a 0.9 mm isotropic voxel size or 375 voxels for a 2 mm isotropic voxel of high-resolution functional or diffusion tensor imaging. Therefore, the novel method presented in the current study could evaluate the hippocampal intra-networks in detail. Furthermore, we investigated the abnormality of the intra-networks in major depressive disorders. A total of 77 patients with first-episode drug-naïve major depressive disorder and 79 healthy subjects were recruited. The independent component analysis extracted seven intra-networks from hippocampal structural images, which were divided into four bilateral networks and three networks along the longitudinal axis. A significant difference was observed in the bilateral hippocampal tail network between patients with major depressive disorder and healthy subjects. In the logistic regression analysis, two bilateral networks were significant predictors of major depressive disorder, with an accuracy of 78.1%. In conclusion, we present a novel method for evaluating intra-networks in the hippocampus. One advantage of this method is that a detailed network can be estimated using conventional structural imaging. In addition, we found novel bilateral networks in the hippocampus that were disturbed in patients with major depressive disorders, and these bilateral networks could predict major depressive disorders.
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Affiliation(s)
- Keita Watanabe
- Open Innovation Institute, Kyoto University, Kyoto 6068501, Japan
| | - Naomichi Okamoto
- Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu 8078555, Japan
| | - Issei Ueda
- Department of Radiology, Graduate School of Medicine, Hirosaki University, Hirosaki 0368502, Japan
| | - Hirofumi Tesen
- Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu 8078555, Japan
| | - Rintaro Fujii
- Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu 8078555, Japan
| | - Atsuko Ikenouchi
- Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu 8078555, Japan
| | - Reiji Yoshimura
- Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu 8078555, Japan
| | - Shingo Kakeda
- Department of Radiology, Graduate School of Medicine, Hirosaki University, Hirosaki 0368502, Japan
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15
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Carcone D, Gardhouse K, Goghari VM, Lee ACH, Ruocco AC. The transdiagnostic relationship of cumulative lifetime stress with memory, the hippocampus, and personality psychopathology. J Psychiatr Res 2022; 155:483-492. [PMID: 36183602 DOI: 10.1016/j.jpsychires.2022.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/19/2022] [Accepted: 09/12/2022] [Indexed: 10/31/2022]
Abstract
Stress has a detrimental impact on memory, the hippocampus, and psychological health. Psychopathology research on stress has centered mainly on psychiatric diagnoses rather than symptom dimensions, and less attention has been given to the neurobiological factors through which stress might be translated into psychopathology. The present work investigates the transdiagnostic relationship of cumulative stress with episodic memory and the hippocampus (both structure and function) and explores the extent to which stress mediates the relationship between personality psychopathology and hippocampal size and activation. Cumulative lifetime stress was assessed in a sample of females recruited to vary in stress exposure and severity of personality psychopathology. Fifty-six participants completed subjective and objective tests of episodic memory, a T2-weighted high-resolution magnetic resonance imaging (MRI) scan of the medial-temporal lobe, and functional MRI (fMRI) scanning during a learning and recognition memory task. Higher cumulative stress was significantly related to memory complaints (but not episodic memory performance), lower bilateral hippocampal volume, and greater encoding-related hippocampal activation during the presentation of novel stimuli. Furthermore, cumulative stress significantly mediated the relationship between personality psychopathology and both hippocampal volume and activation, whereas alternative mediation models were not supported. The findings suggest that structural and functional activation differences in the hippocampus observed in case-control studies of psychiatric diagnoses may share cumulative stress as a common factor, which may mediate broadly reported relationships between psychopathology and hippocampal structure and function.
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Affiliation(s)
- Dean Carcone
- Department of Psychological Clinical Science, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada.
| | - Katherine Gardhouse
- Department of Psychological Clinical Science, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada; Centre for Addiction and Mental Health (CAMH), 60 White Squirrel Way, Toronto, Ontario, M6J 1H4, Canada
| | - Vina M Goghari
- Department of Psychological Clinical Science, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada; Department of Psychology, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada
| | - Andy C H Lee
- Department of Psychological Clinical Science, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada; Department of Psychology, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada; Rotman Research Institute, Baycrest Hospital, 3560 Bathurst St, Toronto, ON, M6A 2E1, Canada
| | - Anthony C Ruocco
- Department of Psychological Clinical Science, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada; Department of Psychology, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario, M1C 1A4, Canada
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16
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Viho EMG, Buurstede JC, Berkhout JB, Mahfouz A, Meijer OC. Cell type specificity of glucocorticoid signaling in the adult mouse hippocampus. J Neuroendocrinol 2022; 34:e13072. [PMID: 34939259 PMCID: PMC9286676 DOI: 10.1111/jne.13072] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/14/2021] [Accepted: 11/18/2021] [Indexed: 12/14/2022]
Abstract
Glucocorticoid stress hormones are powerful modulators of brain function and can affect mood and cognitive processes. The hippocampus is a prominent glucocorticoid target and expresses both the glucocorticoid receptor (GR: Nr3c1) and the mineralocorticoid receptor (MR: Nr3c2). These nuclear steroid receptors act as ligand-dependent transcription factors. Transcriptional effects of glucocorticoids have often been deduced from bulk mRNA measurements or spatially informed individual gene expression. However, only sparse data exists allowing insights on glucocorticoid-driven gene transcription at the cell type level. Here, we used publicly available single-cell RNA sequencing data to assess the cell-type specificity of GR and MR signaling in the adult mouse hippocampus. The data confirmed that Nr3c1 and Nr3c2 expression differs across neuronal and non-neuronal cell populations. We analyzed co-expression with sex hormones receptors, transcriptional coregulators, and receptors for neurotransmitters and neuropeptides. Our results provide insights in the cellular basis of previous bulk mRNA results and allow the formulation of more defined hypotheses on the effects of glucocorticoids on hippocampal function.
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Affiliation(s)
- Eva M. G. Viho
- Division of EndocrinologyDepartment of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Jacobus C. Buurstede
- Division of EndocrinologyDepartment of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Jari B. Berkhout
- Division of EndocrinologyDepartment of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
- Department of Human GeneticsLeiden University Medical CenterLeidenThe Netherlands
| | - Ahmed Mahfouz
- Department of Human GeneticsLeiden University Medical CenterLeidenThe Netherlands
- Delft Bioinformatics LaboratoryDelft University of TechnologyDelftThe Netherlands
- Leiden Computational Biology CenterLeiden University Medical CenterLeidenThe Netherlands
| | - Onno C. Meijer
- Division of EndocrinologyDepartment of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
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17
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Wachowska K, Szemraj J, Śmigielski J, Gałecki P. Inflammatory Markers and Episodic Memory Functioning in Depressive Disorders. J Clin Med 2022; 11:jcm11030693. [PMID: 35160143 PMCID: PMC8837175 DOI: 10.3390/jcm11030693] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 02/01/2023] Open
Abstract
Depression is a psychiatric disorder that is observed to be associated with changes in levels of inflammatory markers and deterioration in cognitive functioning. Here, we combined the biochemical tests of IL-1 and IL-6 serum levels and the expressions of genes encoding these interleukins with cognitive assessment of episodic memories, and examined 50 depressed patients and 37 healthy participants. Results confirmed increased serum levels of IL-1 and IL-6 in the study group when compared to healthy volunteers. Moreover, episodic memory, in terms of answering structured questions (but not free recollection of past events) deteriorated among depressed patients. The described parameters neither correlated with each other nor with the two measures of severity of depression—HDRS score and years of psychiatric treatment. Although both observed dysfunctions—cognitive and immune—among depressed patients are confirmed, they do not seem to covary in the present study.
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Affiliation(s)
- Katarzyna Wachowska
- Department of Adult Psychiatry, Medical University of Lodz, 91-229 Lodz, Poland;
- Correspondence:
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Janusz Śmigielski
- Department of Health Sciences, State University of Applied Sciences in Konin, 62-510 Konin, Poland;
| | - Piotr Gałecki
- Department of Adult Psychiatry, Medical University of Lodz, 91-229 Lodz, Poland;
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18
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Bukkieva T, Pospelova M, Efimtsev A, Fionik O, Alekseeva T, Samochernych K, Gorbunova E, Krasnikova V, Makhanova A, Levchuk A, Trufanov G, Combs S, Shevtsov M. Functional Network Connectivity Reveals the Brain Functional Alterations in Breast Cancer Survivors. J Clin Med 2022; 11:617. [PMID: 35160070 PMCID: PMC8837129 DOI: 10.3390/jcm11030617] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/29/2021] [Accepted: 01/10/2022] [Indexed: 02/04/2023] Open
Abstract
Different neurological and psychiatric disorders such as vertebrobasilar insufficiency, chronic pain syndrome, anxiety, and depression are observed in more than 90% of patients after treatment for breast cancer and may cause alterations in the functional connectivity of the default mode network. The purpose of the present study is to assess changes in the functional connectivity of the default mode network in patients after breast cancer treatment using resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI was performed using a 3.0T MR-scanner on patients (N = 46, women) with neurological disorders (chronic pain, dizziness, headaches, and/or tinnitus) in the late postoperative period (>12 months) after Patey radical mastectomy for breast cancer. According to the intergroup statistical analysis, there were differences in the functional connectivity of the default mode network in all 46 patients after breast cancer treatment compared to the control group (p < 0.01). The use of rs-fMRI in in breast cancer survivors allowed us to identify changes in the functional connectivity in the brain caused by neurological disorders, which correlated with a decreased quality of life in these patients. The results indicate the necessity to improve treatment and rehabilitation methods in this group of patients.
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Affiliation(s)
- Tatyana Bukkieva
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Maria Pospelova
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Aleksandr Efimtsev
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Olga Fionik
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Tatyana Alekseeva
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Konstantin Samochernych
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Elena Gorbunova
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Varvara Krasnikova
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Albina Makhanova
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Anatoliy Levchuk
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Gennadiy Trufanov
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
| | - Stephanie Combs
- Department of Radiation Oncology, Technishe Universität München (TUM), Klinikum rechts der Isar, Ismaningerstr. 22, 81675 Munich, Germany;
| | - Maxim Shevtsov
- Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str., 197341 Saint Petersburg, Russia; (T.B.); (M.P.); (A.E.); (O.F.); (T.A.); (K.S.); (E.G.); (V.K.); (A.M.); (A.L.); (G.T.)
- Department of Radiation Oncology, Technishe Universität München (TUM), Klinikum rechts der Isar, Ismaningerstr. 22, 81675 Munich, Germany;
- Laboratory of Biomedical Nanotechnologies, Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, 194064 Saint Petersburg, Russia
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19
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Wachowska K, Gałecki P. Inflammation and Cognition in Depression: A Narrative Review. J Clin Med 2021; 10:5859. [PMID: 34945157 PMCID: PMC8706670 DOI: 10.3390/jcm10245859] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 12/11/2022] Open
Abstract
The authors aim to present a narrative review of research on the inflammatory aetiology of depression. Depression is a psychiatric disorder, constituting the most common reason of disability due to a health condition. It has been estimated that at least one in six people suffer from depression at some point of their lives. The aetiology of depression, although researched extensively all around the world, still remains unclear. Authors discuss the possible role of inflammation in depression, the neurodevelopmental theory of depression as well as associations between cognition and depression. Possible associations between memory dysfunction among depressive patients and inflammatory markers are included. The associations between the immune system, depression and cognition are observed. Possible mediating factors between these areas include personality traits, hormonal imbalance and functioning of the brain areas. The question as to what mediating factors are involved is still open to research.
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Affiliation(s)
- Katarzyna Wachowska
- Department of Adult Psychiatry, Medical University of Lodz, 91-229 Lodz, Poland;
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20
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James TA, Weiss-Cowie S, Hopton Z, Verhaeghen P, Dotson VM, Duarte A. Depression and episodic memory across the adult lifespan: A meta-analytic review. Psychol Bull 2021; 147:1184-1214. [PMID: 35238585 PMCID: PMC9464351 DOI: 10.1037/bul0000344] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Episodic memory deficits have increasingly been recognized as a cognitive feature of depression. To quantify these deficits and determine how they are moderated by various tasks (e.g., stimulus valence) and participant (e.g., age, depression diagnosis) variables, we conducted a three-level meta-analysis on 995 effect sizes derived from 205 studies with 236 unique comparisons between depressive and control groups on episodic memory measures. Overall, depression was associated with small to moderate deficits in episodic memory, Hedges' g = -0.36, 95% CI [-0.41 to -0.31]. Effects were larger in older age, in diagnosed compared to subthreshold depression, and in those taking medication for depression; effects did not differ between those with current and remitted symptoms. Stimulus valence moderated the effects, such that depression-related deficits were particularly pronounced for positive and neutral stimuli, but not for negative stimuli. Educational attainment served as a sort of protective factor, in that at higher levels of education, depressed group performance was more similar to that of controls. These findings confirm the episodic memory deficits in depression but highlight the important differences in the size of these deficits across a number of task- and participant-related variables. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Affiliation(s)
- Taylor A. James
- School of Psychology, Georgia Institute of Technology
- Department of Neurology, Emory University School of Medicine
| | | | | | | | | | - Audrey Duarte
- School of Psychology, Georgia Institute of Technology
- Department of Psychology, University of Texas at Austin
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21
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Dąbrowska E, Galińska-Skok B, Waszkiewicz N. Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19. Life (Basel) 2021; 11:1056. [PMID: 34685427 PMCID: PMC8541562 DOI: 10.3390/life11101056] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 02/07/2023] Open
Abstract
The dysfunctional effects of the coronavirus disease 2019 (COVID-19) infection on the nervous system are established. The manifestation of neuropsychiatric symptoms during and after infection is influenced by the neuroinvasive and neurotrophic properties of SARS-CoV-2 as well as strong inflammation characterised by a specific "cytokine storm". Research suggests that a strong immune response to a SARS-CoV-2 infection and psychological stressors related to the pandemic may cause chronic inflammatory processes in the body with elevated levels of inflammatory markers contributing to the intensification of neurodegenerative processes. It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.
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Affiliation(s)
- Eliza Dąbrowska
- Department of Psychiatry, Medical University of Bialystok, pl. Brodowicza 1, 16-070 Choroszcz, Poland; (B.G.-S.); (N.W.)
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22
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Hu J, Liu J, Liu Y, Wu X, Zhuang K, Chen Q, Yang W, Xie P, Qiu J, Wei D. Dysfunction of the anterior and intermediate hippocampal functional network in major depressive disorders across the adult lifespan. Biol Psychol 2021; 165:108192. [PMID: 34555480 DOI: 10.1016/j.biopsycho.2021.108192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 11/27/2022]
Abstract
Accumulating evidence indicates that structural and functional abnormalities in hippocampal formation are linked to major depressive disorder (MDD). However, the resting-state functional connectivity (RSFC) of hippocampal subfields in MDD remains unclear. This cross-sectional study aimed to investigate the RSFC of hippocampal subfields in a large sample of MDD patients. The results revealed that patients with MDD showed lower RSFC between the right anterior hippocampus and the insula, and the RSFC was inversely correlated with anxiety symptoms of depression. Depressed patients also showed decreased RSFC between the bilateral intermediate hippocampus and left nucleus accumbens (NAcc), and the hippocampus-NAcc circuit was negatively correlated with core symptoms of depression. The functional connectivity between the right anterior hippocampus and left postcentral gyrus increased with ageing in MDD patients compared with healthy controls. These findings suggest that the functional network of hippocampal subfields may underlie anxiety and core depression symptoms.
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Affiliation(s)
- Jun Hu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Jiahui Liu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Yu Liu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Xianran Wu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Kaixiang Zhuang
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Qunlin Chen
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Wenjing Yang
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Peng Xie
- Institute of Neuroscience, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiang Qiu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China.
| | - Dongtao Wei
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China.
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23
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Sah A, Kharitonova M, Mlyniec K. Neuronal correlates underlying the role of the zinc sensing receptor (GPR39) in passive-coping behaviour. Neuropharmacology 2021; 198:108752. [PMID: 34390690 DOI: 10.1016/j.neuropharm.2021.108752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/04/2021] [Accepted: 08/08/2021] [Indexed: 01/13/2023]
Abstract
The Zn2+ receptor GPR39 is proposed to be involved in the pathophysiology of depression. GPR39 knockout (KO) animals show depressive- and anxiety-like behaviour, and resistance to conventional monoamine-based antidepressants. However, it is unclear as to which brain regions are involved in the pro-depressive phenotype of GPR39KO mice and the resistance to monoamine-targeting antidepressant treatment. Our current study confirmed previous results, showing that mice lacking GPR39 display enhanced passive coping-like behaviour compared with their wild-type controls. Furthermore, this study shows for the first time that GPR39KO displayed aberrant challenge-induced neuronal activity in key brain regions associated with passive coping behaviour. Imipramine induced only a marginal reduction in the enhanced passive coping behaviour in GPR39KO mice, which was associated with attenuation of the hyperactive prefrontal cortex. Similarly, the aberrant activity within the amygdalar subregions was normalized following imipramine treatment in the GPR39KO mice, indicating that imipramine mediates these effects independently of GPR39 in the prefrontal cortex and amygdala. However, imipramine failed to modulate the aberrant brain activity in other brain regions, such as the anterior CA3 and the dentate gyrus, in GPR39KO mice. Normalization of aberrant activity in these areas has been shown previously to accompany successful behavioural effects of antidepressants. Taken together, our data suggest that monoamine-based antidepressants such as imipramine exert their action via GPR39-dependent and -independent pathways. Failure to modulate passive-coping related aberrant activity in important brain areas of the depression circuitry is proposed to mediate/contribute to the greatly reduced antidepressant action of monoamine-based antidepressants in GPR39KO mice.
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Affiliation(s)
- Anupam Sah
- Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Maria Kharitonova
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82/III, A-6020, Innsbruck, Austria
| | - Katarzyna Mlyniec
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688, Krakow, Poland.
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24
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Sneider JT, Cohen-Gilbert JE, Hamilton DA, Seraikas AM, Oot EN, Schuttenberg EM, Nickerson LD, Silveri MM. Brain Activation during Memory Retrieval is Associated with Depression Severity in Women. Psychiatry Res Neuroimaging 2021; 307:111204. [PMID: 33393466 PMCID: PMC7783190 DOI: 10.1016/j.pscychresns.2020.111204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 01/10/2023]
Abstract
Major depressive disorder (MDD) is a debilitating disorder that interferes with daily functioning, and that occurs at higher rates in women than in men. Structural and functional alterations in hippocampus and frontal lobe have been reported in MDD, which likely contribute to the multifaceted nature of MDD. One area impacted by MDD is hippocampal-mediated memory, which can be probed using a spatial virtual Morris water task (MWT). Women (n=24) across a spectrum of depression severity underwent functional magnetic resonance imaging (fMRI) during MWT. Depression severity, assessed via Beck Depression Inventory (BDI), was examined relative to brain activation during task performance. Significant brain activation was evident in areas traditionally implicated in spatial memory processing, including right hippocampus and frontal lobe regions, for retrieval > motor contrast. When BDI was included as a regressor, significantly less functional activation was evident in left hippocampus, and other non-frontal, task relevant regions for retrieval > rest contrast. Consistent with previous studies, depression severity was associated with functional alterations observed during spatial memory performance. These findings may contribute to understanding neurobiological underpinnings of depression severity and associated memory impairments, which may have implications for treatment approaches aimed at alleviating effects of depression in women.
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Affiliation(s)
- Jennifer T Sneider
- Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, MA, USA; Dept. of Psychiatry, Harvard Medical School, Boston, MA, USA.
| | - Julia E Cohen-Gilbert
- Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, MA, USA; Dept. of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Derek A Hamilton
- Dept. of Psychology, University of New Mexico, Albuquerque, NM, USA
| | - Anna M Seraikas
- Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, MA, USA
| | - Emily N Oot
- Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, MA, USA; Boston University School of Medicine, Boston, MA, USA
| | - Eleanor M Schuttenberg
- Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, MA, USA
| | - Lisa D Nickerson
- Applied Neuroimaging Statistics Lab, Belmont, McLean Hospital, MA, USA; Dept. of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Marisa M Silveri
- Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, MA, USA; Dept. of Psychiatry, Harvard Medical School, Boston, MA, USA
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25
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Zheng R, Zhang Y, Yang Z, Han S, Cheng J. Reduced Brain Gray Matter Volume in Patients With First-Episode Major Depressive Disorder: A Quantitative Meta-Analysis. Front Psychiatry 2021; 12:671348. [PMID: 34276443 PMCID: PMC8282212 DOI: 10.3389/fpsyt.2021.671348] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/02/2021] [Indexed: 12/21/2022] Open
Abstract
Background: The findings of many neuroimaging studies in patients with first-episode major depressive disorder (MDD), and even those of previous meta-analysis, are divergent. To quantitatively integrate these studies, we performed a meta-analysis of gray matter volumes using voxel-based morphometry (VBM). Methods: We performed a comprehensive literature search for relevant studies and traced the references up to May 1, 2021 to select the VBM studies between first-episode MDD and healthy controls (HC). A quantitative meta-analysis of VBM studies on first-episode MDD was performed using the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) method, which allows a familywise error rate (FWE) correction for multiple comparisons of the results. Meta-regression was used to explore the effects of demographics and clinical characteristics. Results: Nineteen studies, with 22 datasets comprising 619 first-episode MDD and 707 HC, were included. The pooled and subgroup meta-analysis showed robust gray matter reductions in the left insula, the bilateral parahippocampal gyrus extending into the bilateral hippocampus, the right gyrus rectus extending into the right striatum, the right superior frontal gyrus (dorsolateral part), the left superior frontal gyrus (medial part) and the left superior parietal gyrus. Meta-regression analyses showed that higher HDRS scores were significantly more likely to present reduced gray matter volumes in the right amygdala, and the mean age of MDD patients in each study was negatively correlated with reduced gray matter in the left insula. Conclusions: The present meta-analysis revealed that structural abnormalities in the fronto-striatal-limbic and fronto-parietal networks are essential characteristics in first-episode MDD patients, which may become a potential target for clinical intervention.
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Affiliation(s)
- Ruiping Zheng
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Zhang
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhengui Yang
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shaoqiang Han
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingliang Cheng
- Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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26
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Tianeptine Enhances Energy-related Processes in the Hippocampal Non-synaptic Mitochondria in a Rat Model of Depression. Neuroscience 2020; 451:111-125. [DOI: 10.1016/j.neuroscience.2020.09.061] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 09/27/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022]
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27
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The Interpeduncular-Ventral Hippocampus Pathway Mediates Active Stress Coping and Natural Reward. eNeuro 2020; 7:ENEURO.0191-20.2020. [PMID: 33139320 PMCID: PMC7688303 DOI: 10.1523/eneuro.0191-20.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 09/24/2020] [Accepted: 10/26/2020] [Indexed: 12/16/2022] Open
Abstract
Maladaptive stress-related behaviors are integral to multiple complex psychiatric disorders, and it has been well established that serotonergic signaling mediates various aspects of these maladaptive states. In these studies, we sought to uncover the function of a previously undefined serotonergic pathway, which projects from the interpeduncular nucleus (IPN) to the ventral hippocampus (vHipp). Intersectional retrograde and chemogenetic viral manipulation strategies were employed to manipulate the function of the IPN-vHipp pathway during a variety of behavioral measures in male mice. We found a significant effect of circuit inhibition on behaviors associated with coping strategies and natural reward. Specifically, inhibition of the IPN-vHipp pathway dramatically increased active stress-induced escape behaviors, in addition to moderately affecting sucrose consumption and food self-administration. During inhibition of this pathway, agonist activation of serotonergic 5-HT2A/2C receptors in the vHipp reversed the effects of IPN-vHipp circuit inhibition on active escape behaviors, thereby supporting the synaptic mechanism underlying the behavioral effects evidenced. IPN-vHipp inhibition did not induce differences in generalized locomotion, anxiety-associated behavior, and intravenous nicotine self-administration. Importantly, these findings are in opposition to the canonical understanding of serotonin in such escape behaviors, indicating that serotonin exerts opposing effects on behavior in a pathway-specific manner in the brain. Taken together, these findings thereby have important implications for our understanding of serotonergic signaling and associated therapeutic approaches for the treatment of disease symptomology.
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28
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Koskinen MK, van Mourik Y, Smit AB, Riga D, Spijker S. From stress to depression: development of extracellular matrix-dependent cognitive impairment following social stress. Sci Rep 2020; 10:17308. [PMID: 33057053 PMCID: PMC7560730 DOI: 10.1038/s41598-020-73173-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
Stress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. We profiled the development of an enduring depressive-like state by assessing affective behavior and hippocampal function during the 2 months following social-defeat stress. We measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during the sustained depressive-like state. Affective disturbance and cognitive impairments develop disparately after social stress, with gradual appearance of affective deficits. In contrast, spatial memory was impaired both early after stress and during the late-emerging chronic depressive-like state, while intact in-between. Similarly, we observed a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Together our data (1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, (2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and (3) support a role of the ECM in mediating long-lasting effects on memory. From a translational point of view, it is important to prioritize on temporal phenotypic aspects in animal models to elucidate the underlying mechanisms of depression.
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Affiliation(s)
- Maija-Kreetta Koskinen
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands
| | - Yvar van Mourik
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands
| | - August Benjamin Smit
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands
| | - Danai Riga
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands
- Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
| | - Sabine Spijker
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands.
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29
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Widman AJ, McMahon LL. Effects of ketamine and other rapidly acting antidepressants on hippocampal excitatory and inhibitory transmission. ADVANCES IN PHARMACOLOGY 2020; 89:3-41. [PMID: 32616211 DOI: 10.1016/bs.apha.2020.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior. Intense research has centered on the effects of ketamine, and the other rapidly acting antidepressants, on excitatory and inhibitory circuits in hippocampus and medial prefrontal cortex to determine common mechanisms, including key modifications in synaptic transmission and the precise location of the NMDARs that mediate the rapid and sustained antidepressant response. We review data comparing the effects of ketamine with other NMDAR receptor modulators and the muscarinic M1 acetylcholine receptor antagonist, scopolamine, together with evidence supporting the disinhibition hypothesis and the direct inhibition hypothesis of ketamine's mechanism of action on synaptic circuits using preclinical models.
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Affiliation(s)
- Allie J Widman
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Lori L McMahon
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States.
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30
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Miskowiak KW, Forman JL, Vinberg M, Siebner HR, Kessing LV, Macoveanu J. Impact of pretreatment interhemispheric hippocampal asymmetry on improvement in verbal learning following erythropoietin treatment in mood disorders: a randomized controlled trial. J Psychiatry Neurosci 2020; 45:198-205. [PMID: 31804779 PMCID: PMC7828975 DOI: 10.1503/jpn.180205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Treatment development that targets cognitive impairment is hampered by a lack of biomarkers that can predict treatment efficacy. Erythropoietin (EPO) improves verbal learning and memory in mood disorders, and this scales with an increase in left hippocampal volume. This study investigated whether pretreatment left hippocampal volume, interhemisphere hippocampal asymmetry or both influenced EPO treatment response with respect to verbal learning. METHODS Data were available for 76 of 83 patients with mood disorders from our previous EPO trials (EPO = 37 patients; placebo = 39 patients). We performed cortical reconstruction and volumetric segmentation using FreeSurfer. We conducted multiple linear regression and logistic regression to assess the influence of left hippocampal volume and hippocampal asymmetry on EPO-related memory improvement, as reflected by change in Rey Auditory Verbal Learning Test total recall from baseline to post-treatment. We set up a corresponding exploratory general linear model in FreeSurfer to assess the influence of prefrontal cortex volume on verbal learning improvement, controlling for age, sex and total intracranial volume. RESULTS At baseline, more rightward (left < right) hippocampal asymmetry — but not left hippocampal volume per se — was associated with greater effects of EPO versus placebo on verbal learning (p ≤ 0.05). Exploratory analysis indicated that a larger left precentral gyrus surface area was also associated with improvement of verbal learning in the EPO group compared to the placebo group (p = 0.002). LIMITATIONS This was a secondary analysis of our original EPO trials. CONCLUSION Rightward hippocampal asymmetry may convey a positive effect of EPO treatment efficacy on verbal learning. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov NCT00916552
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Affiliation(s)
- Kamilla W. Miskowiak
- From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark
| | - Julie L. Forman
- From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark
| | - Maj Vinberg
- From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark
| | - Hartwig R. Siebner
- From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark
| | - Lars V. Kessing
- From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark
| | - Julian Macoveanu
- From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark
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Guirado R, Perez-Rando M, Ferragud A, Gutierrez-Castellanos N, Umemori J, Carceller H, Nacher J, Castillo-Gómez E. A Critical Period for Prefrontal Network Configurations Underlying Psychiatric Disorders and Addiction. Front Behav Neurosci 2020; 14:51. [PMID: 32317945 PMCID: PMC7155216 DOI: 10.3389/fnbeh.2020.00051] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/19/2020] [Indexed: 12/24/2022] Open
Abstract
The medial prefrontal cortex (mPFC) has been classically defined as the brain region responsible for higher cognitive functions, including the decision-making process. Ample information has been gathered during the last 40 years in an attempt to understand how it works. We now know extensively about the connectivity of this region and its relationship with neuromodulatory ascending projection areas, such as the dorsal raphe nucleus (DRN) or the ventral tegmental area (VTA). Both areas are well-known regulators of the reward-based decision-making process and hence likely to be involved in processes like evidence integration, impulsivity or addiction biology, but also in helping us to predict the valence of our future actions: i.e., what is “good” and what is “bad.” Here we propose a hypothesis of a critical period, during which the inputs of the mPFC compete for target innervation, establishing specific prefrontal network configurations in the adult brain. We discuss how these different prefrontal configurations are linked to brain diseases such as addiction or neuropsychiatric disorders, and especially how drug abuse and other events during early life stages might lead to the formation of more vulnerable prefrontal network configurations. Finally, we show different promising pharmacological approaches that, when combined with the appropriate stimuli, will be able to re-establish these functional prefrontocortical configurations during adulthood.
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Affiliation(s)
- Ramon Guirado
- Neurobiology Unit, Department of Cell Biology, Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de Valencia, Valencia, Spain.,Neuroscience Center, University of Helsinki, Helsinki, Finland.,Spanish National Network for Research in Mental Health, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Dirección General de Universidades, Gobierno de Aragón, Zaragoza, Spain
| | - Marta Perez-Rando
- MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Antonio Ferragud
- Department of Psychology, Cambridge University, Cambridge, United Kingdom
| | | | - Juzoh Umemori
- Neuroscience Center, University of Helsinki, Helsinki, Finland
| | - Hector Carceller
- Neurobiology Unit, Department of Cell Biology, Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de Valencia, Valencia, Spain
| | - Juan Nacher
- Neurobiology Unit, Department of Cell Biology, Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de Valencia, Valencia, Spain.,Spanish National Network for Research in Mental Health, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Valencia, Spain
| | - Esther Castillo-Gómez
- Spanish National Network for Research in Mental Health, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Department of Medicine, School of Medical Sciences, Universitat Jaume I, Valencia, Spain
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32
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Hao ZY, Zhong Y, Ma ZJ, Xu HZ, Kong JY, Wu Z, Wu Y, Li J, Lu X, Zhang N, Wang C. Abnormal resting-state functional connectivity of hippocampal subfields in patients with major depressive disorder. BMC Psychiatry 2020; 20:71. [PMID: 32066415 PMCID: PMC7026985 DOI: 10.1186/s12888-020-02490-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/10/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Many studies have found that the hippocampus plays a very important role in major depressive disorder (MDD). The hippocampus can be divided into three subfields: the cornu ammonis (CA), dentate gyrus (DG) and subiculum. Each subfield of the hippocampus has a unique function and are differentially associated with the pathological mechanisms of MDD. However, no research exists to describe the resting state functional connectivity of each hippocampal subfield in MDD. METHODS Fifty-five patients with MDD and 25 healthy controls (HCs) matched for gender, age and years of education were obtained. A seed-based method that imposed a template on the whole brain was used to assess the resting-state functional connectivity (rsFC) of each hippocampal subfield. RESULTS Patients with MDD demonstrated increased connectivity in the left premotor cortex (PMC) and reduced connectivity in the right insula with the CA seed region. Increased connectivity was reported in the left orbitofrontal cortex (OFC) and left ventrolateral prefrontal cortex (vlPFC) with the DG seed region. The subiculum seed region revealed increased connectivity with the left premotor cortex (PMC), the right middle frontal gyrus (MFG), the left ventrolateral prefrontal cortex (vlPFC) and reduced connectivity with the right insula. ROC curves confirmed that the differences between groups were statistically significant. CONCLUSION The results suggest that the CA, DG and subiculum have significant involvement with MDD. Specifically, the abnormal functional connectivity of the CA may be related to bias of coding and integration of information in patients with MDD. The abnormal functional connectivity of the DG may be related to the impairment of working memory in patients with MDD, and the abnormal functional connectivity of the subiculum may be related to cognitive impairment and negative emotions in patients with MDD.
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Affiliation(s)
- Zi Yu Hao
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China
| | - Yuan Zhong
- grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China ,grid.260474.30000 0001 0089 5711Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing Normal University, Nanjing, 210097 People’s Republic of China
| | - Zi Juan Ma
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China
| | - Hua Zhen Xu
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China
| | - Jing Ya Kong
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China
| | - Zhou Wu
- grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China
| | - Yun Wu
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China
| | - Jian Li
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China
| | - Xin Lu
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China
| | - Ning Zhang
- grid.452645.40000 0004 1798 8369Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.260474.30000 0001 0089 5711School of Psychology, Nanjing Normal University, Nanjing, 210097 Jiangsu China ,grid.89957.3a0000 0000 9255 8984Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, 210029 Jiangsu China ,grid.89957.3a0000 0000 9255 8984Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, 210029 Jiangsu China
| | - Chun Wang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, Jiangsu, China. .,School of Psychology, Nanjing Normal University, Nanjing, 210097, Jiangsu, China. .,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, 210029, Jiangsu, China. .,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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33
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Cui L, Wang F, Yin Z, Chang M, Song Y, Wei Y, Lv J, Zhang Y, Tang Y, Gong X, Xu K. Effects of the LHPP gene polymorphism on the functional and structural changes of gray matter in major depressive disorder. Quant Imaging Med Surg 2020; 10:257-268. [PMID: 31956547 DOI: 10.21037/qims.2019.12.01] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background A single-nucleotide polymorphism (SNP) of the LHPP gene (rs35936514) has been reported to be associated with major depressive disorder (MDD) in genome-wide association studies. However, the systems-level neural effects of rs35936514 that mediate the association are unknown. We hypothesized that variations in rs35936514 would be associated with structural and functional changes in gray matter (GM) at rest in MDD patients. Methods A total of 50 MDD patients and 113 healthy controls (HCs) were studied. Functional connectivity (FC) was analyzed by defining the bilateral hippocampus as the seed region. Voxel-based morphometry (VBM) was performed to assess the patterns of GM volume. The subjects were further divided into two groups: a CC homozygous group (CC; 24 MDD and 56 HC) and a risk T-allele carrier group (CT/TT genotypes; 26 MDD and 57 HC). A 2×2 analysis of variance (ANOVA: diagnosis × genotype) was used to determine the interaction effects and main effect (P<0.05). Results Significant diagnosis × genotype interaction effects on brain morphology and FC were noted. Compared to other subgroups, the MDD patients with the T allele showed an increased hippocampal FC in the bilateral calcarine cortex and cuneus and a decreased hippocampal FC in the right dorsolateral prefrontal cortex (DLPFC), bilateral anterior cingulate cortex (ACC), and medial prefrontal cortex (MPFC), in addition to reduced GM volume in the right DLPFC, bilateral temporal cortex, and posterior cingulate cortex (PCC). Conclusions LHPP gene polymorphisms may affect functional and structural changes in the GM at rest and may play an important role in the pathophysiological mechanisms of MDD.
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Affiliation(s)
- Lingling Cui
- Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China
| | - Fei Wang
- Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Zhiyang Yin
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Miao Chang
- Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Yanzhuo Song
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Yange Wei
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Jing Lv
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Yifan Zhang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Yanqing Tang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Brain Function Research Sections, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.,Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Xiaohong Gong
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China
| | - Ke Xu
- Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
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34
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The rise and fall of MRI studies in major depressive disorder. Transl Psychiatry 2019; 9:335. [PMID: 31819044 PMCID: PMC6901449 DOI: 10.1038/s41398-019-0680-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 12/28/2022] Open
Abstract
Structural and functional brain alterations are common in patients with major depressive disorder (MDD). In this review, we assessed the recent literature (1995-2018) on the structural and functional magnetic resonance imaging (MRI) studies of MDD. Despite the growing number of MRI studies on MDD, reverse inference is not possible as MRI scans cannot be used to aid in the diagnosis or treatment planning of patients with MDD. Hence, researchers must develop "bridges" to overcome the reverse inference fallacy in order to build effective tools for MDD diagnostics. From our findings, we proposed that the "bridges" may be built using multidisciplinary technologies, such as artificial intelligence, multimodality imaging, and nanotheranostics, allowing for the further study of MDD at the biological level. In return, the "bridges" will aid in the development of future diagnostics for MDD and other mental disorders.
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35
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Liu Y, Admon R, Mellem MS, Belleau EL, Kaiser RH, Clegg R, Beltzer M, Goer F, Vitaliano G, Ahammad P, Pizzagalli DA. Machine Learning Identifies Large-Scale Reward-Related Activity Modulated by Dopaminergic Enhancement in Major Depression. BIOLOGICAL PSYCHIATRY: COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2019; 5:163-172. [PMID: 31784354 DOI: 10.1016/j.bpsc.2019.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 09/30/2019] [Accepted: 10/01/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Theoretical models have emphasized systems-level abnormalities in major depressive disorder (MDD). For unbiased yet rigorous evaluations of pathophysiological mechanisms underlying MDD, it is critically important to develop data-driven approaches that harness whole-brain data to classify MDD and evaluate possible normalizing effects of targeted interventions. Here, using an experimental therapeutics approach coupled with machine learning, we investigated the effect of a pharmacological challenge aiming to enhance dopaminergic signaling on whole-brain response to reward-related stimuli in MDD. METHODS Using a double-blind, placebo-controlled design, we analyzed functional magnetic resonance imaging data from 31 unmedicated MDD participants receiving a single dose of 50 mg amisulpride (MDDAmisulpride), 26 MDD participants receiving placebo (MDDPlacebo), and 28 healthy control subjects receiving placebo (HCPlacebo) recruited through two independent studies. An importance-guided machine learning technique for model selection was used on whole-brain functional magnetic resonance imaging data probing reward anticipation and consumption to identify features linked to MDD (MDDPlacebo vs. HCPlacebo) and dopaminergic enhancement (MDDAmisulpride vs. MDDPlacebo). RESULTS Highly predictive classification models emerged that distinguished MDDPlacebo from HCPlacebo (area under the curve = 0.87) and MDDPlacebo from MDDAmisulpride (area under the curve = 0.89). Although reward-related striatal activation and connectivity were among the most predictive features, the best truncated models based on whole-brain features were significantly better relative to models trained using striatal features only. CONCLUSIONS Results indicate that in MDD, enhanced dopaminergic signaling restores abnormal activation and connectivity in a widespread network of regions. These findings provide new insights into the pathophysiology of MDD and pharmacological mechanism of antidepressants at the system level in addressing reward processing deficits among depressed individuals.
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Affiliation(s)
- Yuelu Liu
- BlackThorn Therapeutics, San Francisco, California
| | - Roee Admon
- Department of Psychology, University of Haifa, Haifa, Israel
| | | | - Emily L Belleau
- McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
| | - Roselinde H Kaiser
- Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado
| | | | | | | | - Gordana Vitaliano
- McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
| | | | - Diego A Pizzagalli
- McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
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36
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Hillerer KM, Slattery DA, Pletzer B. Neurobiological mechanisms underlying sex-related differences in stress-related disorders: Effects of neuroactive steroids on the hippocampus. Front Neuroendocrinol 2019; 55:100796. [PMID: 31580837 PMCID: PMC7115954 DOI: 10.1016/j.yfrne.2019.100796] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/19/2022]
Abstract
Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don't model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses.
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Affiliation(s)
- Katharina M Hillerer
- Department of Obstetrics and Gynaecology, Salzburger Landeskrankenhaus (SALK), Paracelsus Medical University (PMU), Clinical Research Center Salzburg (CRCS), Salzburg, Austria.
| | - David A Slattery
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
| | - Belinda Pletzer
- Department of Psychology, University of Salzburg, Salzburg, Austria; Centre for Cognitive Neuroscience, University of Salzburg, Salzburg, Austria
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Functional disconnectivity of the hippocampal network and neural correlates of memory impairment in treatment-resistant depression. J Affect Disord 2019; 253:248-256. [PMID: 31060011 DOI: 10.1016/j.jad.2019.04.096] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/29/2019] [Accepted: 04/27/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Major depressive disorder (MDD) is a disabling neuropsychiatric condition associated with cognitive impairment. Neuroimaging studies have consistently linked memory deficits with hippocampal atrophy in MDD patients. However, there has been a paucity of research examining how the hippocampus functionally contributes to memory impairments in MDD. The present study examined whether hippocampal networks distinguish treatment-resistant depression (TRD) patients from healthy controls (HCs), and whether these networks underlie declarative memory deficits in TRD. We hypothesized that functional connectivity (FC) of the posterior hippocampus would correlate preferentially with memory in patients, whereas FC pattern of the anterior and intermediate hippocampus would correlate with emotion-mediated regions and show a significant correlation with memory. METHODS Resting-state functional magnetic resonance imaging (fMRI) scans were acquired in 56 patients and 42 age- and sex-matched HCs. We parcellated the hippocampus into three subregions based on a sparse representation-based method recently developed by our group. FC networks of hippocampal subregions were compared between patients and HCs and correlated with clinical measures and cognitive performance. RESULTS Decreased connectivity of the right intermediate hippocampus (RIH) with the limbic regions was a distinguishing feature between TRD and HCs. These functional abnormalities were present in the absence of structural volumetric differences. Furthermore, lower right amygdalar connectivity to the RIH related to a longer current depressive episode. Declarative memory deficits in TRD were significantly associated with left posterior and right intermediate hippocampal FC patterns. LIMITATIONS Our patient samples were treatment-resistant, the conclusions from this study cannot be generalized to all MDD patients directly. Task-based imaging studies are needed to demonstrate hippocampal engagement in the memory deficits of patients. Finally, our findings are strongly in need of replication in independent validation samples. CONCLUSIONS These findings demonstrate a transitional property of the intermediate hippocampal subregion between its anterior and posterior counterparts in TRD patients, and provide new insights into the neural network-level dysfunction of the hippocampus in TRD.
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Ma X, Liu J, Liu T, Ma L, Wang W, Shi S, Wang Y, Gong Q, Wang M. Altered Resting-State Functional Activity in Medication-Naive Patients With First-Episode Major Depression Disorder vs. Healthy Control: A Quantitative Meta-Analysis. Front Behav Neurosci 2019; 13:89. [PMID: 31133831 PMCID: PMC6524692 DOI: 10.3389/fnbeh.2019.00089] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 04/15/2019] [Indexed: 02/05/2023] Open
Abstract
Background: There is an urgent need for a meta-analysis that characterizes the brain states of major depression disorder (MDD) patients and potentially provides reliable biomarkers, because heterogeneity in the results of resting-state functional neuroimaging has been observed between studies, with some patients not showing the consistent changes, or even opposite patterns. Thus, we evaluated consistent regional brain activity alterations in medication-naive patients with first-episode unipolar MDD and compared the results with those in healthy controls (HCs). Methods: A systematic database search was conducted (in PubMed, Ovid, and Web of Knowledge) between January 1984 and July 2016 to select resting-state functional activity studies with a voxel-wise analysis in MDD. We used anisotropic effect size-signed differential mapping to perform a whole-brain meta-analysis, comparing functional alterations between first-episode medication-naive unipolar MDD patients and HCs by integrating the studies. In addition, subgroup meta-analysis was conducted to control for the MRI analysis method. Moreover, the meta-regression analyses were performed to examine the potential effects of mean age, education duration, illness duration, and severity of depressive symptoms. Results: A total of 12 studies were included, comparing 313 MDD patients with 283 HCs. The pooled and subgroup meta-analysis found that the MDD patients showed hyperactivity in the left parahippocampal gyrus, left supplementary motor area, left amygdala, left hippocampus, and left middle frontal gyrus (MFG; orbital part), and hypoactivity in the left lingual gyrus, left middle occipital gyrus, right cuneus cortex, right MFG (orbital part), and left cerebellum. In the meta-regression analyses, the mean illness duration was positively associated with hyper-activation in the left parahippocampal gyrus and hypoactivation in the hemispheric lobule IV/V of the left cerebellum. Conclusions: This meta-analysis indicated that MDD patients had significant and robust resting-state brain activity alteration in amygdala, left hippocampus and other regions, which implicated this finding in the pathophysiology of cognitive and emotional impairment in MDD patients.
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Affiliation(s)
- Xiaoyue Ma
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Henan Key Laboratory of Neurological Imaging, Zhengzhou, China
| | - Jia Liu
- Department of Radiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Taiyuan Liu
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Henan Key Laboratory of Neurological Imaging, Zhengzhou, China
| | - Lun Ma
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Henan Key Laboratory of Neurological Imaging, Zhengzhou, China
| | - Wenhui Wang
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Henan Key Laboratory of Neurological Imaging, Zhengzhou, China
| | - Shaojie Shi
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Henan Key Laboratory of Neurological Imaging, Zhengzhou, China
| | - Yan Wang
- Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Medical School, Henan University, Zhengzhou, China
| | - Qiyong Gong
- Department of Radiology, West China Hospital of Sichuan University, Huaxi MR Research Center (HMRRC), Chengdu, China
| | - Meiyun Wang
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,Department of Radiology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Henan Key Laboratory of Neurological Imaging, Zhengzhou, China.,Medical School, Henan University, Zhengzhou, China.,Henan Provincial Clinical Big Data Analysis and Service Engineering Research Center, Zhengzhou, China
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Altered hippocampal function with preserved cognitive performance in treatment-naive major depressive disorder. Neuroreport 2019; 30:46-52. [PMID: 30422941 DOI: 10.1097/wnr.0000000000001163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The hippocampus is implicated in the pathophysiology of major depressive disorder (MDD), with evidence that morphological changes occur with disease progression. It was hypothesized that treatment-naive patients with depression would show performance deficits in hippocampus-dependent memory trials, with concurrent hippocampal activation deficits on functional magnetic resonance imaging, compared with control participants. Thirteen treatment-naive patients with MDD and 13 control participants completed a hippocampus-dependent memory functional magnetic resonance imaging process-dissociation task. On behavioural measures of habit memory and guessing, there were no significant differences between groups. Functional magnetic resonance imaging analysis indicated that compared with the control group, the MDD group showed increased activation in the parahippocampal gyrus and hippocampus on habit memory and nonitem trials. These alterations in hippocampal functioning with preserved cognitive performance on a test of hippocampus-dependent memory in MDD may be indicative of a compensatory mechanism.
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Abstract
Neuropsychiatric illnesses including mood disorders are accompanied by cognitive impairment, which impairs work capacity and quality of life. However, there is a lack of treatment options that would lead to solid and lasting improvement of cognition. This is partially due to the absence of valid and reliable neurocircuitry-based biomarkers for pro-cognitive effects. This systematic review therefore examined the most consistent neural underpinnings of cognitive impairment and cognitive improvement in unipolar and bipolar disorders. We identified 100 studies of the neuronal underpinnings of working memory and executive skills, learning and memory, attention, and implicit learning and 9 studies of the neuronal basis for cognitive improvements. Impairments across several cognitive domains were consistently accompanied by abnormal activity in dorsal prefrontal (PFC) cognitive control regions-with the direction of this activity depending on patients' performance levels-and failure to suppress default mode network (DMN) activity. Candidate cognition treatments seemed to enhance task-related dorsal PFC and temporo-parietal activity when performance increases were observed, and to reduce their activity when performance levels were unchanged. These treatments also attenuated DMN hyper-activity. In contrast, nonspecific cognitive improvement following symptom reduction was typically accompanied by decreased limbic reactivity and reversal of pre-treatment fronto-parietal hyper-activity. Together, the findings highlight some common neural correlates of cognitive impairments and cognitive improvements. Based on this evidence, studies are warranted to examine the reliability and predictive validity of target engagement in the identified neurocircuitries as a biomarker model of pro-cognitive effects.
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Exposure to Patterned Auditory Stimuli during Acute Stress Prevents Despair-Like Behavior in Adult Mice That Were Previously Housed in an Enriched Environment in Combination with Auditory Stimuli. Neural Plast 2018; 2018:8205245. [PMID: 30627149 PMCID: PMC6304879 DOI: 10.1155/2018/8205245] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 10/11/2018] [Accepted: 11/05/2018] [Indexed: 01/16/2023] Open
Abstract
Several interventions have been shown to counteract the effects of stress that may be related to improved neuroplasticity and neuronal activation. In this sense, environmental enrichment (ENR) protects against acute stress and increases neuroplasticity. It has been suggested that the use of patterned auditory stimuli (PAS) may be beneficial in increasing the effectiveness of ENR on disorders related to stress, such as depression and anxiety. Examples of PAS are classical music compositions that have interesting effects at both clinical and preclinical levels. Thus, we analyzed the effects of the exposure to PAS, represented in this study by Mozart's compositions, during ENR housing for 35 days in adult male Balb/C mice to evaluate depression-associated behavior using the forced-swim test (FST) paradigm with an additional short exposure to PAS. We found that the ENR mice that were exposed to PAS during both housing and behavioral task (ENR + PAS/FST + PAS) show decreased immobility and the number of despair episodes within a higher latency to show the first bout of immobility. Additionally, we found increased neuronal activation evaluated by the identification of activity-regulated cytoskeleton-associated protein- (Arc-) labeled cells in the prefrontal cortex (PFC) in mice exposed to PAS during housing and in the absence or presence of PAS during FST. Moreover, we found increased neuronal activation in the auditory cortex (AuCx) of mice exposed to PAS during FST. Our study suggests that the exposure to PAS during an emotional challenge decreases despair-like behavior in rodents that were previously housed in an enriched environment in combination with auditory stimuli. Thus, our data indicate that the role of the exposure to PAS as an intervention or in combination with positive environment to aid in treating neuropsychiatric disorders is worth pursuing.
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Macoveanu J, Demant KM, Vinberg M, Siebner HR, Kessing LV, Miskowiak KW. Towards a biomarker model for cognitive improvement: No change in memory-related prefrontal engagement following a negative cognitive remediation trial in bipolar disorder. J Psychopharmacol 2018; 32:1075-1085. [PMID: 29969938 DOI: 10.1177/0269881118783334] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Cognitive deficits are prevalent in bipolar disorder during remission but effective cognition treatments are lacking due to insufficient insight into the neurobiological targets of cognitive improvement. Emerging data suggest that dorsal prefrontal cortex target engagement is a key neurocircuitry biomarker of pro-cognitive treatment effects. AIMS In this randomized controlled functional magnetic resonance imaging study, we test this hypothesis by investigating the effects of an ineffective cognitive remediation intervention on dorsal prefrontal response during strategic memory encoding and working memory engagement. METHODS Bipolar disorder patients in partial remission with subjective cognitive difficulties were randomized to receive 12-week group-based cognitive remediation ( n = 13) or to continue their standard treatment ( n = 14). The patients performed a strategic episodic picture encoding task and a spatial n-back working memory task under functional magnetic resonance imaging at baseline and following cognitive remediation or standard treatment. RESULTS The right dorsolateral prefrontal cortex was commonly activated by both strategic memory tasks across all patients. The task-related prefrontal engagement was not altered by cognitive remediation relative to standard treatment. The dorsolateral prefrontal cortex response was not significantly associated with recall accuracy or working memory performance. CONCLUSIONS As hypothesized, no task-related change in prefrontal activity was observed in a negative cognitive remediation trial in remitted bipolar disorder patients. By complementing previous findings linking cognitive improvement with increased dorsolateral prefrontal cortex engagement, our negative findings provide additional validity evidence to the dorsal prefrontal target engagement biomarker model of cognitive improvement by strengthening the proposed causality between modulation of dorsolateral prefrontal cortex engagement and pro-cognitive effects.
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Affiliation(s)
- Julian Macoveanu
- 1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Denmark.,2 Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Denmark
| | - Kirsa M Demant
- 1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Denmark
| | - Maj Vinberg
- 1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Denmark
| | - Hartwig R Siebner
- 2 Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Denmark.,3 Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Lars V Kessing
- 1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Denmark
| | - Kamilla W Miskowiak
- 1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Denmark.,2 Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Denmark.,4 Department of Psychology, University of Copenhagen, Denmark
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Tokuda T, Yoshimoto J, Shimizu Y, Okada G, Takamura M, Okamoto Y, Yamawaki S, Doya K. Identification of depression subtypes and relevant brain regions using a data-driven approach. Sci Rep 2018; 8:14082. [PMID: 30237567 PMCID: PMC6148252 DOI: 10.1038/s41598-018-32521-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 09/10/2018] [Indexed: 12/23/2022] Open
Abstract
It is well known that depressive disorder is heterogeneous, yet little is known about its neurophysiological subtypes. In the present study, we identified neurophysiological subtypes of depression related to specific neural substrates. We performed cluster analysis for 134 subjects (67 depressive subjects and 67 controls) using a high-dimensional dataset consisting of resting state functional connectivity measured by functional MRI, clinical questionnaire scores, and various biomarkers. Applying a newly developed, multiple co-clustering method to this dataset, we identified three subtypes of depression that are characterized by functional connectivity between the right Angular Gyrus (AG) and other brain areas in default mode networks, and Child Abuse Trauma Scale (CATS) scores. These subtypes are also related to Selective Serotonin-Reuptake Inhibitor (SSRI) treatment outcomes, which implies that we may be able to predict effectiveness of treatment based on AG-related functional connectivity and CATS.
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Affiliation(s)
- Tomoki Tokuda
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Okinawa, 904-0495, Japan.
| | - Junichiro Yoshimoto
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Okinawa, 904-0495, Japan.,Graduate School of Information Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0192, Japan
| | - Yu Shimizu
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Okinawa, 904-0495, Japan
| | - Go Okada
- Department of Psychiatry and Neurosciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Masahiro Takamura
- Department of Psychiatry and Neurosciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Yasumasa Okamoto
- Department of Psychiatry and Neurosciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Shigeto Yamawaki
- Department of Psychiatry and Neurosciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Kenji Doya
- Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Okinawa, 904-0495, Japan
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Levy MJF, Boulle F, Steinbusch HW, van den Hove DLA, Kenis G, Lanfumey L. Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression. Psychopharmacology (Berl) 2018; 235:2195-2220. [PMID: 29961124 PMCID: PMC6061771 DOI: 10.1007/s00213-018-4950-4] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023]
Abstract
Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory.
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Affiliation(s)
- Marion J F Levy
- Centre de Psychiatrie et Neurosciences (Inserm U894), Université Paris Descartes, 102-108 rue de la santé, 75014, Paris, France
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- EURON-European Graduate School of Neuroscience, Maastricht, The Netherlands
| | - Fabien Boulle
- Centre de Psychiatrie et Neurosciences (Inserm U894), Université Paris Descartes, 102-108 rue de la santé, 75014, Paris, France
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- EURON-European Graduate School of Neuroscience, Maastricht, The Netherlands
| | - Harry W Steinbusch
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- EURON-European Graduate School of Neuroscience, Maastricht, The Netherlands
| | - Daniël L A van den Hove
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- EURON-European Graduate School of Neuroscience, Maastricht, The Netherlands
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
| | - Gunter Kenis
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- EURON-European Graduate School of Neuroscience, Maastricht, The Netherlands
| | - Laurence Lanfumey
- Centre de Psychiatrie et Neurosciences (Inserm U894), Université Paris Descartes, 102-108 rue de la santé, 75014, Paris, France.
- EURON-European Graduate School of Neuroscience, Maastricht, The Netherlands.
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Gourgouvelis J, Yielder P, Clarke ST, Behbahani H, Murphy BA. Exercise Leads to Better Clinical Outcomes in Those Receiving Medication Plus Cognitive Behavioral Therapy for Major Depressive Disorder. Front Psychiatry 2018; 9:37. [PMID: 29559928 PMCID: PMC5845641 DOI: 10.3389/fpsyt.2018.00037] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 01/29/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE The aim of this study is to investigate the effects of exercise as an add-on therapy with antidepressant medication and cognitive behavioral group therapy (CBGT) on treatment outcomes in low-active major depressive disorder (MDD) patients. We also explored whether exercise reduces the residual symptoms of depression, notably cognitive impairment and poor sleep quality, and aimed to identify putative biochemical markers related to treatment response. METHODS Sixteen low-active MDD patients were recruited from a mental health day treatment program at a local hospital. Eight medicated patients performed an 8-week exercise intervention in addition to CBGT, and eight medicated patients attended the CBGT only. Twenty-two low-active, healthy participants with no history of mental health illness were also recruited to provide normal healthy values for comparison. RESULTS Results showed that exercise resulted in greater reduction in depression symptoms (p = 0.007, d = 2.06), with 75% of the patients showing either a therapeutic response or a complete remission of symptoms vs. 25% of those who did not exercise. In addition, exercise was associated with greater improvements in sleep quality (p = 0.046, d = 1.28) and cognitive function (p = 0.046, d = 1.08). The exercise group also had a significant increase in plasma brain-derived neurotrophic factor (BDNF), p = 0.003, d = 6.46, that was associated with improvements in depression scores (p = 0.002, R2 = 0.50) and sleep quality (p = 0.011, R2 = 0.38). CONCLUSION We provide evidence that exercise as an add-on to conventional antidepressant therapies improved the efficacy of standard treatment interventions. Our results suggest that plasma BDNF levels and sleep quality appear to be good indicators of treatment response and potential biomarkers associated with the clinical recovery of MDD.
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Affiliation(s)
| | - Paul Yielder
- University of Ontario Institute of Technology, Oshawa, ON, Canada
| | - Sandra T Clarke
- University of Ontario Institute of Technology, Oshawa, ON, Canada
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Laine MA, Sokolowska E, Dudek M, Callan SA, Hyytiä P, Hovatta I. Brain activation induced by chronic psychosocial stress in mice. Sci Rep 2017; 7:15061. [PMID: 29118417 PMCID: PMC5678090 DOI: 10.1038/s41598-017-15422-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/27/2017] [Indexed: 02/02/2023] Open
Abstract
Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of ∆FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of ∆FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.
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Affiliation(s)
- Mikaela A Laine
- Department of Biosciences, University of Helsinki, Helsinki, Finland
| | - Ewa Sokolowska
- Department of Biosciences, University of Helsinki, Helsinki, Finland
| | - Mateusz Dudek
- Department of Pharmacology, University of Helsinki, Helsinki, Finland
| | | | - Petri Hyytiä
- Department of Pharmacology, University of Helsinki, Helsinki, Finland.
| | - Iiris Hovatta
- Department of Biosciences, University of Helsinki, Helsinki, Finland.
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Ge R, Blumberger DM, Downar J, Daskalakis ZJ, Tham JC, Lam RW, Vila-Rodriguez F. A sparse representation-based method for parcellation of the resting brain and its application to treatment-resistant major depressive disorder. J Neurosci Methods 2017; 290:57-68. [DOI: 10.1016/j.jneumeth.2017.07.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 06/24/2017] [Accepted: 07/19/2017] [Indexed: 12/17/2022]
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Exercise Promotes Neuroplasticity in Both Healthy and Depressed Brains: An fMRI Pilot Study. Neural Plast 2017; 2017:8305287. [PMID: 28828187 PMCID: PMC5554572 DOI: 10.1155/2017/8305287] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 05/24/2017] [Accepted: 06/07/2017] [Indexed: 12/31/2022] Open
Abstract
Memory impairments are a frequently reported cognitive symptom in people suffering from major depressive disorder (MDD) and often persist despite antidepressant therapy. Neuroimaging studies have identified abnormal hippocampal activity during memory processes in MDD. Exercise as an ad-on treatment for MDD is a promising therapeutic strategy shown to improve mood, cognitive function, and neural structure and function. To advance our understanding of how exercise impacts neural function in MDD, we must also understand how exercise impacts healthy individuals without MDD. This pilot study used a subsequent memory paradigm to investigate the effects of an eight-week exercise intervention on hippocampal function in low-active healthy (n = 8) and low-active MDD (n = 8) individuals. Results showed a marked improvement in depression scores for the MDD group (p < 0.0001) and no change in memory performance for either group (p > 0.05). Functional imaging results showed a marginally significant decrease in hippocampal activity in both groups following the exercise intervention. Our whole brain analysis collapsed across groups revealed a similar deactivation pattern across several memory-associated regions. These results suggest that exercise may enhance neural efficiency in low-fit individuals while still resulting in a substantially greater mood effect for those suffering from MDD. This trial is registered with clinical trials.gov NCT03191994.
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Iñiguez SD, Aubry A, Riggs LM, Alipio JB, Zanca RM, Flores-Ramirez FJ, Hernandez MA, Nieto SJ, Musheyev D, Serrano PA. Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice. Neurobiol Stress 2016; 5:54-64. [PMID: 27981196 PMCID: PMC5154707 DOI: 10.1016/j.ynstr.2016.07.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/16/2016] [Accepted: 07/29/2016] [Indexed: 12/18/2022] Open
Abstract
Social stress, including bullying during adolescence, is a risk factor for common psychopathologies such as depression. To investigate the neural mechanisms associated with juvenile social stress-induced mood-related endophenotypes, we examined the behavioral, morphological, and biochemical effects of the social defeat stress model of depression on hippocampal dendritic spines within the CA1 stratum radiatum. Adolescent (postnatal day 35) male C57BL/6 mice were subjected to defeat episodes for 10 consecutive days. Twenty-four h later, separate groups of mice were tested on the social interaction and tail suspension tests. Hippocampi were then dissected and Western blots were conducted to quantify protein levels for various markers important for synaptic plasticity including protein kinase M zeta (PKMζ), protein kinase C zeta (PKCζ), the dopamine-1 (D1) receptor, tyrosine hydroxylase (TH), and the dopamine transporter (DAT). Furthermore, we examined the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subunit GluA2 as well as colocalization with the post-synaptic density 95 (PSD95) protein, within different spine subtypes (filopodia, stubby, long-thin, mushroom) using an immunohistochemistry and Golgi-Cox staining technique. The results revealed that social defeat induced a depression-like behavioral profile, as inferred from decreased social interaction levels, increased immobility on the tail suspension test, and decreases in body weight. Whole hippocampal immunoblots revealed decreases in GluA2, with a concomitant increase in DAT and TH levels in the stressed group. Spine morphology analyses further showed that defeated mice displayed a significant decrease in stubby spines, and an increase in long-thin spines within the CA1 stratum radiatum. Further evaluation of GluA2/PSD95 containing-spines demonstrated a decrease of these markers within long-thin and mushroom spine types. Together, these results indicate that juvenile social stress induces GluA2- and dopamine-associated dysregulation in the hippocampus - a neurobiological mechanism potentially underlying the development of mood-related syndromes as a consequence of adolescent bullying.
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Affiliation(s)
- Sergio D. Iñiguez
- Department of Psychology, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79902, USA
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - Antonio Aubry
- Department of Psychology, Hunter College, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, USA
| | - Lace M. Riggs
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - Jason B. Alipio
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | | | - Francisco J. Flores-Ramirez
- Department of Psychology, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79902, USA
| | - Mirella A. Hernandez
- Department of Psychology, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79902, USA
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - Steven J. Nieto
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - David Musheyev
- Department of Psychology, Hunter College, New York, NY, 10065, USA
| | - Peter A. Serrano
- Department of Psychology, Hunter College, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, USA
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Miskowiak KW, Macoveanu J, Vinberg M, Assentoft E, Randers L, Harmer CJ, Ehrenreich H, Paulson OB, Knudsen GM, Siebner HR, Kessing LV. Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders. Acta Psychiatr Scand 2016; 134:249-59. [PMID: 27259062 DOI: 10.1111/acps.12597] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/09/2016] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort. METHOD Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or BD in remission were randomized to eight weekly EPO (40 000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall. RESULTS Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure, or medication. CONCLUSION The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement.
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Affiliation(s)
- K W Miskowiak
- Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - J Macoveanu
- Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark
| | - M Vinberg
- Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - E Assentoft
- Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - L Randers
- Psychiatric Centre Copenhagen, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - C J Harmer
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - H Ehrenreich
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - O B Paulson
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.,Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - G M Knudsen
- Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.,Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - H R Siebner
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.,Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - L V Kessing
- Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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