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Lee S, Kim HS, Hong J, Lee E, Kim E, Choi TY, Moon SW, Jung SW, Yoon HJ, Kim HS, Baek JH, Si TM, Kallivayalil RA, Tanra AJ, Nadoushan AHJ, Chee KY, Javed A, Sim K, Pariwatcharakul P, Chong MY, Nakagami Y, Inada T, Moon E, Lin SK, Sartorius N, Shinfuku N, Kato TA, Park SC. Network structure of social withdrawal symptoms in Asian psychiatric patients at high risk of hikikomori: Findings from the REAP-AD3. Asian J Psychiatr 2025; 108:104489. [PMID: 40250201 DOI: 10.1016/j.ajp.2025.104489] [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: 01/23/2025] [Revised: 04/05/2025] [Accepted: 04/11/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Hikikomori is a severe pathological form of social withdrawal that first emerged in Japan in the late 20th century and has since become a global phenomenon. This was recently added to the cultural concept of distress in the DSM-5-TR. OBJECTIVE This study aimed to examine the precise network structure of social withdrawal symptoms in Asian psychiatric patients at high risk of hikikomori using data from Phase 3 of the Research on Asian Psychotropic Prescription Patterns for Antidepressants. METHODS High risk of hikikomori was defined as a score ≥ 42 on the 1-month version of the 25-item Hikikomori Questionnaire (HQ-25M), a scale that measures social withdrawal symptoms. The HQ-25M network structures were estimated separately for patients at high and low risks of hikikomori. The differences in network structure invariance and global strength invariance between the two networks were evaluated. Data from 2993 participants were assessed, including 1939 and 1054 patients at high and low risk of hikikomori, respectively. RESULTS Network analysis revealed that enjoyment of social activities was the most central symptom among patients at high risk of hikikomori, whereas trust issues were the most central among those at low risk of hikikomori. In addition, although no significant differences were identified in the overall network structures, the global strength invariance differed significantly between networks. CONCLUSION While the study has several limitations, the findings may point to potential differences in how social withdrawal symptoms are structured between individuals with high versus low risk of hikikomori, particularly with regard to the overall connectivity among symptoms. A notable finding is that low enjoyment of social interactions may be a main area for early intervention. However, given that the participants were all psychiatric patients receiving antidepressant medication and able to attend in-person evaluations, the applicability of these results to non-clinical groups or individuals with more severe social withdrawal may be restricted.
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Affiliation(s)
- Seonjae Lee
- Department of Psychiatry, Hanyang University Medical Center, Seoul, Republic of Korea
| | - Han Seul Kim
- Department of Psychiatry, Hanyang University Medical Center, Seoul, Republic of Korea
| | - Jiyoung Hong
- Department of Psychiatry, Hanyang University Medical Center, Seoul, Republic of Korea
| | - Eunjae Lee
- Department of Psychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea
| | - Eunkyung Kim
- Department of Premedicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Tae Young Choi
- Department of Psychiatry, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Seok Woo Moon
- Department of Psychiatry, Konkuk University Chungju Hospital, Chungju, Republic of Korea
| | - Sung-Won Jung
- Department of Psychiatry, Keimyung University Dongsan Hospital, Daegu, Republic of Korea
| | - Hyung-Jun Yoon
- Department of Psychiatry, Chosun University Hospital, Gwangju, Republic of Korea
| | - Hyun Soo Kim
- Department of Psychiatry, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Ji Hyun Baek
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Tian-Mei Si
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Centre for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Roy Abraham Kallivayalil
- Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla and Mar Sleeva Medicity, Palai, Kerala, India
| | - Andi J Tanra
- Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Amir Hossein Jalali Nadoushan
- Mental Health Research Center, Psychosocial Health Research Institute, Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kok Yoon Chee
- Department of Psychiatry & Mental Health, Tunku Abdul Rahman Institute of Neurosciences, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
| | - Afzal Javed
- Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan
| | - Kang Sim
- Institute of Mental Health, Buangkok Green Medical Park, Singapore
| | - Pornjira Pariwatcharakul
- Department of Psychiatry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | | | - Toshiya Inada
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Eunsoo Moon
- Department of Psychiatry, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Shih-Ku Lin
- Department of Psychiatry, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; Taipei City Hospital and Psychiatric Center, Taipei, Taiwan
| | - Norman Sartorius
- Association for the Improvement of Mental Health Programs, Geneva, Switzerland
| | - Naotaka Shinfuku
- School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan
| | - Takahiro A Kato
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Seon-Cheol Park
- Department of Psychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea; Department of Psychiatry, Hanyang University College of Medicine, Seoul, Republic of Korea; Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea.
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Davoudi A, Donahue PT, Carlson MC, Dougherty RJ, Wanigatunga AA, Freedman VA, Schrack JA. Physical Activity Patterns and Variability, Cognitive Performance, and Dementia in the National Health and Aging Trends Study. Med Sci Sports Exerc 2025; 57:1221-1228. [PMID: 39992916 DOI: 10.1249/mss.0000000000003656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
INTRODUCTION Physical activity is a modifiable risk factor for dementia. However, the potential reverse effect of adverse cognitive change on physical activity remains underexplored. METHODS Cross-sectional analysis of a subset of National Health and Aging Trends Study (NHATS; N = 706) U.S. Medicare beneficiaries. Dementia status (dementia vs. no dementia) was classified per NHATS protocol. Cognitive performance was assessed in executive function, orientation, and memory domains. Daily physical activity was assessed using wrist-worn accelerometers (Actigraph Insight). RESULTS Compared with participants living without dementia, participants living with dementia had lower daily activity counts (×1000) (-319.3; 95% confidence interval (CI), -471.0 - -167.5), lower activity intensity (-1129.2 maximum counts per day; 95% CI, -1518.4 - -740.0 counts per day), less time spent active (64.3 min/day; 95% CI, 28.1-100.4 min/day), and more fragmented patterns of activity (6.1%; 95% CI, 3.0%-9.2%). One-unit higher cognitive performance in executive function was associated with higher daily activity counts (×1000) (67.9; 95% CI, 19.7-116.0), higher activity intensity (375.4; 95% CI, 232.0-518.7), more time spent active (12.4 min; 95% CI, 2.1-22.7 min), and lower fragmentation (-1.4%; 95% CI, -2.2% - -0.5%). One-unit higher orientation score was associated with higher daily activity counts (×1000) (61.0; 95% CI, 31.9-90.0), higher activity intensity (266.6; 95% CI, 197.9-335.2), more time spent active (11.6 min; 95% CI, 5.2-18.0 more active minutes), greater stability of daily activities (1.1; 95% CI, 0.3-1.9), and lower fragmentation (-1.2%; 95% CI, -1.7% - -0.7%). One-unit higher memory score was associated with higher daily activity counts (×1000) (28.1; 95% CI, 15.0-41.2), higher activity intensity (113.5; 95% CI, 77.0-150.1), and more time spent active (5.2 min; 95% CI, 2.4-8.0 min), as well as lower fragmentation (-0.5%; 95% CI, -0.7% - -0.3%). CONCLUSIONS In a nationally representative sample of older US adults, dementia and lower cognitive performance were associated with lower volume and intensity of daily physical activity, as well as more fragmented and less consistent patterns of physical activity. These associations emphasize the need for considering the impact of cognition on individuals' ability to engage in and maintain regular physical activity and suggest shifts in daily quantities and patterns of activity consistent with cognitive decline and dementia.
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Affiliation(s)
| | - Patrick T Donahue
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
| | - Michelle C Carlson
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
| | - Ryan J Dougherty
- Department of Kinesiology & Health, Rutgers University, New Brunswick, NJ
| | | | - Vicki A Freedman
- Institute for Social Research, University of Michigan, Ann Arbor, MI
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Savitz J, Figueroa-Hall LK, Teague TK, Yeh HW, Zheng H, Kuplicki R, Burrows K, El-Sabbagh N, Thomas M, Ewers I, Cha YH, Guinjoan S, Khalsa SS, Paulus MP, Irwin MR. Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial. Am J Psychiatry 2025; 182:560-568. [PMID: 40264292 DOI: 10.1176/appi.ajp.20240142] [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] [Indexed: 04/24/2025]
Abstract
OBJECTIVE The authors sought to determine whether an inflammatory challenge with lipopolysaccharide (LPS) differentially impacts symptoms of anhedonia in participants with major depressive disorder with high (≥3 mg/L) and low (≤1.5 mg/L) serum C-reactive protein (CRP) concentrations. METHODS Sixty-eight participants with major depressive disorder were randomly assigned, in a 1:1 ratio, to receive LPS (0.8 ng/kg body weight) or placebo (saline) in a parallel-group double-blind design. Participants were stratified according to baseline CRP concentrations, yielding four groups: high-CRP LPS (N=13), low-CRP LPS (N=19), high-CRP placebo (N=13), and low-CRP placebo (N=19). Blood was sampled at baseline, at 1, 1.5, 3.5, 6, and 24 hours, and 1 week after LPS or saline administration, with concurrent assessment of psychological outcomes. The primary outcome measure was the Snaith-Hamilton Pleasure Scale (SHAPS), and the primary contrast of interest was the change between baseline and 1.5 hours (peak of the inflammatory response) in the high-CRP versus low-CRP groups receiving LPS. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) and serum levels of three cytokines: interleukin-6 (IL-6), IL-10, and tumor necrosis factor (TNF). Data were analyzed with linear mixed models. RESULTS Significantly greater increases in self-reported anhedonia (on the SHAPS) and IL-6 levels were observed between baseline and 1.5 hours in the high-CRP versus low-CRP LPS groups. There were no significant differences for TNF and IL-10. The MADRS was not administered at 1.5 hours; secondary analyses showed a significant group-by-condition-by-time interaction driven by a greater decrease in MADRS scores between baseline and 24 hours in the high-CRP group. CONCLUSIONS Depressed individuals with systemic inflammation appeared to be biologically primed to respond more strongly to inflammatory stimuli, and psychologically, this sensitization impacted the symptom of anhedonia, the primary outcome.
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Affiliation(s)
- Jonathan Savitz
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Leandra K Figueroa-Hall
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - T Kent Teague
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Hung-Wen Yeh
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Haixia Zheng
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Rayus Kuplicki
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Kaiping Burrows
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Nour El-Sabbagh
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - MacGregor Thomas
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Isaac Ewers
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Yoon-Hee Cha
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Salvador Guinjoan
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Sahib S Khalsa
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Martin P Paulus
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
| | - Michael R Irwin
- Laureate Institute for Brain Research, Tulsa, OK (Savitz, Figueroa-Hall, Zheng, Kuplicki, Burrows, El-Sabbagh, Ewers, Guinjoan, Khalsa, Paulus); Oxley College of Health and Natural Sciences, University of Tulsa, Tulsa, OK (Savitz, Guinjoan, Khalsa, Paulus); Department of Surgery (Teague, Guinjoan) and Department of Psychiatry (Guinjoan), University of Oklahoma School of Community Medicine, Tulsa, OK; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK (Teague); Division of Health Services and Outcomes Research, Children's Mercy Research Institute, Kansas City, MO (Yeh); School of Medicine, University of Missouri-Kansas City, Kansas City, MO (Yeh); University of Oklahoma School of Medicine, Oklahoma City (Thomas); Department of Neurology, University of Minnesota School of Medicine, Minneapolis (Cha); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles (Khalsa); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, and Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine, UCLA, Los Angeles (Irwin)
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Millar CL, Wolfe A, Baldyga K, Dufour AB, Lipsitz LA. Berries and Steps: a protocol of a randomized, placebo-controlled pilot study testing freeze-dried blueberry powder in sedentary older adults with mild depressive symptoms. Nutr J 2025; 24:87. [PMID: 40442715 PMCID: PMC12123748 DOI: 10.1186/s12937-025-01154-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 05/13/2025] [Indexed: 06/02/2025] Open
Abstract
BACKGROUND Older adults spend the majority of their day engaging in sedentary behavior, which increases risk of mortality by 22%. Despite the well-established health benefits of physical activity, a large portion of older adults remain sedentary. Recent evidence suggests that inflammation contributes to lack of motivation, which is a critical barrier to overcoming sedentary behavior in older adults. Given that inflammation is highly modifiable by diet, an anti-inflammatory dietary strategy may be a viable way to improve inflammation-driven lack of motivation and ultimately increase physical activity in sedentary older adults. However, interventions targeting such a pathway are scarce. We propose a study intervention protocol, which aims to determine the feasibility and preliminary efficacy of daily supplementation of freeze-dried blueberries. Supplementation with blueberries provides 2 anti-inflammatory nutrients (fiber and anthocyanins) to theoretically reduce inflammation-driven lack of motivation and thereby enhance physical activity in older adults with sedentary behavior and mild depressive symptoms. METHODS The current study is planned as a single-site, randomized, double-blind, parallel pilot study in 40 older adults with sedentary behavior and mild depressive symptoms. Individuals with depressive symptoms often lack motivation and have increased levels of inflammatory cytokines, representing an ideal population for an anti-inflammatory dietary intervention to improve motivation. Participants will be randomized to consume either 48 g of freeze-dried blueberry powder (~ 600 mg of anthocyanins and ~ 8 g of fiber) or a nutritionally matched placebo powder (without any known amounts of anthocyanins and fiber) each day for a total of 12 weeks. DISCUSSION Identification of a dietary intervention to target the inflammatory pathways may offer a novel and feasible approach to increase motivation and engagement of physical activity in older adults. If feasible and effective, such a strategy would help avoid the plethora of health consequences associated with sedentary behavior and physical inactivity. TRIAL REGISTRATION The current study is approved by the Advarra IRB (#Pro00064749) and registered at Clinicaltrials.gov (Identifier: NCT05735587).
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Affiliation(s)
- Courtney L Millar
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Hinda and Arthur Marcus Institute for Aging Research, 1200 Centre St, Boston, MA, 02131, USA.
| | - Alex Wolfe
- Hinda and Arthur Marcus Institute for Aging Research, 1200 Centre St, Boston, MA, 02131, USA
| | - Kathryn Baldyga
- Hinda and Arthur Marcus Institute for Aging Research, 1200 Centre St, Boston, MA, 02131, USA
| | - Alyssa B Dufour
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Hinda and Arthur Marcus Institute for Aging Research, 1200 Centre St, Boston, MA, 02131, USA
| | - Lewis A Lipsitz
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Hinda and Arthur Marcus Institute for Aging Research, 1200 Centre St, Boston, MA, 02131, USA
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5
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Mac Giollabhui N, Slaney C, Hemani G, Foley ÉM, van der Most PJ, Nolte IM, Snieder H, Davey Smith G, Khandaker GM, Hartman CA. Role of inflammation in depressive and anxiety disorders, affect, and cognition: genetic and non-genetic findings in the lifelines cohort study. Transl Psychiatry 2025; 15:164. [PMID: 40348744 PMCID: PMC12065825 DOI: 10.1038/s41398-025-03372-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 03/03/2025] [Accepted: 04/02/2025] [Indexed: 05/14/2025] Open
Abstract
Inflammation is associated with a range of neuropsychiatric symptoms, but the issue of causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning at baseline and a follow-up assessment occurring 3.91 years later (SD = 1.21). Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmin = 35,300; Nmax = 57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmin=22,154; Nmax = 23,268). In non-genetic analyses, higher CRP was associated with depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRPGRS was associated with any anxiety disorder (β = 0.002, p = 0.037) whereas GlycAGRS was associated with major depressive disorder (β = 0.001, p = 0.036). Both CRPGRS (β = 0.006, p = 0.035) and GlycAGRS (β = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except sIL-6RGRS which was associated with poorer memory (β = -0.009, p = 0.018). There was a non-significant CRP-anxiety association using MR (β = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that inflammation may impact a broad range of trans-diagnostic affective symptoms.
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Affiliation(s)
- Naoise Mac Giollabhui
- Depression Clinical & Research Program, Department of Psychiatry, Massachusetts General Hospital, Boston, USA.
| | - Chloe Slaney
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK.
| | - Gibran Hemani
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
| | - Éimear M Foley
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK
| | - Peter J van der Most
- University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ilja M Nolte
- University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Harold Snieder
- University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - George Davey Smith
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
| | - Golam M Khandaker
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK
- FRCPsych, MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, UK
- Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UK
| | - Catharina A Hartman
- Interdisciplinary Center Psychopathology and Emotion Regulation, Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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6
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Cătălina GR, Gheorman V, Gheorman V, Forțofoiu MC. The Role of Neuroinflammation in the Comorbidity of Psychiatric Disorders and Internal Diseases. Healthcare (Basel) 2025; 13:837. [PMID: 40218134 PMCID: PMC11988559 DOI: 10.3390/healthcare13070837] [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: 01/29/2025] [Revised: 03/08/2025] [Accepted: 04/02/2025] [Indexed: 04/14/2025] Open
Abstract
Psychiatric disorders and internal diseases frequently co-occur, posing significant challenges due to overlapping symptoms, shared pathophysiological mechanisms, and increased healthcare burdens. Neuroinflammation has emerged as a central mechanism linking these conditions, driven by systemic inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and autonomic nervous system (ANS) imbalance. This review synthesizes current evidence on the role of neuroinflammation in comorbid conditions such as depression, anxiety, cardiovascular disease, and diabetes mellitus, emphasizing bidirectional relationships and shared inflammatory pathways. This analysis identifies gaps in longitudinal studies, biomarker validation, and the integration of multidisciplinary care models. Emerging therapeutic approaches, including IL-6 inhibitors, vagus nerve stimulation, and behavioral interventions, show promise but remain underexplored in combined applications. Furthermore, disparities in research representation limit the generalizability of findings and highlight the need for inclusive clinical trials. Addressing these gaps through precision medicine, advanced biomarker monitoring technologies, and equitable healthcare strategies could transform the management of these complex comorbidities. By advancing our understanding of neuroinflammatory mechanisms and promoting integrated interventions, this review underscores the need for a collaborative, patient-centered approach to improve outcomes and reduce the global burden of psychiatric and internal disease comorbidities.
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Affiliation(s)
| | - Victor Gheorman
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Veronica Gheorman
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Mircea-Cătălin Forțofoiu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
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7
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Qiao D, Qi Y, Zhang X, Wen Y, Huang Y, Li Y, Liu P, Li G, Liu Z. The possible effect of inflammation on non-suicidal self-injury in adolescents with depression: a mediator of connectivity within corticostriatal reward circuitry. Eur Child Adolesc Psychiatry 2025:10.1007/s00787-025-02709-6. [PMID: 40186642 DOI: 10.1007/s00787-025-02709-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/24/2025] [Indexed: 04/07/2025]
Abstract
Non-suicidal self-injury (NSSI) in adolescent depression is a prevalent and clinically significant behavior linked to dysregulated peripheral inflammation and corticostriatal circuitry dysfunction. However, the neuroimmune mechanisms bridging these systems remain poorly understood. Here, we combined peripheral cytokine profiling with static/dynamic functional connectivity (sFC/dFC) analysis to investigate the potential influence of inflammaton on corticostriatal circuit related to NSSI. A set of peripheral blood inflammatory markers and resting-state functional magnetic resonance imaging (rs-fMRI) were collected in depression with NSSI (NSSI+), depression without NSSI (NSSI-), and healthy controls (HC). We first ascertain group differences in level of pro- and anti-inflammatory cytokines. And using ventral/dorsal striatal seeds, we compared whole-brain, voxel-wise sFC and dFC differences across three groups. Further, we tested the mediation effects of connectivity in the association between inflammatory markers and NSSI frequency. NSSI+ group exhibited elevated pro-inflammatory cytokines (C-reactive protein (CRP), interleukin (IL)-1, and IL-6) whereas reduced anti-inflammatory cytokines (IL-10), compared to NSSI- and HC. Neuroimaging analysis revealed corticostriatal dysconnectivity mainly characterized by static hyperconnectivity between dorsal striatum and thalamus, dynamic instability in dorsal striatum-lingual pathways, and dynamic rigidity in ventral striatum-prefrontal/temporal/occipital gyrus circuits. Critically, sFC of dorsal striatum-thalamus and dFC of dorsal striatum-lingual gyrus mediated the prospective association between altered CRP and NSSI frequency, establishing corticostriatal circuits as conduits for inflammatory effects on NSSI. By bridging molecular psychiatry with circuit neuroscience, this work advances precision management of NSSI in adolescent depression, prioritizing biomarker-driven strategies to disrupt neuroimmune maladaptation.
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Affiliation(s)
- Dan Qiao
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Yirun Qi
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Xiaoyu Zhang
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Yujiao Wen
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Yangxi Huang
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Yiran Li
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Penghong Liu
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Gaizhi Li
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China
| | - Zhifen Liu
- Department of Psychiatry, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, China.
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8
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Dobolyi A. Integrating the COM-B model into behavioral neuroscience: A framework for understanding animal behavior. Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111346. [PMID: 40154911 DOI: 10.1016/j.pnpbp.2025.111346] [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: 11/14/2024] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025]
Abstract
In light of the intricate nature of animal behavior regulation, a theoretical model is proposed, grounded in the COM-B (Capability, Opportunity, Motivation - Behavior) framework, which has gained considerable traction in the domain of human behavioral intervention. When extending the COM-B model to behavioral neuroscience, we first discuss the utility of the model in animal research, particularly its capacity to integrate environmental and social factors, and enhance cross-species comparisons, including animal-to-human translations and evolutionary considerations. The subsequent discussion then summarizes the advantages of utilizing the COM-B model in neuroscience are summarized, including the facilitation of a systems-level understanding of behavior and the establishment of a link between neural mechanisms and specific behavioral components. The experimental design for the application of the COM-B model in neuroscience is proposed to elucidate the brain regulatory processes that govern behavior. Finally, three specific examples are provided to illustrate the theoretical considerations, namely feeding and social behavior, and the role of neuromodulators in the control of behavior.
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Affiliation(s)
- Arpád Dobolyi
- Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary; Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, Hungary.
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9
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Treadway MT, Etuk SM, Cooper JA, Hossein S, Hahn E, Betters SA, Liu S, Arulpragasam AR, DeVries BAM, Irfan N, Nuutinen MR, Wommack EC, Woolwine BJ, Bekhbat M, Kragel PA, Felger JC, Haroon E, Miller AH. A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation. Mol Psychiatry 2025; 30:1407-1417. [PMID: 39289477 PMCID: PMC11911248 DOI: 10.1038/s41380-024-02751-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 08/22/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.
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Affiliation(s)
- Michael T Treadway
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA.
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA.
| | - Sarah M Etuk
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA
| | - Jessica A Cooper
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Shabnam Hossein
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, US
| | - Evan Hahn
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA
| | | | - Shiyin Liu
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA
| | | | | | - Nadia Irfan
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA
| | | | - Evanthia C Wommack
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Bobbi J Woolwine
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Philip A Kragel
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Jennifer C Felger
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Ebrahim Haroon
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Andrew H Miller
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA
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10
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Connolly MG, Johnson ZV, Chu L, Johnson ND, Buhr TJ, McNeill EM, Clark PJ, Rhodes JS. Single-Nucleus RNA Sequencing Reveals Enduring Signatures of Acute Stress and Chronic Exercise in Striatal Microglia. GENES, BRAIN, AND BEHAVIOR 2025; 24:e70019. [PMID: 40045485 PMCID: PMC11882474 DOI: 10.1111/gbb.70019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 02/16/2025] [Accepted: 02/19/2025] [Indexed: 03/09/2025]
Abstract
Acute stress has enduring effects on the brain and motivated behavior across species. For example, acute stress produces persisting decreases in voluntary physical activity as well as molecular changes in the striatum, a brain region that regulates voluntary physical activity and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, are positioned at the interface between neural responses to stress and neural coordination of voluntary activity in that they respond to stress, sense molecular changes in the striatum, and modulate neuronal activity. However, the role of striatal microglia in stress-induced long-term suppression of voluntary activity is unknown. Here, we employ single-nucleus RNA sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that striatal microglia display altered activation profiles 6 weeks after an acute stressor. Furthermore, we show that access to a running wheel is associated with an additional and distinct microglial activation profile characterized by upregulation of genes related to complement components and phagocytosis pathways. Finally, we find that distinct gene sets show expression changes associated with general access to a running wheel versus variation in running levels. Taken together, our results deepen our understanding of the diverse molecular states that striatal microglia assume in response to stress and exercise and suggest that microglia exhibit a broader range of functional states than previously thought.
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Affiliation(s)
- Meghan G. Connolly
- Neuroscience ProgramUniversity of Illinois Urbana‐ChampaignUrbanaIllinoisUSA
| | - Zachary V. Johnson
- Department of Psychiatry and Behavioral SciencesEmory UniversityAtlantaGeorgiaUSA
| | - Lynna Chu
- Department of StatisticsIowa State UniversityAmesIowaUSA
| | | | - Trevor J. Buhr
- Department of Food Science and Human NutritionIowa State UniversityAmesIowaUSA
- Neuroscience Graduate ProgramIowa State UniversityAmesIowaUSA
| | | | - Peter J. Clark
- Department of Food Science and Human NutritionIowa State UniversityAmesIowaUSA
- Neuroscience Graduate ProgramIowa State UniversityAmesIowaUSA
| | - Justin S. Rhodes
- Neuroscience ProgramUniversity of Illinois Urbana‐ChampaignUrbanaIllinoisUSA
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
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11
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Cadeddu R, Branca C, Braccagni G, Musci T, Piras IS, Anderson CJ, Capecchi MR, Huentelman MJ, Moos PJ, Bortolato M. Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D 3 dopamine receptors. Mol Psychiatry 2025:10.1038/s41380-025-02970-w. [PMID: 40155412 DOI: 10.1038/s41380-025-02970-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/05/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.
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Affiliation(s)
- Roberto Cadeddu
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Caterina Branca
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Giulia Braccagni
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Teresa Musci
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Collin J Anderson
- Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA
- School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
- School of Biomedical Engineering, University of Sydney, Camperdown, NSW, Australia
| | - Mario R Capecchi
- Department of Human Genetics, College of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Philip J Moos
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
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12
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Cheng J, Sun Z, Zhang H, Zhao D, Wang P, Chen H, Lyv W, Deng Q, Fu Y, Lyv X, Gao T, Xu J, Zhou F, Wu Y, Yang X, Ma P, Tong Z. External stress, formaldehyde, and schizophrenia: a new mouse model for mental illness research. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2025; 11:50. [PMID: 40140372 PMCID: PMC11947252 DOI: 10.1038/s41537-025-00603-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
Although MK801-induced NMDA receptor (NMDAR) hypofunction mimics schizophrenia symptoms, the exact factors causing NMDAR inhibition are unknown. Unexpectedly, external stress elicits formaldehyde (FA) generation; FA can induce depression and cognitive impairments by blocking NMDARs. This study explores using FA injection to establish a schizophrenia-like model in mice. Here, we reported that external stress-derived FA induces schizophrenia-like behaviors. Four experimental methods were used to induce schizophrenia-like symptoms in wild-type mice: double electrode stimulation of the ventral tegmental area (VTA), microinjection of FA or tetrahydroisoquinoline (TIQ) into the VTA, and intraperitoneal injection of MK801. Then the metabolic levels of FA and dopamine (DA) in the prefrontal cortex (PFC) and VTA were quantified using ELISA kits. We found that external stress-electrical stimulation via VTA caused schizophrenia-like behaviors, including despairing behavior as measured by the tail suspension test, anhedonia as evaluated by the sucrose preference test, stereotypical behavior as assessed by the marble burying test (MBT), anxiety-like behavior as measured by the open-field test and memory deficit as detected by the Y-maze. These behaviors correlated with increased DA and TIQ levels in the VTA and decreased DA levels in the PFC. High-resolution mass spectrometry (HRMS) and high-performance liquid chromatography (HPLC) confirmed TIQ formation from FA and DA. Furthermore, injecting TIQ into the VTA induced schizophrenia-like symptoms in mice, marked by higher FA and lower DA levels in the PFC than control mice. Strikingly, injecting FA into the VTA as well as administering MK-801 induced schizophrenia-like behaviors associated with reduced DA levels and low activity of tyrosine hydroxylase (TH) and monoamine oxidase (MAO) in the PFC. Hence, microinfusion of FA into the VTA can be used to prepare schizophrenia-like changes mouse model, suggesting that stress-derived FA may act as an endogenous trigger of schizophrenia-like changes.
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Affiliation(s)
- Junhao Cheng
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
- Wenzhou semir united international school, Wenzhou, China
| | - Zihui Sun
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
- Beijing Geriatric Hospital, Beijing, 100049, China
| | - Hao Zhang
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Danrui Zhao
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Panpan Wang
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Haishu Chen
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Wanjia Lyv
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
- Key Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Qiangfeng Deng
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Yuanyu Fu
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Xingzhou Lyv
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Tingting Gao
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Jinan Xu
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Feiyan Zhou
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
| | - Yiqing Wu
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China
- University of Alberta, Edmonton, AB, Canada
| | - Xu Yang
- Key Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Ping Ma
- Key Laboratory of Environmental Related Diseases and One Health, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China.
| | - Zhiqian Tong
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, P.R. China.
- Beijing Geriatric Hospital, Beijing, 100049, China.
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13
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Wan J, Lin J, Zha T, Ciruela F, Jiang S, Wu Z, Fang X, Chen Q, Chen X. Temporomandibular disorders and mental health: shared etiologies and treatment approaches. J Headache Pain 2025; 26:52. [PMID: 40075300 PMCID: PMC11899861 DOI: 10.1186/s10194-025-01985-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
The biopsychosocial model suggests that temporomandibular disorders (TMDs) often coexist with mental health disorders, particularly depression and anxiety, affecting a significant portion of the global population. The interplay between TMDs and mental health disorders contributes to a complex comorbidity, perpetuating a cycle of mutual influence and reinforcement. This review investigates the neurobiological mechanisms and epidemiological evidence supporting the shared etiology of TMDs and mental health disorders, exploring potential shared vulnerabilities and bidirectional causal relationships. Shared vulnerabilities between TMDs and mental health disorders may stem from genetic and epigenetic predispositions, psychosocial factors, and behavioral aspects. Inflammatory cytokines, neurotransmitters, neurotrophins, and neuropeptides play pivotal roles in both peripheral and central sensitization as well as neuroinflammation. Brain imaging studies suggest that TMDs and mental health disorders exhibit overlapping brain regions indicative of reward processing deficits and anomalies within the triple network model. Future research efforts are crucial for developing a comprehensive understanding of the underlying mechanisms and confirming the reciprocal causal effects between TMDs and mental health disorders. This review provides valuable insights for oral healthcare professionals, stressing the importance of optimizing treatment strategies for individuals dealing with concurrent TMDs and mental health issues through a personalized, holistic, and multidisciplinary approach.
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Affiliation(s)
- Jiamin Wan
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Jiu Lin
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Tingfeng Zha
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Francisco Ciruela
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Neuropharmacology & Pain Group, Neuroscience Program, IDIBELL-Bellvitge Institute for Biomedical Research, Barcelona, Spain
| | - Shaokang Jiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Zuping Wu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Xinyi Fang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
| | - Qianming Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
| | - Xiaoyan Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
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14
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Zhao ZW, Wang YC, Chen PC, Tzeng SF, Chen PS, Kuo YM. Dopamine D1 receptor agonist alleviates post-weaning isolation-induced neuroinflammation and depression-like behaviors in female mice. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2025; 21:6. [PMID: 40065395 PMCID: PMC11895232 DOI: 10.1186/s12993-025-00269-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders. RESULTS Adolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation. CONCLUSIONS This study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.
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Affiliation(s)
- Zi-Wei Zhao
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yun-Chen Wang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Pei-Chun Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Shun-Fen Tzeng
- Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Po-See Chen
- Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 70101, Taiwan
- Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yu-Min Kuo
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
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15
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Varela RB, Macpherson H, Walker AJ, Houghton T, Yates C, Yates NJ, Daygon VD, Tye SJ. Inflammation and metabolic dysfunction underly anhedonia-like behavior in antidepressant resistant male rats. Brain Behav Immun 2025; 127:170-182. [PMID: 40064431 DOI: 10.1016/j.bbi.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 02/17/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025] Open
Abstract
Inflammation and metabolic dysfunction impair dopamine neurotransmission, which is thought to serve as a critical mechanism underpinning motivational deficits such as anhedonia across a range of psychiatric and neurological disorders. This difficult-to-treat transdiagnostic symptom has important implications for treatment resistant depression (TRD), and may warrant more targeted therapeutic approaches that address the underlying pathophysiological mechanisms. Using the adrenocorticotrophic hormone (ACTH) model of antidepressant treatment resistance we characterized the relationship between antidepressant-like and anhedonia-like behavioral responses to bupropion, mesocortical tyrosine hydroxylase (TH) expression, chronic low-grade inflammation, and metabolic changes in male rats. We demonstrate that chronic ACTH elicited both an antidepressant resistant- and anhedonia-like phenotype in forced swim and effort-related choice behavioral tasks, respectively. This was associated with decreased TH expression in the brain, increased central and peripheral markers of inflammation, and peripheral metabolic disturbances, including impairment of immune cell insulin action. Multivariate analysis revealed that peripheral interleukin-6 (IL-6) levels, immune cell glucose uptake and disturbance of nucleotide metabolism were strongly associated with anhedonia-like behavior. Post-hoc analyses further confirmed strong correlations between TH expression, inflammation and behavioral performance. These data suggest that stress hormone-induced upregulation of inflammation concurrent with the impairment of insulin-mediated glucose uptake into immune cells is associated with disruption of nucleotide metabolism, and potential impaired central dopamine synthesis contributing to the behavioral expression of anhedonia. These results suggest that immunometabolic perturbations concomitant with impaired insulin action at the level of the immune cell result in a metabolically deficient state that directly impacts nucleotide precursors essential for dopamine synthesis and effortful behavior. These results highlight the potential for immune and metabolic markers for individualized treatment of refractory depression and anhedonia.
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Affiliation(s)
- Roger B Varela
- Functional Neuromodulation and Novel Therapeutics Laboratory, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.
| | - Heather Macpherson
- Functional Neuromodulation and Novel Therapeutics Laboratory, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
| | - Adam J Walker
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States; Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Tristan Houghton
- Functional Neuromodulation and Novel Therapeutics Laboratory, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia; Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
| | - Clarissa Yates
- Functional Neuromodulation and Novel Therapeutics Laboratory, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
| | - Nathanael J Yates
- Functional Neuromodulation and Novel Therapeutics Laboratory, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
| | - Venea D Daygon
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia
| | - Susannah J Tye
- Functional Neuromodulation and Novel Therapeutics Laboratory, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States; Department of Psychiatry and Behavioral Science, Emory University, Atlanta, GA, United States.
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16
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Huwart SJP, Morales-Puerto N, Everard A. Gut microbiota-related neuroinflammation at the crossroad of food reward alterations: implications for eating disorders. Gut 2025:gutjnl-2024-333397. [PMID: 39961644 DOI: 10.1136/gutjnl-2024-333397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025]
Abstract
The link between gut microbiome and eating behaviours, especially palatable food intake, is a growing focus of scientific investigation. The complex ecosystem of microorganisms in the gut influences host metabolism, immune function and neurobehavioural signalling. This review explores the role of neuroinflammation in dysregulations of food-induced reward signalling and the potential causal role of the gut microbiota on these proinflammatory processes. Particular attention is given to eating disorders (ED, specifically anorexia nervosa, binge eating disorder and bulimia nervosa) and potential links with the gut microbiota, food reward alterations and neuroinflammation. Finally, we propose gut microbiota modulation as a promising therapeutic strategy in food reward alterations and ED.
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Affiliation(s)
- Sabrina J P Huwart
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
- Walloon Excellence in Life BIOtechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium
| | - Nuria Morales-Puerto
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
- Walloon Excellence in Life BIOtechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium
| | - Amandine Everard
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
- Walloon Excellence in Life BIOtechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium
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17
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Bekhbat M, Li Z, Dunlop BW, Treadway MT, Mehta ND, Revill KP, Lucido MJ, Hong C, Ashchi A, Wommack EC, Goldsmith DR, Haroon E, Miller AH, Felger JC. Sustained effects of repeated levodopa (L-DOPA) administration on reward circuitry, effort-based motivation, and anhedonia in depressed patients with higher inflammation. Brain Behav Immun 2025; 125:240-248. [PMID: 39694342 PMCID: PMC11903141 DOI: 10.1016/j.bbi.2024.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024] Open
Abstract
Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and have been associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order. Resting-state (rs) and task-based (tb; monetary incentive delay) fMRI, effort-based motivation, and exploratory measures of anhedonia and depression severity were assessed at baseline and after one week of placebo and each dose of L-DOPA. Responses to individual doses of L-DOPA varied across outcomes. For example, VS-vmPFC rs-FC was significantly increased by L-DOPA at 150 and 450 mg/day/week (p < 0.01), whereby approximately half of patients responded optimally to 150 mg/day L-DOPA and approximately half required higher doses for maximum effect. While effort-based motivation was only significantly increased by L-DOPA at 150 mg/day (p < 0.05), it correlated with VS-vmPFC rs-FC at this dose (r = 0.64, p = 0.024), and all L-DOPA doses met a clinically significant threshold of ≥ 10 % increase versus placebo. When comparing the maximum response at any L-DOPA dose to placebo, high effect sizes were observed for these primary outcomes and tb-FC during reward anticipation (dz = 0.82-0.98, p < 0.01), as well as secondary and exploratory measures of anhedonia and depression severity (dz = 0.48-0.97, p < 0.05). Sustained effects on reward circuitry, effort-based motivation, and anhedonia by repeated L-DOPA administration support the therapeutic potential of agents that increase dopamine in depressed patients with higher inflammation.
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Affiliation(s)
- Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - Zhihao Li
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; BlueHalo, Rockville, MD, 20855
| | - Boadie W Dunlop
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - Michael T Treadway
- Department of Psychology, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322
| | - Neeti D Mehta
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; Supernus Pharmaceuticals, Rockville, MD, 20850
| | - Kate P Revill
- Facility for Education and Research in Neuroscience, Emory University, Atlanta, GA, USA
| | - Michael J Lucido
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - Changdo Hong
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - Andrea Ashchi
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - Evanthia C Wommack
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - David R Goldsmith
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - Ebrahim Haroon
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322
| | - Andrew H Miller
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322
| | - Jennifer C Felger
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322.
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18
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Câmara AB, Brandão IA. The neuroinflammatory effects of Nociceptin/Orphanin FQ receptor activation can be related to depressive-like behavior. J Psychiatr Res 2025; 183:174-188. [PMID: 39978292 DOI: 10.1016/j.jpsychires.2025.02.012] [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: 03/06/2024] [Revised: 05/08/2024] [Accepted: 02/07/2025] [Indexed: 02/22/2025]
Abstract
There is limited information on the role of the Nociceptin/Orphanin FQ receptor (NOPR) in neuroinflammation, and there is growing interest in the participation of the NOPR in depression etiology. This study aims to evaluate the neuroinflammatory effects of the NOPR activation in mice submitted to social defeat protocol (SDP). Firstly, male Swiss mice were submitted to the social defeat protocol during 10 or 20 days and treated with the NOPR agonist Ro 65-6570 (1.5 or 2 mg/kg; ip). Subsequently, behavioral tests were applied to evaluate depressive-like behaviors. Finally, inflammatory cytokines were measured in the animals' brains and blood. A meta-analysis, including 11 experiments, was also conducted to evaluate if the NOPR activation contributes to inflammation. The studies' weights, odds ratios, and confidence intervals were used to calculate the average effect size as the main outcome measure. The software SPSS v.29 and R programming language were used to analyze the data. The SDP and/or NOP agonist reduced distance traveled and exploration rate in the open field test. The SDP and/or the NOP agonist also increased immobility time in the tail suspension test, as well as reduced social interaction. Additionally, the NOP agonist increased the concentration of IL-6 and TNF alpha in the hippocampus, as well as reduced the IL-10 concentration in the hippocampus, but not in prefrontal cortex and serum. The SDP increased the concentration of IL-6 and TNF alpha in animals' serum and prefrontal cortex, but not in the hippocampus. The role of NOPR in neuroinflammation was regardless of the social defeat stress in the hippocampus. Meta-analysis also demonstrated the participation of NOPR activation in inducing inflammation in mice models. We suggest that upregulation of NOPR can activate signaling pathways involved in neuroinflammation, contributing to depression etiology.
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Affiliation(s)
| | - Igor Augusto Brandão
- Bioinformatics Multidisciplinary Environment, Federal University of Rio Grande do Norte, Brazil
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19
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Bekhbat M, Block AM, Dickinson SY, Tharp GK, Bosinger SE, Felger JC. Neurotransmitter and metabolic effects of interferon-alpha in association with decreased striatal dopamine in a non-human primate model of cytokine-Induced depression. Brain Behav Immun 2025; 125:308-318. [PMID: 39826580 PMCID: PMC11903159 DOI: 10.1016/j.bbi.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/13/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025] Open
Abstract
Inflammatory stimuli administered to humans and laboratory animals affect mesolimbic and nigrostriatal dopaminergic pathways in association with impaired motivation and motor activity. Alterations in dopaminergic corticostriatal reward and motor circuits have also been observed in depressed patients with increased peripheral inflammatory markers. The effects of peripheral inflammation on dopaminergic pathways and associated neurobiologic mechanisms and consequences have been difficult to measure in patients. Postmortem tissue (n = 11) from an established, translationally-relevant non-human primate model of cytokine-induced depressive behavior involving chronic interferon-alpha (IFN-a) administration was utilized herein to explore the molecular mechanisms of peripheral cytokine effects on striatal dopamine. Dopamine (but not serotonin or norepinephrine) was decreased in the nucleus accumbens (NAcc) and putamen of IFN-a-treated animals (p < 0.05). IFN-a had no effect on number of striatal neurons or dopamine terminal density, suggesting no overt neurodegenerative changes. RNA sequencing examined in the caudate, putamen, substantia nigra, and prefrontal cortical subregions revealed that while IFN-a nominally up-regulated limited numbers of genes enriching inflammatory signaling pathways in all regions, robust, whole genome-significant effects of IFN-a were observed specifically in putamen. Genes upregulated in the putamen primarily enriched synaptic signaling, glutamate receptor signaling, and inflammatory/metabolic pathways downstream of IFN-a, including MAPK and PI3K/AKT cascades. Conversely, gene transcripts reduced by IFN-a enriched oxidative phosphorylation (OXPHOS), protein translation, and pathways regulated by dopamine receptors. Unsupervised clustering identified a gene co-expression module in the putamen that was associated with both IFN-a treatment and low dopamine levels, which enriched similar inflammatory, metabolic, and synaptic signaling pathways. IFN-a-induced reductions in dopamine further correlated with genes related to excitotoxic glutamate, kynurenine, and altered dopamine receptor signaling (r = 0.78-97, p < 0.05). These findings provide insight into the immunologic mechanisms and neurobiological consequences of peripheral inflammation effects on dopamine, which may inform novel treatment strategies targeting inflammatory, metabolic or neurotransmitter systems in depressed patients with high inflammation.
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Affiliation(s)
- Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
| | - Andrew M Block
- Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT 06030, USA
| | - Sarah Y Dickinson
- Neuroscience and Behavior Program, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Gregory K Tharp
- Emory Nonhuman Primate Genomics Core, Division of Microbiology and Immunology, Emory National Primate Research Center (EPC), Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Steven E Bosinger
- Emory Nonhuman Primate Genomics Core, Division of Microbiology and Immunology, Emory National Primate Research Center (EPC), Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pathology and Laboratory Medicine, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Jennifer C Felger
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
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20
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Ponce-Regalado MD, Becerril-Villanueva E, Maldonado-García JL, Moreno-Lafont MC, Martínez-Ramírez G, Jacinto-Gutiérrez S, Arreola R, Sánchez-Huerta K, Contis-Montes de Oca A, López-Martínez KM, Bautista-Rodríguez E, Chin-Chan JM, Pavón L, Pérez-Sánchez G. Comprehensive view of suicide: A neuro-immune-endocrine approach. World J Psychiatry 2025; 15:98484. [PMID: 39974471 PMCID: PMC11758041 DOI: 10.5498/wjp.v15.i2.98484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 11/26/2024] [Accepted: 12/23/2024] [Indexed: 01/14/2025] Open
Abstract
Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.
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Affiliation(s)
- María D Ponce-Regalado
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos 47620, Jalisco, Mexico
| | - Enrique Becerril-Villanueva
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - José Luis Maldonado-García
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11350, Mexico
| | - Martha C Moreno-Lafont
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11350, Mexico
| | - Gabriela Martínez-Ramírez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
- Facultad de Medicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional autónoma de México, Tlalnepantla 54090, Mexico
| | - Salomón Jacinto-Gutiérrez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - Rodrigo Arreola
- Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - Karla Sánchez-Huerta
- Laboratorio de Neurociencias, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
| | - Arturo Contis-Montes de Oca
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | | | | | - José Miguel Chin-Chan
- Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Campeche, Campeche 24039, Mexico
| | - Lenin Pavón
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - Gilberto Pérez-Sánchez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
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21
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Steardo L, D'Angelo M, Monaco F, Di Stefano V, Steardo L. Decoding neural circuit dysregulation in bipolar disorder: Toward an advanced paradigm for multidimensional cognitive, emotional, and psychomotor treatment. Neurosci Biobehav Rev 2025; 169:106030. [PMID: 39894420 DOI: 10.1016/j.neubiorev.2025.106030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/09/2025] [Accepted: 01/25/2025] [Indexed: 02/04/2025]
Abstract
Bipolar disorder (BD) is characterized by a complex constellation of emotional, cognitive, and psychomotor disturbances, each deeply intertwined with underlying dysfunctions in large-scale brain networks and neurotransmitter systems. This manuscript integrates recent advances in neuroimaging, neuromodulation, and pharmacological research to provide a comprehensive view of BD's pathophysiology, emphasizing the role of network-specific dysfunctions and their clinical manifestations. We explore how dysregulation within the fronto-limbic network, particularly involving the prefrontal cortex (PFC) and amygdala, underpins the emotional instability that defines both manic and depressive episodes. Additionally, impairments in the central executive network (CEN) and default mode network (DMN) are linked to cognitive deficits, with hyperactivity in the DMN driving rumination and cognitive inflexibility, while CEN underactivity contributes to attentional lapses and impaired executive function. Psychomotor symptoms, which oscillate between hyperactivity in mania and retardation in depression, are closely associated with imbalances in neurotransmitter systems, particularly dopamine and serotonin, within the basal ganglia-thalamo-cortical motor pathway. Recent studies indicate that these psychomotor disturbances are further exacerbated by disruptions in network connectivity, leading to impairments in both motor control and emotional regulation. Emerging therapeutic strategies are discussed, with a focus on neuromodulation techniques such as transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS), which show promise in restoring balance within these critical networks. Furthermore, pharmacological interventions that modulate synaptic functioning and neuronal plasticity offer potential for addressing both the emotional and motor symptoms of BD. This manuscript underscores the need for an integrative treatment approach that simultaneously targets neural circuits and neurotransmitter systems to address the full spectrum of symptoms in BD. Drawing on recent advancements in neurobiological models and therapeutic frameworks, this proposal outlines a pathway for the development of precision-tailored interventions. These approaches are designed to optimize cognitive, emotional, and psychomotor outcomes, ultimately striving to elevate the quality of life for individuals living with bipolar disorder (BD), while remaining firmly grounded in the latest empirical evidence and theoretical insights.
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Affiliation(s)
- Luca Steardo
- Psychiatry Unit, Department of Health Sciences, University of Catanzaro Magna Graecia, Catanzaro 88100, Italy
| | - Martina D'Angelo
- Psychiatry Unit, Department of Health Sciences, University of Catanzaro Magna Graecia, Catanzaro 88100, Italy.
| | - Francesco Monaco
- Department of Mental Health, Azienda Sanitaria Locale Salerno, Salerno, Italy; European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.
| | - Valeria Di Stefano
- Psychiatry Unit, Department of Health Sciences, University of Catanzaro Magna Graecia, Catanzaro 88100, Italy.
| | - Luca Steardo
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome 00185, Italy; Department of Clinical Psychology, University Giustino Fortunato, Benevento 82100, Italy.
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22
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Singh A, Bekhbat M, Goldsmith DR, Le NA, Wommack EC, Li Z, Haroon E, Felger JC. Lipids and C-reactive protein predict anhedonia and reward circuit functional connectivity responses to anti-cytokine and dopaminergic therapies in patients with depression. COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY 2025; 21:100284. [PMID: 39981264 PMCID: PMC11840189 DOI: 10.1016/j.cpnec.2025.100284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/14/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Increased inflammation and associated metabolic disturbances have been shown to affect neurotransmitters and brain circuits, contributing to an immunometabolic phenotype of anhedonic depression. To extend our previous findings on relationships between plasma lipids and antidepressant response to anti-cytokine therapy, we explored in secondary analyses whether lipid-related biomarkers similarly predicted change in anhedonia or functional connectivity (FC) in dopamine-rich corticostriatal reward circuitry in medically-stable, depressed patients with a range of inflammation levels (indexed by plasma C-reactive protein [CRP]) who were administered inflammation-targeted therapies. Relationships were examined between baseline lipids (plasma cholesterols, triglycerides and non-esterified fatty acids) and reduction of anhedonia symptoms in Study 1 (n = 60) after three infusions of infliximab or placebo and change in resting-state FC in Study 2 (n = 31) after acute, within-subject challenge with levodopa (L-DOPA) and placebo. A treatment by inflammation interaction revealed lower anhedonia after infliximab versus placebo (F[1,49] = 5.5, p < 0.05) in patients with, but not without, CRP>3 mg/L (n = 27). A composite score of lipid-related biomarkers (with increasing values reflecting higher concentrations) also precited anhedonia response (post-treatment minus baseline) to infliximab (r = -0.46, p < 0.05) but not placebo (r = 0.14, p = 0.56). Lipid scores similarly predicted CRP-related increases in reward circuit FC after L-DOPA (r = 0.53, p < 0.01) but not placebo (r = 0.20, p = 0.34). Responses to infliximab and L-DOPA were strongest in patients with versus without clinically elevated CRP (>3 mg/L) and/or cholesterol (>150 mg/dL)(p < 0.05). Results highlight a role for dyslipidemia in immunometabolic depression, biomarkers of which, together with CRP, have potential to classify patients indicated for therapies that block inflammation or its effects on neurotransmitters like dopamine.
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Affiliation(s)
- Aditya Singh
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - David R. Goldsmith
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Ngoc-Anh Le
- Biomarker Core Laboratory, Foundation for Atlanta Veterans Education and Research, Atlanta, VAHSC, Decatur, GA, 30033, USA
| | - Evanthia C. Wommack
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Zhihao Li
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- BlueHalo, Rockville, MD, 20855, USA
| | - Ebrahim Haroon
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- The Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Jennifer C. Felger
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- The Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
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23
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Zwiep JC, Milaneschi Y, Giltay EJ, Vinkers CH, Penninx BWJH, Lamers F. Depression with immuno-metabolic dysregulation: Testing pragmatic criteria to stratify patients. Brain Behav Immun 2025; 124:115-122. [PMID: 39615605 DOI: 10.1016/j.bbi.2024.11.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/13/2024] [Accepted: 11/27/2024] [Indexed: 01/20/2025] Open
Abstract
INTRODUCTION Inflammatory and metabolic processes are linked to depression, but only 25-30% of depressed patients show low-grade inflammation and metabolic dysregulation associated with atypical, energy-related symptoms (AES). Interventions targeting immuno-metabolic dysregulation could benefit depressed patients, but currently no consensus exists how to best select patients with immuno-metabolic dysregulations. Therefore, we investigated which combinations of circulating C-reactive protein (CRP) and AES could identify those depressed individuals with significant immuno-metabolic dysregulation. METHODS Data are from 1,077 persons with a current Major Depressive Disorder (MDD) of the Netherlands Study of Depression and Anxiety. Immuno-metabolic markers were Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), glycoprotein acetyls, body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Strata for CRP (≤ 1, < 1 CRP ≤ 3, > 3 mg/L) and AES (score of ≤ 3, 4-5, ≥ 6) were compared on immuno-metabolic markers using analyses of covariance. RESULTS Across strata of CRP and AES, there was a dose-response pattern with all higher immuno-metabolic marker levels across higher strata of CRP and AES, with the exception for an association between AES and TNF-α. Persons with both elevated CRP (> 1 mg/L) and high AES (≥ 6) showed a more dysregulated inflammatory and metabolic profile compared to persons with lower CRP and/or AES (p < 0.001). CONCLUSION Our results show a dose-response relationship between both CRP levels and AES with immuno-metabolic risk biomarkers, indicating that CRP and AES combined can capture immuno-metabolic features of MDD. Combining these available and scalable indexes may be an effective strategy to select a patient sample with immuno-metabolic dysregulation who may benefit from treatments targeting inflammatory or metabolic pathways.
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Affiliation(s)
- J C Zwiep
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands.
| | - Y Milaneschi
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands; Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
| | - E J Giltay
- Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands; Department of Public Health and Primary Care, Health Campus The Hague, Leiden University Medical Center, The Hague, the Netherlands
| | - C H Vinkers
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands; Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands; GGZ inGeest Mental Health Care, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Boelelaan 1117, Amsterdam, the Netherlands
| | - B W J H Penninx
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands; Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
| | - F Lamers
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Boelelaan 1117, Amsterdam, the Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands
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McIntosh R. Structural and functional brain correlates of the neutrophil- and monocyte-to-lymphocyte ratio in neuropsychiatric disorders. Brain Behav Immun Health 2025; 43:100940. [PMID: 39877850 PMCID: PMC11773257 DOI: 10.1016/j.bbih.2024.100940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 11/03/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Skews in the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) increasingly demonstrate prognostic capability in a range of acute and chronic mental health conditions. There has been a recent uptick in structural and functional magnetic responance imaging data corroborating the role of NLR and MLR in a cluster of neuropsychiatric disorders that are characterized by cognitive, affective, and psychomotor dysfunction. Moreover, these deficits are mostly evident in setting of acute and chronic disease comorbidity implicating aging and immunosenescent processes in the manifestation of these geriatric syndromes. The studies reviewed in this special edition implicate neutrophil and monocyte expansion relative to lymphocytopenia in the sequelae of depression, cognitive and functional decline, as well as provide support from a range of neuroimaging techniques that identify brain alteartions concommitant with expansion of the NLR or MLR and the sequelae of depression, dementia, and functional decline.
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Affiliation(s)
- Roger McIntosh
- Department of Psychology, University of Miami, 5665 Ponce de Leon Blvd, Coral Gables, FL, 33146, USA
- Department of Medicine, University of Miami Miller School of Medicine, 1150 NW 14th Street, Miami, FL, 33136, USA
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25
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Garcia KJ, Theismann JT, Schneider TD, LeComte RS, Jarmolowicz DP, Johnson MA. Doxorubicin treatment has a biphasic effect over time on dopamine release and impulsive behavior in Wistar rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03766-5. [PMID: 39820646 DOI: 10.1007/s00210-024-03766-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
Doxorubicin (Dox) is a chemotherapy agent commonly used to treat multiple types of cancers and is associated with cognitive impairment. The goal of this work was to determine the effect of Dox treatment on dopamine release and uptake and behavior in rats. Rats received one dose per week of Dox (2.5 mg/kg, I.V.) and were sacrificed after two or four weeks. Dopamine release and uptake was measured in brain slices with fast-scan cyclic voltammetry (FSCV). A set of rats that received treatment also underwent behavioral testing with the 5-choice serial reaction timed task (5CSRTT) to measure degree of impulsiveness and attention throughout the course of treatment. Dopamine release and uptake increased substantially after treatment with Dox for two weeks compared to controls. After four weeks of treatment, release levels decreased to less than controls while there were no differences in uptake. Treatment of brain slices with pramipexole revealed that dopamine release was equally sensitive to autoregulation after two weeks of Dox treatment, but less sensitive after four weeks. Measurements from the 5CSRTT indicated that, while Dox did not affect attention, it increased impulsiveness after two and three weeks of treatment, but not after four weeks. Treatment with Dox for a short time may elevate dopamine system activity and increase impulsiveness, while longer administration then leads to an underactive dopamine system. To our knowledge this work demonstrates for the first time that Dox can have a biphasic neurochemical and behavioral effect.
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Affiliation(s)
- Kiersten J Garcia
- Ralph N. Adams Institute for Bioanalytical Chemistry, Lawrence, KS, 66047, USA
- Chemistry Department, University of Kansas, Lawrence, KS, 66045, USA
| | - Jacob T Theismann
- Ralph N. Adams Institute for Bioanalytical Chemistry, Lawrence, KS, 66047, USA
- Chemistry Department, University of Kansas, Lawrence, KS, 66045, USA
| | - Tadd D Schneider
- Department of Applied Behavioral Science, University of Kansas, Lawrence, KS, 66045, USA
| | - Robert S LeComte
- Department of Applied Behavioral Science, University of Kansas, Lawrence, KS, 66045, USA
- Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA
| | - David P Jarmolowicz
- Department of Applied Behavioral Science, University of Kansas, Lawrence, KS, 66045, USA
| | - Michael A Johnson
- Ralph N. Adams Institute for Bioanalytical Chemistry, Lawrence, KS, 66047, USA.
- Chemistry Department, University of Kansas, Lawrence, KS, 66045, USA.
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26
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Penninx BW, Lamers F, Jansen R, Berk M, Khandaker GM, De Picker L, Milaneschi Y. Immuno-metabolic depression: from concept to implementation. THE LANCET REGIONAL HEALTH. EUROPE 2025; 48:101166. [PMID: 39801616 PMCID: PMC11721223 DOI: 10.1016/j.lanepe.2024.101166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 01/03/2025]
Abstract
Major depressive disorder is a common, disabling mental disorder characterized by extensive etiological and phenotypic heterogeneity. This heterogeneity makes treatment approaches imprecise and often ineffective. Insight into the underlying biological mechanisms underpinning depression and its subtypes may enable more personalized treatments. In this review, we provide an overview of immuno-metabolic depression and illustrate that significant immuno-metabolic dysregulations are present in about 20-30% of people with depression. Such immuno-metabolic depression is characterized by the clustering of 1) atypical, energy-related depressive symptoms such as hypersomnia, fatigue, hyperphagia, and possibly anhedonia, 2) systemic low-grade inflammation with elevated levels of e.g., C-reactive protein, cytokines and glycoprotein acetyls, and 3) metabolic abnormalities involving e.g., obesity, dyslipidaemia, insulin and leptin resistance. Persons with immuno-metabolic depression are at a higher risk for cardiometabolic diseases and seem to respond less well to standard antidepressant treatment. Interventions targeting inflammation, metabolism or lifestyle may be more effective treatment options for individuals with immuno-metabolic depression, in line with principles of precision psychiatry.
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Affiliation(s)
- Brenda W.J.H. Penninx
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije University, Amsterdam, the Netherlands
| | - Femke Lamers
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije University, Amsterdam, the Netherlands
| | - Rick Jansen
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije University, Amsterdam, the Netherlands
| | - Michael Berk
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Golam M. Khandaker
- Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
- Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- National Institute for Health and Care Research Bristol Biomedical Research Centre, United Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UK
| | - Livia De Picker
- Collaborative Antwerp Psychiatric Research Institute, Faculty of Health Sciences, University of Antwerp, Antwerp, Belgium
- University Psychiatric Hospital Campus Duffel, Duffel, Belgium
| | - Yuri Milaneschi
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije University, Amsterdam, the Netherlands
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27
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Alvarez GM, Jolink TA, West TN, Cardenas MN, Feldman MJ, Cohen JR, Muscatell KA. Differential effects of social versus monetary incentives on inhibitory control under acute inflammation. Brain Behav Immun 2025; 123:950-964. [PMID: 39293694 DOI: 10.1016/j.bbi.2024.09.010] [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: 11/16/2023] [Revised: 08/25/2024] [Accepted: 09/07/2024] [Indexed: 09/20/2024] Open
Abstract
While the impact of chronic, low-grade inflammation on cognitive functioning is documented in the context of neurodegenerative disease, less is known about the association between acute increases in inflammation and cognitive functioning in daily life. This study investigated how changes in interleukin-6 (IL-6) levels were associated with performance on an inhibitory control task, the go/no-go task. We further examined whether the opportunity to earn different incentive types (social or monetary) and magnitudes (high or low) was associated with differential performance on the task, depending on IL-6 levels. Using a within-participant design, individuals completed an incentivized go/no-go task before and after receiving the annual influenza vaccine. Multilevel logistic regressions were performed on the trial-level data (Nobs = 30,528). For no-go trials, we did not find significant associations in IL-6 reactivity and changes in trial accuracy between sessions. For go trials, we found significant differences in the associations between IL-6 reactivity and changes in accuracy as a function of the incentive condition. Notably, greater IL-6 reactivity was consistently associated with fewer omission errors (i.e., greater accuracy on go trials) on high-magnitude social incentives (i.e., viewing a picture of a close-other) when compared to both low-magnitude social and high-magnitude monetary incentives. Together, these results suggest that mild fluctuations in inflammation might alter the valuation of an incentive, and possibly a shift toward devoting greater attentional resources when a large social incentive is on the line. Overall, this study sheds light on how everyday, low-grade fluctuations in inflammation may influence cognitive abilities essential for daily life and effective inhibitory control.
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Affiliation(s)
- Gabriella M Alvarez
- Department of Psychology, University of Pittsburgh, Pittsburgh, PA USA; Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
| | - Tatum A Jolink
- Department of Psychology, University of Michigan, Ann Arbor, MI USA; Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Taylor N West
- Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Megan N Cardenas
- Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Mallory J Feldman
- Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Jessica R Cohen
- Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Keely A Muscatell
- Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA; Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
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28
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Wang J, Zhou Q, Zhang Y, Zhao S, Li L, Zeng Z, Chen J, Meng Y, Zhao X, Wang T, Meng Z, Yuan H, Ran J, Wang G, Li CZ, Zang G. Electrochemical Probing of Dopamine Dynamics During Poly(I:C)-Induced Neuroinflammation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2407685. [PMID: 39564758 DOI: 10.1002/smll.202407685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/23/2024] [Indexed: 11/21/2024]
Abstract
Viruses can infiltrate the central nervous system and contribute to depression, which may include alterations in dopamine (DA) metabolism triggered by immune responses though the specific mechanisms involved remain unclear. Here, an electrochemical system to realize the real-time dynamic monitoring of DA with high sensitivity is proposed and it is demonstrated that the viral simulator polyinosinic-polycytidylic acid (poly(I:C)) can inhibit the release of DA (from 5.595 to 0.137 µm) in neurons from the perspective of single cells, cell populations and even in vivo through the combination of multiscale electrodes, including single nanowires, carbon fibers (CFs) and 2D flexible electrodes. These findings are associated with the increase in reactive oxygen species (ROS) produced by microglia. At the molecular level, poly(I:C) significantly decreases the expression of α-synuclein and increases its phosphorylation level, whereas ROS inhibitors can reverse these pathological changes and salvage DA release to half the initial level (≈2.6 µM). These results suggest that viruses may indirectly inhibit DA system function through ROS produced in inflammatory responses and that antioxidant activity may be a potential therapeutic strategy.
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Affiliation(s)
- Jian Wang
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Qiang Zhou
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Yuchan Zhang
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Shuang Zhao
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, P. R. China
- Jinfeng Laboratory, Chongqing, 401329, P. R. China
| | - Li Li
- School of Life Science, Technology, Harbin Institute of Technology, Harbin, 150080, P. R. China
| | - Zhongyuan Zeng
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Jiajia Chen
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Yangmingxu Meng
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Xianglong Zhao
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Tianqi Wang
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Zexuan Meng
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Haihan Yuan
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Jianhua Ran
- Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Guixue Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, P. R. China
- Jinfeng Laboratory, Chongqing, 401329, P. R. China
| | - Chen-Zhong Li
- Bioelectronics and Biosensors Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Avenue, Longgang District, Shenzhen, 518172, P. R. China
| | - Guangchao Zang
- Chongqing Medical University, Chongqing, 400016, P. R. China
- Jinfeng Laboratory, Chongqing, 401329, P. R. China
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Yang D, Chen F, Ren J, Wang L, Zhu Z, Wu Z, Jin Q, Luo Y, Huang H, Zhu B, Zhang Y, Lin Y, Zhou L, Mu G, Chen G. Longitudinal associations between cerebrospinal fluid glial activation markers, depression, and dopamine transporter availability in patients with Parkinson's disease. J Neurol 2024; 272:23. [PMID: 39666148 DOI: 10.1007/s00415-024-12779-2] [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: 08/23/2024] [Revised: 10/14/2024] [Accepted: 10/14/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND Depression and decreased dopamine transporter (DAT) availability are prevalent in Parkinson's disease (PD), yet early predictive biomarkers are lacking. This study investigates the longitudinal associations between cerebrospinal fluid (CSF) neuroglial activation markers, sTREM2 and YKL-40, and depression, as well as DAT availability, in PD patients. METHODS We analyzed data from 172 PD subjects and 80 matched healthy controls from a large longitudinal study. A generalized linear mixed-effects model assessed the longitudinal associations of CSF sTREM2 and YKL-40 with depression and DAT availability. Causal mediation analysis determined if DAT decline mediated the effects of sTREM2 and YKL-40 on depression. RESULTS Cross-sectional analysis revealed a negative correlation between CSF sTREM2 and baseline depression scores in PD patients. CSF YKL-40 negatively correlated with baseline left caudate nucleus, left anterior putamen, and right anterior putamen specific binding ratios (SBR). Longitudinally, higher baseline CSF sTREM2 predicted faster depression progression (β = 0.828, p < 0.001) and a rapid decline in right putamen SBR (β = 0.072, p = 0.016). Similarly, higher baseline CSF YKL-40 predicted faster depression progression (β = 0.586, p = 0.004) and a decline in left anterior putamen SBR (β = 0.058, p = 0.035). Causal mediation analysis indicated that baseline CSF sTREM2 accelerated depression progression via its effect on right putamen and right anterior putamen SBR (Indirect effect = 0.103, p = 0.020; Indirect effect = 0.129, p = 0.016). CONCLUSION CSF sTREM2 and YKL-40 are effective predictors for depression and DAT decline in PD, suggesting that neuroglial activation-induced dopaminergic neuron apoptosis significantly contributes to depression onset in PD.
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Affiliation(s)
- Dehao Yang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Feng Chen
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junli Ren
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lingsheng Wang
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhangjing Zhu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zihao Wu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiaoqiao Jin
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuwen Luo
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haoyang Huang
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Baoyi Zhu
- The School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yang Zhang
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuchen Lin
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Linxuan Zhou
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guozhu Mu
- Department of Radiology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Guangyong Chen
- Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, No.108 Wansong Road, Wenzhou, 325000, Zhejiang, China.
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Huang C, You H, Zhang Y, Li Z, Li M, Feng X, Shao N. Association between C-reactive protein-triglyceride glucose index and depressive symptoms in American adults: results from the NHANES 2005 to 2010. BMC Psychiatry 2024; 24:890. [PMID: 39639290 PMCID: PMC11619689 DOI: 10.1186/s12888-024-06336-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND The novel serum C-reactive protein-triglyceride glucose index (CTI) has been identified as an ideal parameter that integrates inflammation and insulin resistance, which are potential mechanisms underlying depressive symptoms. Our research aimed to investigate the association between CTI and depressive symptoms. METHODS Our cross-sectional investigation utilized data from the National Health and Nutrition Examination Survey conducted between 2005 and 2010. The integrated CTI was calculated as 0.412 × Ln (C-reactive protein) (mg/dL) + Ln [triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The severity of depressive symptoms was evaluated through the continuous Patient Health Questionnaire-9 (PHQ-9) scores, and the categorical definition of depressive symptoms (PHQ-9 score ≥ 10) reflected moderate to severe symptoms. Survey-weighted linear and logistic regression models were conducted to establish the correlation between CTI and PHQ-9 scores, and between CTI and depressive symptoms. Moreover, subgroup analyses, interaction tests, and smoothed curve fitting were performed to scrutinize the steadiness of the results. RESULTS A total of 5,954 participants were enrolled in our study, including 477 with depressive symptoms and 5,477 without. The results revealed a significant positive relationship between CTI and PHQ-9 scores (β: 0.40, 95% CI: 0.25,0.55, p < 0.001) and depressive symptoms (OR: 1.30, 95% CI: 1.06,1.61, p = 0.02). Additionally, individuals in the fourth quartile of CTI exhibited a higher likelihood of depressive symptoms than those in the first quartile (PHQ-9 score: β: 0.83, 95% CI: 0.39,1.26, p < 0.001; depressive symptoms: OR: 2.00, 95% CI:1.19,3.36, p = 0.01). Smooth curve fitting and subgroup analyses consistently demonstrated the positive relationship. CONCLUSIONS Elevated CTI was correlated with a higher risk of depressive symptoms, underscoring CTI as a potential clinical indicator for identifying and stratifying depressive symptoms. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Chaojuan Huang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hongtao You
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Yuyang Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhiwei Li
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mingxu Li
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xingliang Feng
- Department of Urology, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China.
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
| | - Naiyuan Shao
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
- Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China.
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Chen H, Li J, Huang Z, Fan X, Wang X, Chen X, Guo H, Liu H, Li S, Yu S, Li H, Huang X, Ma X, Deng X, Wang C, Liu Y. Dopaminergic system and neurons: Role in multiple neurological diseases. Neuropharmacology 2024; 260:110133. [PMID: 39197818 DOI: 10.1016/j.neuropharm.2024.110133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/24/2024] [Accepted: 08/25/2024] [Indexed: 09/01/2024]
Abstract
The dopaminergic system is a complex and powerful neurotransmitter system in the brain. It plays an important regulatory role in motivation, reward, cognition, and motor control. In recent decades, research in the field of the dopaminergic system and neurons has increased exponentially and is gradually becoming a point of intervention in the study and understanding of a wide range of neurological diseases related to human health. Studies have shown that the dopaminergic system and neurons are involved in the development of many neurological diseases (including, but not limited to Parkinson's disease, schizophrenia, depression, attention deficit hyperactivity disorder, etc.) and that dopaminergic neurons either have too much stress or too weak function in the dopaminergic system can lead to disease. Therefore, targeting dopaminergic neurons is considered key to treating these diseases. This article provides a comprehensive review of the dopaminergic system and neurons in terms of brain region distribution, physiological function and subtypes of dopaminergic neurons, as well as the role of the dopaminergic system and neurons in a variety of diseases.
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Affiliation(s)
- Heng Chen
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Jieshu Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhixing Huang
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaoxiao Fan
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaofei Wang
- Beijing Normal University, Beijing, 100875, China
| | - Xing Chen
- University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Haitao Guo
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Hao Liu
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shuqi Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shaojun Yu
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Honghong Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xinyu Huang
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xuehua Ma
- Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Xinqi Deng
- Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Chunguo Wang
- Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Yonggang Liu
- Beijing University of Chinese Medicine, Beijing, 102488, China.
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Arnold AR, Prochaska T, Fickenwirth M, Powers A, Smith AK, Chahine EB, Stevens JS, Michopoulos V. A systematic review on the bidirectional relationship between trauma-related psychopathology and reproductive aging. JOURNAL OF MOOD AND ANXIETY DISORDERS 2024; 8:100082. [PMID: 39803367 PMCID: PMC11721711 DOI: 10.1016/j.xjmad.2024.100082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Objective Natural variation in ovarian steroid hormones across the female lifespan contributes to an increased risk for depressive and posttraumatic stress disorder (PTSD) symptoms in women. However, minimal work has focused on understanding the impacts of reproductive aging on the brain and behavioral health of trauma-exposed women. This systematic review examines the bidirectional relationship between trauma-related psychopathology and reproductive aging. Method Following PRISMA guidelines, a systematic review of PubMed, PsychInfo, and Medline databases was undertaken to identify controlled studies on how trauma history impacts psychopathology and menopause symptoms during reproductive aging. Results Twenty-one studies met the eligibility criteria, with only four utilizing the gold standard STRAW+ 10 criteria for defining reproductive aging stages. The peri and postmenopausal periods appear to be particularly vulnerable phases for individuals with trauma exposure. Menopause symptoms and trauma-related psychopathology symptom severity increase during reproductive aging with increases in the degree of trauma exposure. However, mechanistic insights that may explain this interaction are currently neglected in this area of research. Conclusion There is a significant lack of understanding regarding how reproductive aging and its related neuroendocrine changes impact the brain to influence PTSD and depression symptoms related to trauma exposure. This lack of basic understanding impedes the ability to identify, assess, and treat PTSD and depressive symptoms in trauma-exposed women most effectively, and mitigate the long-term consequences of these behavioral health symptoms on morbidity and mortality in aging women.
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Affiliation(s)
- Amanda R. Arnold
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Trinidi Prochaska
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Maximilian Fickenwirth
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Abigail Powers
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Alicia K. Smith
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
| | - E. Britton Chahine
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Jennifer S. Stevens
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Vasiliki Michopoulos
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
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You Y, Oginni OA, Rijsdijk FV, Lim KX, Zavos HMS, McAdams TA. Exploring associations between ADHD symptoms and emotional problems from childhood to adulthood: shared aetiology or possible causal relationship? Psychol Med 2024:1-12. [PMID: 39552389 DOI: 10.1017/s0033291724002514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
BACKGROUND ADHD symptoms are associated with emotional problems such as depressive and anxiety symptoms from early childhood to adulthood, with the association increasing with age. A shared aetiology and/or a causal relationship could explain their correlation. In the current study, we explore these explanations for the association between ADHD symptoms and emotional problems from childhood to adulthood. METHODS Data were drawn from the Twins Early Development Study (TEDS), including 3675 identical and 7063 non-identical twin pairs. ADHD symptoms and emotional symptoms were reported by parents from childhood to adulthood. Self-report scales were included from early adolescence. Five direction of causation (DoC) twin models were fitted to distinguish whether associations were better explained by shared aetiology and/or causal relationships in early childhood, mid-childhood, early adolescence, late adolescence, and early adulthood. Follow-up analyses explored associations for the two subdomains of ADHD symptoms, hyperactivity-impulsivity and inattention, separately. RESULTS The association between ADHD symptoms and emotional problems increased in magnitude from early childhood to adulthood. In the best-fitting models, positive genetic overlap played an important role in this association at all stages. A negative causal effect running from ADHD symptoms to emotional problems was also detected in early childhood and mid-childhood. When distinguishing ADHD subdomains, the apparent protective effect of ADHD symptoms on emotional problems in childhood was mostly driven by hyperactivity-impulsivity. CONCLUSIONS Genetic overlap plays an important role in the association between ADHD symptoms and emotional problems. Hyperactivity-impulsivity may protect children from emotional problems in childhood, but this protective effect diminishes after adolescence.
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Affiliation(s)
- Yuan You
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Olakunle A Oginni
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- Department of Mental Health, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Fruhling V Rijsdijk
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- Department of Psychology, Faculty of Social Sciences, Anton de Kom University, Paramaribo, Suriname
| | - Kai X Lim
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Helena M S Zavos
- Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, UK
| | - Tom A McAdams
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- Promenta Centre, University of Oslo, Norway
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Zhang Y, Fan A, Du J, Shi X, Yang S, Gao N, Pan L, Li T. Risk factors and prognosis of depression in Takayasu arteritis patients. Ther Adv Musculoskelet Dis 2024; 16:1759720X241296414. [PMID: 39525977 PMCID: PMC11544677 DOI: 10.1177/1759720x241296414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Background Takayasu arteritis (TA) is associated with an increased risk of developing complicated comorbidities, which can bring both psychological and physical burdens to the patients. Objective TA is found to carry a high risk of developing depression. This research aimed to investigate the risk factors and prognosis of depression in TA patients. Design A longitudinal observation cohort was conducted on TA patients with or without depression to explore the clinical characteristics. Methods In this cohort study, 90 TA patients were split into two groups with or without depression. Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS) in TA patients. TA patients with depression were followed up for at least 3 months. We used multivariate logistic regression analysis to find the risk factors and Kaplan-Meier curve analysis to determine the prognosis. Results We concluded 90 TA patients in this research, 29 of whom were in depression. Indian Takayasu's Arteritis Activity Score (ITAS2010) ⩾2 (odds ratio (OR) (95% confidence interval, CI) 26.664 (2.004-354.741), p = 0.013), interleukin-6 (IL-6) (OR (95% CI) 1.070 (1.022-1.121), p = 0.004), prednisone equivalents (OR (95% CI) 1.101 (1.030-1.177), p = 0.005), and carotidynia (OR (95% CI) 5.829 (1.142-29.751), p = 0.034) have been shown independent risk factors for depression in TA patients. We also identified the association between disease remission with the improvement of HADS-D score (Log-rank p = 0.005, hazard ratio (HR) 0.25) and depression (Log-rank p = 0.043, HR 0.28). Conclusion Aggressive treatment to achieve remission can promote improvement of depression in patients with TA. Screening for depression should also be performed in patients with elevated disease activity, IL-6, glucocorticoid use, and carotidynia.
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Affiliation(s)
- Yaxin Zhang
- Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Anyuyang Fan
- Department of the National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital and the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Juan Du
- Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xuemei Shi
- Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Shiyu Yang
- Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Na Gao
- Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lili Pan
- Department of Rheumatology, Capital Medical University Affiliated Anzhen Hospital, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China
| | - Taotao Li
- Department of Rheumatology, Capital Medical University Affiliated Anzhen Hospital, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China
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Kajumba MM, Kakooza-Mwesige A, Nakasujja N, Koltai D, Canli T. Treatment-resistant depression: molecular mechanisms and management. MOLECULAR BIOMEDICINE 2024; 5:43. [PMID: 39414710 PMCID: PMC11485009 DOI: 10.1186/s43556-024-00205-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 09/03/2024] [Indexed: 10/18/2024] Open
Abstract
Due to the heterogeneous nature of depression, the underlying etiological mechanisms greatly differ among individuals, and there are no known subtype-specific biomarkers to serve as precise targets for therapeutic efficacy. The extensive research efforts over the past decades have not yielded much success, and the currently used first-line conventional antidepressants are still ineffective for close to 66% of patients. Most clinicians use trial-and-error treatment approaches, which seem beneficial to only a fraction of patients, with some eventually developing treatment resistance. Here, we review evidence from both preclinical and clinical studies on the pathogenesis of depression and antidepressant treatment response. We also discuss the efficacy of the currently used pharmacological and non-pharmacological approaches, as well as the novel emerging therapies. The review reveals that the underlying mechanisms in the pathogenesis of depression and antidepressant response, are not specific, but rather involve an interplay between various neurotransmitter systems, inflammatory mediators, stress, HPA axis dysregulation, genetics, and other psycho-neurophysiological factors. None of the current depression hypotheses sufficiently accounts for the interactional mechanisms involved in both its etiology and treatment response, which could partly explain the limited success in discovering efficacious antidepressant treatment. Effective management of treatment-resistant depression (TRD) requires targeting several interactional mechanisms, using subtype-specific and/or personalized therapeutic modalities, which could, for example, include multi-target pharmacotherapies in augmentation with psychotherapy and/or other non-pharmacological approaches. Future research guided by interaction mechanisms hypotheses could provide more insights into potential etiologies of TRD, precision biomarker targets, and efficacious therapeutic modalities.
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Affiliation(s)
- Mayanja M Kajumba
- Department of Mental Health and Community Psychology, Makerere University, P. O. Box 7062, Kampala, Uganda.
| | - Angelina Kakooza-Mwesige
- Department of Pediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
- Department of Pediatrics and Child Health, Mulago National Referral Hospital, Kampala, Uganda
| | - Noeline Nakasujja
- Department of Psychiatry, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Deborah Koltai
- Duke Division of Global Neurosurgery and Neurology, Department of Neurosurgery, Durham, NC, USA
- Department of Neurology, Duke University School of Medicine, Durham, NC, USA
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, USA
| | - Turhan Canli
- Department of Psychology, Stony Brook University, New York, USA
- Department of Psychiatry, Stony Brook University, New York, USA
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Zheng Z, Chen D, Lv J, Du J, Liu K. Causal effects of plasma metabolites on autoimmune hepatitis (AIH): a bidirectional two-sample mendelian randomization study. Sci Rep 2024; 14:22944. [PMID: 39362997 PMCID: PMC11449928 DOI: 10.1038/s41598-024-74387-4] [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: 12/13/2023] [Accepted: 09/25/2024] [Indexed: 10/05/2024] Open
Abstract
Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10- 5, OR: 1.64, 95% CI 1.30-2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10- 5,OR: 0.62, 95% CI 0.49-0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10- 5, OR: 1.64, 95% CI 1.30-2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67-1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.
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Affiliation(s)
- Zhen Zheng
- Department of Chemoradiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Dahua Chen
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Jiaming Lv
- Department of Chemoradiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Juan Du
- Department of Chemoradiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Kaitai Liu
- Department of Chemoradiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China.
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Bekhbat M. Glycolytic metabolism: Food for immune cells, fuel for depression? Brain Behav Immun Health 2024; 40:100843. [PMID: 39263313 PMCID: PMC11387811 DOI: 10.1016/j.bbih.2024.100843] [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: 12/17/2023] [Revised: 07/16/2024] [Accepted: 08/10/2024] [Indexed: 09/13/2024] Open
Abstract
Inflammation is one biological pathway thought to impact the brain to contribute to major depressive disorder (MDD) and is reliably associated with resistance to standard antidepressant treatments. While peripheral immune cells, particularly monocytes, have been associated with aspects of increased inflammation in MDD and symptom severity, significant gaps in knowledge exist regarding the mechanisms by which these cells are activated to contribute to behavioral symptoms in MDD. One concept that has gained recent appreciation is that metabolic rewiring to glycolysis in activated myeloid cells plays a crucial role in facilitating these cells' pro-inflammatory functions, which may underlie myeloid contribution to systemic inflammation and its effects on the brain. Given emerging evidence from translational studies of depression that peripheral monocytes exhibit signs of glycolytic activation, better understanding the immunometabolic phenotypes of monocytes which are known to be elevated in MDD with high inflammation is a critical step toward comprehending and treating the impact of inflammation on the brain. This narrative review examines the extant literature on glycolytic metabolism of circulating monocytes in depression and discusses the functional implications of immunometabolic shifts at both cellular and systemic levels. Additionally, it proposes potential therapeutic applications of existing immunomodulators that target glycolysis and related metabolic pathways in order to reverse the impact of elevated inflammation on the brain and depressive symptoms.
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Affiliation(s)
- Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, 30322, USA
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Emmons HA, Fordahl SC. Moderate-intensity aerobic exercise enhanced dopamine signaling in diet-induced obese female mice without preventing body weight gain. Neuroscience 2024; 555:1-10. [PMID: 39032807 PMCID: PMC11344652 DOI: 10.1016/j.neuroscience.2024.07.020] [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: 02/28/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Obesity continues to rise in prevalence and financial burden despite strong evidence linking it to an increased risk of developing several chronic diseases. Dopamine response and receptor density are shown to decrease under conditions of obesity. However, it is unclear if this could be a potential mechanism for treatment without drugs that have a potential for abuse. Therefore, the aim of this study was to investigate whether moderate-intensity exercise could reduce body weight gain and the associated decreases in dopamine signaling observed with high-fat diet-induced adiposity. We hypothesized that exercise would attenuate body weight gain and diet-induced inflammation in high-fat (HF)-fed mice, resulting in dopamine signaling (release and reuptake rate) comparable to sedentary, low-fat (LF)-fed counterparts. This hypothesis was tested using a mouse model of diet-induced obesity (DIO) and fast-scan cyclic voltammetry to measure evoked dopamine release and reuptake rates. Although the exercise protocol employed in this study was not sufficient to prevent significant body weight gain, there was an enhancement of dopamine signaling observed in female mice fed a HF diet that underwent treadmill running. Additionally, aerobic treadmill exercise enhanced the sensitivity to amphetamine (AMPH) in this same group of exercised, HF-fed females. The estrous cycle might influence the ability of exercise to enhance dopamine signaling in females, an effect not observed in male groups. Further research into females by estrous cycle phase, in addition to determining the optimal intensity and duration of aerobic exercise, are logical next steps.
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Affiliation(s)
| | - Steve C Fordahl
- UNC Greensboro, Department of Nutrition, Greensboro NC, USA.
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Kearns R. The Kynurenine Pathway in Gut Permeability and Inflammation. Inflammation 2024:10.1007/s10753-024-02135-x. [PMID: 39256304 DOI: 10.1007/s10753-024-02135-x] [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: 05/15/2024] [Revised: 07/09/2024] [Accepted: 08/21/2024] [Indexed: 09/12/2024]
Abstract
The gut-brain axis (GBA) is a crucial communication network linking the gastrointestinal (GI) tract and the central nervous system (CNS). The gut microbiota significantly influences metabolic, immune, and neural functions by generating a diverse array of bioactive compounds that modulate brain function and maintain homeostasis. A pivotal mechanism in this communication is the kynurenine pathway, which metabolises tryptophan into various derivatives, including neuroactive and neurotoxic compounds. Alterations in gut microbiota composition can increase gut permeability, triggering inflammation and neuroinflammation, and contributing to neuropsychiatric disorders. This review elucidates the mechanisms by which changes in gut permeability may lead to systemic inflammation and neuroinflammation, with a focus on the kynurenine pathway. We explore how probiotics can modulate the kynurenine pathway and reduce neuroinflammation, highlighting their potential as therapeutic interventions for neuropsychiatric disorders. The review integrates experimental data, discusses the balance between neurotoxic and neuroprotective kynurenine metabolites, and examines the role of probiotics in regulating inflammation, cognitive development, and gut-brain axis functions. The insights provided aim to guide future research and therapeutic strategies for mitigating GI complaints and their neurological consequences.
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Affiliation(s)
- Rowan Kearns
- Ulster University, Life and Health Sciences, Newry, Northern Ireland, United Kingdom.
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Feng H, Ping K, Yang Y, Liu Z, Song Q, Chen S, Meng Y, He Q, Hu Y, Dong J. Quercetin alleviates difenoconazole-induced growth inhibition in carp through intestinal-brain axis. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 204:106066. [PMID: 39277382 DOI: 10.1016/j.pestbp.2024.106066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/01/2024] [Accepted: 07/29/2024] [Indexed: 09/17/2024]
Abstract
Difenoconazole (DIF) is frequently used for the management of fungal infections in fruit and vegetables and excessive residues in the aquatic environment can have adverse effects on fish such as growth inhibition. A treatment based on the dietary additive quercetin (QUE) is a promising approach to positively regulate the state of fish growth. This study focused on whether and how QUE alleviated DIF-induced growth inhibition in fish. In this study, carp were exposed to DIF (0.3906 mg/L) for consecutive 30 d, which showed growth inhibition. Disruption of the intestinal barrier led to elevated levels of intestinal lipopolysaccharide (LPS) and an inflammatory response. Through the intestinal-brain axis, LPS entered the brain where it disrupted the blood-brain barrier, triggered neuroinflammation, caused brain cell apoptosis, and damaged nerves in addition to other things. The dietary supplementation of QUE (400 mg/kg) reduced the levels of LPS in the intestinal and brain, while reducing inflammation and increasing the expression of appetite factors, thereby reducing growth inhibition in carp. This work provided evidence for QUE from the intestinal-brain axis perspective as a potential candidate for alleviating growth inhibition in fish.
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Affiliation(s)
- Huimiao Feng
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Kaixin Ping
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Yue Yang
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Zhijun Liu
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Qimei Song
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Si Chen
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Yu Meng
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Qian He
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Yuxuan Hu
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Jingquan Dong
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
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Yuan JP, Jaeger EL, Coury SM, Uy JP, Buthmann JL, Ho TC, Gotlib IH. Socioeconomic Disadvantage Moderates the Association of Systemic Inflammation With Amygdala Volume in Adolescents Over a 2-Year Interval: An Exploratory Study. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2024; 9:896-904. [PMID: 38815859 PMCID: PMC11381175 DOI: 10.1016/j.bpsc.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/03/2024] [Accepted: 05/09/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Research has demonstrated an association between elevated systemic inflammation and changes in brain function. Affective areas of the brain involved in processing threat (e.g., amygdala) and reward (e.g., nucleus accumbens) appear to be sensitive to inflammation. Early-life stress, such as experiencing low socioeconomic status (SES), may also potentiate this association, but relevant evidence has come primarily from cross-sectional studies of brain function. It is unclear whether similar associations are present between early-life stress, inflammation, and brain structure, particularly in typically developing populations. METHODS We recruited and assessed 50 adolescents (31 females/19 males) from the community (mean [SD] age = 15.5 [1.1] years, range = 13.1-17.5 years) and examined in exploratory analyses whether changes in C-reactive protein (ΔCRP) from blood spots predict changes in gray matter volume (ΔGMV) in the bilateral amygdala and nucleus accumbens over a 2-year period. We also investigated whether experiencing early-life stress, operationalized using a comprehensive composite score of SES disadvantage at the family and neighborhood levels, significantly moderated the association between ΔCRP and ΔGMV. RESULTS We found that ΔCRP was negatively associated with Δamygdala GMV (i.e., increasing CRP levels were associated with decreasing amygdala volume; β = -0.84, p = .012). This effect was stronger in youths who experienced greater SES disadvantage (β = -0.56, p = .025). CONCLUSIONS These findings suggest that increases in systemic inflammation are associated with reductions in amygdala GMV in adolescents, potentially signaling accelerated maturation, and that these neuroimmune processes are compounded in adolescents who experienced greater SES disadvantage. Our findings are consistent with theoretical frameworks of neuroimmune associations and suggest that they may influence adolescent neurodevelopment.
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Affiliation(s)
- Justin P Yuan
- Department of Psychology, Stanford University, Stanford, California.
| | - Emma L Jaeger
- Department of Psychology, Stanford University, Stanford, California
| | - Saché M Coury
- Department of Psychology, Stanford University, Stanford, California; Department of Psychology, University of California, Los Angeles, Los Angeles, California
| | - Jessica P Uy
- Department of Psychology, Stanford University, Stanford, California
| | | | - Tiffany C Ho
- Department of Psychology, University of California, Los Angeles, Los Angeles, California
| | - Ian H Gotlib
- Department of Psychology, Stanford University, Stanford, California
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Han Q, Li W, Chen P, Wang L, Bao X, Huang R, Liu G, Chen X. Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression. Neural Regen Res 2024; 19:1890-1898. [PMID: 38227513 DOI: 10.4103/1673-5374.390964] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/22/2023] [Indexed: 01/17/2024] Open
Abstract
Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.
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Affiliation(s)
- Qiuqin Han
- Department of Scientific Research, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Wenhui Li
- Department of Scientific Research, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Peiqing Chen
- Department of Scientific Research, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Lijuan Wang
- Department of Scientific Research, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Xiwen Bao
- Department of Scientific Research, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Renyan Huang
- Department of Traditional Chinese Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guobin Liu
- Department of Traditional Chinese Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaorong Chen
- Department of Physiology, Laboratory of Neurodegenerative Diseases, Changzhi Medical College, Changzhi, Shanxi Province, China
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Giollabhui NM, Slaney C, Hemani G, Foley E, van der Most P, Nolte I, Snieder H, Davey Smith G, Khandaker G, Hartman C. Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study. RESEARCH SQUARE 2024:rs.3.rs-4379779. [PMID: 39149475 PMCID: PMC11326402 DOI: 10.21203/rs.3.rs-4379779/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Inflammation is associated with a range of neuropsychiatric symptoms; however, the nature of the causal relationship is unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈ 55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning. Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In non-genetic analyses, higher CRP was associated with a depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRPgrs was associated with any anxiety disorder (β = 0.002, p = 0.037) whereas GlycAGRS was associated with major depressive disorder (β = 0.001, p = 0.036). Both CRPgrs (β = 0.006, p = 0.035) and GlycAGRS (β = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except slL-6RGRS which was associated with poorer memory (β=-0.009, p = 0.018). There was weak evidence for a CRP-anxiety association using MR (β = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms.
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Affiliation(s)
| | | | | | | | | | - Ilja Nolte
- University of Groningen, University Medical Center Groningen
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Xu Y, Lin Y, Yu M, Zhou K. The nucleus accumbens in reward and aversion processing: insights and implications. Front Behav Neurosci 2024; 18:1420028. [PMID: 39184934 PMCID: PMC11341389 DOI: 10.3389/fnbeh.2024.1420028] [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: 04/19/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
The nucleus accumbens (NAc), a central component of the brain's reward circuitry, has been implicated in a wide range of behaviors and emotional states. Emerging evidence, primarily drawing from recent rodent studies, suggests that the function of the NAc in reward and aversion processing is multifaceted. Prolonged stress or drug use induces maladaptive neuronal function in the NAc circuitry, which results in pathological conditions. This review aims to provide comprehensive and up-to-date insights on the role of the NAc in motivated behavior regulation and highlights areas that demand further in-depth analysis. It synthesizes the latest findings on how distinct NAc neuronal populations and pathways contribute to the processing of opposite valences. The review examines how a range of neuromodulators, especially monoamines, influence the NAc's control over various motivational states. Furthermore, it delves into the complex underlying mechanisms of psychiatric disorders such as addiction and depression and evaluates prospective interventions to restore NAc functionality.
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Affiliation(s)
| | | | | | - Kuikui Zhou
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China
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Rodríguez-Pérez MP, Pérez-de-Heredia-Torres M, Rodríguez-Ledo P, Fernández-Gómez G, García-Bravo C, Cano-de-la-Cuerda R, Sánchez-Herrera-Baeza P. Post-COVID-19 Condition: How Sociodemographic Factors, Physical Well-Being and Functionality Influence Quality of Life and Mental Health Symptoms. Healthcare (Basel) 2024; 12:1551. [PMID: 39120254 PMCID: PMC11312060 DOI: 10.3390/healthcare12151551] [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: 06/18/2024] [Revised: 07/27/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Long COVID-19 syndrome remains a global public health problem, with more than 145 million people affected with multisystemic symptoms. Addressing the requirements of individuals impacted by a syndrome characterised by a complex and variable clinical presentation is of utmost importance. Identifying the variables that can exert influence and understanding their progression is essential for directing treatment strategies aimed at enhancing both independence and quality of life. Therefore, the aim of this study was to analyse the influence of sociodemographic and clinical variables on existence and their relationship with asthenia, anxiety symptoms and low mood. METHODS An analytical study secondary to an observational cross-sectional descriptive study. RESULTS Logistic regression showed significant univariate effects on asthenia [sex (p = 0.034); age (p = 0.042); Activities of Daily Living Questionnaire [ADQL (p = 0.002)] [physical functioning (p < 0.001) and general health (p = 0.014)] and multivariate [sex (p = 0.019), adult age (p = 0.01) and physical functioning (p = 0.04)]]; low mood [time of evolution (p = 0.028) and multivariate [time course (p = 0.007), ADLQ (p = 0.011), role physical (p = 0.013) and general health (p = 0.001)]] and anxiety [physical functioning (p = 0.046) and multivariate [physical functioning (p = 0.034), age (p = 0.011), time of evolution (p = 0.001) and ADQL (p = 0.011)]]. CONCLUSIONS Increased age, gender and longer evolution time seem to favour the prevalence and occurrence of mental health symptoms; greater independence and good physical functioning are protective factors with respect to the occurrence of mental health-related symptoms in patients affected by post-COVID-19 condition.
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Affiliation(s)
- Mᵃ Pilar Rodríguez-Pérez
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Rey Juan Carlos University, 28922 Alcorcón, Spain; (M.P.R.-P.); (G.F.-G.); (C.G.-B.); (R.C.-d.-l.-C.); (P.S.-H.-B.)
- Research Group in Evaluation and Assessment of Capacity, Functionality and Disability (TO + IDI), Health Sciences Faculty, Rey Juan Carlos University, Avenida de Atenas s/n, 28922 Alcorcón, Spain
| | - Marta Pérez-de-Heredia-Torres
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Rey Juan Carlos University, 28922 Alcorcón, Spain; (M.P.R.-P.); (G.F.-G.); (C.G.-B.); (R.C.-d.-l.-C.); (P.S.-H.-B.)
- Research Group in Evaluation and Assessment of Capacity, Functionality and Disability (TO + IDI), Health Sciences Faculty, Rey Juan Carlos University, Avenida de Atenas s/n, 28922 Alcorcón, Spain
| | - Pilar Rodríguez-Ledo
- Long COVID Working Group of the Spanish Society of General and Family Physicians (SEMG), Spanish Society of General Practitioners and Family Doctors (SEMG), Spanish Research Network on Long COVID (REiCOP), Management of the Health Area of Lugo, A Mariña and Monforte de Lemos, 27002 Lugo, Spain;
| | - Gemma Fernández-Gómez
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Rey Juan Carlos University, 28922 Alcorcón, Spain; (M.P.R.-P.); (G.F.-G.); (C.G.-B.); (R.C.-d.-l.-C.); (P.S.-H.-B.)
- Research Group in Evaluation and Assessment of Capacity, Functionality and Disability (TO + IDI), Health Sciences Faculty, Rey Juan Carlos University, Avenida de Atenas s/n, 28922 Alcorcón, Spain
| | - Cristina García-Bravo
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Rey Juan Carlos University, 28922 Alcorcón, Spain; (M.P.R.-P.); (G.F.-G.); (C.G.-B.); (R.C.-d.-l.-C.); (P.S.-H.-B.)
- Research Group in Evaluation and Assessment of Capacity, Functionality and Disability (TO + IDI), Health Sciences Faculty, Rey Juan Carlos University, Avenida de Atenas s/n, 28922 Alcorcón, Spain
| | - Roberto Cano-de-la-Cuerda
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Rey Juan Carlos University, 28922 Alcorcón, Spain; (M.P.R.-P.); (G.F.-G.); (C.G.-B.); (R.C.-d.-l.-C.); (P.S.-H.-B.)
- Research Group, Motion Analysis, Biomechanics, Ergonomy and Motor Control Laboratory (LAMBECOM), Faculty of Health Sciences, Rey Juan Carlos University, Alcorcón, 28922 Madrid, Spain
| | - Patricia Sánchez-Herrera-Baeza
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Rey Juan Carlos University, 28922 Alcorcón, Spain; (M.P.R.-P.); (G.F.-G.); (C.G.-B.); (R.C.-d.-l.-C.); (P.S.-H.-B.)
- Research Group in Evaluation and Assessment of Capacity, Functionality and Disability (TO + IDI), Health Sciences Faculty, Rey Juan Carlos University, Avenida de Atenas s/n, 28922 Alcorcón, Spain
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Nusslock R, Kogan SM, Yu T, Armstrong CC, Chen E, Miller GE, Brody GH, Sweet LH. Higher substance use is associated with low executive control neural activity and higher inflammation. Brain Behav Immun 2024; 120:532-542. [PMID: 38925415 DOI: 10.1016/j.bbi.2024.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 05/14/2024] [Accepted: 06/23/2024] [Indexed: 06/28/2024] Open
Abstract
Individuals with substance use problems show lower executive control and alterations in prefrontal brain systems supporting emotion regulation and impulse control. A separate literature suggests that heightened inflammation also increases risk for substance use, in part, through targeting brain systems involved in executive control. Research on neural and inflammatory signaling in substance use, however, has occurred in parallel. Drawing on recent neuroimmune network models, we used fMRI to examine the relationships between executive control-related brain activity (as elicited by an n-back working memory task), peripheral inflammation, as quantified by inflammatory cytokines and C-reactive protein (CRP), and substance use for the past month in 93 participants [mean age = 24.4 (SD = 0.6)]. We operationalized low executive control as a neural inefficiency during the n-back task to achieve normative performance, as reflected in higher working memory-related brain activity and lower activity in the default mode network (DMN). Consistent with prediction, individuals with low executive control and high inflammation reported more substance use over the past month, controlling for behavioral performance on the n-back, sex, time between assessments, body-mass-index (BMI), and personal socioeconomic status (SES) (interaction between inflammation and working memory-related brain activity, b = 0.210, p = 0.005; interaction between inflammation and DMN, b = -0.219, p < 0.001). Findings suggest that low executive control and high inflammation may be associated with higher substance use. This has implications for understanding psychological, neural, and immunological risk for substance use problems and the development of interventions to target each of these components.
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Affiliation(s)
- Robin Nusslock
- Department of Psychology, Northwestern University, USA; Institute for Policy Research, Northwestern University, USA.
| | | | - Tianyi Yu
- Center for Family Research, University of Georgia, USA
| | | | - Edith Chen
- Department of Psychology, Northwestern University, USA; Institute for Policy Research, Northwestern University, USA
| | - Gregory E Miller
- Department of Psychology, Northwestern University, USA; Institute for Policy Research, Northwestern University, USA
| | - Gene H Brody
- Center for Family Research, University of Georgia, USA
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Kéri S, Kancsev A, Kelemen O. Algorithm-Based Modular Psychotherapy Alleviates Brain Inflammation in Generalized Anxiety Disorder. Life (Basel) 2024; 14:887. [PMID: 39063640 PMCID: PMC11278507 DOI: 10.3390/life14070887] [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: 06/27/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Generalized anxiety disorder (GAD) is marked by prolonged and excessive worry, physical signs of anxiety, and associated neuroinflammation. Traditional treatments, like pharmacotherapy and cognitive-behavioral therapy (CBT), often leave residual symptoms and have high relapse rates. This study aimed to explore the efficacy of algorithm-based modular psychotherapy (MoBa), a combination of CBT and mindfulness meditation as validated by the research domain criteria (RDoC), in reducing anxiety and neuroinflammation in GAD. A longitudinal design was used, with 50 patients with GAD undergoing a 12-week MoBa treatment. The patients were investigated pre- and post-treatment using MRI to measure neuroinflammatory markers (DBSI-RF, diffusion-basis spectral imaging-based restricted fraction) in the hippocampus, amygdala, and neocortex. Clinical symptoms were assessed using the Hamilton Anxiety Rating Scale (HAM-A) and the Generalized Anxiety Disorder 7-item scale (GAD-7). Results indicated significant reductions in both anxiety symptoms and MRI RF values in the amygdala, suggesting decreased neuroinflammation. A reduction in anxiety was associated with the amelioration of neuroinflammation in the amygdala. These results suggest that MoBa is effective in alleviating both the psychological and neuroinflammatory aspects of GAD, offering a promising personalized treatment approach. Future research should focus on long-term effects and the mechanisms through which MoBa impacts neuroinflammation and anxiety.
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Affiliation(s)
- Szabolcs Kéri
- Sztárai Institute, University of Tokaj, 3944 Sárospatak, Hungary
- Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, 6720 Szeged, Hungary
| | - Alexander Kancsev
- Department of Psychiatry and Psychotherapy, András Jósa Hospital, 4400 Nyíregyháza, Hungary;
| | - Oguz Kelemen
- Department of Behavioral Sciences, Albert Szent-Györgyi Medical School, University of Szeged, 6720 Szeged, Hungary;
- Department of Psychiatry and Psychotherapy, Bács-Kiskun County Hospital, 6000 Kecskemét, Hungary
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Fu L, Ren J, Lei X, Wang Y, Chen X, Zhang R, Li Q, Teng X, Guo C, Wu Z, Yu L, Wang D, Chen Y, Qin J, Yuan A, Zhang C. Association of anhedonia with brain-derived neurotrophic factor and interleukin-10 in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2024; 133:111023. [PMID: 38701878 DOI: 10.1016/j.pnpbp.2024.111023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/19/2024] [Accepted: 04/30/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Anhedonia, a core symptom of major depressive disorder (MDD), manifests in two forms: anticipatory and consummatory, reflecting a diminished capacity to anticipate or enjoy pleasurable activities. Prior studies suggest that brain-derived neurotrophic factor (BDNF) and interleukin-10 (IL-10) may play key roles in the emergence of anhedonia in MDD. The specific relationships between these biomarkers and the two forms of anhedonia remain unclear. This study investigated the potential links between BDNF, IL-10, and both forms of anhedonia in MDD patients. METHODS This study included 43 participants diagnosed with MDD and 58 healthy controls. It involved detailed assessments of depression and anxiety levels, anticipatory and consummatory pleasure, cognitive functions, and a broad spectrum of plasma biomarkers, such as C-reactive protein, various interleukins, and BDNF. Using partial correlation, variables related to pleasant experiences were identified. Stepwise multiple linear regression analysis was applied to pinpoint the independent predictors of anhedonia in the MDD group. RESULTS Demographically, both groups were comparable in terms of age, sex, body mass index, educational year, and marital status. Individuals with MDD displayed markedly reduced levels of anticipatory and consummatory pleasure, higher anxiety, and depression scores compared to healthy controls. Additionally, cognitive performance was notably poorer in the MDD group. These patients also had lower plasma diamine oxidase levels. Analysis linked anhedonia to impaired delayed memory. Regression results identified IL-10 and BDNF as independent predictors of anticipatory and consummatory anhedonia, respectively. CONCLUSION These findings demonstrate that anticipatory and consummatory anhedonia are influenced by independent factors, thereby providing critical insights into the distinct neuroimmunological mechanisms that underlie various forms of anhedonia. Clinicl Trial Registration Number: NCT03790085.
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Affiliation(s)
- Lirong Fu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juanjuan Ren
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxia Lei
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yewei Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaochang Chen
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingyi Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinyue Teng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaoyue Guo
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zenan Wu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingfang Yu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dandan Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Chen
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinmei Qin
- Mental Health Center of Xuhui District, Shanghai, China.
| | - Aihua Yuan
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Chen Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Hird EJ, Slanina-Davies A, Lewis G, Hamer M, Roiser JP. From movement to motivation: a proposed framework to understand the antidepressant effect of exercise. Transl Psychiatry 2024; 14:273. [PMID: 38961071 PMCID: PMC11222551 DOI: 10.1038/s41398-024-02922-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 03/28/2024] [Accepted: 05/10/2024] [Indexed: 07/05/2024] Open
Abstract
Depression is the leading cause of disability worldwide, exerting a profound negative impact on quality of life in those who experience it. Depression is associated with disruptions to several closely related neural and cognitive processes, including dopamine transmission, fronto-striatal brain activity and connectivity, reward processing and motivation. Physical activity, especially aerobic exercise, reduces depressive symptoms, but the mechanisms driving its antidepressant effects are poorly understood. Here we propose a novel hypothesis for understanding the antidepressant effects of exercise, centred on motivation, across different levels of explanation. There is robust evidence that aerobic exercise decreases systemic inflammation. Inflammation is known to reduce dopamine transmission, which in turn is strongly implicated in effort-based decision making for reward. Drawing on a broad range of research in humans and animals, we propose that by reducing inflammation and boosting dopamine transmission, with consequent effects on effort-based decision making for reward, exercise initially specifically improves 'interest-activity' symptoms of depression-namely anhedonia, fatigue and subjective cognitive impairment - by increasing propensity to exert effort. Extending this framework to the topic of cognitive control, we explain how cognitive impairment in depression may also be conceptualised through an effort-based decision-making framework, which may help to explain the impact of exercise on cognitive impairment. Understanding the mechanisms underlying the antidepressant effects of exercise could inform the development of novel intervention strategies, in particular personalised interventions and boost social prescribing.
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Affiliation(s)
- E J Hird
- Institute of Cognitive Neuroscience, University College London, London, UK.
| | - A Slanina-Davies
- Institute of Cognitive Neuroscience, University College London, London, UK
| | - G Lewis
- Division of Psychiatry, University College London, London, UK
| | - M Hamer
- Institute of Sport, Exercise and Health, University College London, London, UK
| | - J P Roiser
- Institute of Cognitive Neuroscience, University College London, London, UK
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50
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Ho DH, Kim H, Nam D, Seo MK, Park SW, Son I. Expression of G2019S LRRK2 in Rat Primary Astrocytes Mediates Neurotoxicity and Alters the Dopamine Synthesis Pathway in N27 Cells via Astrocytic Proinflammatory Cytokines and Neurotrophic Factors. Curr Issues Mol Biol 2024; 46:4324-4336. [PMID: 38785531 PMCID: PMC11119058 DOI: 10.3390/cimb46050263] [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: 12/04/2023] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/25/2024] Open
Abstract
Astrocytes in the brain contribute to various essential functions, including maintenance of the neuronal framework, survival, communication, metabolic processes, and neurotransmitter levels. Leucine-rich repeat kinase 2 (LRRK2) is associated with the pathogenesis of Parkinson's disease (PD). LRRK2 is expressed in neurons, microglia, and astrocytes and plays diverse roles in these cell types. We aimed to determine the effects of mutant human G2019S-LRRK2 (GS-hLRRK2) in rat primary astrocytes (rASTROs). Transfection with GS-hLRRK2 significantly decreased cell viability compared to transfection with the vector and wild-type human LRRK2 (WT-hLRRK2). GS-hLRRK2 expression significantly reduced the levels of nerve growth factor and increased the levels of proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) compared to the vector and WT-hLRRK2 expression. Furthermore, GS-hLRRK2 expression in rASTROs promoted astrogliosis, which was characterized by increased expression of glial fibrillary acidic protein and vimentin. Treatment with the conditioned medium of G2019S LRRK2-expressing rASTROs decreased N27 cell viability compared to treatment with that of WT-hLRRK2-expressing rASTROs. Consequently, the regulation of the dopamine synthesis pathway was affected in N27 cells, thereby leading to altered levels of tyrosine hydroxylase, dopamine transporter, Nurr1, and dopamine release. Overall, the G2019S LRRK2 mutation disrupted astrocyte function, thereby aggravating PD progression.
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Affiliation(s)
- Dong Hwan Ho
- InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si 15865, Republic of Korea; (H.K.); (D.N.)
| | - Hyejung Kim
- InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si 15865, Republic of Korea; (H.K.); (D.N.)
| | - Daleum Nam
- InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si 15865, Republic of Korea; (H.K.); (D.N.)
| | - Mi Kyoung Seo
- Paik Institute for Clinical Research, Inje University, Busan-si 47392, Republic of Korea; (M.K.S.); (S.W.P.)
| | - Sung Woo Park
- Paik Institute for Clinical Research, Inje University, Busan-si 47392, Republic of Korea; (M.K.S.); (S.W.P.)
- Department of Convergence Biomedical Science, Inje University College of Medicine, Busan-si 47392, Republic of Korea
| | - Ilhong Son
- InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si 15865, Republic of Korea; (H.K.); (D.N.)
- Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si 15865, Republic of Korea
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