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Shu YP, Zhang Q, Li D, Liu JY, Wang XM, He Q, Hou YZ. Vulnerable brain regions in adolescent attention deficit hyperactivity disorder: An activation likelihood estimation meta-analysis. World J Psychiatry 2025; 15:102215. [PMID: 40309601 PMCID: PMC12038653 DOI: 10.5498/wjp.v15.i4.102215] [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: 10/11/2024] [Revised: 12/20/2024] [Accepted: 02/05/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in adolescents characterized by inattention, hyperactivity, and impulsivity, which impact cognitive, behavioral, and emotional functioning. Resting-state functional magnetic resonance imaging (rs-fMRI) provides critical insights into the functional architecture of the brain in ADHD. Despite extensive research, specific brain regions consistently affected in ADHD patients during these formative years have not been comprehensively delineated. AIM To identify consistent vulnerable brain regions in adolescent ADHD patients using rs-fMRI and activation likelihood estimation (ALE) meta-analysis. METHODS We conducted a comprehensive literature search up to August 31, 2024, to identify studies investigating functional brain alterations in adolescents with ADHD. We utilized regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), dynamic ALFF (dALFF) and fractional ALFF (fALFF) analyses. We compared the regions of aberrant spontaneous neural activity in adolescents with ADHD with those in healthy controls (HCs) using ALE. RESULTS Fifteen studies (468 adolescent ADHD patients and 466 HCs) were included. Combining the ReHo and ALFF/fALFF/dALFF data, the results revealed increased activity in the right lingual gyrus [LING, Brodmann Area (BA) 18], left LING (BA 18), and right cuneus (CUN, BA 23) in adolescent ADHD patients compared with HCs (voxel size: 592-32 mm³, P < 0.05). Decreased activity was observed in the left medial frontal gyrus (MFG, BA 9) and left precuneus (PCUN, BA 31) in adolescent ADHD patients compared with HCs (voxel size: 960-456 mm³, P < 0.05). Jackknife sensitivity analyses demonstrated robust reproducibility in 11 of the 13 tests for the right LING, left LING, and right CUN and in 11 of the 14 tests for the left MFG and left PCUN. CONCLUSION We identified specific brain regions with both increased and decreased activity in adolescent ADHD patients, enhancing our understanding of the neural alterations that occur during this pivotal stage of development.
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Affiliation(s)
- Yan-Ping Shu
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
| | - Qin Zhang
- Department of Radiology, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
| | - Da Li
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
| | - Jiao-Ying Liu
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
| | - Xiao-Ming Wang
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
| | - Qiang He
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
| | - Yong-Zhe Hou
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang 550004, Guizhou Province, China
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Wadan AHS, Shaaban AH, El-Sadek MZ, Mostafa SA, Moshref AS, El-Hussein A, Ellakwa DES, Mehanny SS. Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04014-0. [PMID: 40163151 DOI: 10.1007/s00210-025-04014-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 03/04/2025] [Indexed: 04/02/2025]
Abstract
Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.
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Affiliation(s)
- Al-Hassan Soliman Wadan
- Department of Oral Biology, Faculty of Dentistry, Galala University, Galala Plateau, Attaka, Suez Governorate, 15888, Egypt.
| | - Ahmed H Shaaban
- Department of Biology, Faculty of Science, Galala University, Galala Plateau, Attaka,, Suez Governorate, 15888, Egypt
| | - Mohamed Z El-Sadek
- Department of Biology, Faculty of Science, Galala University, Galala Plateau, Attaka,, Suez Governorate, 15888, Egypt
| | | | - Ahmed Sherief Moshref
- Faculty of Dentistry, Galala University, Galala Plateau, Attaka, Suez Governorate, 15888, Egypt
| | - Ahmed El-Hussein
- Department of Biology, Faculty of Science, Galala University, Galala Plateau, Attaka,, Suez Governorate, 15888, Egypt
- Department of Laser Applications in Meteorology, Photochemistry, and Biotechnology, The National Institute of Laser Enhanced Science, Cairo University, Cairo, 11316, Egypt
| | - Doha El-Sayed Ellakwa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt
| | - Samah S Mehanny
- Department of Oral Biology, Faculty of Dentistry, Galala University, Galala Plateau, Attaka, Suez Governorate, 15888, Egypt
- Department of Oral Biology, Faculty of Dentistry, Cairo University, Cairo, Egypt
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Zhou BY, Li ZX, Li YW, Li JN, Liu WT, Liu XY, Hu ZB, Zhao L, Chen JY, Hu L, Song NN, Feng X, Wang G, Xu L, Ding YQ. Central Med23 deficiency leads to malformation of dentate gyrus and ADHD-like behaviors in mice. Neuropsychopharmacology 2025:10.1038/s41386-025-02088-1. [PMID: 40114018 DOI: 10.1038/s41386-025-02088-1] [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: 10/17/2024] [Revised: 02/25/2025] [Accepted: 03/06/2025] [Indexed: 03/22/2025]
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a prevalent psychiatric disorder with high heritability, while its etiology and pathophysiology remain unclear. Med23 is a subunit of the Mediator complex, a key regulator of gene expression by linking transcription factors to RNA polymerase II. The mutations of Med23 are associated with several brain diseases including microcephaly, epilepsy and intellectual disability, but its biological roles in brain development and possible behavioral consequence have not been explored in the animal model. In this study, Emx1-Cre mice were used to generate Med23 conditional knockout (Med23 CKO) mice that showed severe hypoplasia of the dentate gyrus (DG) with malformation of the dendritic tree and spines along with impaired short-term synaptic plasticity. Interestingly, Med23 CKO mice exhibited ADHD-like behaviors as shown by hyperactivity, inattention and impulsivity, as well as impaired sensory gating and working memory. Importantly, methylphenidate (MPH), a common drug for ADHD ameliorated these deficits in the CKO mice. Furthermore, we also revealed that the impaired synaptic plasticity was partially restored by MPH in an N-methyl-d-aspartate (NMDA) receptor-dependent way. Collectively, our data demonstrate Med23 deficiency causes DG malformation and ADHD-like behaviors, suggesting a novel mechanism underlying relevant brain diseases.
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Affiliation(s)
- Bing-Yao Zhou
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, 200032, China
| | - Ze-Xuan Li
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Yi-Wei Li
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Jin-Nan Li
- Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, the Chinese Academy of Science, Kunming, 650223, China
| | - Wei-Tang Liu
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China
| | - Xi-Yue Liu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, 200032, China
| | - Zhi-Bin Hu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, 200032, China
| | - Li Zhao
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Jia-Yin Chen
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Ling Hu
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Ning-Ning Song
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Xue Feng
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China
| | - Gang Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Lin Xu
- Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, the Chinese Academy of Science, Kunming, 650223, China.
| | - Yu-Qiang Ding
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, 200032, China.
- Laboratory Animal Center, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China.
- Huashan Institute of Medicine (HS-IOM), Huashan Hospital, Fudan University, Shanghai, 200040, China.
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Berthier J, Endomba FT, Lecendreux M, Mauries S, Geoffroy PA. Cerebral blood flow in attention deficit hyperactivity disorder: A systematic review. Neuroscience 2025; 567:67-76. [PMID: 39631658 DOI: 10.1016/j.neuroscience.2024.11.075] [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: 07/16/2024] [Revised: 11/28/2024] [Accepted: 11/29/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND AND OBJECTIVES Attention deficit hyperactivity disorder (ADHD) is one of the most frequent and disabling neurodevelopmental disorders. Recent research on cerebral blood flow (CBF) has enhanced understanding of the underlying pathophysiology in neuropsychiatric disorders. This systematic review aims to synthesize the existing literature on CBF anomalies among individuals with ADHD in comparison to controls. METHODS Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach, a systematic literature search was conducted using PubMed, PsycInfo, and Web of Science to identify relevant studies on CBF in ADHD. RESULTS Twenty studies, encompassing a total of 1652 participants with ADHD and 580 controls, were included, employing measurements from SPECT (n = 9), ASL (n = 6), PET (n = 4), and BOLD-derived quantitative maps (n = 1). In individuals with ADHD during resting state, hypoperfusion was frequently observed in the right orbitofrontal gyrus, temporal cortex, basal ganglia and putamen. Conversely, hyperperfusion was noted in frontal lobes, left postcentral gyrus, and occipital lobes. During cognitive tasks, hyperperfusion was observed in frontal areas, temporal regions, cingulate cortex and the precuneus. Furthermore, the administration of methylphenidate was associated with increased CBF in striatal and posterior periventricular regions, the right thalamus, and the precentral gyrus. CONCLUSION This review highlights diverse CBF anomalies in ADHD. The most consistently reported findings suggest hypoperfusion during resting state in prefrontal and temporal areas, along with the basal ganglia, while there is a hyperperfusion in frontal, parietal and occipital regions. Further research, including longitudinal studies, is essential to develop a comprehensive understanding of CBF implications in ADHD.
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Affiliation(s)
- Johanna Berthier
- Centre ChronoS, GHU Paris - Psychiatry & Neurosciences, Paris, France
| | - Francky Teddy Endomba
- University of Burgundy, Dijon, France; PADYS team, INSERM Research Center U1231, Dijon, France; Department of Psychiatry, Dijon University Hospital (CHU), Dijon, France.
| | - Michel Lecendreux
- AP-HP, Pediatric Sleep Center, Robert-Debré Hospital, National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome, INSERM CIC1426, Paris, France
| | - Sibylle Mauries
- Department of Psychiatry and Addictology, AP-HP, GHU Paris Nord, DMU Neurosciences, Bichat-Claude Bernard Hospital, Paris, France; Université Paris Cité, NeuroDiderot, Inserm, Paris, France
| | - Pierre A Geoffroy
- Centre ChronoS, GHU Paris - Psychiatry & Neurosciences, Paris, France; Department of Psychiatry and Addictology, AP-HP, GHU Paris Nord, DMU Neurosciences, Bichat-Claude Bernard Hospital, Paris, France; Université Paris Cité, NeuroDiderot, Inserm, Paris, France
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Karaman AK, Sarıgedik E, Eryılmaz OK, Küçükdağ M, Naldemir İF. Cerebral blood flow differences in cognitive disengagement syndrome and attention deficit hyperactivity disorder: Doppler ultrasonography findings. J Psychiatr Res 2025; 182:161-165. [PMID: 39813960 DOI: 10.1016/j.jpsychires.2025.01.024] [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: 11/09/2024] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 01/18/2025]
Abstract
OBJECTIVE The present study aims to investigate potential differences in cerebral blood flow between children with Cognitive Disengagement Syndrome (CDS) and those with Attention Deficit Hyperactivity Disorder (ADHD) using Doppler ultrasound. METHODS In this single-center prospective study, we included 24 cases in the ADHD group with CDS symptoms, 29 cases in the ADHD group without CDS symptoms and, 26 children in the healthy controls. The children ranged in age from 6 to 15. Participants were evaluated by diagnostic interviews and standardized measures. Doppler ultrasound was performed to measure peak systolic velocity and blood flow volume (BFV) in the internal carotid (ICA) and vertebral arteries for each participant. RESULTS The right ICA and total ICA BFVs were significantly lower in the CDS group compared to the ADHD and control groups (p = 0.007 and p = 0.003, respectively). In addition, there was a weak negative correlation between right ICA BFV and CDS scores, suggesting a possible link between reduced cerebral blood flow and CDS symptom severity. CONCLUSION This study provides a noteworthy starting point for research on the neurovascular basis of CDS. Our findings indicated significant differences in cerebral blood flow between CDS and ADHD, supporting the idea that CDS is a unique attentional disorder with distinct neurobiological characteristics from ADHD.
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Affiliation(s)
- Ahmet Kursat Karaman
- Department of Radiology, Sureyyapasa Chest Diseases and Thoracic Surgery Training Hospital, Istanbul, Türkiye
| | - Enes Sarıgedik
- Department of Child and Adolescent Psychiatry, Sakarya University Faculty of Medicine, Sakarya, Türkiye.
| | | | - Meltem Küçükdağ
- Department of Child and Adolescent Psychiatry, Düzce University, Faculty of Medicine, Düzce, Türkiye
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Zou T, Chen C, Chen H, Wang X, Gan L, Wang C, Gao Q, Zhang C, Liao W, Cheng J, Li R. Structural-functional connectivity decoupling in multiscale brain networks in Parkinson's disease. BMC Neurosci 2024; 25:78. [PMID: 39725901 DOI: 10.1186/s12868-024-00918-4] [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: 09/09/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Parkinson's disease (PD) is a progressive neurodegenerative disease associated with functional and structural alterations beyond the nigrostriatal dopamine projection. However, the structural-functional (SC-FC) coupling changes in combination with subcortical regions at the network level are rarely investigated in PD. METHODS SC-FC coupling networks were systematically constructed using the structural connectivity obtained by diffusion tensor imaging and the functional connectivity obtained by resting-state functional magnetic resonance imaging in 53 PD and 72 age- and sex-matched healthy controls (HCs). Then, we explored how SC-FC coupling varied within and between several well-defined functional domains. RESULTS Results showed that the SC-FC coupling in patients with PD was globally reduced in comparison with HCs. Specifically, regional SC-FC decoupled in the inferior parietal lobule, occipitotemporal cortex, motor cortex, and higher-order association cortex in patients with PD. Moreover, PD showed intranetwork SC-FC decoupling in the visual network (VIS), limbic and higher-order association networks. Furthermore, internetwork decoupling mainly linked to the VIS, the somatomotor network (SOM), the dorsal attention network, and the default mode network, was observed, increased internetwork coupling was found between the subcortical network and the SOM in PD (all p < 0.05, FDR corrected). CONCLUSIONS These findings suggest that PD is characterized by SC-FC decoupling in topological organization of multiscale brain networks, providing insights into the brain network mechanisms in PD.
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Affiliation(s)
- Ting Zou
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
| | - Chen Chen
- Department of MRI, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China
| | - Huafu Chen
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China.
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China.
| | - Xuyang Wang
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
| | - Lin Gan
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
| | - Chong Wang
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
| | - Qing Gao
- School of Mathematical Sciences, University of Electronic Science and Technology of China, Chengdu, 611731, P.R. China
| | - Chunyan Zhang
- Department of MRI, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China
| | - Wei Liao
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China
| | - Jingliang Cheng
- Department of MRI, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.
| | - Rong Li
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China.
- School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 610054, P.R. China.
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Ferreira R, Bastos-Leite AJ. Arterial spin labelling magnetic resonance imaging and perfusion patterns in neurocognitive and other mental disorders: a systematic review. Neuroradiology 2024; 66:1065-1081. [PMID: 38536448 PMCID: PMC11150205 DOI: 10.1007/s00234-024-03323-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 02/24/2024] [Indexed: 04/18/2024]
Abstract
We reviewed 33 original research studies assessing brain perfusion, using consensus guidelines from a "white paper" issued by the International Society for Magnetic Resonance in Medicine Perfusion Study Group and the European Cooperation in Science and Technology Action BM1103 ("Arterial Spin Labelling Initiative in Dementia"; https://www.cost.eu/actions/BM1103/ ). The studies were published between 2011 and 2023 and included participants with subjective cognitive decline plus; neurocognitive disorders, including mild cognitive impairment (MCI), Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI); as well as schizophrenia spectrum disorders, bipolar and major depressive disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, panic disorder and alcohol use disorder. Hypoperfusion associated with cognitive impairment was the major finding across the spectrum of cognitive decline. Regional hyperperfusion also was reported in MCI, AD, frontotemporal dementia phenocopy syndrome and VCI. Hypoperfused structures found to aid in diagnosing AD included the precunei and adjacent posterior cingulate cortices. Hypoperfused structures found to better diagnose patients with FTLD were the anterior cingulate cortices and frontal regions. Hypoperfusion in patients with DLB was found to relatively spare the temporal lobes, even after correction for partial volume effects. Hyperperfusion in the temporal cortices and hypoperfusion in the prefrontal and anterior cingulate cortices were found in patients with schizophrenia, most of whom were on medication and at the chronic stage of illness. Infratentorial structures were found to be abnormally perfused in patients with bipolar or major depressive disorders. Brain perfusion abnormalities were helpful in diagnosing most neurocognitive disorders. Abnormalities reported in VCI and the remaining mental disorders were heterogeneous and not generalisable.
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Affiliation(s)
- Rita Ferreira
- Faculty of Medicine, University of Porto, Porto, Portugal
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Chen Z, Xu T, Liu X, Becker B, Li W, Xia L, Zhao W, Zhang R, Huo Z, Hu B, Tang Y, Xiao Z, Feng Z, Chen J, Feng T. Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures. Psychiatry Clin Neurosci 2024; 78:309-321. [PMID: 38334172 DOI: 10.1111/pcn.13649] [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: 10/03/2023] [Revised: 01/16/2024] [Accepted: 01/18/2024] [Indexed: 02/10/2024]
Abstract
AIMS This study aimed to illuminate the neuropathological landscape of attention deficit hyperactivity disorder (ADHD) by a multiscale macro-micro-molecular perspective from in vivo neuroimaging data. METHODS The "ADHD-200 initiative" repository provided multi-site high-quality resting-state functional connectivity (rsfc-) neuroimaging for ADHD children and matched typically developing (TD) cohort. Diffusion mapping embedding model to derive the functional connectome gradient detecting biologically plausible neural pattern was built, and the multivariate partial least square method to uncover the enrichment of neurotransmitomic, cellular and chromosomal gradient-transcriptional signatures of AHBA enrichment and meta-analytic decoding. RESULTS Compared to TD, ADHD children presented connectopic cortical gradient perturbations in almost all the cognition-involved brain macroscale networks (all pBH <0.001), but not in the brain global topology. As an intermediate phenotypic variant, such gradient perturbation was spatially enriched into distributions of GABAA/BZ and 5-HT2A receptors (all pBH <0.01) and co-varied with genetic transcriptional expressions (e.g. DYDC2, ATOH7, all pBH <0.01), associated with phenotypic variants in episodic memory and emotional regulations. Enrichment models demonstrated such gradient-transcriptional variants indicated the risk of both cell-specific and chromosome- dysfunctions, especially in enriched expression of oligodendrocyte precursors and endothelial cells (all pperm <0.05) as well enrichment into chromosome 18, 19 and X (pperm <0.05). CONCLUSIONS Our findings bridged brain macroscale neuropathological patterns to microscale/cellular biological architectures for ADHD children, demonstrating the neurobiologically pathological mechanism of ADHD into the genetic and molecular variants in GABA and 5-HT systems as well brain-derived enrichment of specific cellular/chromosomal expressions.
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Affiliation(s)
- Zhiyi Chen
- Experimental Research Center of Medical and Psychological Science, School of Psychology, Third Military Medical University, Chongqing, China
- Key Laboratory of Cognition and Personality, Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China
| | - Ting Xu
- Department of Psychology, The University of Hong Kong, Hong Kong, China
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuerong Liu
- Experimental Research Center of Medical and Psychological Science, School of Psychology, Third Military Medical University, Chongqing, China
| | - Benjamin Becker
- Department of Psychology, The University of Hong Kong, Hong Kong, China
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Wei Li
- Experimental Research Center of Medical and Psychological Science, School of Psychology, Third Military Medical University, Chongqing, China
| | - Lei Xia
- Experimental Research Center of Medical and Psychological Science, School of Psychology, Third Military Medical University, Chongqing, China
| | - Wenqi Zhao
- Experimental Research Center of Medical and Psychological Science, School of Psychology, Third Military Medical University, Chongqing, China
| | - Rong Zhang
- Key Laboratory of Cognition and Personality, Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China
| | - Zhenzhen Huo
- Key Laboratory of Cognition and Personality, Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China
| | - Bowen Hu
- Key Laboratory of Cognition and Personality, Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China
| | - Yancheng Tang
- School of Business and Management, Shanghai International Studies University, Shanghai, China
| | - Zhibing Xiao
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China
| | - Zhengzhi Feng
- Experimental Research Center of Medical and Psychological Science, School of Psychology, Third Military Medical University, Chongqing, China
- Key Laboratory of Cognition and Personality, Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China
| | - Ji Chen
- Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou, China
- Department of Psychiatry, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China
| | - Tingyong Feng
- Key Laboratory of Cognition and Personality, Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China
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Collignon A, Dion-Albert L, Ménard C, Coelho-Santos V. Sex, hormones and cerebrovascular function: from development to disorder. Fluids Barriers CNS 2024; 21:2. [PMID: 38178239 PMCID: PMC10768274 DOI: 10.1186/s12987-023-00496-3] [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: 08/11/2023] [Accepted: 11/29/2023] [Indexed: 01/06/2024] Open
Abstract
Proper cerebrovascular development and neurogliovascular unit assembly are essential for brain growth and function throughout life, ensuring the continuous supply of nutrients and oxygen. This involves crucial events during pre- and postnatal stages through key pathways, including vascular endothelial growth factor (VEGF) and Wnt signaling. These pathways are pivotal for brain vascular growth, expansion, and blood-brain barrier (BBB) maturation. Interestingly, during fetal and neonatal life, cerebrovascular formation coincides with the early peak activity of the hypothalamic-pituitary-gonadal axis, supporting the idea of sex hormonal influence on cerebrovascular development and barriergenesis.Sex hormonal dysregulation in early development has been implicated in neurodevelopmental disorders with highly sexually dimorphic features, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Both disorders show higher prevalence in men, with varying symptoms between sexes, with boys exhibiting more externalizing behaviors, such as aggressivity or hyperactivity, and girls displaying higher internalizing behaviors, including anxiety, depression, or attention disorders. Indeed, ASD and ADHD are linked to high prenatal testosterone exposure and reduced aromatase expression, potentially explaining sex differences in prevalence and symptomatology. In line with this, high estrogen levels seem to attenuate ADHD symptoms. At the cerebrovascular level, sex- and region-specific variations of cerebral blood flow perfusion have been reported in both conditions, indicating an impact of gonadal hormones on the brain vascular system, disrupting its ability to respond to neuronal demands.This review aims to provide an overview of the existing knowledge concerning the impact of sex hormones on cerebrovascular formation and maturation, as well as the onset of neurodevelopmental disorders. Here, we explore the concept of gonadal hormone interactions with brain vascular and BBB development to function, with a particular focus on the modulation of VEGF and Wnt signaling. We outline how these pathways may be involved in the underpinnings of ASD and ADHD. Outstanding questions and potential avenues for future research are highlighted, as uncovering sex-specific physiological and pathological aspects of brain vascular development might lead to innovative therapeutic approaches in the context of ASD, ADHD and beyond.
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Affiliation(s)
- Adeline Collignon
- Department of Psychiatry & Neuroscience and CERVO Brain Research Center, Universite Laval, Quebec City, Canada
| | - Laurence Dion-Albert
- Department of Psychiatry & Neuroscience and CERVO Brain Research Center, Universite Laval, Quebec City, Canada
| | - Caroline Ménard
- Department of Psychiatry & Neuroscience and CERVO Brain Research Center, Universite Laval, Quebec City, Canada
| | - Vanessa Coelho-Santos
- Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
- University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, Institute of Physiology, Coimbra, Portugal.
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10
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Wang M, Wang T, Li X, Yuan Y. Low-intensity ultrasound stimulation modulates cortical neurovascular coupling in an attention deficit hyperactivity disorder rat model. Cereb Cortex 2023; 33:11646-11655. [PMID: 37874023 DOI: 10.1093/cercor/bhad398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/25/2023] Open
Abstract
Attention deficit hyperactivity disorder is accompanied by changes in cranial nerve function and cerebral blood flow (CBF). Low-intensity ultrasound stimulation can modulate brain neural activity in attention deficit hyperactivity disorder. However, to date, the modulatory effects of low-intensity ultrasound stimulation on CBF and neurovascular coupling in attention deficit hyperactivity disorder have not been reported. To address this question, Sprague-Dawley, Wistar-Kyoto, and spontaneously hypertensive (attention deficit hyperactivity disorder (ADHD) rat model) rats were divided into the control and low-intensity ultrasound stimulation (LIUS) groups. Cortical electrical stimulation was used to induce cortical excitability in different types of rats, and a penetrable laser speckle contrast imaging (LSCI) system and electrodes were used to evaluate the electrical stimulation-induced CBF, cortical excitability, and neurovascular coupling in free-moving rats. The CBF, cortical excitability, and neurovascular coupling (NVC) under cortical electrical stimulation in the attention deficit hyperactivity disorder rats were significantly different from those in the Sprague-Dawley and Wistar-Kyoto rats. We also found that low-intensity ultrasound stimulation significantly interfered with the cortical excitability and neurovascular coupling induced by cortical electrical stimulation in rats with attention deficit hyperactivity disorder. Our findings suggest that neurovascular coupling is a potential biomarker for attention deficit hyperactivity disorder. Furthermore, low-intensity ultrasound stimulation can improve abnormal brain function in attention deficit hyperactivity disorder and lay a research foundation for its application in the clinical treatment of attention deficit hyperactivity disorder.
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Affiliation(s)
- Mengran Wang
- School of Electrical Engineering, Yanshan University, Qinhuangdao 066004, China
- Key Laboratory of Intelligent Rehabilitation and Neuromodulation of Hebei Province, Yanshan University, Qinhuangdao 066004, China
| | - Teng Wang
- School of Electrical Engineering, Yanshan University, Qinhuangdao 066004, China
- Key Laboratory of Intelligent Rehabilitation and Neuromodulation of Hebei Province, Yanshan University, Qinhuangdao 066004, China
| | - Xin Li
- School of Electrical Engineering, Yanshan University, Qinhuangdao 066004, China
| | - Yi Yuan
- School of Electrical Engineering, Yanshan University, Qinhuangdao 066004, China
- Key Laboratory of Intelligent Rehabilitation and Neuromodulation of Hebei Province, Yanshan University, Qinhuangdao 066004, China
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11
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Ogrodnik M, Karsan S, Cirone V, Heisz JJ. Exploring the Relationship between Cardiorespiratory Fitness and Executive Functioning in Adults with ADHD. Brain Sci 2023; 13:673. [PMID: 37190638 PMCID: PMC10136722 DOI: 10.3390/brainsci13040673] [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: 03/06/2023] [Revised: 04/04/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
OBJECTIVE Associations between measures of executive functioning (EF) and cardiorespiratory fitness (CRF) were examined for adults with and without ADHD. METHOD Measures of executive functioning including the Stroop task, Wisconsin Card Sorting task, and Operation Span Task were completed virtually (n = 36 ADHD; n = 36 Control). Participants completed the Six-Minute Walk Test to estimate CRF. RESULTS Mean performance measures of executive function did not differ by group. However, higher estimated CRF was associated with better Stroop task performance, and the association was strongest for individuals with ADHD. CONCLUSION In adults with ADHD, higher estimated CRF was associated with better inhibitory control, but not with other measures of executive functioning.
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Affiliation(s)
- Michelle Ogrodnik
- Department of Kinesiology, Faculty of Science, McMaster University, Hamilton, ON L8S 4L8, Canada
- Department of Kinesiology and Health Sciences, Faculty of Health, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Sameena Karsan
- Department of Kinesiology, Faculty of Science, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Victoria Cirone
- Department of Physical Therapy, Djavad Mowafaghian Centre for Brain Health, Vancouver Coastal Health Research Institute, The Centre for Aging SMART, The University of British Columbia, Vancouver, BC V1Y 1T3, Canada
| | - Jennifer J. Heisz
- Department of Kinesiology, Faculty of Science, McMaster University, Hamilton, ON L8S 4L8, Canada
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12
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Dion-Albert L, Dudek KA, Russo SJ, Campbell M, Menard C. Neurovascular adaptations modulating cognition, mood, and stress responses. Trends Neurosci 2023; 46:276-292. [PMID: 36805768 DOI: 10.1016/j.tins.2023.01.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/11/2023] [Accepted: 01/25/2023] [Indexed: 02/19/2023]
Abstract
The neurovascular unit (NVU) is a dynamic center for substance exchange between the blood and the brain, making it an essential gatekeeper for central nervous system (CNS) homeostasis. Recent evidence supports a role for the NVU in modulating brain function and cognition. In addition, alterations in NVU processes are observed in response to stress, although the mechanisms via which they can affect mood and cognitive functions remain elusive. Here, we summarize recent studies of neurovascular regulation of emotional processes and cognitive function, including under stressful conditions. We also highlight relevant RNA-sequencing (RNA-seq) databases aiming to profile the NVU along with innovative tools to study and manipulate NVU function that can be exploited in the context of cognition and stress research throughout development, aging, or brain disorders.
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Affiliation(s)
- Laurence Dion-Albert
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, QC, Canada
| | - Katarzyna A Dudek
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, QC, Canada
| | - Scott J Russo
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai and Center for Affective Neuroscience, 1 Gustave L Levy Place, New York, NY, USA
| | - Matthew Campbell
- Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate, Dublin 2, Ireland
| | - Caroline Menard
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Quebec City, QC, Canada.
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13
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Zhang K, Yuan J, Pei X, Fu Z, Zhao Y, Hu N, Wang Y, Yang L, Cao Q. Cerebral blood flow characteristics of drug-naïve attention-deficit/hyperactivity disorder with social impairment: Evidence for region-symptom specificity. Front Neurosci 2023; 17:1149703. [PMID: 37025372 PMCID: PMC10070692 DOI: 10.3389/fnins.2023.1149703] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 03/03/2023] [Indexed: 04/08/2023] Open
Abstract
Background Social deficits are among the most important functional impairments in attention-deficit/hyperactivity disorder (ADHD). However, the relationship between social impairment and ADHD core symptoms as well as the underlying cerebral blood flow (CBF) characteristics remain unclear. Methods A total of 62 ADHD subjects with social deficits (ADHD + SD), 100 ADHD subjects without social deficits (ADHD-SD) and 81 age-matched typically developing controls (TDC) were enrolled. We first examined the correlation between the Social Responsiveness Scale (SRS-1) and ADHD core symptoms (inattention, hyperactivity, and impulsion) and then explored categorical and dimensional ADHD-related regional CBF by arterial spin labeling (ASL). For the categorical analysis, a voxel-based comparison of CBF maps between the ADHD + SD, ADHD-SD, and TDC groups was performed. For the dimensional analysis, the whole-brain voxel-wise correlation between CBF and ADHD symptoms (inattention, hyperactivity/impulsivity, and total scores) was evaluated in three groups. Finally, correlations between the SRS-1 and ADHD-related regional CBF were investigated. We applied Gaussian random field (GRF) for the correction of multiple comparisons in imaging results (voxel-level P < 0.01, and cluster-level P < 0.05). Results The clinical characteristics analysis showed that social deficits positively correlated with ADHD core symptoms, especially in social communication and autistic mannerisms domains. In the categorical analysis, we found that CBF in the left middle/inferior temporal gyrus in ADHD groups was higher than TDCs and was negatively correlated with the social motivation scores. Moreover, in dimensional analysis, we found that CBF in the left middle frontal gyrus was negatively correlated with the inattention scores, SRS total scores and autistic mannerisms scores in ADHD + SD subjects. Conclusion The present study shows that inattention, hyperactivity, and impulsivity may be responsible for the occurrence of social deficits in ADHD, with autistic traits being another significant contributing factor. Additionally, CBF in the left middle/inferior temporal gyrus and the left middle frontal gyrus might represent the corresponding physiological mechanisms underlying social deficits in ADHD.
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Sogard AS, Mickleborough TD. The therapeutic potential of exercise and caffeine on attention-deficit/hyperactivity disorder in athletes. Front Neurosci 2022; 16:978336. [PMID: 36033633 PMCID: PMC9412016 DOI: 10.3389/fnins.2022.978336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is characterized by evident and persistent inattention, hyperactivity, impulsivity, and social difficulties and is the most common childhood neuropsychiatric disorder, and which may persist into adulthood. Seventy to 80% of children and adults with ADHD are treated with stimulant medication, with positive response rates occurring for both populations. Medicated ADHD individuals generally show sustained and improved attention, inhibition control, cognitive flexibility, on-task behavior, and cognitive performance. The ethics of ADHD medication use in athletics has been a debated topic in sport performance for a long time. Stimulants are banned from competition in accordance with World Anti-Doping Association and National Collegiate Athletic Association regulations, due to their ability to not only enhance cognitive performance but also exercise performance. Limited research has been conducted looking at the differences in exercise performance variables in unmedicated ADHD verses medicated ADHD. Not all ADHD athletes choose stimulant medication in their treatment plan due to personal, financial, or other reasons. Non-stimulant treatment options include non-stimulant medication and behavioral therapy. However, the use of caffeinated compounds and exercise has both independently been shown to be effective in the management of ADHD symptoms in human studies and animal models. This mini review will discuss the effect of exercise and caffeine on neurobehavioral, cognitive, and neurophysiological factors, and exercise performance in ADHD athletes, and whether exercise and caffeine should be considered in the treatment plan for an individual with ADHD.
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15
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Chen G, Hu J, Ran H, Nie L, Tang W, Li X, Li Q, He Y, Liu J, Song G, Xu G, Liu H, Zhang T. Alterations of Cerebral Perfusion and Functional Connectivity in Children With Idiopathic Generalized Epilepsy. Front Neurosci 2022; 16:918513. [PMID: 35769697 PMCID: PMC9236200 DOI: 10.3389/fnins.2022.918513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/25/2022] [Indexed: 12/02/2022] Open
Abstract
Background Studies have demonstrated that adults with idiopathic generalized epilepsy (IGE) have functional abnormalities; however, the neuropathological pathogenesis differs between adults and children. This study aimed to explore alterations in the cerebral blood flow (CBF) and functional connectivity (FC) to comprehensively elucidate the neuropathological mechanisms of IGE in children. Methods We obtained arterial spin labeling (ASL) and resting state functional magnetic resonance imaging data of 28 children with IGE and 35 matched controls. We used ASL to determine differential CBF regions in children with IGE. A seed-based whole-brain FC analysis was performed for regions with significant CBF changes. The mean CBF and FC of brain areas with significant group differences was extracted, then its correlation with clinical variables in IGE group was analyzed by using Pearson correlation analysis. Results Compared to controls, children with IGE had CBF abnormalities that were mainly observed in the right middle temporal gyrus, right middle occipital gyrus (MOG), right superior frontal gyrus (SFG), left inferior frontal gyrus (IFG), and triangular part of the left IFG (IFGtriang). We observed that the FC between the left IFGtriang and calcarine fissure (CAL) and that between the right MOG and bilateral CAL were decreased in children with IGE. The CBF in the right SFG was correlated with the age at IGE onset. FC in the left IFGtriang and left CAL was correlated with the IGE duration. Conclusion This study found that CBF and FC were altered simultaneously in the left IFGtriang and right MOG of children with IGE. The combination of CBF and FC may provide additional information and insight regarding the pathophysiology of IGE from neuronal and vascular integration perspectives.
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Chen X, Yao T, Cai J, Zhang Q, Li S, Li H, Fu X, Wu J. A novel cis-regulatory variant modulating TIE1 expression associated with attention deficit hyperactivity disorder in Han Chinese children. J Affect Disord 2022; 300:179-188. [PMID: 34942230 DOI: 10.1016/j.jad.2021.12.066] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/07/2021] [Accepted: 12/19/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The genetic factors of attention deficit hyperactivity disorder (ADHD) are far from fully elucidated. This study aims to get additional insight into the genetic structure of ADHD. METHODS First, a transcriptome-wide association study and summary data-based Mendelian randomization analysis were performed to identify ADHD susceptibility genes. Then, genetic variants influencing the expression of the identified susceptibility genes were tested for association with ADHD risk in a sample of Han Chinese children (543 cases and 560 controls). Dual-luciferase reporter gene assays and electrophoretic mobility shift assays were performed to verify the transcriptional regulatory functions of the identified ADHD-associated variants. Additionally, real-time quantitative polymerase chain reaction was applied to quantify the expression levels of target genes in blood samples. RESULTS Both TIE1 and MED8 were identified as ADHD susceptibility genes. Furthermore, we first found the G allele of rs3768046 was significantly associated with an increased risk of ADHD (recessive model: GG vs AA+AG, OR= 1.659, 95% CI= (1.262, 2.181); additive model: GG vs GA vs AA, OR= 1.493, 95% CI= (1.179, 1.890)). Additionally, in vitro functional experiments revealed that rs3768046 might alter TIE1 expression by affecting the binding sites of transcription factors. Moreover, the expression level of TIE1 in the blood samples of patients was significantly higher than that of controls. LIMITATIONS Given the moderate statistical power of this study, it is necessary to verify our findings in other larger samples. CONCLUSIONS Together, this study presents the first systematic evidence of TIE1 with potential implications for the genetic basis of ADHD.
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Affiliation(s)
- Xinzhen Chen
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Ting Yao
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jinliang Cai
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Qi Zhang
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shanyawen Li
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Huiru Li
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xihang Fu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jing Wu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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Gonchigsuren O, Harada M, Hisaoka S, Higashi K, Matsumoto Y, Sumida N, Mori T, Ito H, Mori K, Miyoshi M. Brain abnormalities in children with attention-deficit/hyperactivity disorder assessed by multi-delay arterial spin labeling perfusion and voxel-based morphometry. Jpn J Radiol 2022; 40:568-577. [DOI: 10.1007/s11604-021-01239-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/12/2021] [Indexed: 12/21/2022]
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Quantitative susceptibility mapping reveals brain iron deficiency in children with attention-deficit/hyperactivity disorder: a whole-brain analysis. Eur Radiol 2022; 32:3726-3733. [DOI: 10.1007/s00330-021-08516-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 11/18/2021] [Accepted: 12/10/2021] [Indexed: 11/04/2022]
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Xu Y, Lin S, Tao J, Liu X, Zhou R, Chen S, Vyas P, Yang C, Chen B, Qian A, Wang M. Correlation research of susceptibility single nucleotide polymorphisms and the severity of clinical symptoms in attention deficit hyperactivity disorder. Front Psychiatry 2022; 13:1003542. [PMID: 36213906 PMCID: PMC9538111 DOI: 10.3389/fpsyt.2022.1003542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE To analyze the correlation between susceptibility single nucleotide polymorphisms (SNPs) and the severity of clinical symptoms in children with attention deficit hyperactivity disorder (ADHD), so as to supplement the clinical significance of gene polymorphism and increase our understanding of the association between genetic mutations and ADHD phenotypes. METHODS 193 children with ADHD were included in our study from February 2017 to February 2020 in the Children's ADHD Clinic of the author's medical institution. 23 ADHD susceptibility SNPs were selected based on the literature, and multiple polymerase chain reaction (PCR) targeted capture sequencing technology was used for gene analysis. A series of ADHD-related questionnaires were used to reflect the severity of the disease, and the correlation between the SNPs of specific sites and the severity of clinical symptoms was evaluated. R software was used to search for independent risk factors by multivariate logistic regression and the "corplot" package was used for correlation analysis. RESULTS Among the 23 SNP loci of ADHD children, no mutation was detected in 6 loci, and 2 loci did not conform to Hardy-Weinberg equilibrium. Of the remaining 15 loci, there were 9 SNPs, rs2652511 (SLC6A3 locus), rs1410739 (OBI1-AS1 locus), rs3768046 (TIE1 locus), rs223508 (MANBA locus), rs2906457 (ST3GAL3 locus), rs4916723 (LINC00461 locus), rs9677504 (SPAG16 locus), rs1427829 (intron) and rs11210892 (intron), correlated with the severity of clinical symptoms of ADHD. Specifically, rs1410739 (OBI1-AS1 locus) was found to simultaneously affect conduct problems, control ability and abstract thinking ability of children with ADHD. CONCLUSION There were 9 SNPs significantly correlated with the severity of clinical symptoms in children with ADHD, and the rs1410739 (OBI1-AS1 locus) may provide a new direction for ADHD research. Our study builds on previous susceptibility research and further investigates the impact of a single SNP on the severity of clinical symptoms of ADHD. This can help improve the diagnosis, prognosis and treatment of ADHD.
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Affiliation(s)
- Yunyu Xu
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shuangxiang Lin
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Jiejie Tao
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xinmiao Liu
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ronghui Zhou
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shuangli Chen
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Punit Vyas
- School of Medicine, Indiana University, Indianapolis, IN, United States
| | - Chuang Yang
- Department of Psychiatry, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Andan Qian
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Meihao Wang
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
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Chen Y, Cui Q, Sheng W, Tang Q, Lu F, Pang Y, Nan X, He Z, Li D, Lei T, Chen H. Anomalous neurovascular coupling in patients with generalized anxiety disorder evaluated by combining cerebral blood flow and functional connectivity strength. Prog Neuropsychopharmacol Biol Psychiatry 2021; 111:110379. [PMID: 34111495 DOI: 10.1016/j.pnpbp.2021.110379] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 05/06/2021] [Accepted: 06/04/2021] [Indexed: 01/10/2023]
Abstract
Coupling between neuronal activity and blood perfusion is termed neurovascular coupling, and it provides a new mechanistic perspective into understanding numerous brain diseases. Although abnormal brain activity and blood supply have been separately reported in generalized anxiety disorder (GAD), whether anomalous neurovascular coupling would still be presented in such disease is hitherto unknown. In this study, the neuronal activity and blood supply were measured using the functional connectivity strength (FCS) and cerebral blood flow (CBF). The voxel-wise CBF-FCS correlations and CBF/FCS ratio were separately used to assess global and local neurovascular coupling in participants. Patients with GAD showed decreased voxel-wise CBF-FCS correlation, implicating global neurovascular decoupling. They also exhibited increased CBF/FCS ratio in the right superior parietal gyrus (SPG), and the enhanced CBF/FCS ratio in this region was negatively correlated with the self-esteem scores of GAD. The abnormal neurovascular coupling of GAD may indicate the disrupted balance between the intrinsic functional organization of the brain and corresponding blood perfusion of patients, and the abnormally increased local neurovascular coupling of the right SPG may be correlated with the abnormal self in GAD. These findings provide new information in understanding the brain dysfunction and abnormal cognition of GAD from the perspective of neurovascular coupling.
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Affiliation(s)
- Yuyan Chen
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Qian Cui
- School of Public Affairs and Administration, University of Electronic Science and Technology of China, Chengdu, China.
| | - Wei Sheng
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Qin Tang
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Fengmei Lu
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yajing Pang
- School of Electrical Engineering, Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Nan
- School of Public Affairs and Administration, University of Electronic Science and Technology of China, Chengdu, China
| | - Zongling He
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Di Li
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Ting Lei
- School of Public Affairs and Administration, University of Electronic Science and Technology of China, Chengdu, China
| | - Huafu Chen
- The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China; MOE Key Lab for Neuroinformation; High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, China; Department of Radiology, First Affiliated Hospital to Army Medical University, Chongqing, China.
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21
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Sun H, He Y, Cao H. Functional magnetic resonance imaging research in China. CNS Neurosci Ther 2021; 27:1259-1267. [PMID: 34492160 PMCID: PMC8504522 DOI: 10.1111/cns.13725] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 01/11/2023] Open
Abstract
Functional magnetic resonance imaging (fMRI) non-invasively measures the activity of the human brain and provides a unique technological tool for investigating aspects of the human brain including cognition, development, and disorders. As one of the main funding agencies for basic research in China, the National Natural Scientific Foundation of China (NSFC) has initiated various research programs during the last two decades that are related to fMRI research. In this review, we collected and analyzed the metadata of the projects and published studies in research fields using fMRI that were funded by the NSFC. We observed a trend of increasing funding amounts from the NSFC for fMRI research, typically from the General Program and Key Program. Leading research institutes from economically developed municipalities and provinces received the most support and formed close collaboration relationships. Finally, we reviewed several representative achievements from research institutions in china, involving data analysis methods, brain connectomes, and computational platforms in addition to their applications in brain disorders.
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Affiliation(s)
- Hongzan Sun
- Department of RadiologyShengjing Hospital of China Medical UniversityShenyangChina
| | - Yong He
- State Key Laboratory of Cognitive Neuroscience and LearningBeijing Normal UniversityBeijingChina
- Beijing Key Laboratory of Brain Imaging and ConnectomicsBeijing Normal UniversityBeijingChina
- IDG/McGovern Institute for Brain ResearchBeijing Normal UniversityBeijingChina
- Chinese Institute for Brain ResearchBeijingChina
| | - Heqi Cao
- Department of Health SciencesNational Natural Science Foundation of ChinaBeijingChina
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22
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Wu X, Ya J, Zhou D, Ding Y, Ji X, Meng R. Nonthrombotic internal jugular venous stenosis may facilitate cerebral venous thrombosis. CNS Neurosci Ther 2021; 27:1396-1408. [PMID: 34397153 PMCID: PMC8504525 DOI: 10.1111/cns.13719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 11/30/2022] Open
Abstract
AIMS To explore the effect of nonthrombotic internal jugular venous stenosis (IJVS) exerted on cerebral venous thrombosis (CVT). METHODS Patients with imaging confirmed CVT were enrolled into this real-world case-control study consecutively from January 2018 through April 2021, and were divided into CVT and IJVS-CVT groups, according to whether or not with non-thrombotic IJVS. Chi-square and logistic regression models were utilized for between-group comparison of thrombotic factors. RESULTS A total of 199 eligible patients entered into final analysis, including 92 cases of CVT and 107 cases of IJVS-CVT. Chi-square revealed that thrombophilic conditions were found in majority of CVT, while only minority in the IJVS-CVT group (83.7% vs. 20.6%, p < 0.001). Multivariate logistic regression indicated that most identified thrombophilia were negatively related to IJVS-CVT (all p < 0.05), including oral contraceptive use (β = -1.38), hyperhomocysteinemia (β = -1.58), hematology (β = -2.05), protein C/S deficiency (β = -2.28), connective tissue disease (β = -1.18) and infection (β = -2.77). All recruited patients underwent standard anticoagulation, 10 cases in IJVS-CVT group also received jugular angioplasty for IJVS correction. Most participants obtained alleviations during 1-year follow-up. However, both clinical and imaging outcomes in IJVS-CVT group were not as good as those in CVT group (both p < 0.05). Moreover, 8 cases with CVT and 7 cases with IJVS-CVT were rehospitalized for CVT recurrences and underwent customized treatment. CONCLUSION Nonthrombotic IJVS may be one of the risk factors of CVT. Anticoagulation might need to be suggested for IJVS patients.
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Affiliation(s)
- Xiaoqin Wu
- Department of NeurologyXuanwu HospitalCapital Medical UniversityBeijingChina
- Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
- Department of China‐America Institute of NeuroscienceXuanwu HospitalCapital Medical UniversityBeijingChina
| | - Jingyuan Ya
- Department of NeurologyXuanwu HospitalCapital Medical UniversityBeijingChina
- Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
- Department of China‐America Institute of NeuroscienceXuanwu HospitalCapital Medical UniversityBeijingChina
- Division of Clinical NeuroscienceUniversity of NottinghamNottinghamUK
| | - Da Zhou
- Department of NeurologyXuanwu HospitalCapital Medical UniversityBeijingChina
- Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
- Department of China‐America Institute of NeuroscienceXuanwu HospitalCapital Medical UniversityBeijingChina
| | - Yuchuan Ding
- Department of China‐America Institute of NeuroscienceXuanwu HospitalCapital Medical UniversityBeijingChina
- Department of NeurosurgeryWayne State University School of MedicineDetroitMIUSA
| | - Xunming Ji
- Department of NeurologyXuanwu HospitalCapital Medical UniversityBeijingChina
- Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
- Department of China‐America Institute of NeuroscienceXuanwu HospitalCapital Medical UniversityBeijingChina
| | - Ran Meng
- Department of NeurologyXuanwu HospitalCapital Medical UniversityBeijingChina
- Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
- Department of China‐America Institute of NeuroscienceXuanwu HospitalCapital Medical UniversityBeijingChina
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23
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Xue YY, Huang XR, Dong HL, Wu ZY, Li HF. Identification of a large homozygous SPG21 deletion in a Chinese patient with Mast syndrome. CNS Neurosci Ther 2021; 27:1251-1253. [PMID: 34492745 PMCID: PMC8446208 DOI: 10.1111/cns.13723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/10/2021] [Accepted: 08/10/2021] [Indexed: 11/30/2022] Open
Affiliation(s)
- Yan-Yan Xue
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue-Rong Huang
- Department of Neurology, Ruian City People's Hospital, Ruian, China
| | - Hai-Lin Dong
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhi-Ying Wu
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Hong-Fu Li
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
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24
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Rock CR, White TA, Piscopo BR, Sutherland AE, Miller SL, Camm EJ, Allison BJ. Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments. Int J Mol Sci 2021; 22:ijms22147555. [PMID: 34299174 PMCID: PMC8303639 DOI: 10.3390/ijms22147555] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/05/2021] [Accepted: 07/08/2021] [Indexed: 01/25/2023] Open
Abstract
Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).
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Affiliation(s)
- Charmaine R. Rock
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Tegan A. White
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Beth R. Piscopo
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Amy E. Sutherland
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
| | - Suzanne L. Miller
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Emily J. Camm
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Beth J. Allison
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (C.R.R.); (T.A.W.); (B.R.P.); (A.E.S.); (S.L.M.); (E.J.C.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
- Correspondence:
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Genetic variations influence brain changes in patients with attention-deficit hyperactivity disorder. Transl Psychiatry 2021; 11:349. [PMID: 34091591 PMCID: PMC8179928 DOI: 10.1038/s41398-021-01473-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55-66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD. Integrating the neuroimaging-derived phenotypes with genomics deciphers various neurobiological pathways that can be leveraged for the development of novel clinical biomarkers, new treatment modalities as well as therapeutic interventions for ADHD patients. In this review, we discuss the neurobiology of ADHD with particular emphasis on structural and functional changes in the ADHD brain and their interactions with complex genomic variations utilizing imaging genetics methodologies. We also highlight the genetic variants supposedly allied with the development of ADHD and how these, in turn, may affect the brain circuit function and related behaviors. In addition to reviewing imaging genetic studies, we also examine the need for complementary approaches at various levels of biological complexity and emphasize the importance of combining and integrating results to explore biological pathways involved in ADHD disorder. These approaches include animal models, computational biology, bioinformatics analyses, and multimodal imaging genetics studies.
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26
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Fu G, Chen W, Li H, Wang Y, Liu L, Qian Q. A potential association of RNF219-AS1 with ADHD: Evidence from categorical analysis of clinical phenotypes and from quantitative exploration of executive function and white matter microstructure endophenotypes. CNS Neurosci Ther 2021; 27:603-616. [PMID: 33644999 PMCID: PMC8025624 DOI: 10.1111/cns.13629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/25/2021] [Accepted: 02/07/2021] [Indexed: 01/01/2023] Open
Abstract
AIMS Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder of substantial heritability, yet emerging evidence suggests that key risk variants might reside in the noncoding regions of the genome. Our study explored the association of lncRNAs (long noncoding RNAs) with ADHD as represented at three different phenotypic levels guided by the Research Domain Criteria (RDoC) framework: (i) ADHD caseness and symptom dimension, (ii) executive functions as functional endophenotype, and (iii) potential genetic influence on white matter architecture as brain structural endophenotype. METHODS Genotype data of 107 tag single nucleotide polymorphisms (SNP) from 10 candidate lncRNAs were analyzed in 1040 children with ADHD and 630 controls of Chinese Han descent. Executive functions including inhibition and set-shifting were assessed by STROOP and trail making tests, respectively. Imaging genetic analyses were performed in a subgroup of 33 children with ADHD and 55 controls using fractional anisotropy (FA). RESULTS One SNP rs3908461 polymorphism in RNF219-AS1 was found to be significantly associated with ADHD caseness: with C-allele detected as the risk genotype in the allelic model (P = 8.607E-05) and dominant genotypic model (P = 9.628E-05). Nominal genotypic effects on inhibition (p = 0.020) and set-shifting (p = 0.046) were detected. While no direct effect on ADHD core symptoms was detected, mediation analysis suggested that SNP rs3908461 potentially exerted an indirect effect through inhibition function [B = 0.21 (SE = 0.12), 95% CI = 0.02-0.49]. Imaging genetic analyses detected significant associations between rs3908461 genotypes and FA values in corpus callosum, left superior longitudinal fasciculus, left posterior limb of internal capsule, left posterior thalamic radiate (include optic radiation), and the left anterior corona radiate (P FWE corrected < 0.05). CONCLUSION Our present study examined the potential roles of lncRNA in genetic etiological of ADHD and provided preliminary evidence in support of the potential RNF219-AS1 involvement in the pathophysiology of ADHD in line with the RDoC framework.
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Affiliation(s)
- Guang‐Hui Fu
- Peking University Sixth Hospital/Institute of Mental HealthBeijingChina
- National Clinical Research Center for Mental Disorders & The Key Laboratory of Mental HealthMinistry of Health (Peking UniversityBeijingChina
| | - Wai Chen
- Mental Health ServiceFiona Stanley HospitalPerthAustralia
- Graduate School of EducationThe University of Western AustraliaPerthAustralia
- School of MedicineThe University of Notre Dame AustraliaFremantleAustralia
- School of PsychologyMurdoch UniversityPerthAustralia
| | - Hai‐Mei Li
- Peking University Sixth Hospital/Institute of Mental HealthBeijingChina
- National Clinical Research Center for Mental Disorders & The Key Laboratory of Mental HealthMinistry of Health (Peking UniversityBeijingChina
| | - Yu‐Feng Wang
- Peking University Sixth Hospital/Institute of Mental HealthBeijingChina
- National Clinical Research Center for Mental Disorders & The Key Laboratory of Mental HealthMinistry of Health (Peking UniversityBeijingChina
| | - Lu Liu
- Peking University Sixth Hospital/Institute of Mental HealthBeijingChina
- National Clinical Research Center for Mental Disorders & The Key Laboratory of Mental HealthMinistry of Health (Peking UniversityBeijingChina
| | - Qiu‐Jin Qian
- Peking University Sixth Hospital/Institute of Mental HealthBeijingChina
- National Clinical Research Center for Mental Disorders & The Key Laboratory of Mental HealthMinistry of Health (Peking UniversityBeijingChina
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27
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Guo X, Liu L, Li T, Zhao Q, Li H, Huang F, Wang Y, Qian Q, Cao Q, Wang Y, Calhoun VD, Sui J, Sun L. Inhibition-directed multimodal imaging fusion patterns in adults with ADHD and its potential underlying "gene-brain-cognition" relationship. CNS Neurosci Ther 2021; 27:664-673. [PMID: 33724699 PMCID: PMC8111492 DOI: 10.1111/cns.13625] [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: 10/21/2020] [Revised: 01/27/2021] [Accepted: 01/30/2021] [Indexed: 11/30/2022] Open
Abstract
Aims Inhibition deficits have been suggested to be a core cognitive impairment in attention‐deficit/hyperactivity disorder (ADHD). Exploring imaging patterns and the potential genetic components associated with inhibition deficits would definitely promote our understanding of the neuropathological mechanism of ADHD. This study aims to investigate the multimodal imaging fusion features related to inhibition deficits in adults with ADHD (aADHD) and to make an exploratory analysis of the role of inhibition‐related gene, NOS1, on those brain alterations. Methods Specifically, multisite canonical correlation analysis with reference plus joint independent component analysis (MCCAR + jICA) was conducted to identify the joint co‐varying gray matter volume (GMV) and the functional connectivity (FC) features related to inhibition in 69 aADHD and 44 healthy controls. Then, mediation analysis was employed to detect the relationship among inhibition‐related imaging features, NOS1 ex1f‐VNTR genotypes, and inhibition. Results Inhibition‐directed multimodal imaging fusion patterns of aADHD were reduced GMV and FC in inhibition network and increased GMV and FC in default mode network. The results showed a significant indirect effect of NOS1 ex1f‐VNTR on inhibition via FC component [effect size = −0.54 (SE = 0.29), 95% CI = −1.16 to −0.01]. In addition, the results indicated a significant indirect effect of GMV on the inhibition via FC component [effect size = 0.43 (SE = 0.23), 95% CI = 0.12 to 1.00]. Conclusion The findings suggested that reduced GMV and FC in inhibition network and increased GMV and FC in default mode network were jointly responsible for inhibition deficits in aADHD. Both the NOS1 ex1f‐VNTR genotypes and GMV might influence the inhibition through the mediation effect of the aforementioned FC (NOS1/GMV→FC→Inhibition).
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Affiliation(s)
- Xiaojie Guo
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Lu Liu
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Tiantian Li
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Qihua Zhao
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Hui Li
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Fang Huang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Yanfei Wang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Qiujin Qian
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Qingjiu Cao
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Yufeng Wang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
| | - Vince D Calhoun
- Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) [Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, GA, USA
| | - Jing Sui
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,CAS Center for Excellence in Brain Science, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Li Sun
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China
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28
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Wei Y, Wu L, Wang Y, Liu J, Miao P, Wang K, Wang C, Cheng J. Disrupted Regional Cerebral Blood Flow and Functional Connectivity in Pontine Infarction: A Longitudinal MRI Study. Front Aging Neurosci 2020; 12:577899. [PMID: 33328960 PMCID: PMC7710811 DOI: 10.3389/fnagi.2020.577899] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/12/2020] [Indexed: 11/28/2022] Open
Abstract
Abnormal cerebral blood flow (CBF) and resting-state functional connectivity (rs-FC) are sensitive biomarkers of disease progression and prognosis. This study investigated neural underpinnings of motor and cognitive recovery by longitudinally studying the changes of CBF and FC in pontine infarction (PI). Twenty patients underwent three-dimensional pseudo-continuous arterial spin labeling (3D-pcASL), resting-state functional magnetic resonance imaging (rs-fMRI) scans, and behavioral assessments at 1 week, 1, 3, and 6 months after stroke. Twenty normal control (NC) subjects underwent the same examination once. First, we investigated CBF changes in the acute stage, and longitudinal changes from 1 week to 6 months after PI. Brain regions with longitudinal CBF changes were then used as seeds to investigate longitudinal FC alterations during the follow-up period. Compared with NC, patients in the left PI (LPI) and right PI (RPI) groups showed significant CBF alterations in the bilateral cerebellum and some supratentorial brain regions at the baseline stage. Longitudinal analysis revealed that altered CBF values in the right supramarginal (SMG_R) for the LPI group, while the RPI group showed significantly dynamic changes of CBF in the left calcarine sulcus (CAL_L), middle occipital gyrus (MOG_L), and right supplementary motor area (SMA_R). Using the SMG_R as the seed in the LPI group, FC changes were found in the MOG_L, middle temporal gyrus (MTG_L), and prefrontal lobe (IFG_L). Correlation analysis showed that longitudinal CBF changes in the SMG_R and FC values between the SMG_R and MOG_L were associated with motor and memory scores in the LPI group, and longitudinal CBF changes in the CAL_L and SMA_R were related to memory and motor recovery in the RPI group. These longitudinal CBF and accompany FC alterations may provide insights into the neural mechanism underlying functional recovery after PI, including that of motor and cognitive functions.
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Affiliation(s)
- Ying Wei
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Luobing Wu
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingying Wang
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingchun Liu
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
| | - Peifang Miao
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kaiyu Wang
- GE Healthcare MR Research, Beijing, China
| | - Caihong Wang
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingliang Cheng
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Tan YW, Liu L, Wang YF, Li HM, Pan MR, Zhao MJ, Huang F, Wang YF, He Y, Liao XH, Qian QJ. Alterations of cerebral perfusion and functional brain connectivity in medication-naïve male adults with attention-deficit/hyperactivity disorder. CNS Neurosci Ther 2019; 26:197-206. [PMID: 31231983 PMCID: PMC6978256 DOI: 10.1111/cns.13185] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/01/2019] [Accepted: 06/04/2019] [Indexed: 12/17/2022] Open
Abstract
Aims Functional brain abnormalities, including altered cerebral perfusion and functional connectivities, have been illustrated in adults with attention‐deficit/hyperactivity disorder (aADHD). The present study attempted to explore the alterations of cerebral blood flow (CBF) and resting‐state functional connectivity (RSFC) simultaneously to understand the neural mechanisms for adults with ADHD comprehensively. Methods Resting‐state arterial spin labeling (ASL) and blood oxygenation level‐dependent (BOLD) magnetic resonance imaging (MRI) data were acquired for 69 male aADHD and 69 matched healthy controls (HCs). The altered CBFs associated with aADHD were explored based on both categorical (aADHD vs HCs) and dimensional (correlation with aADHD core symptoms) perspectives. Then, the seed‐based RSFC analyses were developed for the regions showing significant alterations of CBF. Results Significantly decreased CBF in the large‐scale resting‐state networks regions (eg, ventral attentional network, somatomotor network, limbic network) and subcortical regions was indicated in aADHD compared with HCs. The correlation analyses indicated that the hypoperfusion in left putamen/global pallidum and left amygdala/hippocampus was correlated with ADHD inattentive and total symptoms, respectively. Further, weaker negative functional connectivity between left amygdala and bilateral supplementary motor area, bilateral superior frontal gyrus, and left medial frontal gyrus was found in adults with ADHD. Conclusion The present findings suggested alterations of both cerebral perfusion and functional connectivity for the left amygdala in aADHD. The combination of CBF and RSFCs may help to interpret the neuropathogenesis of ADHD more comprehensively.
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Affiliation(s)
- Ya-Wen Tan
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Lu Liu
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Yan-Fei Wang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Hai-Mei Li
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Mei-Rong Pan
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Meng-Jie Zhao
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Fang Huang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Yu-Feng Wang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
| | - Yong He
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China.,Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China
| | - Xu-Hong Liao
- School of Systems Science, Beijing Normal University, Beijing, China
| | - Qiu-Jin Qian
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & the NHC Key Laboratory of Mental Health (Peking University), Beijing, China
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