RESUMO
BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder. Integrity of white matter microstructure plays a key role in the neural mechanism of ADHD presentations. However, the relationships between specific behavioural dimensions and white matter microstructure are less well known. This study aimed to identify associations between white matter and a broad set of clinical features across children and adolescent with and without ADHD using a data-driven multivariate approach. METHOD: We recruited a total of 130 children (62 controls and 68 ADHD) and employed regularized generalized canonical correlation analysis to characterize the associations between white matter and a comprehensive set of clinical measures covering three domains, including symptom, cognition and behaviour. We further applied linear discriminant analysis to integrate these associations to explore potential developmental effects. RESULTS: We delineated two brain-behaviour dimensional associations in each domain resulting a total of six multivariate patterns of white matter microstructural alterations linked to hyperactivity-impulsivity and mild affected; executive functions and working memory; externalizing behaviour and social withdrawal, respectively. Apart from executive function and externalizing behaviour sharing similar white matter patterns, all other dimensions linked to a specific pattern of white matter microstructural alterations. The multivariate dimensional association scores showed an overall increase and normalization with age in ADHD group while remained stable in controls. CONCLUSIONS: We found multivariate neurobehavioral associations exist across ADHD and controls, which suggested that multiple white matter patterns underlie ADHD heterogeneity and provided neural bases for more precise diagnosis and individualized treatment.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Substância Branca , Humanos , Criança , Adolescente , Substância Branca/diagnóstico por imagem , Encéfalo , Função Executiva , CogniçãoRESUMO
Obsessive-compulsive disorder (OCD) displays alterations in regional brain activity represented by the amplitude of low-frequency fluctuation (ALFF), but the time-varying characteristics of this local neural activity remain to be clarified. We aimed to investigate the dynamic changes of intrinsic brain activity in a relatively large sample of drug-naïve OCD patients using univariate and multivariate analyses. We applied a sliding-window approach to calculate the dynamic ALFF (dALFF) and compared the difference between 73 OCD patients and age- and sex-matched healthy controls (HCs). We also utilized multivariate pattern analysis to determine whether dALFF could differentiate OCD patients from HCs at the individual level. Compared with HCs, OCD patients exhibited increased dALFF mainly within regions of the cortical-striatal-thalamic-cortical (CSTC) circuit, including the bilateral dorsal anterior cingulate cortex, medial prefrontal cortex and striatum, and right dorsolateral prefrontal cortex (dlPFC). Decreased dALFF was identified in the bilateral inferior parietal lobule (IPL), posterior cingulate cortex, insula, fusiform gyrus, and cerebellum. Moreover, we found negative correlations between illness duration and dALFF values in the right IPL and between dALFF values in the left cerebellum and Hamilton Depression Scale scores. Furthermore, dALFF can distinguish OCD patients from HCs with the most discriminative regions located in the IPL, dlPFC, middle occipital gyrus, and cuneus. Taken together, in the current study, we demonstrated a characteristic pattern of higher variability of regional brain activity within the CSTC circuits and lower variability in regions outside the CSTC circuits in drug-naïve OCD patients.
Assuntos
Cerebelo/fisiopatologia , Córtex Cerebral/fisiopatologia , Conectoma , Corpo Estriado/fisiopatologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Adulto , Cerebelo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Fatores de Tempo , Adulto JovemRESUMO
The hippocampus and amygdala are important structures in the posttraumatic stress disorder (PTSD); however, the exact relationship between these structures and stress or PTSD remains unclear. Moreover, they consist of several functionally distinct subfields/subregions that may serve different roles in the neuropathophysiology of PTSD. Here we present a subregional profile of the hippocampus and amygdala in 145 survivors of a major earthquake and 56 non-traumatized healthy controls (HCs). We found that the bilateral hippocampus and left amygdala were significantly smaller in survivors than in HCs, and there was no difference between survivors with (n = 69) and without PTSD (trauma-exposed controls [TCs], n = 76). Analyses revealed similar results in most subfields/subregions, except that the right hippocampal body (in a head-body-tail segmentation scheme), right presubiculum, and left amygdala medial nuclei (Me) were significantly larger in PTSD patients than in TCs but smaller than in HCs. Larger hippocampal body were associated with the time since trauma in PTSD patients. The volume of the right cortical nucleus (Co) was negatively correlated with the severity of symptoms in the PTSD group but positively correlated with the same measurement in the TC group. This correlation between symptom severity and Co volume was significantly different between the PTSD and TCs. Together, we demonstrated that generalized smaller volumes in the hippocampus and amygdala were more likely to be trauma-related than PTSD-specific, and their subfields/subregions were distinctively affected. Notably, larger left Me, right hippocampal body and presubiculum were PTSD-specific; these could be preexisting factors for PTSD or reflect rapid posttraumatic reshaping.
Assuntos
Tonsila do Cerebelo/patologia , Hipocampo/patologia , Trauma Psicológico/patologia , Transtornos de Estresse Pós-Traumáticos/patologia , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Terremotos , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Trauma Psicológico/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Sobreviventes , Fatores de TempoRESUMO
BACKGROUND: Major depressive disorder (MDD) is a clinically and biologically heterogeneous syndrome. Identifying discrete subtypes of illness with distinguishing neurobiological substrates and clinical features is a promising strategy for guiding personalised therapeutics. AIMS: This study aimed to identify depression subtypes with correlated patterns of functional network connectivity and clinical symptoms by clustering patients according to a weighted linear combination of both features in a relatively large, medication-naïve depression sample. METHOD: We recruited 115 medication-naïve adults with MDD and 129 matched healthy controls, and evaluated all participants with magnetic resonance imaging. We used regularised canonical correlation analysis to identify component mapping relationships between functional network connectivity and symptom profiles, and K-means clustering was used to define distinct subtypes of patients. RESULTS: Two subtypes of MDD were identified: insomnia-dominated subtype 1 and anhedonia-dominated subtype 2. Subtype 1 was characterised by abnormal hyperconnectivity within the ventral attention network and sleep maintenance insomnia. Subtype 2 was characterised by abnormal hypoconnectivity in the subcortical and dorsal attention networks, and prominent anhedonia symptoms. CONCLUSIONS: Our study identified two distinct subtypes of patients with specific neurobiological and clinical symptom profiles. These findings advance understanding of the biological and clinical heterogeneity of MDD, offering a pathway for defining categorical subtypes of illness via consideration of both biological and clinical features.
Assuntos
Transtorno Depressivo Maior , Distúrbios do Início e da Manutenção do Sono , Adulto , Anedonia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Análise por Conglomerados , Transtorno Depressivo Maior/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagemRESUMO
Background: The specific role of the corticospinal tract with respect to inattention and impulsive symptoms in children with attention-deficit/hyperactivity disorder (ADHD) has been explored in the past. However, to our knowledge, no study has identified the exact regions of the corticospinal tract that are affected in ADHD. We aimed to determine comprehensive alterations in the white matter microstructure of the corticospinal tract and underlying neuropsychological substrates in ADHD. Methods: We recruited 38 drug-naïve children with ADHD and 34 typically developing controls. We employed a tract-based quantitative approach to measure diffusion parameters along the trajectory of the corticospinal tract, and we further correlated alterations with attention and response inhibition measures. Results: Compared with controls, children with ADHD demonstrated significantly lower fractional anisotropy and higher radial diffusivity at the level of cerebral peduncle, and higher fractional anisotropy at the level of the posterior limb of the internal capsule in the right corticospinal tract only. As well, increased fractional anisotropy in the posterior limb of the internal capsule was negatively correlated with continuous performance test attention quotients and positively correlated with reaction time on the Stroop ColourWord Test; increased radial diffusivity in the right peduncle region was positively correlated with omissions in the Stroop test. Limitations: The sample size was relatively small. Moreover, we did not consider the different subtypes of ADHD and lacked sufficient power to analyze subgroup differences. Higher-order diffusion modelling is needed in future white matter studies. Conclusion: We demonstrated specific changes in the right corticospinal tract in children with ADHD. Correlations with measures of attention and response inhibition underscored the functional importance of corticospinal tract disturbance in ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Tratos Piramidais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Teste de StroopRESUMO
Background: The amygdala has been implicated in obsessive-compulsive disorder (OCD), a common, disabling illness. However, the regional distribution of anatomic alterations in this structure and their association with the symptoms of OCD remains to be established. Methods: We collected high-resolution 3D T1-weighted images from 81 untreated patients with OCD and no lifetime history of comorbid psychotic, affective or anxiety disorders, and from 95 age- and sex-matched healthy controls. We extracted the volume of the central nucleus of the amygdala (CeA) and the basolateral complex of the amygdala (BLA) and compared them across groups using FreeSurfer 6.0. In exploratory analyses, we evaluated other subnuclei, including the cortical medial nuclei, the anterior amygdaloid area, and the corticoamygdaloid transition area. Results: Patients with OCD had reduced amygdala volume bilaterally compared with healthy controls (left, p = 0.034; right, p = 0.002). Volume reductions were greater in the CeA (left: -11.9%, p = 0.002; right: -13.3%, p < 0.001) than in the BLA (left lateral nucleus: -3.3%, p = 0.029; right lateral nucleus: -3.9%, p = 0.018; right basal nucleus: -4.1%, p = 0.017; left accessory basal nucleus: -6.5%, p = 0.001; right accessory basal nucleus: -9.3%, p < 0.001). Volume reductions in the CeA were associated with illness duration. Exploratory analysis revealed smaller medial (left: -15.4%, p < 0.001, η2 = 0.101) and cortical (left: -9.1%, p = 0.001, η2 = 0.058; right: -15.4%, p < 0.001, η2 = 0.175) nuclei in patients with OCD compared with healthy controls. Limitations: Although the strict exclusion criteria used in the study helped us to identify OCD-specific alterations, they may have limited generalizability to the broader OCD population. Conclusion: Our results provide a comprehensive anatomic profile of alterations in the amygdala subnuclei in untreated patients with OCD and highlight a distinctive pattern of volume reductions across subnuclei in OCD. Based on the functional properties of the amygdala subnuclei established from preclinical research, CeA impairment may contribute to behavioural inflexibility, and BLA disruption may be responsible for altered fear conditioning and the affective components of OCD.
Assuntos
Complexo Nuclear Basolateral da Amígdala/patologia , Núcleo Central da Amígdala/patologia , Transtorno Obsessivo-Compulsivo/patologia , Adulto , Complexo Nuclear Basolateral da Amígdala/diagnóstico por imagem , Núcleo Central da Amígdala/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: Exploring white matter (WM) microstructural alterations is a momentous step for gaining insights about underlying mechanisms of obsessive-compulsive disorder (OCD) and improving the efficacy of therapies for this condition. Many tract-based spatial statistics (TBSS) studies have revealed abnormalities of fractional anisotropy (FA; an index of WM integrity) in OCD. However, research works have not drawn robust conclusions. Therefore, we integrated the findings of TBSS studies to identify the most consistent FA changes in OCD using meta-analytical approach. METHODS: Online databases were systematically searched for all TBSS studies comparing FA between patients with OCD and controls. A coordinate-based meta-analysis was performed using anisotropic effect size version of the seed-based d mapping software. Meanwhile, meta-regression was used to explore the potential association of clinical characteristics with regional FA abnormalities. RESULTS: Our meta-analysis included 488 OCD patients and 519 controls across 17 datasets. FA reductions were identified in the genu of the corpus callosum and the left orbitofrontal WM in OCD patients relative to controls. Metaregression analyses showed that the FA in the left orbitofrontal WM was negatively and independently correlated with symptom severity and illness duration in patients with OCD. CONCLUSIONS: The current study provides a quantitative overview of TBSS findings in OCD and demonstrates the most prominent and replicable WM abnormalities in OCD are in the anterior part of the brain including interhemispheric connection and orbitofrontal region. Additionally, our findings suggest that FA reduction in the orbitofrontal WM might be a potential biomarker in predicting disease severity and progression in patients with OCD.
Assuntos
Transtorno Obsessivo-Compulsivo , Substância Branca , Anisotropia , Encéfalo/diagnóstico por imagem , Corpo Caloso , Imagem de Tensor de Difusão , Humanos , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
In this study, we sought to identify alterations of hippocampal shape and subfield volumes in a relatively large sample of medication-free obsessive-compulsive disorder (OCD) patients without comorbid depression. 3D T1-weighted Magnetic Resonance Imaging scans were collected from 81 medication-free OCD patients and 95 age- and sex-matched healthy controls (HC). Total hippocampal volume and volume of eight bilateral subfields were measured using FreeSurfer software. Subregional shape deformity was examined via FSL software. Volumetric and shape differences between groups and correlations with OCD symptoms were examined. The volume of right hippocampus was significantly reduced in OCD patients (p = .001, η2 = 0.065). Follow-up analysis of right hemisphere subfields showed reduced volume in right subiculum (p < .001, η2 = 0.081), presubiculum (p < .001, η2 = 0.125), CA2/3 (p = .001, η2 = 0.06), and hippocampal tail (p < 0.001, η2 = 0.105), while the volume of right fimbria was increased (p = .001, η2 = 0.058). Shape analysis revealed a bilateral outward bending in the hippocampal body related to a lateral displacement of hippocampus from the body to the tail. Symptom severity was correlated with volumes of presubiculum (with compulsions, r = -0.25, p = .024) and fimbria (with obsessions, r = -0.28, p = .012), and with the lateral shift of middle and posterior hippocampus (with obsessions). Alterations across hippocampal subfields and overall shape may contribute to the distinctive cognitive and affective abnormalities associated with OCD.
Assuntos
Hipocampo/patologia , Transtorno Obsessivo-Compulsivo/patologia , Adulto , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Estudos ProspectivosRESUMO
Altered resting-state functional connectivity (rsFC) has been noted in large-scale functional networks in attention-deficit/hyperactivity disorder (ADHD). However, identifying consistent abnormalities of functional networks is difficult due to varied methods and results across studies. To integrate rsFC alterations and search for coherent patterns of intrinsic functional network impairments in ADHD, this research conducts a coordinate-based meta-analysis of voxel-wise seed-based rsFC studies comparing rsFC between ADHD patients and healthy controls. A total of 25 datasets from 21 studies including 700 ADHD patients and 580 controls were analyzed. We extracted the coordinates of seeds and between-group effects. Each seed was then categorized into a seed-network by its location within priori 7-network parcellations. Then, pooled meta-analyses were conducted for the default mode network (DMN), frontoparietal network (FPN) and affective network (AN) separately, but not for the ventral attention network (VAN), dorsal attention network (DAN), somatosensory network (SSN) and visual network due to a lack of primary studies. The results showed that ADHD was characterized by hyperconnectivity between the FPN and regions of the DMN and AN as well as hypoconnectivity between the FPN and regions of the VAN and SSN. These findings not only support the triple-network model of pathophysiology associated with ADHD but also extend this model by highlighting the involvement of the SSN and AN in the mechanisms of network interactions that may account for motor hyperactivity and impulsive symptoms.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Lobo Frontal/fisiopatologia , Lobo Parietal/fisiopatologia , Descanso , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/fisiopatologiaRESUMO
BACKGROUND: Previous studies had proved that hippocampal volume has predictive value for antidepressant response in patients with major depressive disorder (MDD). However, the exact subregion of the hippocampus relevant to the predictive role of antidepressants response is not known. PURPOSE: To explore which hippocampal subfield volumes might predict an early response to first-time use of antidepressants in drug-naïve MDD patients. STUDY TYPE: Prospective. POPULATION: Thirty-eight drug-naïve MDD patients (mean illness duration = 1.6 years) and 55 healthy control subjects (HCS). FIELD STRENGTH/SEQUENCE: 3.0T MRI, T1 -weighted, 3D, SPGR sequence. ASSESSMENT: The hippocampal subfields and total intracranial volume were measured with FreeSurfer. The response to antidepressants was evaluated by the reduction rate of the Hamilton Rating Scale for Depression score (RRS) after a 6-week routine clinical antidepressant treatment. STATISTICAL TESTS: The relationship between hippocampal subfield volumes and RRS was explored using partial correlation analysis. Volume differences among early responding patients (ERP), nonresponding patients (NRP), and HCS were examined by multivariate analysis of covariance. Receiver operating characteristic (ROC) curve analysis was used to evaluate the sensitivity and specificity of volumes as predictors. RESULTS: NRP had significantly larger volumes than both ERP and HCS in bilateral subiculum, cornu ammonis (CA) 1 and left CA2/3, CA4/dentate gyrus (DG) (all P < 0.01, false discovery rate corrected). Significant negative correlations were found between the RRS and volumes of left subiculum (P = 0.004), CA2/3 (P = 0.008), and CA4/DG (P = 0.004) in the whole MDD group. ROC analysis demonstrated that the left subiculum exhibited the highest accuracy for differentiating NRP from ERP, with a sensitivity of 76.9% and specificity of 80%. DATA CONCLUSION: These findings propose that volumes of certain hippocampal subfields may be associated with antidepressant treatment and this has potential use in clinical applications for treatment selection in patients with MDD at an early stage. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;49:1760-1768.
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Antidepressivos/farmacologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Amygdala-based network dysfunction has been found to be centrally implicated in major depressive disorder (MDD). However, relatively little is known about how different forms of effective or cognitive dysfunction are modulated in MDD. Therefore, in the current study, we aimed to examine the alteration of amygdala subregional networks in adult patients with MDD to explore whether different parts of the amygdala that are functionally connected to different regions contribute differently to the cerebral network mechanism of depression. METHODS: Resting-state fMRI scans were obtained from 70 medication-free adults with MDD and 70 age- and sex-matched healthy controls (HC). Functional connectivity maps of four distinct regions of the amygdala, including the amygdalostriatal transition area (AStr) and the basolateral (BLA), centromedial (CM) and superficial (SF) amygdala, were generated and compared between the two groups. RESULTS: Compared with HC, patients with MDD showed hypoconnectivity between the AStr/BLA and the orbitofrontal cortex (OFC), between the CM/SF and the brainstem/cerebellum, and within AStr/CM/SF-thalamic/striatal networks. Hyperconnectivity was observed between the left AStr/BLA and the fusiform gyrus. There was no difference in the gray matter volume of the amygdala or any of its subregions between the two groups. CONCLUSIONS: These findings suggest that amygdala subregional-network dysfunction in MDD is independent of structural changes and, more important, that hypoconnectivity and hyperconnectivity in different subregional networks may reflect imbalanced network function, which may modulate different forms of emotional and cognitive dysfunction in MDD.
Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Adulto , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and accounts for over 90% of all primary liver cancers. Increasing evidence suggests that microRNAs (miRNAs) mediate signaling pathways by gene expression regulation. METHODS: In this study, we evaluated the role of miR-29a-3p in HCC progression. MiR-29a-3p was found significantly down-regulated in HCC tissues compared to adjacent non-tumor tissues. Meantime, PTEN expression was up-regulated in HCC tissues. Moreover, NF-κB activity was decreased following PTEN up-regulation. RESULTS: In vitro assays in the HCC cell line BEL7402 demonstrated that miR-29a-3p suppresses cell proliferation. CONCLUSIONS: miR-29a-3p participates in the HCC progression by regulation of NF-κB pathway via targeting PTEN.
Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , NF-kappa B/metabolismo , Alcoolismo/complicações , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Transdução de SinaisRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurodevelopmental disorder in childhood and is characterized by inattention, impulsivity, and hyperactivity. Observations of distributed functional abnormalities in ADHD suggest aberrant large-scale brain network connectivity. However, few studies have measured the voxel-wise network centrality of boys with ADHD, which captures the functional relationships of a given voxel within the entire connectivity matrix of the brain. Here, to examine the network patterns characterizing children with ADHD, we recruited 47 boys with ADHD and 21 matched control boys who underwent resting-state functional imaging scanning in a 3.0 T MRI unit. We measured voxel-wise network centrality, indexing local functional relationships across the entire brain connectome, termed degree centrality (DC). Then, we chose the brain regions with altered DC as seeds to examine the remote functional connectivity (FC) of brain regions. We found that boys with ADHD exhibited (1) decreased centrality in the left superior temporal gyrus (STG) and increased centrality in the left superior occipital lobe (SOL) and right inferior parietal lobe (IPL); (2) decreased FC between the STG and the putamen and thalamus, which belong to the cognitive cortico-striatal-thalamic-cortical (CSTC) loop, and increased FC between the STG and medial/superior frontal gyrus within the affective CSTC loop; and (3) decreased connectivity between the SOL and cuneus within the dorsal attention network. Our results demonstrated that patients with ADHD show a connectivity-based pathophysiological process in the cognitive and affective CSTC loops and attention network.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Estudos de Casos e Controles , Criança , Humanos , MasculinoRESUMO
BACKGROUND/AIMS: Erinacine, which is extracted from the medicinal mushroom Hericium erinaceus, is known to play anticancer roles in human cancers. The following study aims to investigate the role of erinacine in the opening of the mitochondrial permeability transition pore (MPTP) in hepatocellular carcinoma (HCC) through the PI3K/Akt/GSK-3ß signaling pathway and highlights the applicability of erinacine in HCC treatments. METHODS: HCC and paracancerous tissues were obtained from 85 HCC patients who've undergone surgical resection. Immunohistochemistry was adopted to detect positive expression of PI3K, Akt, and GSK-3ß. Treatment of HepG-2 with LY294002 (an inhibitor of the PI3K/Akt/GSK-3ß signaling pathway) and different concentration of erinacine was performed to determine the involvement of LY294002 in erinacine action. The expressions of PI3K, Akt, GSK-3ß, CyclinD1, Vimentin, ß-catenin, Bcl-2, E-cadherin, Bax, and caspase-9 were determined by RT-qPCR and Western blot analysis. Cell viability, colony formation rate, migration, invasion, cycle, and apoptosis were detected by MTT, colony formation, wound healing assay, Transwell assay, and flow cytometry, respectively. The size and weight of xenograft tumors were observed in nude mice. Mitochondrial membrane potential in HepG-2 was determined using laser scanning confocal microscopy following JC-1 staining. Mitochondrial Ca2+ indicator Rhod-2, AM was used to detect the changes of mitochondrial Ca2+, while western blot analysis was employed to detect the presence levels of cytochrome C (cyt-C). RESULTS: The results revealed that PI3K, Akt, and GSK-3ß were up-regulated in HCC tissues. Erinacine or LY294002 led to a decrease in mitochondrial membrane potential, increase in intracellular mitochondrial Ca2+, and the release of cyt-C in mitochondria. In addition, Erinacine was found to decrease the mitochondrial membrane potential, expression of PI3K, Akt, GSK-3ß, CyclinD1, Vimentin, ß-catenin, and Bcl-2, cell proliferation, colony formation ability, migration, invasion, and xenograft tumor size, while E-cadherin, Bax, and caspase-9 expression, and cell apoptosis were elevated in a dose-dependent manner. Erinacine also stimulated the effects of LY294002 on the HCC. Following the addition of 500 µM Erinacine and MPTP opening inhibitor CsA, we found that the mitochondrial membrane potential level increased, while mitochondrial Ca2+ and Cyt-C decreased from the mitochondria. CONCLUSION: The results from the study demonstrated that erinacine induced MPTP opening, facilitates the release of cyt-C, and inhibited cell proliferation, migration, and invasion, while it promotes apoptosis by inactivating the PI3K/Akt/GSK-3ß signaling pathway, preventing the progression of HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Diterpenos/farmacologia , Neoplasias Hepáticas/patologia , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cromonas/farmacologia , Feminino , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
A great number of studies have demonstrated functional abnormalities in children with attention-deficit/hyperactivity disorder (ADHD), although conflicting results have also been reported. And few studies analyzed homotopic functional connectivity between hemispheres. In this study, resting-state functional magnetic resonance imaging (MRI) data were recorded from 45 medication-naïve ADHD children and 26 healthy controls. The regional homogeneity (ReHo), degree centrality (DC) and voxel-mirrored homotopic connectivity (VMHC) values were compared between the two groups to depict the intrinsic brain activities. We found that ADHD children exhibited significantly lower ReHo and DC values in the right middle frontal gyrus and the two values correlated with each other; moreover, lower VMHC values were found in the bilateral occipital lobes of ADHD children, which was negatively related with anxiety scores of Conners' Parent Rating Scale (CPRS-R) and positively related with completed categories of Wisconsin Card Sorting Test (WCST). Our results might suggest that less spontaneous neuronal activities of the right middle frontal gyrus and the bilateral occipital lobes in ADHD children.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Encéfalo , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criança , Lobo Frontal , Humanos , Imageamento por Ressonância Magnética , Lobo OccipitalRESUMO
AIMS: Altered brain functional connectivity has been proposed as the neurobiological underpinnings of attention-deficit/hyperactivity disorder (ADHD), and the default mode interference hypothesis is one of the most popular neuropsychological models. Here, we explored whether this hypothesis is supported in adults with ADHD and the association with high-risk genetic variants and treatment outcomes. METHODS: Voxel-based whole-brain connectome analysis was conducted on resting-state functional MRI data from 84 adults with ADHD and 89 healthy controls to identify functional connectivity substrates corresponding to ADHD-related alterations. The candidate genetic variants and 12-week cognitive behavioral therapy data were leveraged from the same population to assess these associations. RESULTS: We detected breakdowns of functional connectivity in the precuneus and left middle temporal gyrus in adults with ADHD, with exact contributions from decreased connectivity within the default mode, dorsal and ventral attention networks, as well as increased connectivity among them with the middle temporal gyrus serving as a crucial 'bridge'. Additionally, significant associations between the altered functional connectivity and genetic variants in both MAOA and MAOB were detected. Treatment restored brain function, with the amelioration of connectivity of the middle temporal gyrus, accompanied by improvements in ADHD core symptoms. CONCLUSIONS: These findings support the interference of default mode on attention in adults with ADHD and its association with genetic risk variants and clinical management, providing insights into the underlying pathogenesis of ADHD and potential biomarkers for treatment evaluation.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Conectoma , Rede de Modo Padrão , Imageamento por Ressonância Magnética , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Masculino , Feminino , Adulto , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/fisiopatologia , Resultado do Tratamento , Adulto Jovem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Atenção/fisiologia , Variação Genética/genética , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Terapia Cognitivo-Comportamental/métodosRESUMO
This study evaluated the effect of biochar and compost on physiochemical properties, heavy metal content, microbial biomass, enzyme activities, and plant growth in Pb-Zn mine tailings. In this study, a pot experiment was conducted to evaluate the effects of biochar, compost, and their combination on the availability of heavy metals, physicochemical features, and enzyme activities in mining soil. Compared to separate addition, the combined application of biochar and compost was more effective to improve soil pH, soil organic carbon (SOC), total nitrogen (TN), available phosphorus (AP), and potassium (AK). All amendments significantly decreased CaCl2-extractable Pb, Zn, Cu, and Cd. Soil enzyme activities were activated by biochar and compost. Meanwhile, the addition of biochar and compost decreased heavy metal content in plant tissues and increased plant biomass. Pearson's correlation analysis showed that plant biomass was positively correlated with nutrient levels, microbial biomass, and enzyme activities, whereas it was negatively correlated with CaCl2-extractable heavy metals. These results enhance our understanding of the ecological functions of biochar and compost on the restoration of mining soil and reveal the potential benefit of organic amendments on the improvement of mining soil quality.
Assuntos
Compostagem , Metais Pesados , Poluentes do Solo , Solo/química , Carbono , Chumbo/análise , Cloreto de Cálcio , Poluentes do Solo/análise , Metais Pesados/análise , Carvão Vegetal/química , Zinco/análiseRESUMO
Changes in the brain of patients with Huntington's disease (HD) begin years before clinical onset, so it remains critical to identify biomarkers to track these early changes. Metrics derived from tensor modeling of diffusion-weighted MRIs (DTI), that indicate the microscopic brain structure, can add important information to regional volumetric measurements. This study uses two large-scale longitudinal, multicenter datasets, PREDICT-HD and IMAGE-HD, to trace changes in DTI of HD participants with a broad range of CAP scores (a product of CAG repeat expansion and age), including those with pre-manifest disease (i.e., prior to clinical onset). Utilizing a fully automated data-driven approach to study the whole brain divided in regions of interest, we traced changes in DTI metrics (diffusivity and fractional anisotropy) versus CAP scores, using sigmoidal and linear regression models. We identified points of inflection in the sigmoidal regression using change-point analysis. The deep gray matter showed more evident and earlier changes in DTI metrics over CAP scores, compared to the deep white matter. In the deep white matter, these changes were more evident and occurred earlier in superior and posterior areas, compared to anterior and inferior areas. The curves of mean diffusivity vs. age of HD participants within a fixed CAP score were different from those of controls, indicating that the disease has an additional effect to age on the microscopic brain structure. These results show the regional and temporal vulnerability of the white matter and deep gray matter in HD, with potential implications for experimental therapeutics.
Assuntos
Doença de Huntington , Substância Branca , Humanos , Substância Branca/diagnóstico por imagem , Doença de Huntington/diagnóstico por imagem , Estudos Transversais , Substância Cinzenta/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Encéfalo/diagnóstico por imagemRESUMO
Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus.
RESUMO
Background: Cortical functional network alterations have been widely accepted as the neural basis of attention-deficit/hyperactivity disorder (ADHD). Recently, white matter has also been recognized as a novel neuroimaging marker of psychopathology and has been used as a complement to cortical functional networks to investigate brain-behavior relationships. However, disorder-specific features of white matter functional networks (WMFNs) are less well understood than those of gray matter functional networks. In the current study, we constructed WMFNs using a new strategy to characterize behavior-related network features in ADHD. Methods: We recruited 46 drug-naïve boys with ADHD and 46 typically developing (TD) boys, and used clustering analysis on resting-state functional magnetic resonance imaging data to generate WMFNs in each group. Intrinsic activity within each network was extracted, and the associations between network activity and behavior measures were assessed using correlation analysis. Results: Nine WMFNs were identified for both ADHD and TD participants. However, boys with ADHD showed a splitting of the inferior corticospinal-cerebellar network and lacked a cognitive control network. In addition, boys with ADHD showed increased activity in the dorsal attention network and somatomotor network, which correlated positively with attention problems and hyperactivity symptom scores, respectively, while they presented decreased activity in the frontoparietal network and frontostriatal network in association with poorer performance in response inhibition, working memory, and verbal fluency. Conclusions: We discovered a dual pattern of white matter network activity in drug-naïve ADHD boys, with hyperactive symptom-related networks and hypoactive cognitive networks. These findings characterize two distinct types of WMFN in ADHD psychopathology.