Specific brain imaging alterations underlying autistic traits in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Autistic traits (ATs) are frequently reported in children with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aimed to examine ATs in children with ADHD from both behavioral and neuroimaging perspectives. METHODS: We used the Autism Spectrum Screening Questionnaire (ASSQ) to assess and define subjects with and without ATs. For behavioral analyses, 67 children with ADHD and ATs (ADHD + ATs), 105 children with ADHD but without ATs (ADHD - ATs), and 44 typically developing healthy controls without ATs (HC - ATs) were recruited. We collected resting-state functional magnetic resonance imaging (rs-fMRI) data and analyzed the mean amplitude of low-frequency fluctuation (mALFF) values (an approach used to depict different spontaneous brain activities) in a sub-sample. The imaging features that were shared between ATs and ADHD symptoms or that were unique to one or the other set of symptoms were illustrated as a way to explore the "brain-behavior" relationship. RESULTS: Compared to ADHD-ATs, the ADHD + ATs group showed more global impairment in all aspects of autistic symptoms and higher hyperactivity/impulsivity (HI). Partial-correlation analysis indicated that HI was significantly positively correlated with all aspects of ATs in ADHD. Imaging analyses indicated that mALFF values in the left middle occipital gyrus (MOG), left parietal lobe (PL)/precuneus, and left middle temporal gyrus (MTG) might be specifically related to ADHD, while those in the right MTG might be more closely associated with ATs. Furthermore, altered mALFF in the right PL/precuneus correlated with both ADHD and ATs, albeit in diverse directions. CONCLUSIONS: The co-occurrence of ATs in children with ADHD manifested as different behavioral characteristics and specific brain functional alterations. Assessing ATs in children with ADHD could help us understand the heterogeneity of ADHD, further explore its pathogenesis, and promote clinical interventions.

Exploring the Potential "Brain-Cognition-Behavior" Relationship in Children With ADHD Based on Resting-State Brain Local Activation and Functional Connectivity.

OBJECTIVE: Exploring how abnormal brain function in children with ADHD affects executive function and ultimately leads to behavioral impairment provides a theoretical basis for clinically targeted neurotherapy and cognitive training. METHOD: Amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo), and seed-based FC were analyzed in 53 ADHD and 52 healthy controls. The "brain-cognition-behavior" relationship was further explored using mediation analysis. RESULTS: ADHD showed abnormal local activation in the middle temporal gyrus (MTG), inferior occipital gyrus and inferior frontal gyrus (IFG) and reduced FC between the IFG and the cerebellum. ADHD diagnosis may affect ALFF of MTG and further modulate shift and finally affect inattentive symptoms. It may also affect the total symptoms through the FC of the IFG with the cerebellum. CONCLUSION: ADHD showed extensive spontaneous activity abnormalities and frontal-cerebellar FC impairments. Localized functional abnormalities in the MTG may affect the shift in EF, resulting in attention deficit behavior.

Serum alkaline phosphatase was independently associated with depression in patients with cerebrovascular disease.

Background and purpose: Blood markers have important value in the diagnosis of depressive disorders. Serum alkaline phosphatase (ALP) not only predicts stroke recurrence and poor functional prognosis in cerebrovascular disease (CVD) patients but also increases significantly in middle-aged women with depression. Thus, it has not been reported whether serum ALP is associated with the development of depression and/or vascular depression (VDe) in CVD patients. Methods: This was a cross-sectional study of 353 CVD patients (stroke patients, n = 291; cerebral small vessel disease (CSVD) patients, n = 62). Baseline demographic information, fasting blood markers (such as blood counts, liver function, kidney function and lipids), and brain CT/MRI scans were collected. CVD patients were divided into non-depression, suspected vascular depression (SVD), and positive vascular depression (PVD) groups according to their Hamilton Rating Scale for Depression (HAMD) scores. Univariate analysis of baseline data, blood markers, and the prevalence of lesions (> 1.5 cm) was performed. Subsequently, the diagnostic performance of the univariate and combined variables for SVD and PVD was analyzed using binary logistic regression. The diagnostic value of the multivariate model for VDe was analyzed by ordinal logistic regression. Results: (1) Serum ALP (p = 0.003) and hypersensitive C-reactive protein (hs-CRP, p = 0.001) concentrations increased as HAMD scores increased, and the prevalence of brain atrophy (p = 0.016) and lesions in the basal ganglia (p = 0.001) and parietal (p = 0.001), temporal (p = 0.002), and frontal lobes (p = 0.003) also increased, whereas the concentrations of hemoglobin (Hb, p = 0.003), cholinesterase (ChE, p = 0.001), and high-density lipoprotein cholesterol (HDL-C, p = 0.005) declined. Among these variables, hs-CRP (r = 0.218, p < 0.001) had a weak positively association with HAMD scores, and ChE (r = -0.226, p < 0.001) had a weak negative association. (2) The combination of Hb, hs-CRP, ChE, ALP, and HDL-C improved diagnostic performance for VDe [AUC = 0.775, 95% CI (0.706, 0.844), p < 0.001]. (3) Hb (OR = 0.986, p = 0.049), ChE (OR = 0.999, p = 0.020), ALP (OR = 1.017, p = 0.003), and basal ganglia lesions (OR = 2.197, p < 0.001) were important factors impacting VDe development. After adjusting for Hb, hs-CRP, ChE, HDL-C, lesions in the above mentioned four locations, sex, age and the prevalence of CSVD and brain atrophy, ALP [OR = 1.016, 95% CI (1.005, 1.027), p = 0.004] was independently associated with VDe. Conclusion: Hb, hs-CRP, ChE, ALP, and HDL-C concentrations are potential blood markers of depression in CVD patients and, when combined, may improve diagnostic performance for VDe. Serum ALP was independently associated with VDe in patients with CVD.

Neuroglobin Facilitates Neuronal Oxygenation through Tropic Migration under Hypoxia or Anemia in Rat: How Does the Brain Breathe?

The discovery of neuroglobin (Ngb), a brain- or neuron-specific member of the hemoglobin family, has revolutionized our understanding of brain oxygen metabolism. Currently, how Ngb plays such a role remains far from clear. Here, we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia. We found that Ngb was present in, co-localized to, and co-migrated with mitochondria in the cell body and neurites of neurons. Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane (CM) or cell surface in living neurons, and this was accompanied by the mitochondria. In vivo, hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio. Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase (SDH) and ATPase activity in neuronal N2a cells. Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia. Mutation of Ngb at its oxygen-binding site (His64) significantly increased SDH activity and reduced ATPase activity in N2a cells. Taken together, Ngb was physically and functionally linked to mitochondria. In response to an insufficient oxygen supply, Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation. This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.

Different functional alteration in attention-deficit/hyperactivity disorder across developmental age groups: A meta-analysis and an independent validation of resting-state functional connectivity studies.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a highly complex and heterogeneous disorder. Abnormal brain connectivity in ADHD might be influenced by developmental ages which might lead to the lacking of significant spatial convergence across studies. However, the developmental patterns and mechanisms of ADHD brain connectivity remain to be fully uncovered. METHODS: In the present study, we searched PubMed, Scopus, Web of Science, and Embase for seed-based whole-brain resting-state functional connectivity studies of ADHD published through October 12th, 2020. The seeds meeting inclusion criteria were categorized into the cortex group and subcortex group, as previous studies suggested that the cortex and subcortex have different temporal patterns of development. Activation likelihood estimation meta-analysis was performed to investigate the abnormal connectivity in different age groups (all-age group, younger: <12 years, older: ≥12 years). Moreover, significant convergence of reported foci was used as seeds for validation with our independent dataset. RESULTS: As with previous studies, scarce results were found in the all-age group. However, we found that the younger group consistently exhibited hyper-connectivity between different parts of the cortex and left middle frontal gyrus, and hypo-connectivity between different parts of the cortex and left putamen/pallidus/amygdala. Whereas, the older group (mainly for adults) showed hyper-connectivity between the cortex and right precuneus/sub-gyral/cingulate gyrus. Besides, the abnormal cortico-cortical and cortico-subcortical functional connectivity in children, and the abnormal cortico-cortical functional connectivity in adults were verified in our independent dataset. CONCLUSION: Our study emphasizes the importance of developmental age effects on the study of brain networks in ADHD. Further, we proposed that cortico-cortical and cortico-subcortical connectivity might play an important role in the pathophysiology of children with ADHD, while abnormal cortico-cortical connections were more important for adults with ADHD. This work provided a potential new insight to understand the neurodevelopmental mechanisms and possible clinical application of ADHD.

Emotion dysregulation in adults with ADHD: The role of cognitive reappraisal and expressive suppression.

BACKGROUND: Emotion dysregulation (ED) is a common clinical feature of attention-deficit/hyperactivity disorder (ADHD). The present study examined the role of cognitive reappraisal (CR) and expressive suppression (ES) in adults with ADHD. In addition, resting-state fMRI (rs-fMRI) data were analyzed to identify neural substrates of CR/ES-ED relationships. METHODS: A total of 309 adults with ADHD and 163 healthy controls were recruited. ED was assessed using the 'emotional control' (EC) subscale from Behavior Rating Inventory of Executive Function-Adult Version. The Emotion Regulation Questionnaire was used to measure CR and ES. The functional connectivities (FCs) with the amygdala as Region of Interest, were analyzed in a subsample to explore their association with CR, ES and EC, respectively. RESULTS: Higher EC scores (indicative of lesser emotional control), as well as lower CR and higher ES utilization were detected in adults with ADHD compared with healthy controls. CR and ES were both negatively correlated with EC in adults with ADHD. Mediation analysis detected a potential effect of ADHD diagnosis on EC via CR. In addition, a unique significant mediation effect was found between ES-related FC of the right amygdala-prefrontal cortex and ED expression in adults with ADHD, confirming the '↑ES → ↓FCs [amygR-PFC] →↓EC' relationship. LIMITATIONS: Only self-reported scales and rs-fMRI data were included in these analyses. CONCLUSIONS: Our findings provide preliminary evidence that in adults with ADHD, less frequent use of CR accounts for ED expression, while more frequent use of ES may play a unique compensatory role in emotion regulation.

NGF/TrkA promotes the vitality, migration and adhesion of bone marrow stromal cells in hypoxia by regulating the Nrf2 pathway.

BACKGROUND: Bone marrow stromal cells (BMSCs) transplantation is a treatment strategy for ischemic stroke (IS) with great potential. However, the vitality, migration and adhesion of BMSCs are greatly impaired due to the harsh environment of the ischemic area, which affects the therapeutic effects. Herein, we aimed to investigate the roles of nerve growth factor (NGF) in regulating cell behaviors of BMSCs in IS. METHODS: The mRNA and protein expressions were assessed using qRT-PCR and western blot, respectively. To simulate ischemic-like conditions in vitro, Brain microvascular (bEnd.3) cells were exposed to oxygen and glucose deprivation (OGD). Cell viability and cell proliferation were evaluated by MTT assay and BrdU assay, respectively. Transwell migration and cell adhesion assays were carried out to determine cell migration and adhesion of BMSCs, respectively, coupled with flow cytometry to evaluate cell apoptosis of bEnd.3 cells. Finally, angiogenesis assay was performed to assess the angiogenesis ability of bEnd.3 cells. RESULTS: NGF overexpression resulted in increased cell vitality, adhesion and migration of BMSCs, while NGF knockdown presented the opposite effects. We subsequently discovered that TrkA was a receptor for NGF, and TrkA knockdown significantly inhibited the cell viability, migration and adhesion of BMSCs. Besides, Nrf2 was confirmed as the downstream target of NGF/TrkA to promote the viability, adhesion and migration of BMSC cells. Finally, NGF-silenced BMSCs could not effectively restore the OGD-induced brain microvascular cell damage. CONCLUSIONS: NGF/TrkA promoted the viability, migration and adhesion of BMSCs in IS via activating Nrf2 pathway.

Affective-cognitive-behavioral heterogeneity of Attention-Deficit/Hyperactivity Disorder (ADHD): Emotional dysregulation as a sentinel symptom differentiating "ADHD-simplex" and "ADHD-complex" syndromes?

BACKGROUND: Current DSM and ICD classifications of Attention-Deficit/Hyperactivity Disorder (ADHD) exclude emotional dysregulation (ED) in their diagnostic criteria, despite ED symptoms frequently co-occurring in ADHD and likely sharing common neurobiological substrates. In this study, we examined whether consideration of ED symptoms could delineate more informative "ADHD+ED" subphenotypes. METHOD: 4106 children with ADHD were recruited. ED and inattentive (IA) and hyperactive/impulsive (HI) symptoms were profiled using latent class analyses (LCA). The derived latent class (LC) subphenotypes were evaluated and validated in relation to comorbidity patterns, executive functions, and functional impairments. RESULTS: Five LC subphenotypes with ED symptoms were identified: IA/HI + ED profile (LC1); HI + ED profile (LC2); IA + ED profile (LC3); IA/HI profile (LC4); and IA profile (LC5). Cross-validation of the LCA model using support vector machine analysis confirmed 83% accuracy. ED positive (ED+ve) subphenotypes were associated with higher rates of oppositional defiant disorder, mood disorders, anxiety disorders, as well as more severe autistic traits and sluggish cognitive tempo symptoms. Higher rates of ecological executive functioning impairments (BRIEF ratings) were found among ED+ve subphenotypes (though no differences were detected by laboratory-based measures). Functional impairments were also more severe among participants with ED+ve subphenotypes. LIMITATIONS: The data for our LCA were cross-sectional and based primarily on parent ratings. CONCLUSION: Our classification model has parcellated IA, HI, and ED symptoms into novel informative subphenotypes. These classifications provide preliminary evidence that ED symptoms could serve as sentinel features to identify a potential "ADHD-complex" syndrome, which demarcates a more pervasive condition of greater severity, complexity, and impairment.

Non-enzymatic detection of serum glucose using a fluorescent nanopolymer probe.

A fluorescent probe is described for the determination of serum glucose after hepatotoxin-induced liver injury. The probe is based on the use of a water-soluble polymer and has been prepared from a multi-functional azlactone polymer as the linker, amino boronic acid, and Alizarin Red as the signalling moiety. The excitation/emission peaks of the polymeric fluorescent probe are at 468/567 nm. Fluorescence is reduced on addition of glucose. Intensity drops linearly in the 0.1 mM to 14 mM glucose concentration range. The probe was applied to non-enzymatic detection of glucose in rat serum after CCl4-induced liver damage. Graphical abstract A polymer based fluorescent probe has been constructed and applied for non-enzymatic monitoring of serum glucose following hepatotoxin induced liver injury.

Fluorescence turn-on assay for detection of serum D-penicillamine based on papain@AuNCs-Cu2+ complex.

Papain-stabilized gold nanoclusters (papain@AuNCs) with a red fluorescence emission at 639 nm have been generated successfully in aqueous solution. The fluorescence of papain@AuNCs could be quenched in the addition of Cu2+. Subsequently, a unique fluorescent probe based on papain@AuNCs-Cu2+ complex has been constructed for sensitive, selective and "turn-on" detection of D-penicillamine (D-pen). The sensing probe has exhibited a remarkable fluorescence enhancement in the presence of D-pen, which can be measured ranging from 30.0 µM to 2.0 mM (r2 = 0.991) with the detection limit of 5.0 µM. Furthermore, the developed assay has been utilized to explore the metabolic process of D-pen in rats after intraperitoneal injection. As far as we concerned, the present study has reported the first analytical method for sensing serum D-pen in real time by using the fluorescent papain@AuNCs-Cu2+ complex. Our strategy paves a way for digging up the biological and clinical application of the fluorescent AuNCs.

Preparation of Polymer@AuNPs with Droplets Approach for Sensing Serum Copper Ions.

A microfluidic droplet synthesis approach for the preparation of poly N-isopropylacrylamide protected gold nanoparticles (PNIPAm@AuNPs) was presented here. Well-dispersed PNIPAm@AuNPs could be generated within 8 min. On the basis of the aggregation-induced UV-vis adsorption intensity increasing mechanism, the PNIPAm@AuNPs-based colorimetric probe displayed high sensitivity and good selectivity for sensing copper ions. A linear calibration of relative UV-vis adsorption intensity increasing versus copper ions concentration was obtained within 5.0-750.0 µM, and the limit of detection was 2.5 µM. Furthermore, after copper ions were injected in rat, a metabolic assay was developed with the proposed probe. The results indicated that the droplet microfluidic synthesis system could provide a new way for preparation of polymer@AuNPs with good polydispersity index and showed great potential of polymer@AuNPs-based sensing probe for application in biological and clinical analysis.