Pathophysiology Of Attention-deficit/hyperactivity Disorder Research Articles

Subcortico-Cortical Dysconnectivity in ADHD: A Voxel-Wise Mega-Analysis Across Multiple Cohorts.

A large body of functional MRI research has examined a potential role for subcortico-cortical loops in the pathogenesis of attention deficit hyperactivity disorder (ADHD), but has produced inconsistent findings. The authors performed a mega-analysis of six neuroimaging data sets to examine associations between ADHD diagnosis and traits and subcortico-cortical connectivity. Group differences were examined in the functional connectivity of four subcortical seeds in 1,696 youths with ADHD diagnoses (66.39% males; mean age, 10.83 years [SD=2.17]) and 6,737 unaffected control subjects (47.05% males; mean age, 10.33 years [SD=1.30]). The authors examined associations between functional connectivity and ADHD traits (total N=9,890; 50.3% males; mean age, 10.77 years [SD=1.96]). Sensitivity analyses were used to examine specificity relative to commonly comorbid internalizing and non-ADHD externalizing problems. The authors further examined results within motion-matched subsamples, and after adjusting for estimated intelligence. In the group comparison, youths with ADHD showed greater connectivity between striatal seeds and temporal, fronto-insular, and supplementary motor regions, as well as between the amygdala and dorsal anterior cingulate cortex, compared with control subjects. Similar findings emerged when ADHD traits were considered and when alternative seed definitions were adopted. Dominant associations centered on the connectivity of the caudate bilaterally. Findings were not driven by in-scanner motion and were not shared with commonly comorbid internalizing and externalizing problems. Effect sizes were small (largest peak d, 0.15). The findings from this large-scale mega-analysis support established links with subcortico-cortical circuits, which were robust to potential confounders. However, effect sizes were small, and it seems likely that resting-state subcortico-cortical connectivity can capture only a fraction of the complex pathophysiology of ADHD.

BDNF, proBDNF and proBDNF/BDNF ratio with electroencephalographic abnormalities in children with attention deficit hyperactivity disorder: Possible relations to cognition and severity.

Attention deficit hyperactivity disorder (ADHD) with and without subclinical epileptogenic discharges (SED) have been suggested to negatively affect cognitive abilities of children with ADHD. The role of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in ADHD is in need of being investigated. The aims were to evaluate the levels of serum BDNF, proBDNF and the proBDNF/BDNF ratio in addition to the potential impacts of SED on the children's cognitive abilities and the severity of ADHD. The included participants with ADHD were 30 children with normal electroencephalogram (EEG) (G1) and 30 children with SED (G2), together with 30 healthy children (G3). The cognitive abilities and severity of the disorder were evaluated. The biochemical measures were determined by ELISA. The presence of coexisting SED and nocturnal enuresis has led to a deleterious effect on cognitive processes but not on the severity. The focal epileptogenic discharge was the most common among children in G2. The levels of BDNF in Groups 1 and 2 were less than those in G3. The higher proBDNF/BDNF ratio could be related to the low BDNF levels rather than high proBDNF levels. The findings of this study highlight the importance of investigating the presence of SED and nocturnal enuresis in children with ADHD. Targeting strengthening of cognitive abilities in children with coexisting ADHD and SED is advised. The role of proBDNF in the pathophysiology of ADHD needs further investigation.

Associations between neurological soft signs, executive functions, and brain-derived neurotrophic factor in boys with attention-deficit hyperactivity disorder.

To determine the association between neurological soft signs, executive functions, and serum brain-derived neurotrophic factor (BDNF) levels in children with attention-deficit hyperactivity disorder (ADHD). Serum BDNF levels were measured in 87 drug-naive boys with ADHD, aged 7-12 years. The Revised Physical and Neurological Examination for Subtle Signs for neurological soft signs, Stroop Color-Word Test for attention functions, and Judgment of Line Orientation Test (JLOT) for visuospatial abilities were performed. Age correlated negatively with dysrhythmia, total time, and total overflow in timed movements, Stroop Color-Word Time (SCWT), and serum BDNF levels. The JLOT significantly negatively correlated with Total Gaits and Stations (P1) and Total Time in Timed Movements (adjusted R 2 = 0.247). In addition, SCWT maintained a significant correlation with Total Overflow in Timed Movements (adjusted R 2 = 0.206). There was no correlation between serum BDNF levels and NSS. The association between NSS, visuospatial abilities, and selective attention may express a maturational delay in ADHD pathophysiology. Moreover, BDNF may play a role in this maturational delay. Future studies should investigate the contribution of BDNF to neuronal maturation in ADHD.

Parvalbumin interneuron deficiency in the prefrontal and motor cortices of spontaneously hypertensive rats: an attention-deficit hyperactivity disorder animal model insight.

Attention deficit hyperactivity disorder (ADHD) is characterized by impairments in developmental-behavioral inhibition, resulting in impulsivity and hyperactivity. Recent research has underscored cortical inhibition deficiencies in ADHD via the gamma-aminobutyric acid (GABA)ergic system, which is crucial for maintaining excitatory-inhibitory balance in the brain. This study explored postnatal changes in parvalbumin (PV) immunoreactivity, indicating GABAergic interneuron types, in the prefrontal (PFC) and motor (MC) cortices of spontaneously hypertensive rats (SHRs), an ADHD animal model. Examining PV- positive (PV+) cells associated with dopamine D2 receptors (D2) and the impact of dopamine on GABA synthesis, we also investigated changes in the immunoreactivity of D2 and tyrosine hydroxylase (TH). Brain sections from 4- to 10-week-old SHRs and Wistar Kyoto rats (WKYs) were immunohistochemically analyzed, comparing PV+, D2+ cells, and TH+ fiber densities across age-matched SHRs and WKYs in specific PFC/MC regions. The results revealed significantly reduced PV+ cell density in SHRs: prelimbic (~20% less), anterior cingulate (~15% less), primary (~15% less), and secondary motor (~17% less) cortices. PV+ deficits coincided with the upregulation of D2 in prepubertal SHRs and the downregulation of TH predominantly in pubertal/postpubertal SHRs. Reduced PV+ cells in various PFC regions could contribute to inattention/behavioral alterations in ADHD, while MC deficits could manifest as motor hyperactivity. D2 upregulation and TH deficits may impact GABA synthesis, exacerbating behavioral deficits in ADHD. These findings not only shed new light on ADHD pathophysiology but also pave the way for future research endeavors.

Cannabinoids in the Treatment of Selected Mental Illnesses: Practical Approach and Overview of the Literature.

Although an increasing number of patients suffering from mental illnesses self-medicate with cannabis, current knowledge about the efficacy and safety of cannabis-based medicine in psychiatry is still extremely limited. So far, no cannabis-based finished product has been approved for the treatment of a mental illness. There is increasing evidence that cannabinoids may improve symptoms in autism spectrum disorder (ASD), Tourette syndrome (TS), anxiety disorders, and post-traumatic stress disorder (PTSD). According to surveys, patients often use cannabinoids to improve mood, sleep, and symptoms of attention deficit/hyperactivity disorder (ADHD). There is evidence suggesting that tetrahydrocannabinol (THC) and THC-containing cannabis extracts, such as nabiximols, can be used as substitutes in patients with cannabis use disorder.Preliminary evidence also suggests an involvement of the endocannabinoid system (ECS) in the pathophysiology of TS, ADHD, and PTSD. Since the ECS is the most important neuromodulatory system in the brain, it possibly induces beneficial effects of cannabinoids by alterations in other neurotransmitter systems. Finally, the ECS is an important stress management system. Thus, cannabinoids may improve symptoms in patients with mental illnesses by reducing stress.Practically, cannabis-based treatment in patients with psychiatric disorders does not differ from other indications. The starting dose of THC-containing products should be low (1-2.5 mg THC/day), and the dose should be up-titrated slowly (by 1-2.5 mg every 3-5 days). The average daily dose is 10-20 mg THC. In contrast, cannabidiol (CBD) is mainly used in high doses>400 mg/day.

Human transcriptome array analysis and diffusion tensor imaging in attention-deficit/hyperactivity disorder

The mRNA markers identified using microarray assay and diffusion tensor magnetic resonance imaging (DTI) were applied to elucidate the pathophysiology of attention-deficit hyperactivity disorder (ADHD). First, we obtained total RNA from leukocytes from three children with ADHD and three healthy controls for analysis with microarray assays. Subsequently, we applied real-time quantitative polymerase chain reaction (qRT‒PCR) assays to validate the differential expression of 7 genes (COX7B, CYCS, TFAM, UTP14A, ZNF280C, IFT57 and NDUFB5) between 130 ADHD patients and 70 controls, and we built an ADHD prediction model based on the ΔCt values of aforementioned seven genes (AUROC = 0.98). Finally, in a validation group (28 patients with ADHD and 27 healthy controls), mRNA expression of the above seven genes also significantly differentiated ADHD patients from controls (AUROC value = 0.91). The DTI analysis showed increased fractional anisotropy (FA) of the forceps minor, superior corona radiata, posterior corona radiata and anterior corona radiata in ADHD patients. Moreover, the FA of the right superior corona radiata tract was positively correlated with ΔCt levels of the COX7B gene and the IFT57 gene. The results shed a new light on a genetic profile of ADHD that may help in deciphering the white matter microstructural features in disease pathogenesis.

Is Histamine and Not Acetylcholine the Missing Link between ADHD and Allergies? Speer Allergic Tension Fatigue Syndrome Re-Visited.

Speer allergic tension-fatigue syndrome (SATFS) is a classic allergy syndrome characterized by allergy-like symptoms, muscle tension, headaches, chronic fatigue, and other particular behaviors that were initially described in the fifties. The particular behaviors displayed include symptoms such as hyperkinesis, hyperesthesia (i.e., insomnia), restlessness, and distractibility, among others. Interestingly, these symptoms are very similar to descriptions of attention deficit hyperactivity disorder (ADHD), the most prevalent neurodevelopmental disorder worldwide, which is characterized by inattention, hyperactivity, and impulsivity. The clinical description of SATFS precedes the nomination of ADHD in 1960 by Stella Chess. In this conceptual paper, we stress that there is a gap in the research on the relationship between ADHD and allergic pathologies. The hypotheses of this conceptual paper are (1) SATFS is probably one of the first and best historical descriptions of ADHD alongside a common comorbidity (allergy) displayed by these patients; (2) SATFS (ADHD) is a systemic disease that includes both somatic and behavioral manifestations that may influence each other in a bidirectional manner; (3) The role of neuroinflammation and histamine is key for understanding the pathophysiology of ADHD and its frequent somatic comorbidities; (4) The deficiency of the diamine oxidase (DAO) enzyme, which metabolizes histamine extracellularly, may play a role in the pathophysiology of ADHD. Decreased DAO activity may lead to an accumulation of histamine, which could contribute to core ADHD symptoms and comorbid disorders. Further empirical studies are needed to confirm our hypotheses.

Assessment of the natural killer cell, IFN-ƒ× and IL-10 blood levels in children with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, affects millions of youngsters and typically persists into adulthood. The pathophysiology of ADHD may be due to an impaired immune response, common genetics, and environmental linkages, as all have been suggested as potential underlying mechanisms for ADHD. During systemic inflammation, natural killer (NK) cells can produce pro-inflammatory cytokines like interferon (IFN- g) and anti-inflammatory cytokines like interleukin (IL-10); this demonstrates the importance of both of their roles as regulators to counteract inflammation and prevent immune-mediated host damage. In this work we aimed to determine the role of inflammation in children with ADHD by measuring the level of NK cells in peripheral blood compared to typically developing children besides estimating the inflammatory cytokines INF-g and IL -10 in both groups. This study included 50 children diagnosed with ADHD based on the Diagnostic and Statistical Manual of Mental Disorders-5th edition and 50 age and sex- matched normally developed children, as controls. The estimation of NK was done using flow cytometry, while the studied cytokines were measured using the ELISA technique. We found that children with ADHD had a significantly higher level of NK cells in peripheral blood compared to controls (p<0.001). Furthermore, increased IFN –g, while decreased IL-10 serum levels were observed in children with ADHD compared to their control group. In conclusion our findings suggested that children with ADHD may have impaired immune responses, as NK cells were increased in peripheral blood compared to the control group. Also, the serum level of IFN –g was higher, while the serum level of IL-10 was lower in ADHD children as compared to controls.

Role of Glutamate Receptor-related Biomarkers in the Etiopathogenesis of ADHD.

: Pathways associated with glutamate receptors are known to play a role in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). However, cyclin-dependent kinase 5 (CDK5), microtubule-associated protein-2 (MAP2), guanylate kinase-associated protein (GKAP), and postsynaptic density 95 (PSD95), all of which are biomarkers involved in neurodevelopmental processes closely related to glutamatergic pathways, have not previously been studied in patients with ADHD. The main purpose of this study was to evaluate the plasma levels of CDK5, MAP2, GKAP, and PSD95 in children with ADHD and investigate whether these markers have a role in the etiology of ADHD. : Ninety-six children with ADHD between 6 and 15 years of age and 72 healthy controls were included in the study. Five milliliters of blood samples were taken from all participants. The samples were stored at -80°C until analyzed by the enzyme-linked immunosorbent assay method. : Statistically significantly lower CDK5 levels were observed in children with ADHD than in healthy controls (p = 0.037). The MAP2, GKAP, and PSD95 levels were found to be statistically significantly higher in the ADHD group than in healthy controls (p = 0.012, p = 0.009, and p = 0.024, respectively). According to binary regression analysis, CDK5 and MAP2 levels were found to be predictors of ADHD. : In conclusion, we found that a close relationship existed between ADHD and glutamatergic pathways, and low levels of CDK5 and high levels of MAP2 and GKAP played a role in the etiopathogenesis of ADHD.

Reduced levels of plasma strong antioxidant uric acid in children with Autism Spectrum Disorder and Attention deficit-hyperactivity disorder

Objective: Uric acid (UA) is one of the most powerful antioxidants in human body fluids, as well as being the end product of purine metabolism. UA alone constitutes half of the scavenging effect of oxidant substances in the plasma.It has proinflammatory and metal chelation effects. In this study, UA levels and UA situation according to the normal range were investigated in patients with Autism Spectrum Disorder (ASD), and Attention deficit-hyperactivity disorder (ADHD). Methods: Eighty-two ASD, 28 ADHD patients and 66 healthy control subjects were compared and serum UA levels were measured. ASD and ADHD severity were determined by CARS and Atilla Turgay ADHD scale. K-SADS-PL was administered to all subjects over the age of 6 years. Results: UA levels were found to be significantly lower in the ASD and ADHD groups. UA levels were found to be lower than the normal range in nearly half of the ASD and ADHD groups. This rate was found to be 18.2% in the control group. Conclusion: it was determined that UA levels were low in ASD and ADHD patients. It can be suggested that it may play a role in the pathophysiology of ASD and ADHD. UA may be a potential treatment target.

The association between Attention-Deficit-Hyperactivity-Disorder (ADHD) symptoms and disease severity in people with Cystic Fibrosis (pwCF)

BackgroundThe hallmarks of Cystic fibrosis (CF), chronic infection and inflammation, require intensive daily treatment to maintain and improve quality of life and outcome. The incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is increased in chronic inflammatory diseases. Previous studies suggested that the prevalence of ADHD in people with CF (pwCF) is higher than in the general population. The objective of this study was to evaluate the association between ADHD symptoms and parameters of CF disease severity, measured by demographic and clinical data. MethodsBased on our previous study, the results of ADHD questionnaires and the MOXOCPT (continuous performance task) from 143 pwCF (7–68 years old) were analyzed and linked to patient data such as forced expiratory volume in 1 second (FEV1)%predicted, body mass index (BMI), number of pulmonary exacerbations, days of antibiotic (Abx) treatment and serum inflammatory markers. ResultsA positive correlation between FEV1 and ADHD questionnaire's score (p = 0.046) was observed in the children's group. Furthermore, BMI, white blood cells (WBC) count, and days of Abx treatment showed a positive correlation with some of the MOXOCPT parameters. ConclusionThere is an association between ADHD symptoms and some parameters of CF disease severity. These results highlight the need for an early diagnosis of ADHD in pwCF, which have the potential to improve their ability to deal with the burden of their disease and consequently their quality of life. Additional research is needed to understand the full spectrum of ADHD pathophysiology and the relationship with chronic inflammatory diseases such as CF.

Gender Differences in Dynamic Functional Network Connectivity in Pediatric and Adult Patients with Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) persistence into adulthood depends on gender, with 60% female and 35% male cases. This study sought to investigate gender differences in dynamic functional network connectivity (FNC) using resting-state functional magnetic resonance imaging data of pediatric ADHD patients (female: N = 24; 11.02 ± 2.60 years, male: N = 20;11.87 ± 2.62 years) and adult ADHD patients (female = 19; 31.11 ± 10.40 years, males: N = 20;32.05 ± 10.10 years). We identified nine and eight networks in pediatrics and adult data, respectively, using group independent component analysis (GICA). Each age group was clustered into four states using K-means. Significant gender differences in the pediatric group were only found in temporal profiles, particularly in "fraction of time" (FOT) and "mean dwell time" (MDT), but not in FNC. FOT spent by the female pediatric group in state 4 showed a negative relationship with hyperactivity severity. Compared with the adult male group, reduced connectivity was observed within the visual network (VN), between the VN and default-mode network (DMN), and frontoparietal network, as well as between the DMN and cerebellum networks in female adult ADHD patients. Significant FOT and MDT differences were observed between the two groups in state 3. Our results imply gender differences in ADHD, especially in the adult group. Furthermore, given the gender differences observed, our work provides insights into the pathophysiology of ADHD subserved by gender. Impact statement Attention-deficit/hyperactivity disorder (ADHD) symptoms differ between genders; however, little has been done to determine gender differences in pediatric and adult ADHD patients. The present work presents the first gender-specific dynamic functional network connectivity study for different age groups of ADHD patients and highlights the discrepancies between male and female ADHD patients, particularly in the adult group, which may be due to the persistence of inattentive symptoms in female ADHD patients from childhood into adulthood. Given the gender differences observed in the current study, clinicians could consider treatment strategies that target each gender in each age group. The present work provides further insight into the connectivity patterns of the resting-state network in ADHD and may also serve as a basis for future sex-specific studies in different age groups in other disorders.

Gut Leakage Markers and Cognitive Functions in Patients with Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a commonly seen mental disorder in children. Intestinal permeability may be associated with the pathogenesis of ADHD. The study herein investigated the role of gut leakage biomarkers in the susceptibility of ADHD. A total of 130 children with ADHD and 73 healthy controls (HC) individuals were recruited. Serum concentrations of zonulin, occludin, and defensin (DEFA1) were determined. Visual attention was assessed with Conners' continuous performance test (CPT). In order to rate participants' ADHD core symptoms at home and school, their parents and teachers completed the Swanson, Nolan, and Pelham-Version IV Scale (SNAP-IV), respectively. We found significantly lower DEFA1 levels in the ADHD group compared to that in the HC group (p = 0.008), but not serum levels of zonulin and occludin. The serum levels of DEFA1 showed an inverse correlation with the inattention scores in the SNAP-IV parent form (p = 0.042) and teacher form (p = 0.010), and the hyperactivity/impulsivity scores in the SNAP-IV teacher form (p = 0.014). The serum levels of occludin showed a positive correlation with the subtest of detectability in the CPT (p = 0.020). Our study provides new reference into the relation between gut leakage markers and cognition, which may advance research of the pathophysiology of ADHD.

Network-Based Differences in Top-Down Multisensory Integration between Adult ADHD and Healthy Controls-A Diffusion MRI Study.

Attention-deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder neurobiologically conceptualized as a network disorder in white and gray matter. A relatively new branch in ADHD research is sensory processing. Here, altered sensory processing i.e., sensory hypersensitivity, is reported, especially in the auditory domain. However, our perception is driven by a complex interplay across different sensory modalities. Our brain is specialized in binding those different sensory modalities to a unified percept-a process called multisensory integration (MI) that is mediated through fronto-temporal and fronto-parietal networks. MI has been recently described to be impaired for complex stimuli in adult patients with ADHD. The current study relates MI in adult ADHD with diffusion-weighted imaging. Connectome-based and graph-theoretic analysis was applied to investigate a possible relationship between the ability to integrate multimodal input and network-based ADHD pathophysiology. Multishell, high-angular resolution diffusion-weighted imaging was performed on twenty-five patients with ADHD (six females, age: 30.08 (SD: 9.3) years) and twenty-four healthy controls (nine females; age: 26.88 (SD: 6.3) years). Structural connectome was created and graph theory was applied to investigate ADHD pathophysiology. Additionally, MI scores, i.e., the percentage of successful multisensory integration derived from the McGurk paradigm, were groupwise correlated with the structural connectome. Structural connectivity was elevated in patients with ADHD in network hubs mirroring altered default-mode network activity typically reported for patients with ADHD. Compared to controls, MI was associated with higher connectivity in ADHD between Heschl's gyrus and auditory parabelt regions along with altered fronto-temporal network integrity. Alterations in structural network integrity in adult ADHD can be extended to multisensory behavior. MI and the respective network integration in ADHD might represent the maturational cortical delay that extends to adulthood with respect to sensory processing.

Structural differences among children, adolescents, and adults with attention-deficit/hyperactivity disorder and abnormal Granger causality of the right pallidum and whole-brain.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood mental health disorder that often persists to adulthood and is characterized by inattentive, hyperactive, or impulsive behaviors. This study investigated structural and effective connectivity differences through voxel-based morphometry (VBM) and Granger causality analysis (GCA) across child, adolescent, and adult ADHD patients. Structural and functional MRI data consisting of 35 children (8.64 ± 0.81 years), 40 adolescents (14.11 ± 1.83 years), and 39 adults (31.59 ± 10.13 years) was obtained from New York University Child Study Center for the ADHD-200 and UCLA dataset. Structural differences in the bilateral pallidum, bilateral thalamus, bilateral insula, superior temporal cortex, and the right cerebellum were observed among the three ADHD groups. The right pallidum was positively correlated with disease severity. The right pallidum as a seed precedes and granger causes the right middle occipital cortex, bilateral fusiform, left postcentral gyrus, left paracentral lobule, left amygdala, and right cerebellum. Also, the anterior cingulate cortex, prefrontal cortex, left cerebellum, left putamen, left caudate, bilateral superior temporal pole, middle cingulate cortex, right precentral gyrus, and the left supplementary motor area demonstrated causal effects on the seed region. In general, this study showed the structural differences and the effective connectivity of the right pallidum amongst the three ADHD age groups. Our work also highlights the evidence of the frontal-striatal-cerebellar circuits in ADHD and provides new insights into the effective connectivity of the right pallidum and the pathophysiology of ADHD. Our results further demonstrated that GCA could effectively explore the interregional causal relationship between abnormal regions in ADHD.

A Potential Role for Neuroinflammation in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder in children and adolescents. Although increases in oxidative stress and disturbances of neurotransmitter system such as the dopaminergic and abnormalities in several brain regions have been demonstrated, the pathophysiology of ADHD is not fully understood. Nevertheless, ADHD involves several factors that have been associated with an increase in neuroinflammation. This chapter presents an overview of factors that may increase neuroinflammation and play a potential role in the development and pathophysiology of ADHD. The altered immune response, polymorphisms in inflammatory-related genes, ADHD comorbidity with autoimmune and inflammatory disorders and prenatal exposure to inflammation are associated with alterations in offspring brain development and are a risk factor; genetic and environmental risk factors that may increase the risk for ADHD and medications can increase neuroinflammation. Evidence of an association between these factors has been an invaluable tool for research on inflammation in ADHD. Therefore, evidence studies have made it possible to generate alternative therapeutic interventions using natural products as anti-inflammatories that could have great potential against neuroinflammation in ADHD.

Potential Inflammatory Biomarker in Patients with Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder that can diminish the quality of life of both children and adults in academic, occupational, and social contexts. The kynurenine pathway (KP) contains a set of enzymatic reactions involved in tryptophan (TRP) degradation. It is known to be associated with the risk of developing ADHD. This review will address the KP and underlying mechanism of inflammation in ADHD. Potential inflammatory biomarkers reported in the most recent studies are summarized. Although a strong neuroimmunological basis has been established due to the advances of recent neurobiological research, the pathophysiology of ADHD remains unclear.

Evaluation of fronto-cerebellar neurometabolites in youth with ADHD compared to the healthy group and their associations with cognitive and behavioral characteristics: A proton magnetic spectroscopy study

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders, characterized by specific cognitive and behavioral symptoms. A fronto-cerebellar circuit is implicated in ADHD, and despite its role in cognitive/behavioral aspects, the neurochemical alterations in this circuit are not well understood. The present study aimed to compare neurometabolite ratios of the fronto-cerebellar circuit between ADHD and control participants, using proton magnetic resonance spectroscopy (1H MRS), and investigate whether neurometabolites related to cognitive/behavioral characteristics. Fifteen children and adolescents with ADHD and 19 healthy control participants were enrolled in this study. Two single voxel spectra localized in the right dorsolateral prefrontal cortex (DLPFC) and left Crus 1 were taken using PRESS sequence. Also, neuropsychological performance and behavioral characteristics were evaluated. Results revealed that ADHD group had different choline/creatine and glutamate/creatine ratios in the fronto-cerebellar circuit, compared to healthy controls. The current study also found significant correlations between neurometabolite ratios in the both region of interests (ROIs) and cognitive/behavioral characteristics. These results suggest that alterations in fronto-cerebellar metabolites may be related to cognitive and behavioral deficits in ADHD, and also, our findings highlight that the cerebellum may be involved in the pathophysiology of ADHD.

Association between Gut Microbiota and Emotional-Behavioral Symptoms in Children with Attention-Deficit/Hyperactivity Disorder

Previous studies have explored the role of the microbiome in attention-deficit/hyperactivity disorder (ADHD). However, whether the microbiome is correlated with emotional–behavioral disturbances, the most common comorbid symptom of ADHD, remains unclear. We established a cross-sectional study in which 6- to 18-year-old children with ADHD who were receiving no medication and a healthy control group of children without ADHD were recruited to analyze their microbiome composition. Microbiota of fecal samples were collected and analyzed using a 16s rRNA gene sequencing approach. In comparison with the healthy control group, the gut microbiota in children with ADHD exhibited significantly lower beta diversity. The abundance of the phylum Proteobacteria and the genera Agathobacter, Phascolarctobacterium, Prevotella_2, Acidaminococcus, Roseburia, and Ruminococcus gnavus group was increased in the ADHD group compared with the healthy group. Linear discriminant effect size (LEfSe) analysis was used to highlight specific bacteria phylotypes that were differentially altered between the ADHD and control groups. A regression analysis was performed to investigate the association between microbiota and emotional–behavioral symptoms in children with ADHD. A significant association was noted between withdrawal and depression symptoms and Agathobacter (p = 0.044), and between rule-breaking behavior and the Ruminococcus gnavus group (p = 0.046) after adjusting for sex, age, and the ADHD core symptoms score. This study advances the knowledge of how gut microbiota composition may contribute to emotional–behavioral symptoms in children with ADHD. The detailed mechanisms underlying the role of the gut microbiota in ADHD pathophysiology still require further investigation.

Low serum allopregnanolone levels in children with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) has increasing evidence for the role of neurohormones in its etiopathogenesis. It has been suggested that the effects of neurosteroids on the brain in the early developmental period may predispose to neurodevelopmental pathologies. In our study, we examined serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and allopregnanolone levels in children with ADHD and whether these neurosteroids differ in the presence of specific learning disorder (SLD) and oppositional defiant disorder (ODD) comorbidities (ADHD+SLD and ADHD+ODD). We also investigated the relationship between neurosteroid levels and the severity of ADHD symptoms. Thirty-five prepubertal children with ADHD and 33 prepubertal healthy children, all aged 6–10 years, were included in this study. The severity of ADHD symptoms was assessed with the parent-rated and teacher-rated Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S). Serum allopregnanolone levels were significantly lower in the ADHD group compared to healthy controls. When analyzed according to comorbidity status, serum allopregnanolone levels were lower in ADHD+SLD and ADHD+ODD groups compared to healthy controls. However, when compared to healthy children, serum DHEA and DHEA-S levels in children with ADHD were not significantly different. Serum allopregnanolone levels were negatively associated with teacher-rated T-DSM-IV-S hyperactivity/impulsivity scores for all participants only. These findings suggest that allopregnanolone may play a role in the pathophysiology of ADHD, especially in the presence of ODD and SLD comorbidities.