Pathophysiology Of Attention-deficit/hyperactivity Disorder Research Articles

Evidence of Altered Habenular Intrinsic Functional Connectivity in Pediatric ADHD

Objective: The habenula is a small region in the epithalamus that contributes to the regulation of midbrain dopaminergic circuits implicated in attention-deficit hyperactivity disorder (ADHD). This investigation aims to evaluate the intrinsic functional connectivity (iFC) of the habenula in children with ADHD. Method: A total of 112 children (5-9 years; 75 ADHD, 37 healthy comparisons) completed anatomical and resting-state functional magnetic resonance imaging (MRI) scans. Habenula regions of interest (ROIs) were identified individually on normalized T1-weighted anatomical images. Seed-based iFC analyses and group comparisons were conducted for habenula ROIs, as well as thalamic ROIs to test the specificity of habenula findings. Results: Children with ADHD exhibited reduced habenula–putamen iFC compared with healthy comparisons. Group differences in thalamic iFC showed no overlap with habenular findings. Conclusion: These preliminary findings suggest that habenula–putamen iFC may be disrupted in children with ADHD. Further work is needed to confirm and elucidate the role of this circuit in ADHD pathophysiology.

Morphological features of the ventral tegmental area: a brainstem structure related to attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder of the childhood and more interest is raised by clinical investigators nowadays. In spite of being the most studied neurobehavioral condition in child psychiatry, the pathophysiology of ADHD remains elusive. The ventral tegmental area (VTA) has been implicated in the etiology of ADHD. This part of the midbrain needs to be investigated further due to its complex cytoarchitecture and connectivity in order to gain insight into the neurobiology of ADHD. In this review, we will first briefly explain the history of the VTA researches and then summarize the anatomical features and connectivity of this region.

The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD?

Attention-deficit/hyperactivity disorder (ADHD) is highly associated with the delayed sleep phase disorder, a circadian rhythm sleep-wake disorder, which is prevalent in 73-78% of children and adults with ADHD. Besides the delayed sleep phase disorder, various other sleep disorders accompany ADHD, both in children and in adults. ADHD is either the cause or the consequence of sleep disturbances, or they may have a shared etiological and genetic background. In this review, we present an overview of the current knowledge on the relationship between the circadian rhythm, sleep disorders, and ADHD. We also discuss the various pathways explaining the connection between ADHD symptoms and delayed sleep, ranging from genetics, behavioral aspects, daylight exposure, to the functioning of the eye. The treatment options discussed are focused on improvement of sleep quality, quantity, and phase-resetting, by means of improving sleep hygiene, chronotherapy, treatment of specific sleep disorders, and by strengthening certain neuronal networks involved in sleep, e.g., by sensorimotor rhythm neurofeedback. Ultimately, the main question is addressed: whether ADHD needs to be redefined. We propose a novel view on ADHD, where a part of the ADHD symptoms are the result of chronic sleep disorders, with most evidence for the delayed circadian rhythm as the underlying mechanism. This substantial subgroup should receive treatment of the sleep disorder in addition to ADHD symptom treatment.

Hyperactivity/restlessness is associated with increased functional connectivity in adults with ADHD: a dimensional analysis of resting state fMRI

BackgroundAdult attention-deficit/hyperactivity disorder (ADHD) is a serious and frequent psychiatric disorder of multifactorial pathogenesis. Several lines of evidence support the idea that ADHD is, in its core, a disorder of dysfunctional brain connectivity within and between several neurofunctional networks. The primary aim of this study was to investigate associations between the functional connectivity within resting state brain networks and the individual severity of core ADHD symptoms (inattention, hyperactivity, and impulsivity).MethodsResting state functional magnetic resonance imaging (rs-fMRI) data of 38 methylphenidate-naïve adults with childhood-onset ADHD (20 women, mean age 40.5 years) were analyzed using independent component analysis (FSL’s MELODIC) and FSL’s dual regression technique. For motion correction, standard volume-realignment followed by independent component analysis-based automatic removal of motion artifacts (FSL’s ICA-AROMA) were employed. To identify well-established brain networks, the independent components found in the ADHD group were correlated with brain networks previously found in healthy participants (Smith et al. PNAS 2009;106:13040–5). To investigate associations between functional connectivity and individual symptom severity, sex, and age, linear regressions were performed.ResultsDecomposition of resting state brain activity of adults with ADHD resulted in similar resting state networks as previously described for healthy adults. No significant differences in functional connectivity were seen between women and men. Advanced age was associated with decreased functional connectivity in parts of the bilateral cingulate and paracingulate cortex within the executive control network. More severe hyperactivity was associated with increased functional connectivity in the left putamen, right caudate nucleus, right central operculum and a portion of the right postcentral gyrus within the auditory/sensorimotor network.ConclusionsThe present study supports and extends our knowledge on the involvement of the striatum in the pathophysiology of ADHD, in particular, in the pathogenesis of hyperactivity. Our results emphasize the usefulness of dimensional analyses in the study of ADHD, a highly heterogeneous disorder.Trial registrationISRCTN12722296 (https://doi.org/10.1186/ISRCTN12722296).

Do food bioactives play a role in attention-deficit/ hyperactivity disorder?

Attention-deficit/hyperactivity disorder (ADHD) is a common diagnosis in children, which may persist into adulthood. Short-term benefits of pharmacological treatment have been shown, but concerns regarding long-term efficacy and safety have led to a search for alternative treatments. Nutrition may be an important factor in psychiatric disorders. At group level, food bioactives do not appear to play a significant pathogenetic or therapeutic role in ADHD. Benefits of treatment with omega-3 fatty acids, vitamins and minerals may be confined to individuals deficient in these micronutrients. Dietary patterns may be of greater importance than individual nutrients. However, both diet and consumption of certain nutrients may be precursors or consequences of ADHD. The controversy surrounding the clinical and pathogenetic heterogeneity of ADHD complicates the assessment of food bioactives. The identification of a potential role of food bioactives in ADHD is hindered by the ill-defined nature of the disorder and the lack of biological markers underpinning its validity. The therapeutic efficacy of food bioactives cannot be tested by evaluating their effect on the pathophysiology of ADHD but only by observing their effects on symptom severity.

Expression of BDNF and GDNF in brain of attention deficit hyperactivity disorder rats

Objective To observe the changes of protein and mRNA expression levels of brain derived neurotrophic factor(BDNF) and glial cell line derived neurotrophic factor(GDNF) in the prefrontal cortex, hippocampus and striatum of the attention deficit hyperactivity disorder(ADHD) model animal, and to explore the relationship between BDNF, GDNF and ADHD. Methods Junior spontsneously hyoertensive rat(SHR) rats were used as ADHD model group and Wistar Kyoto rats(WKY) as control group.The protein and mRNA expression levels of BDNF and GDNF in prefrontal cortex, hippocampus and striatum were detected by Western blot and RT-PCR methods. Results The expression of BDNF and GDNF protein was (0.561±0.095) and (0.507±0.155) in the prefrontal cortex, (0.606±0.054) and (0.457±0.198) in hippocampus and (0.558±0.191) and (0.554±0.267) in striatum of SHR rats.The expression of BDNF and GDNF protein of WKY rats were (0.855±0.211) and (0.891±0.244) in the prefrontal cortex, (0.827±0.163) and (0.898±0.207) in hippocampus and (0.998±0.220) and (0.955±0.146) in striatum.The expression of BDNF and GDNF mRNA was (0.636±0.141) and (0.544±0.161) in the prefrontal cortex, (0.996±0.196) and (0.563±0.302) in hippocampus and (0.664±0.145) and (0.689±0.049) in striatum of SHR rats.The expression of BDNF and GDNF mRNA of WKY rats were (0.861±0.232) and (0.840±0.124) in prefrontal cortex, (1.372±0.423) and (1.180±0.441) in hippocampus, and (1.107±0.185) and (0.950±0.247) in striatum.The protein and mRNA expression levels of BDNF and GDNF in prefrontal cortex, hippocampus and striatum of ADHD rats were significantly lower than those in the control group (all P<0.05). Conclusion The low expression of BDNF and GDNF in the prefrontal cortex, hippocampus and striatum of SHR rats may be related to the pathophysiology of ADHD. Key words: Attention deficit hyperactivity disorder; Spontsneously hyoertensive rat; Brain derived neurotrophic factor; Glial cell line derived neurotrophic factor

Altered hypothalamus-pituitary-adrenal axis function: A relevant factor in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder?

Epidemiological data show a significant association between childhood atopic eczema (AE) and an increased risk to develop attention deficit/hyperactivity disorder (ADHD). However, the underlying mechanisms of the comorbidity of AE and ADHD are mostly unknown. We investigated whether alterations of hypothalamus-pituitary-adrenal (HPA) axis function represent a shared feature of AE and ADHD potentiating AE-ADHD comorbidity. Children aged 6–12 years with AE, ADHD, or comorbid AE + ADHD and healthy control (HC) children were examined cross-sectionally (N = 145). To evaluate HPA axis function, salivary cortisol in response to psychosocial stress (Trier Social Stress Test for Children, TSST-C), after awakening (cortisol awakening response, CAR), and throughout the day (short diurnal profile) and hair cortisol capturing long-term HPA axis activity were assessed. Quantile regression analyses showed an attenuated cortisol response (% maximum change) to the TSST-C in children with ADHD compared to HC. A diminished cortisol response to acute stress was also observed in the comorbid AE + ADHD group, in which the reduction was numerically even more pronounced. Contrary to our previous findings, no alteration of the cortisol response to the TSST-C was observed in children with AE. However, in children with AE, increased ADHD-like behavior (i.e., inattention, impulsivity, and overall ADHD symptom severity) was associated with a reduced HPA axis response to acute stress. No such associations were observed in children without AE. Groups did not differ in CAR, short diurnal profile, and hair cortisol. These findings underscore the potential relevance of HPA axis function in the pathophysiology of AE and ADHD with emphasis on stress reactivity. Additional studies are required to further explore the separate and joint role of the HPA axis in the pathophysiology of AE and ADHD.

Differential effects of chemogenetic inhibition of dopamine and norepinephrine neurons in the mouse 5-choice serial reaction time task

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, aberrant impulsivity, and hyperactivity. Although the underlying pathophysiology of ADHD remains unclear, dopamine and norepinephrine signaling originating from the ventral tegmental area (VTA) and locus coeruleus (LC) is thought to be critically involved. In this study, we employ Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) together with the mouse 5-Choice Serial Reaction Time Task (5-CSRTT) to investigate the necessary roles of these catecholamines in ADHD-related behaviors, including attention, impulsivity, and motivation. By selective inhibition of tyrosine hydroxylase (TH)-positive VTA dopamine neurons expressing the Gi-coupled DREADD (hM4Di), we observed a marked impairment of effort-based motivation and subsequently speed and overall vigor of responding. At the highest clozapine N-oxide (CNO) dose tested (i.e. 2 mg/kg) to activate hM4Di, we detected a reduction in locomotor activity. DREADD-mediated inhibition of LC norepinephrine neurons reduced attentional performance in a variable stimulus duration test designed to increase task difficulty, specifically by increasing trials omissions, reducing mean score, and visual processing speed. These findings show that VTA dopamine and LC norepinephrine neurons differentially affect attention, impulsive and motivational control. In addition, this study highlights how molecular genetic probing of selective catecholamine circuits can provide valuable insights into the mechanisms underlying ADHD-relevant behaviors.

Sociodemographic, Electrophysiological, and Biochemical Profiles in Children with Attention Deficit Hyperactivity Disorder and/or Epilepsy.

Attention deficit hyperactivity disorder (ADHD) is among the most prevalent neurobehavioral disorders affecting children worldwide. The prevalence of ADHD is higher in children with epilepsy. Despite the plethora of conducted work, the precise cause of ADHD is not identified yet. We studied here the sociodemographic, clinical, electrophysiological, and biochemical profiles of children with ADHD, epilepsy, and ADHD with epilepsy. Subjects were divided into 4 groups (25 child/group): I—control, II—ADHD, III—epilepsy, and IV—ADHD with epilepsy. Male to female ratio was significantly (p < 0.05) higher in the ADHD (3.1) and ADHD with epilepsy (2.1) groups when compared to the control (1.08) or epilepsy (1.08) groups. Positive family history was significantly evident in patients with epilepsy and ADHD with epilepsy, but not in the control or ADHD groups. Speech development was significantly delayed in the ADHD and ADHD with epilepsy groups. EEG abnormalities were detected in patients with ADHD (12%) and ADHD with epilepsy (68%). Focal frontal activities were significantly detectable in the ADHD (100%) and ADHD with epilepsy (77.8%) groups, whereas focal temporal activity was significantly present in the epilepsy (83.3%) group. Serum ferritin was significantly lower in the ADHD group (110.27 ± 6.64 ηg/ml) when compared to the control (134.23 ± 14.82 ηg/ml), epilepsy (159.66 ± 33.17 ηg/ml), and ADHD with epilepsy (203.04 ± 50.64 ηg/ml) groups. Serum zinc was significantly higher in the ADHD, epilepsy, and ADHD with epilepsy groups (236.63 ± 20.89, 286.74 ± 43.84, and 229.95 ± 67.34 μg/dl, respectively), when compared to the control group (144.21 ± 17.40 μg/dl). Serum adenosine deaminase was insignificantly different among the groups. Our results indicate that gender and family history are significant moderators in the aetiology of ADHD and epilepsy or their comorbidity. We also demonstrated that EEG could be central in the assessment of ADHD with epilepsy cases. Serum ferritin and zinc alteration may contribute significantly in ADHD and epilepsy pathophysiology.

Abstract 17023: Early Incidence of First Myocardial Infarction in Adult Attention Deficit Hyperactivity Disorder Patients in the United States

Background: Behavioral patterns and pharmaceutical interventions in patients with attention deficit hyperactivity disorder(ADHD) might increase the risk of cardiovascular disease. Studies evaluating the differences in risk profiles and outcomes during first myocardial infarction in ADHD patients compared to the general population in the US are lacking. Methods: We performed a retrospective cohort analysis of the US National Inpatient Sample years 2005 - 2015 using appropriate ICD-9 codes to identify a weighted sample of hospitalizations for a first acute myocardial infarction (AMI) in adults. In this AMI cohort, patients with ADHD were identified. Differences in demographics, comorbidities, and outcomes were compared between patients with and without ADHD. Results: Of 4,285,185 first AMI cases, ADHD was present in 5379 (~1 in 1000). At the time of first AMI, patients with ADHD were 15 years younger (mean age 52 vs 67 years, p&lt;.001) and were more likely to be men (72% vs 58%, p&lt;.001) than those without. More patients with ADHD had private insurance and were in higher income categories; TABLE. Patients with ADHD had higher prevalence of substance abuse, smoking, obesity, dyslipidemia and depression whereas patients without ADHD had a higher prevalence of hypertension and diabetes mellitus. While the type of AMI was similar in both the groups, mechanical revascularization was more frequently performed in ADHD patients (69.4% vs 59.1%, p&lt;.001). All-cause inhospital mortality during the first AMI was significantly lower in ADHD patients (1.3% vs 6.1%, p&lt;.001). Conclusion: In the US, patients with ADHD had first AMI at a much younger age and had substantial differences in risk factor profile and outcomes compared to the general population. The influence of behavior patterns, underlying ADHD pathophysiology, and medical interventions in ADHD patients leading to the earlier AMI onset should be further explored.

Downregulation of Dopamine D1-like Receptor Pathways of GABAergic Interneurons in the Anterior Cingulate Cortex of Spontaneously Hypertensive Rats

Deficits in dopaminergic function are thought to underlie attention-deficit/hyperactivity disorder (ADHD). Dopaminergic neurons are the main source of dopamine (DA), a neurotransmitter that acts as a neuromodulator of cognitive function in the prefrontal cortex, including the anterior cingulate cortex (ACC), which receives dopaminergic inputs from the ventral tegmental area. The spontaneously hypertensive rat (SHR) has been widely studied as an animal model of ADHD. The aim of the current study was to investigate the pathophysiological mechanisms of ADHD by examining DA modulation of γ-aminobutyric acid neural (GABAergic) transmission recorded from layer V pyramidal cells of the ACC in SHR compared to control Wistar–Kyoto rats (WKY). Our results showed that DA activity increased the frequency of both miniature and spontaneous inhibitory postsynaptic currents (IPSCs) in control WKY, but not in SHRs. Furthermore, DA activity enhanced the amplitude of evoked and unitary IPSCs from fast-spiking interneurons; the amplitude was also larger in control WKY than in SHRs. Notably, the amplitude of evoked IPSCs was enhanced by the activation of D1-like receptor-mediated pathways. These results suggest that hypofunction of D1-like receptor-mediated regulation of GABAergic inhibitory synaptic transmission onto layer V pyramidal cells of the ACC may contribute to the pathophysiology of ADHD.

Association between Level of Vitamin D with Environmental and Bioelement Factors in Children with Attention Deficit Hyperactivity Disorder (ADHD)

Background: Attention deficit hyperactivity disorder (ADHD) is a behavioral disorder. The exact pathophysiology of ADHD is not completely recognized. Previous studies have shown the role of different genetic and environmental factors in it. This study investigates the relationship between vitamin D and environmental factors in ADHD. Methods: In this study, 182 children from 2 to 18 years with confirmed ADHD were allocated in this cross-sectional study. Patients with a history of any chronic disease, anticonvulsants and corticosteroids consumption were excluded from the study. The ADHD severity was assessed by Conners’ parent scale test. The level of serum vitamin D, ferritin, iron, total iron binding capacity, zinc, magnesium, calcium and routine complete blood count (CBC) were measured. Results: Although the results showed a U shaped pattern between vitamin D levels and ADHD severity, the correlation between vitamin D level did not show any significant relation with ADHD symptoms severity (p=0.786). Our data showed significant relation between level of vitamin D and ferritin in patients with ADHD (p=0.003). The analysis demonstrates significant relation between vitamin D level and duration of daily TV watching in children with ADHD (p=0.002). Conclusion: The vitamin D supplementation may improve ADHD symptoms in patients with vitamin D deficiency. In addition, due to the proved effect of ferritin level in ADHD and significant relation with vitamin D level in this study, treatment of vitamin D deficiency is necessary in children with ADHD. Replacing TV watching by more outdoor activity may improve ADHD symptoms.

The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are often classified as (1) predominantly hyperactive-impulsive, (2) predominantly inattentive, and (3) combined type. There is a growing interest in developing specific animal models that would recapitulate specific clinical forms of ADHD, with the goal of developing specific therapeutic strategies. In our previous study, we have identified Ataxin-7 (Atxn7) as a hyperactivity-associated gene. Here, we generated Atxn7 overexpressing (Atxn7 OE) mice to investigate whether the increased Atxn7 expression in the brain correlates with ADHD-like behaviors. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed overexpression of the Atxn7 gene and protein in the prefrontal cortex (PFC) and striatum (STR) of the Atxn7 OE mice. The Atxn7 OE mice displayed hyperactivity and impulsivity, but not inattention. Interestingly, treatment with the ADHD drug, atomoxetine (3 mg/kg, intraperitoneal), attenuated ADHD-like behaviors and reduced Atxn7 gene expression in the PFC and STR of these mice. These findings suggest that Atxn7 plays a role in the pathophysiology of ADHD, and that the Atxn7 OE mice can be used as an animal model of the hyperactive-impulsive phenotype of this disorder. Although confirmatory studies are warranted, the present study provides valuable information regarding the potential genetic underpinnings of ADHD.

Relationship between serum vitamin D and iron level in children with attention-deficit hyperactivity disorder

Objectives The aim of this study was to determine the association between iron, ferritin, and vitamin D deficiency with attention-deficit hyperactivity disorder (ADHD) and the effect of their deficiency on the development of ADHD in children. Background ADHD is one of the most prevalent mental health disorders. It has been reported that iron, ferritin, and vitamin D deficiency may be related to the pathophysiology of ADHD. Patients and methods Our study includes 60 children with ADHD aged 3–18 years and 20 controls aged 3–18 years. Sociodemographic and clinical data were collected. The health status of the patients was assessed by symptoms and clinical presentations, family history, Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V), and laboratory investigations, including serum level of iron, ferritin, and 25-hydroxyvitamin D. Result Mean age (SD in years) for ADHD and control children was (7.13 ± 1.89 vs. 7.95 ± 1.84). There were statistically significant differences between ADHD versus control children for serum iron (44.05 ± 25.28 vs. 91.15 ± 33.83 μg/dl), ferritin (15.76 ± 18.06 vs. 98.2 ± 52.37 ng/ml), and vitamin D (13.1 ± 5.66 vs. 32.9 ± 9.12 ng/ml). There were many factors that were sought to be associated with increased risk of developing ADHD. Conclusion The study indicates that low serum iron, ferritin, and vitamin D deficiency may be related to ADHD pathophysiology.

Dietary and nutrient status of children with attention-deficit/ hyperactivity disorder: a case-control study.

Nutritional and dietary habits may affect children's behaviors and learning. The etiology of attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder in children, may be associated with unhealthy diets or nutrients deficiencies. The purpose of this study was to examine whether children with ADHD exhibited different dietary habits or nutrient profiles from healthy control subjects. We recruited 42 patients with ADHD (mean age: 8.1 years) and 36 healthy children as the control group (mean age: 9.8 years). We adopted the ADHD Rating Scale and the Swanson, Nolan, and Pelham Version IV Scale to interview both the ADHD patients and the control subjects and then evaluated participants' dietary intake with a food frequency questionnaire. Logistic regression models were utilized to produce a composite dietary/nutrient score, while receiver operating characteristic (ROC) was adopted to differentiate between the two participant groups. Compared to the control children, children with ADHD demonstrated a higher intake proportion of refined grains (p=0.026) and a lower proportion of dairy (p=0.013), calcium (p=0.043), and vitamin B-2 (p=0.024). We observed that the composite score of dietary and nutrient could significantly distinguish patients with ADHD from healthy controls (p<0.001). The composite dietary/nutrient score demonstrated a significant correlation with the severity of ADHD clinical symptoms (p<0.05). ADHD children and healthy controls have different dietary patterns and that dietary and nutrient factors may play a role in the pathophysiology of ADHD. Clinicians should consider dietary habits and specific nutrients in the routine assessment of children with ADHD.

Transcranial direct current stimulation improves long-term memory deficits in an animal model of attention-deficit/hyperactivity disorder and modulates oxidative and inflammatory parameters

BackgroundTranscranial direct current stimulation (tDCS) is a technique that modulates neuronal activity and has been proposed as a potential therapeutic tool for attention-deficit/hyperactivity disorder (ADHD) symptoms. Although pilot studies have shown evidence of efficacy, its mechanism of action remains unclear. Objective/HypothesisWe evaluated the effects of tDCS on behavioral (working and long-term memory) and neurochemical (oxidative and inflammatory parameters) outcomes related to ADHD pathophysiology. We used the most widely accepted animal model of ADHD: spontaneously hypertensive rats (SHR). The selected behavioral outcomes have been shown to be altered in both ADHD patients and animal models, and were chosen for their relation to the proposed mechanistic action of tDCS. MethodsAdult male SHR and their control, the Wistar Kyoto rats (WKY), were subjected to 20 min of bicephalic tDCS or sham stimulation for 8 consecutive days. Working memory, long-term memory, and neurochemical outcomes were evaluated. ResultsTDCS improved long-term memory deficits presented by the SHR. No change in working memory performance was observed. In the hippocampus, tDCS increased both the production of reactive oxygen species in SHR and the levels of the antioxidant molecule glutathione in both strains. TDCS also modulated inflammatory response in the brains of WKY by downregulating pro-inflammatory cytokines. ConclusionTDCS had significant effects that were specific for strain, type of behavioral and neurochemical outcomes. The long-term memory improvement in the SHR may point to a possible therapeutic role of tDCS in ADHD that does not seem to be mediated by inflammatory markers. Additionally, the anti-inflammatory effects observed in the brain of WKY after tDCS needs to be further explored.

Hypersomnia with ADHD: a possible subtype of narcolepsy type 2

Patients with attention deficit/hyperactivity disorder (ADHD) suffer from hypersomnia; indeed, we have often encountered ADHD patients that fulfill the diagnostic criteria for narcolepsy type 2 (NA 2). Because not all patients with NA 2 carry the HLA-DQB1*06:02 allele, which is closely associated with narcolepsy type 1 (NA 1), NA 2 is believed to be heterogeneous. To reveal the contribution of ADHD in hypersomnia, we studied the characteristics of hypersomnia patients with ADHD, especially those diagnosed with NA 2. Participants were 77 of 185 consecutive outpatients who were diagnosed with NA 2 or idiopathic hypersomnia. We investigated sleep variables in (a) participants with hypersomnia with/without ADHD and (b) patients with NA 2 with/without ADHD and those with/without the DQB1*06:02 allele. The proportion of those diagnosed with NA 2 was higher in hypersomnia patients with ADHD compared to those without ADHD. None of the NA 2 patients with ADHD carried the narcolepsy-specific DQB1*06:02 allele. These patients with NA 2 with ADHD exhibited short REM latencies on the MSLT (similarly to DQB1*06:02-positive patients with NA 2 without ADHD), but less REM-related phenomena than patients with NA 2 without ADHD. Hypersomnia patients with ADHD tended to show short REM latencies, and fulfilled NA 2 diagnostic criteria in the absence of the DQB1*06:02 allele, suggesting a different etiology from NA 1. These findings support the hypotheses of noradrenergic dysregulation and delayed brain maturation that have been proposed for the pathophysiology of ADHD.

Abnormal Resting-State Functional Connectivity of Insular Subregions and Disrupted Correlation with Working Memory in Adults with Attention Deficit/Hyperactivity Disorder.

Executive function (EF) deficits are major impairments in adults with attention deficit/hyperactivity disorder (ADHD). Previous studies have shown that the insula is involved in cognitive and EFs. However, the insula is highly heterogeneous in function, and few studies have focused on functional networks which related to specific insular subregions in adults with ADHD. We explored the functional networks of the insular subregions [anterior insula (AI), mid-insula (MI), and posterior insula (PI)]. Furthermore, their correlations with self-ratings of ecological EFs, including inhibition, shifting, and working memory were investigated. Resting-state functional magnetic resonance imaging data in 28 adults with ADHD and 30 matched healthy controls (HCs) were analyzed. The seed-based resting-state functional connectivity (RSFC) of the insular subregions was evaluated. We also investigated their associations with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) inhibition, working memory, and shifting factor scores. Compared with HCs, adults with ADHD showed altered RSFC of the AI, with the precuneus, precentral gyrus, and inferior temporal gyrus extended to the middle temporal gyrus, lingual gyrus, and superior occipital gyrus, respectively. There were no significant differences in RSFC of the MI and PI between the two groups. Within the HC group, working memory scores were associated with the RSFC of AI with precuneus and temporal gyrus. However, there was no correlation between these variables in the ADHD group. The study evaluated RSFC patterns of the insular subregions in adults with ADHD for the first time. Altered RSFC of the AI which is a crucial region of salience network (SN) and part of regions in default mode network (DMN), were detected in adults with ADHD in both results with and without global signal regression (GSR), suggesting that disrupted SN-DMN functional connectivity may be involved in EF impairments in adults with ADHD, especially with respect to working memory. Deficits of the AI which is involved in salient stimuli allocation, might be associated with the pathophysiology of ADHD. The inconsistent results of MI and PI between analyses with and without GSR need further exploration.

Manual morphometry of hippocampus and amygdala in adults with attention-deficit hyperactivity disorder

Previous studies have pointed to the involvement of limbic structures in the genesis of attention deficit hyperactivity disorder (ADHD). The present researchers manually segmented magnetic resonance images of 30 individuals with ADHD and 30 individually matched controls, focusing on amygdala and hippocampus volumes. Neither hippocampus nor amygdala volume differed significantly between individuals with and without ADHD. However, ADHD patients with higher hyperactivity scores had significantly smaller left amygdala volumes. This finding suggests that limbic alterations are significant in hyperactive symptoms in the pathophysiology of ADHD.

Serum brain-derived neurotrophic factor levels in treatment-naïve boys with attention-deficit/hyperactivity disorder treated with methylphenidate: an 8-week, observational pretest-posttest study.

Brain-derived neurotrophic factor (BDNF) is an important neurotrophin in the brain that modulates dopaminergic neurons. In this study, we aimed to investigate the changes in serum BDNF levels of children with attention-deficit/hyperactivity disorder (ADHD) in response to OROS methylphenidate treatment. We also aimed to determine whether there were any pre-post-differences between ADHD subtypes and comorbid psychiatric disorders in serum BDNF levels. Fifty male children with ADHD and 50 male healthy controls within the age range of 6-12years were recruited to the study. The psychiatric diagnoses were determined by applying a structured interview with Kiddie schedule for affective disorders and schizophrenia for school-age children-present and lifetime version. The symptom severity of ADHD was measured using the Clinical Global Impression ADHD Severity Scale (CGI-S). Physicians completed Du Paul ADHD questionnaires. The levels of serum BDNF were assessed before and after 8weeks of treatment with effective dosages of OROS methylphenidate. In the present study, the mean serum BDNF levels of boys with ADHD and of the healthy controls were 2626.33±1528.05 and 2989.11±1420.08pg/mL, respectively. Although there were no statistically significant difference between the ADHD group and healthy controls at baseline (p=0.22), the increase of serum BDNF was statistically significant from baseline to endpoint in the ADHD group (p=0.04). The mean serum BDNF levels at baseline and endpoint of the ADHD group were 2626.33±1528.05 and 3255.80±1908.79pg/mL, respectively. The serum BDNF levels of ADHD-inattentive subtype were significantly lower at baseline (p=0.02), whereas BDNF levels post-treatment showed no significant difference. The increase of serum BDNF levels with methylphenidate treatment after 8weeks was significantly higher in the inattentive group (p=0.005). The increase of serum BDNF levels with methylphenidate treatment after 8weeks in boys with ADHD may support the potential role of BDNF in the pathophysiology of ADHD. The role of BDNF in ADHD subtypes in particular should be evaluated with further, larger studies.