Additive and Interactive Effects of Attention-Deficit/Hyperactivity Disorder and Tic Disorder on Brain Connectivity.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and persistent tic disorder (PTD) are two neurodevelopmental disorders that frequently co-occur. Contributions of each disorder to cognitive and behavioral deficits have been reported. In this paper, we tested 3 models of pathophysiology for the two disorders (additive, interactive, and phenotypic) using resting-state connectivity associated with each disorder separately and together. METHODS: Participants were 148 children (55 with ADHD only, 33 with ADHD and PTD, 27 with PTD only, and 33 healthy control subjects) at ages 8 to 12 years. Following diagnostic interviews and behavioral assessment, participants underwent a 128-channel electroencephalography recording. Resting-state, cortical source-level effective connectivity was analyzed across the 4 groups using a 2 × 2 factorial design with factors of ADHD (with/without) and PTD (with/without). RESULTS: ADHD diagnosis was the primary driver of cognitive and behavioral deficits, while deficits associated with PTD were primarily with thought problems and internalizing problems when compared with controls. Subadditive effects were observed in co-occurring ADHD+PTD for parent-rated behavioral problems and cognitive functions. Aberrant effective connectivity was primarily associated with ADHD, more specifically with lower posterior and occipital-frontal connectivity, while children with PTD exhibited greater left postcentral to precuneus connectivity. Weaker ADHD-related connectivity was associated with more severe behavioral problems, including internalizing behaviors, thought problems, and working memory deficits. CONCLUSIONS: Similar to general behavioral deficits, aberrant resting-state neural connectivity in pediatric ADHD and PTD combines additively in co-occurring cases. The findings of this study support ADHD as a focus of treatment in comorbid cases, given the driving role of ADHD in both behavioral and neurophysiological deficits.

Combining neuroimaging and behavior to discriminate children with attention deficit-hyperactivity disorder with and without prenatal alcohol exposure.

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone.

Cortical gyrification in children with attention deficit-hyperactivity disorder and prenatal alcohol exposure.

BACKGROUND: An improved understanding of the neurodevelopmental differences between attention deficit hyperactivity disorder with and without prenatal alcohol exposure (ADHD + PAE and ADHD-PAE, respectively) is needed. Herein, we evaluated gyrification (cortical folding) in children with ADHD + PAE compared to that in children with familial ADHD-PAE and typically developing (TD) children. METHODS: ADHD + PAE (n = 37), ADHD-PAE (n = 25), and TD children (n = 27), aged 8-13 years, were compared on facial morphological, neurobehavioral, and neuroimaging assessments. Local gyrification index (LGI) maps were compared between groups using general linear modelling. Relationships between LGI and clincobehavioral parameters in children with ADHD ± PAE were evaluated using multivariate partial least squares. RESULTS: ADHD + PAE and ADHD-PAE groups showed significantly lower LGI (relative to TD) in numerous regions, overlapping in medial prefrontal, parietal, and temporo-occipital cortices (p < 0.001). However, LGI in left mid-dorsolateral prefrontal cortex was uniquely lower in the ADHD + PAE group (p < 0.001). Partial least squares analysis identified one significant latent variable (accounting for 59.3 % of the crossblock correlation, p < 0.001), reflecting a significant relationship between a profile of lower LGI in prefrontal (including left mid-dorsolateral), insular, cingulate, temporal, and parietal cortices and a clinicobehavioral profile of PAE, including a flat philtrum and upper vermillion border, lower IQ, poorer behavioral regulation scores, and greater hyperactivity/impulsivity. CONCLUSIONS: Children with ADHD + PAE uniquely demonstrate lower mid-dorsolateral LGI, with widespread lower LGI related to more severe facial dysmorphia and neurobehavioral impairments. These findings add insight into the brain bases of PAE symptoms, potentially informing more targeted ADHD treatments based on an objective differential diagnosis of ADHD + PAE vs. ADHD-PAE.

Inhibitory control in children with tic disorder: aberrant fronto-parietal network activity and connectivity.

Chronic tic disorders, including Tourette syndrome, are typically thought to have deficits in cognitive inhibition and top down cognitive control due to the frequent and repetitive occurrence of tics, yet studies reporting task performance results have been equivocal. Despite similar behavioural performance, individuals with chronic tic disorder have exhibited aberrant patterns of neural activation in multiple frontal and parietal regions relative to healthy controls during inhibitory control paradigms. In addition to these top down attentional control regions, widespread alterations in brain activity across multiple neural networks have been reported. There is a dearth, however, of studies examining event-related connectivity during cognitive inhibitory paradigms among affected individuals. The goal of this study was to characterize neural oscillatory activity and effective connectivity, using a case-control design, among children with and without chronic tic disorder during performance of a cognitive inhibition task. Electroencephalogram data were recorded in a cohort of children aged 8-12 years old (60 with chronic tic disorder, 35 typically developing controls) while they performed a flanker task. While task accuracy did not differ by diagnosis, children with chronic tic disorder displayed significant cortical source-level, event-related spectral power differences during incongruent flanker trials, which required inhibitory control. Specifically, attenuated broad band oscillatory power modulation within the anterior cingulate cortex was observed relative to controls. Whole brain effective connectivity analyses indicated that children with chronic tic disorder exhibit greater information flow between the anterior cingulate and other fronto-parietal network hubs (midcingulate cortex and precuneus) relative to controls, who instead showed stronger connectivity between central and posterior nodes. Spectral power within the anterior cingulate was not significantly correlated with any connectivity edges, suggesting lower power and higher connectivity are independent (versus resultant) neural mechanisms. Significant correlations between clinical features, task performance and anterior cingulate spectral power and connectivity suggest this region is associated with tic impairment (r = -0.31, P = 0.03) and flanker task incongruent trial accuracy (r's = -0.27 to -0.42, P's = 0.0008-0.04). Attenuated activation of the anterior cingulate along with dysregulated information flow between and among nodes within the fronto-parietal attention network may be neural adaptations that result from frequent engagement of neural pathways needed for inhibitory control in chronic tic disorder.

Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure.

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.

Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response.

OBJECTIVE: The current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial. METHOD: Children aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of ≥25%, whereas nonresponders (NR) had <25% reduction posttreatment. Assessments included weekly behavioral ratings and pre-/posttreatment cognitive EEG measures. RESULTS: The final sample was 25 RESP and 26 NR comprising 34 male and 17 female children, with a mean (SD) age of 10.3 (1.4) years. Baseline measures that significantly differentiated RESP from NR included: lower working memory, lower spelling and mathematics achievement, deficits on behavioral ratings of executive function (BRIEF), and lower resting state EEG power in the right frontal (F4) region (all p values <.05). Compared to NRs, responders showed significantly increased right frontal EEG power with TNS treatment, which was predictive of improved executive functions and ADHD symptomatology (ß = 0.65, p < .001). When EEG findings and behavior were modeled together, the area under the curve (AUC) for BRIEF Working Memory scale was 0.83 (p = .003), indicating moderate prediction of treatment response. CONCLUSION: Children with ADHD who have executive dysfunction are more likely to be TNS responders and show modulation of right frontal brain activity, improved/normalized executive functions, and ADHD symptom reduction. CLINICAL TRIAL REGISTRATION INFORMATION: Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov; NCT02155608.

Modulation of Frontal Oscillatory Power during Blink Suppression in Children: Effects of Premonitory Urge and Reward.

There is a dearth of studies examining the underlying mechanisms of blink suppression and the effects of urge and reward, particularly those measuring subsecond electroencephalogram (EEG) brain dynamics. To address these issues, we designed an EEG study to ask 3 questions: 1) How does urge develop? 2) What are EEG-correlates of blink suppression? 3) How does reward change brain dynamics related to urge suppression? This study examined healthy children (N = 26, age 8-12 years) during blink suppression under 3 conditions: blink freely (i.e., no suppression), blink suppressed, and blink suppressed for reward. During suppression conditions, children used a joystick to indicate their subjective urge to blink. Results showed that 1) half of the trials were associated with clearly defined urge time course of ~7 s, which was accompanied by EEG delta (1-4 Hz) power reduction localized at anterior cingulate cortex (ACC); 2) the EEG correlates of blink suppression were found in left prefrontal theta (4-8 Hz) power elevation; and 3) reward improved blink suppression performance while reducing the EEG delta power observed in ACC. We concluded that the empirically supported urge time course and underlying EEG modulations provide a subsecond chronospatial model of the brain dynamics during urge- and reward-mediated blink suppression.

Neural activation and connectivity during cued eye blinks in Chronic Tic Disorders.

OBJECTIVE: The pathophysiology of Chronic Tic Disorders (CTDs), including Tourette Syndrome, remains poorly understood. The goal of this study was to compare neural activity and connectivity during a voluntary movement (VM) paradigm that involved cued eye blinks among children with and without CTDs. Using the precise temporal resolution of electroencephalography (EEG), we used the timing and location of cortical source resolved spectral power activation and connectivity to map component processes such as visual attention, cue detection, blink regulation and response monitoring. We hypothesized that neural activation and connectivity during the cued eye blink paradigm would be significantly different in regions typically associated with effortful control of eye blinks, such as frontal, premotor, parietal, and occipital cortices between children with and without CTD. METHOD: Participants were 40 children (23 with CTD, 17 age-matched Healthy Control [HC]), between the ages of 8-12 (mean age = 9.5) years old. All participants underwent phenotypic assessment including diagnostic interviews, behavior rating scales and 128-channel EEG recording. Upon presentation of a cue every 3 s, children were instructed to make an exaggerated blink. RESULTS: Behaviorally, the groups did not differ in blink number, latency, or ERP amplitude. Within source resolved clusters located in left dorsolateral prefrontal cortex, posterior cingulate, and supplemental motor area, children with CTD exhibited higher gamma band spectral power relative to controls. In addition, significant diagnostic group differences in theta, alpha, and beta band power in inferior parietal cortex emerged. Spectral power differences were significantly associated with clinical characteristics such as tic severity and premonitory urge strength. After calculating dipole density for 76 anatomical regions, the CTD and HC groups had 70% overlap of top regions with the highest dipole density, suggesting that similar cortical networks were used across groups to carry out the VM. The CTD group exhibited significant information flow increase and dysregulation relative to the HC group, particularly from occipital to frontal regions. CONCLUSION: Children with CTD exhibit abnormally high levels of neural activation and dysregulated connectivity among networks used for regulation and effortful control of voluntary eye blinks.

M Cells: Intelligent Engineering of Mucosal Immune Surveillance.

M cells are specialized intestinal epithelial cells that provide the main machinery for sampling luminal microbes for mucosal immune surveillance. M cells are usually found in the epithelium overlying organized mucosal lymphoid tissues, but studies have identified multiple distinct lineages of M cells that are produced under different conditions, including intestinal inflammation. Among these lineages there is a common morphology that helps explain the efficiency of M cells in capturing luminal bacteria and viruses; in addition, M cells recruit novel cellular mechanisms to transport the particles across the mucosal barrier into the lamina propria, a process known as transcytosis. These specializations used by M cells point to a novel engineering of cellular machinery to selectively capture and transport microbial particles of interest. Because of the ability of M cells to effectively violate the mucosal barrier, the circumstances of M cell induction have important consequences. Normal immune surveillance insures that transcytosed bacteria are captured by underlying myeloid/dendritic cells; in contrast, inflammation can induce development of new M cells not accompanied by organized lymphoid tissues, resulting in bacterial transcytosis with the potential to amplify inflammatory disease. In this review, we will discuss our own perspectives on the life history of M cells and also raise a few questions regarding unique aspects of their biology among epithelia.

Improving refugee integration through data-driven algorithmic assignment.

Developed democracies are settling an increased number of refugees, many of whom face challenges integrating into host societies. We developed a flexible data-driven algorithm that assigns refugees across resettlement locations to improve integration outcomes. The algorithm uses a combination of supervised machine learning and optimal matching to discover and leverage synergies between refugee characteristics and resettlement sites. The algorithm was tested on historical registry data from two countries with different assignment regimes and refugee populations, the United States and Switzerland. Our approach led to gains of roughly 40 to 70%, on average, in refugees' employment outcomes relative to current assignment practices. This approach can provide governments with a practical and cost-efficient policy tool that can be immediately implemented within existing institutional structures.

Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens Intensity and Breadth of Antigen-specific Antibody Responses in Young and Aged mice.

The hallmark of vaccines is their ability to prevent the spread of infectious pathogens and thereby serve as invaluable public health tool. Despite their medical relevance, there is a gap in our understanding of the physiological factors that mediate innate and adaptive immune response to vaccines. The endocannabinoid (eCB) system is a critical modulator of homeostasis in vertebrates. Our results indicate that macrophages and dendritic cells produce the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG) upon antigen activation. We have also established that 2-AG levels are upregulated in the serum and in the lymph node of mice during vaccination. We hypothesized that the intrinsic release of eCBs from immune cells during activation by pathogenic antigens mitigate inflammation, but also suppress overall innate and adaptive immune response. Here we demonstrate, for the first time, that transient administration of the cannabinoid receptor 2 antagonist AM630 (10 mg/kg) or inverse agonist JTE907 (3 mg/kg) during immunization heightens the intensity and breadth of antigen-specific immune responses in young and aged mice through the upregulation of immunomodulatory genes in secondary lymphoid tissues.