NPP-669, a prodrug of cidofovir, is highly efficacious against human adenovirus infection in the permissive Syrian hamster model.

Human adenoviruses can cause serious, disseminated infections in immunocompromised patients. For pediatric allogeneic stem cell transplant patients, the case fatality rate can reach 80%. Still, there is no available antiviral drug that is specifically approved by the Food and Drug Administration for the treatment of adenovirus infections. To fill this pressing medical need, we have developed NPP-669, a prodrug of cidofovir with broad activity against double-stranded DNA viruses, including adenoviruses. Here, we report on the in vivo anti-adenoviral efficacy of NPP-669. Using the immunosuppressed Syrian hamster as the model, we show that NPP-669 is highly efficacious when dosed orally at 1 mg/kg and 3 mg/kg. In a delayed administration experiment, NPP-669 was more effective than brincidofovir, a similar compound that reached Phase III clinical trials. Furthermore, parenteral administration of NPP-669 increased its efficacy approximately 10-fold compared to oral dosing without apparent toxicity, suggesting that this route may be preferable in a hospital setting. Based on these findings, we believe that NPP-669 is a promising new compound that needs to be further investigated.

A prospective 5-year longitudinal study detects neurocognitive and imaging correlates of seizure remission in self-limiting Rolandic epilepsy.

OBJECTIVE: Self-limiting Rolandic epilepsy (RE) is the most common epilepsy in school-age children. Seizures are generally infrequent, but cognitive, language, and motor coordination problems can significantly impact the child's life. To better understand brain structure and function changes in RE, we longitudinally assessed neurocognition, cortical thickness, and subcortical volumes. METHODS: At baseline, we recruited 30 participants diagnosed with RE and 24-healthy controls and followed up for 4.94 ± 0.8 years when the participants with RE were in seizure remission. Measures included were as follows: T1-weighted magnetic resonance brain imaging (MRI) with FreeSurfer analysis and detailed neuropsychological assessments. MRI and neuropsychological data were compared between baseline and follow-up in seizure remission. RESULTS: Longitudinal MRI revealed excess cortical thinning in the left-orbitofrontal (p = 0.0001) and pre-central gyrus (p = 0.044). There is a significant association (p = 0.003) between a reduction in cortical thickness in the left-orbitofrontal cluster and improved processing of filtered words. Longitudinal neuropsychology revealed significant improvements in the symptoms of developmental coordination disorder (DCD, p = 0.005) in seizure remission. CONCLUSIONS: There is evidence for altered development of neocortical regions between active seizure state and seizure remission in RE within two clusters maximal in the left-orbitofrontal and pre-central gyrus. There is significant evidence for improvement in motor coordination between active seizures and seizure remission and suggestive evidence for a decline in fluid intelligence and gains in auditory processing.

Comorbid mental health disorders in persons living with HIV: Adherence to antiretroviral therapy.

This is a secondary data analysis exploring adherence to antiretroviral therapy (ART) in persons living with HIV (PLWH) with a comorbid mental health disorder. Logistic regression analyses indicated that PLWH who had reliable housing were over six times more adherent than those with unreliable housing. Descriptive odds ratio analyses showed directional relationships for ART adherence with coping, employment, and social support. These results indicate areas for future investigation in PLWH and comorbid mental health disorders, and the potential to find ways to foster certain emotional or living conditions that promote ART adherence.

Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption.

Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as APCs. Cross-presentation of Ags by osteoclasts leads to expression of CD25 and Foxp3, markers of regulatory T cells in the CD8 T cells. Octeoclast-induced Foxp3(+) CD25(+) regulatory CD8 T cells (OC-iTcREG) suppress priming of CD4 and CD8 T cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. In this study, we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet, and Eomes production by TcREG Furthermore, we show, using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoters. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of TNFR-associated factor 6 in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ(-/-) T cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose receptor activator of NF-κB ligand. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish an important role for IFN-γ in TcREG-mediated protection from bone loss.

Testing the specificity of executive functioning impairments in adolescents with ADHD, ODD/CD and ASD.

Current diagnostic systems conceptualise attention deficit hyperactivity disorder (ADHD), oppositional defiant/conduct disorder (ODD/CD) and autism spectrum disorder (ASD) as separate diagnoses. However, all three demonstrate executive functioning (EF) impairments. Whether these impairments are trans-diagnostic or disorder-specific remains relatively unexplored. Four groups of 10-16 year-olds [typically developing (TD; N = 43), individuals clinically diagnosed with ADHD (N = 21), ODD/CD (N = 26) and ASD (N = 41)] completed Go/NoGo and Switch tasks. Group differences were tested using analysis of co-variance (ANCOVA) including age, IQ, sex, conduct problems and ADHD symptoms as co-variates. Results indicated some disorder-specificity as only the ASD group demonstrated decreased probability of inhibition in the Go/NoGo task compared to all other groups. However, shared impairments were also found; all three diagnostic groups demonstrated increased reaction time variability (RTV) compared to the TD group, and both the ODD/CD and the ASD group demonstrated increased premature responses. When controlling for ADHD symptoms and conduct problems, group differences in RTV were no longer significant; however, the ASD group continued to demonstrate increased premature responses. No group differences were found in cognitive flexibility in the Switch task. A more varied response style was present across all clinical groups, although this appeared to be accounted for by sub-threshold ODD/CD and ADHD symptoms. Only the ASD group was impaired in response inhibition and premature responsiveness relative to TD adolescents. The findings suggest that some EF impairments typically associated with ADHD may also be found in individuals with ASD.

A specific deficit of auditory processing in children with Rolandic Epilepsy and their relatives.

Previous research shows that children with Rolandic Epilepsy have deficits of auditory processing. We wanted to confirm the nature of this deficit and whether it aggregates in families. We compared 40 children with Rolandic Epilepsy and 32 unaffected siblings with 99 typically developing children and 71 parents of RE children with 31 healthy adults on a battery of auditory processing tests. We also examined ear advantage in children with RE, their siblings and parents using population norms and measured non-word reading performance. We found a specific deficit for competing words in patients, their siblings and their parents, suggesting that this particular impairment of auditory processing present in children with RE, is heritable and likely to be persistent. Importantly, scores on this subtest in patients and siblings were significantly correlated with non-word reading performance. We saw increased rates of atypical left ear advantage in patients and siblings but no evidence of this in parents. We present these findings as evidence of familial incidence of dichotic listening and ear advantage abnormalities in relatives of children with Rolandic Epilepsy.

A meta-analysis of literacy and language in children with rolandic epilepsy.

AIM: Rolandic epilepsy is the most common childhood epilepsy, often presenting with neuropsychological impairments. The aim of the study was to formally assimilate the findings of existing studies varying widely in methodology, thereby confirming the nature and prevalence of impairments in literacy and language. METHODS: Using meta-analytical techniques, we evaluated 22 studies of literacy and/or language skills in children with rolandic epilepsy, published after 2000, among participants with IQs>70 and in which effect sizes could be acquired. Diagnosis required the presence of classical centrotemporal spikes arising from a normal background on electroencephalograms; a clinical history including at least one seizure; and no additional neurological condition. Overall effect size and heterogeneity were measured for single-word reading, phonological processing, and expressive and receptive language. RESULTS: Mean effect sizes (Cohen's d) ranged from 0.50 (95% confidence interval [CI] 0.23-0.78) for phonological processing, through 0.71 (95% CI 0.52-0.90) for word reading and 0.72 (95% CI 0.34-1.1) for receptive language, to 0.75 (95% CI 0.45-1.05) for expressive language. While group differences for reading measures were consistent, those for language were heterogeneous and varied across studies explained by age and IQ of samples. INTERPRETATION: The presence of reading and phonological processing deficits in children with rolandic epilepsy highlights the importance of early literacy and language assessment in this population.

Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys.

The stimulant methylphenidate (MPX) and the nonstimulant atomoxetine (ATX) are the most commonly prescribed medications for attention deficit hyperactivity disorder (ADHD). However, no functional magnetic resonance imaging (fMRI) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX. A randomized, double-blind, placebo-controlled, crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX, ATX, and placebo during a stop task, combined with fMRI within 19 medication-naive ADHD boys, and their potential normalization effects relative to 29 age-matched healthy boys. Compared with controls, ADHD boys under placebo showed bilateral ventrolateral prefrontal, middle temporal, and cerebellar underactivation. Within patients, MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation, which correlated with enhanced inhibitory capacity. Relative to controls, both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo, while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX. The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX.

Pattern classification of response inhibition in ADHD: toward the development of neurobiological markers for ADHD.

The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) is based on subjective measures despite evidence for multisystemic structural and functional deficits. ADHD patients have consistent neurofunctional deficits in motor response inhibition. The aim of this study was to apply pattern classification to task-based functional magnetic resonance imaging (fMRI) of inhibition, to accurately predict the diagnostic status of ADHD. Thirty adolescent ADHD and thirty age-matched healthy boys underwent fMRI while performing a Stop task. fMRI data were analyzed with Gaussian process classifiers (GPC), a machine learning approach, to predict individual ADHD diagnosis based on task-based activation patterns. Traditional univariate case-control analyses were also performed to replicate previous findings in a relatively large dataset. The pattern of brain activation correctly classified up to 90% of patients and 63% of controls, achieving an overall classification accuracy of 77%. The regions of the discriminative network most predictive of controls included later developing lateral prefrontal, striatal, and temporo-parietal areas that mediate inhibition, while regions most predictive of ADHD were in earlier developing ventromedial fronto-limbic regions, which furthermore correlated with symptom severity. Univariate analysis showed reduced activation in ADHD in bilateral ventrolateral prefrontal, striatal, and temporo-parietal regions that overlapped with areas predictive of controls, suggesting the latter are dysfunctional areas in ADHD. We show that significant individual classification of ADHD patients of 77% can be achieved using whole brain pattern analysis of task-based fMRI inhibition data, suggesting that multivariate pattern recognition analyses of inhibition networks can provide objective diagnostic neuroimaging biomarkers of ADHD.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

A neurocognitive endophenotype associated with rolandic epilepsy.

PURPOSE: Children with rolandic epilepsy (RE) experience difficulties with reading, language, and attention. Their siblings are at high risk of dyslexia but are not otherwise known to have neurocognitive deficits. We therefore sought evidence for an RE-associated neurocognitive endophenotype. METHODS: Thirteen probands (male-to-female ratio 9:4) and 11 epilepsy-free siblings (male-to-female ratio 5:6) completed a neurocognitive evaluation within the domains of reading, language, and attention. Frequencies of impairment were compared, and mean standardized scores of children with RE and their siblings were each compared against population means. KEY FINDINGS: Frequency of impairment in each domain was comparable for siblings and probands: 9% of siblings and 31% of probands were reading impaired; 36% of siblings and 54% of probands were language impaired; and 70% of siblings and 67% of probands had attention impairments. Comparison of differences between sample and population means revealed evidence of a similar pattern of language deficits in both groups, specifically for picture naming and attention to competing words. For measures of attention, both groups made significantly higher omission errors and were impaired in their ability to sustain attention. SIGNIFICANCE: Children with RE and unaffected siblings demonstrate neurocognitive impairments in the domains of language and attention that are likely to remain undetected with general clinical protocols. Neurocognitively impaired probands and siblings showed a remarkably similar profile of deficits in language and attention that could explain poor academic performance. Early evaluation and intervention may benefit these children academically.

Developmental effects of reward on sustained attention networks.

Adolescence is typified by significant maturation in higher-level attention functions coupled with less developed control over motivation, and enhanced sensitivity to novelty and reward. This study used event-related functional magnetic resonance imaging (fMRI) in seventy male and female participants aged between 10 and 43 years to identify age-related linear changes in cognitive sustained attention systems and the impact of reward on these systems, using a sustained attention task with and without a rewarded condition. For the non-rewarded sustained attention contrast, increasing age was associated with activation increases in typical regions of sustained attention including right inferior frontal, superior temporo-parietal and cerebellar cortices. Age-related activation decreases were observed within more posterior regions including posterior cingulate, insula and posterior cerebellar cortices, presumably mediating visual-spatial saliency detection. The effect of reward on sustained attention networks was associated with increased activation with age in regions associated with both executive attention control and reward processing, including dorsolateral, inferior and ventromedial prefrontal cortices (PFC), striatum, and temporo-parietal regions, suggestive of greater integration and executive control of motivation and cognition with maturity. Activation in paralimbic posterior cingulate and inferior temporal brain regions of visual-spatial saliency processing was progressively reduced in activation with increasing development. Thus, with increasing development between adolescence and adulthood, reward appears to enhance maturing cognitive sustained attention and executive reward-processing networks, whilst reducing paralimbic regions of saliency detection. These findings may be the neural underpinnings for the progressive maturation of motivational control over risk taking behaviours between adolescence and adulthood.

Neurodevelopmental origins of self-limiting rolandic epilepsy: Systematic review of MR imaging studies.

OBJECTIVE: Recent neuroimaging studies have revealed differences in cortical and white matter brain structure in children with self-limiting rolandic epilepsy (RE). Despite this, reproducibility of the findings has been difficult, and there is no consensus about where and when structural differences are most apparent. We performed a systematic review of quantitative neuroimaging studies in children with RE to explore these questions. METHODS: Using PRISMA guidelines, we used a multilayered search strategy to identify neuroimaging studies in RE. Publications were included if they were quantitative and derived from controlled group studies and passed a quality assessment. Findings of the studies were presented and stratified by duration of epilepsy and age of participants. RESULTS: We identified six gray matter studies and five white matter studies. Consistent findings were found inside and outside the central sulcus, predominantly within the bilateral frontal and parietal lobes, striatal structures, such as the putamen and white matter, mainly involving the left superior longitudinal fasciculus and connections between the left pre- and postcentral gyrus. Stratification of the T1 studies by age found that cortical thickness differences varied between the under and over 10 year olds. Furthermore, the longer the duration of epilepsy, the less likely differences were detected. In white matter studies, there was a reduction in differences with increased age and duration of epilepsy. SIGNIFICANCE: These findings would suggest that the development of regions of the cortex in children with RE is abnormal. These regions are more widespread than the suspected seizure onset zone. Moreover, the findings would suggest that these differences are evidence of neurodevelopmental delay rather than apparent "damage" from the epilepsy.

Trait impulsivity in Juvenile Myoclonic Epilepsy.

OBJECTIVE: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs). METHODS: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects. RESULTS: The mean BIS-brief score in JME was 18.1 ± 4.4 compared with 16.2 ± 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse effects. INTERPRETATION: Trait impulsivity is elevated in JME and comparable to scores in personality and neurotic disorders. Increased seizure frequency and absence of circadian seizure pattern moderate BIS score, suggesting disruption of both cortico-striatal and thalamocortical networks as a shared mechanism between seizures and impulsivity in JME. These findings warrant consideration of impulsivity as a distinct target of intervention, and as a stratifying factor for AED treatment in JME, and perhaps other types of epilepsy. The role of impulsivity in treatment adherence and psychosocial outcome requires further investigation.

Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder.

BACKGROUND: Inhibitory dysfunction is a key behavioral and cognitive phenotype of attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Both disorders show neuropsychological deficits and fronto-striatal dysfunction during tasks of motor response inhibition and cognitive flexibility. This study investigates differences and commonalities in functional neural networks mediating inhibitory control between adolescents with ADHD and those with OCD to identify disorder-specific neurofunctional markers that distinguish these two inhibitory disorders. METHODS: Event-related fMRI was used to compare brain activation between 20 healthy boys, 18 (Stop task) or 12 boys (Switch task) with ADHD, and 10 boys with OCD during a tracking Stop task that measures inhibition and stopping failure and during a visual-spatial switching task measuring cognitive flexibility. RESULTS: Both patient groups shared brain dysfunction compared to healthy controls in right orbitofrontal (successful inhibition) and left dorsolateral prefrontal cortices (failed inhibition). Right inferior prefrontal dysfunction, however, was disorder-specific to ADHD during both tasks. Left inferior prefrontal dysfunction during the Switch task was significant in children with ADHD relative to controls, but only reached a trend in patients with OCD. Patients with ADHD furthermore showed disorder-specific dysfunction in left basal ganglia and cingulate gyrus during the Switch task. CONCLUSIONS: Patients with ADHD compared to those with OCD have both common and distinct dysfunctions during inhibitory control. The most consistently reported functional abnormality in children with ADHD in right inferior prefrontal cortex during inhibitory control appears to be disorder-specific when compared to patients with OCD and may be a specific neurofunctional biomarker of ADHD.

Sex-dependent age modulation of frontostriatal and temporo-parietal activation during cognitive control.

Developmental functional imaging studies of cognitive control show progressive age-related increase in task-relevant fronto-striatal activation in male development from childhood to adulthood. Little is known, however, about how gender affects this functional development. In this study, we used event related functional magnetic resonance imaging to examine effects of sex, age, and their interaction on brain activation during attentional switching and interference inhibition, in 63 male and female adolescents and adults, aged 13 to 38. Linear age correlations were observed across all subjects in task-specific frontal, striatal and temporo-parietal activation. Gender analysis revealed increased activation in females relative to males in fronto-striatal areas during the Switch task, and laterality effects in the Simon task, with females showing increased left inferior prefrontal and temporal activation, and males showing increased right inferior prefrontal and parietal activation. Increased prefrontal activation clusters in females and increased parietal activation clusters in males furthermore overlapped with clusters that were age-correlated across the whole group, potentially reflecting more mature prefrontal brain activation patterns for females, and more mature parietal activation patterns for males. Gender by age interactions further supported this dissociation, revealing exclusive female-specific age correlations in inferior and medial prefrontal brain regions during both tasks, and exclusive male-specific age correlations in superior parietal (Switch task) and temporal regions (Simon task). These findings show increased recruitment of age-correlated prefrontal activation in females, and of age-correlated parietal activation in males, during tasks of cognitive control. Gender differences in frontal and parietal recruitment may thus be related to gender differences in the neurofunctional maturation of these brain regions.

Shared and disorder-specific prefrontal abnormalities in boys with pure attention-deficit/hyperactivity disorder compared to boys with pure CD during interference inhibition and attention allocation.

BACKGROUND: Inhibitory and attention deficits have been suggested to be shared problems of disruptive behaviour disorders. Patients with attention deficit hyperactivity disorder (ADHD) and patients with conduct disorder (CD) show deficits in tasks of attention allocation and interference inhibition. However, functional magnetic resonance imaging (fMRI) of inhibitory and attention control has only been investigated in patients with ADHD, including comorbidity with CD, finding fronto-striatal and temporo-parietal dysfunction. This study investigates differences and commonalities in functional neural networks mediating interference inhibition and attention allocation between medication-naïve children and adolescents with pure CD and those with pure ADHD. METHODS: Event-related fMRI was used to compare brain activation of 13 boys with non-comorbid CD, 20 boys with non-comorbid ADHD and 20 healthy comparison boys during a Simon task that measures interference inhibition and controls for attention allocation, thus tapping into interference inhibition and selective attention networks. RESULTS: During interference inhibition, both patient groups shared reduced activation compared to controls in right superior temporal lobe and in predominantly right precuneus. During the oddball condition, both patient groups showed reduced activation compared to healthy control children in right medial prefrontal lobe. However, only ADHD patients showed a disorder-specific under-activation compared to the other two groups in an extensive activation cluster in left inferior prefrontal cortex. CONCLUSIONS: This study shows shared dysfunction in both patients groups in right hemispheric temporal and parietal brain regions during interference inhibition and in right dorsolateral prefrontal cortex during attention allocation. Ventrolateral prefrontal dysfunction, however, was specific to ADHD and not observed in patients with CD in the context of attention allocation. The findings suggest that the typically reduced functional activation in patients with ADHD in ventrolateral prefrontal cortex may be specific to the disorder, at least when compared to patients with CD.

Reduced activation in right lateral prefrontal cortex and anterior cingulate gyrus in medication-naïve adolescents with attention deficit hyperactivity disorder during time discrimination.

BACKGROUND: Patients with attention deficit hyperactivity disorder (ADHD) under-perform when discriminating between durations differing by several hundred milliseconds. This function involves right prefrontal and anterior cingulate (AC) brain regions, which are structurally and functionally compromised in this patient group during executive tasks. We investigated the neuro-anatomical substrates mediating fine temporal discrimination in adolescents with ADHD compared with controls, using functional magnetic resonance imaging (fMRI). METHODS: Twenty-one male medication-naïve adolescents aged 10-15 years with a DSM-IV diagnosis of ADHD (combined subtype) and without comorbid Axis I disorders (except conduct disorder) were compared to a group of 17 age- and IQ-matched healthy adolescents. Using fMRI on a 1.5T scanner, we compared brain activation and performance between adolescents with ADHD and controls during a time discrimination task contrasted with a temporal order task. RESULTS: Despite comparable performance, patients with ADHD showed decreased activation in right dorsolateral and inferior prefrontal cortex and AC during time discrimination compared with controls. CONCLUSIONS: Right hemispheric fronto-cingulate abnormalities in ADHD, previously observed during inhibitory and executive functions, are also associated with temporal perception. Furthermore, recruitment of medication-naïve patients precludes the possibility that deficits are attributable to stimulant exposure.

The Effects of Sleep on Emotional Target Detection Performance: A Novel iPad-Based Pediatric Game.

Background: Consolidation of learning occurs during sleep but when it is disturbed there may be an adverse impact upon these functions. While research has focused upon how sleep affects cognition in adulthood, the effects of disrupted sleep are likely to impact more heavily on learning among children and adolescents. We aimed to investigate whether a night's sleep impacts upon executive function compared with an equivalent wakefulness period. We also wanted to know whether restricting sleep would reduce these effects on performance. To investigate this issue in children, we adapted existing research methods to make them more suitable for this population. Methods: Using a cross-over trial design, 22 children aged 7-14 completed an updated but previously validated, continuous performance task (CPT) designed to be appealing to children, containing emotional and neutral targets and presented on an iPad. We measured omission and commission errors, mean and variability of reaction times (RTs) immediately and after a delay spent in the following three ways: 11-h intervals of unrestricted and restricted sleep in the style of a 'sleepover' and daytime wakefulness. We examined differences in immediate and delayed testing for each dependent variable. Both sleep nights were spent in a specialist sleep lab where polysomnography data were recorded. Results: While there were no significant main effects of sleep condition, as expected we observed significantly faster and more accurate performance in delayed compared with immediate testing across all conditions for omission errors, RT and variability of RT. Importantly, we saw a significant interaction for commission errors to emotional targets (p = 0.034): while they were comparable across all conditions during immediate testing, for delayed testing there were significantly more errors after wakefulness compared with unrestricted sleep (p = 0.019) and at a trend level for restricted sleep (p = 0.063). Performance improvement after restricted sleep was inversely correlated with sleep opportunity time (p = 0.03), total sleep time (p = 0.01) and total non-REM time (p = 0.005). Conclusion: This tool, designed to be simple to use and appealing to children, revealed a preserving effect of typical and disrupted sleep periods on performance during an emotionally themed target detection task compared with an equivalent wakefulness period.

Temporal lobe dysfunction in medication-naïve boys with attention-deficit/hyperactivity disorder during attention allocation and its relation to response variability.

BACKGROUND: Patients with attention-deficit/hyperactivity disorder (ADHD) typically show fronto-striatal abnormalities during functions of cognitive control. In this study we investigate whether medication-naïve children with ADHD are impaired in temporo-parietal neural networks that mediate purely perceptual attention allocation to a behaviorally neutral oddball task. Furthermore, we explore the relationship between the neural substrates of attention allocation and response variability, typically increased in patients. METHOD: Event-related functional magnetic resonance imaging was used to compare brain activation of 17 medication-naïve boys with ADHD with that of 18 handedness- and IQ-matched healthy comparison boys during a visual oddball task that required the same response to oddball and standard trials. Furthermore, to explore the relationship between behavioral dispersion and attention networks, regression analyses were conducted between response variability and brain activation networks. RESULTS: Patients showed significantly reduced brain activation in left and right superior temporal lobes, basal ganglia, and posterior cingulate during the oddball versus standard contrast. The activation differences in superior temporal lobes correlated inversely with response variability in control subjects but not in patients with ADHD. CONCLUSIONS: Brain abnormalities in patients with ADHD are not confined to fronto-striatal networks mediating executive functions but are also observed in temporo-striatal and cingulate regions during perceptive visual attention processes. Furthermore, temporal lobe dysfunction in the context of perceptual attention might be related to their behavioral problems with response variability.