Intra-subject variability in attention-deficit hyperactivity disorder

BACKGROUND: This study is based on a comprehensive survey of the neuropsychological attention-deficit hyperactivity disorder (ADHD) literature and presents the first psychometric analyses of different parameters of intra-subject variability (ISV) in patients with ADHD compared to healthy controls, using the Continuous Performance Test, a Go-NoGo task, a Stop Signal Task, as well as N-back tasks. METHODS: Data of 57 patients with ADHD and 53 age- and gender-matched controls were available for statistical analysis. Different parameters were used to describe central tendency (arithmetic mean, median), dispersion (standard deviation, coefficient of variation, consecutive variance), and shape (skewness, excess) of reaction time distributions, as well as errors (commissions and omissions). RESULTS: Group comparisons revealed by far the strongest effect sizes for measures of dispersion, followed by measures of central tendency, and by commission errors. Statistical control of ISV reduced group differences in the other measures substantially. One (patients) or two (controls) principal components explained up to 67% of the inter-individual differences in intra-individual variability. CONCLUSIONS: Results suggest that, across a variety of neuropsychological tests, measures of ISV contribute best to group discrimination, with limited incremental validity of measures of central tendency and errors. Furthermore, increased ISV might be a unitary construct in ADHD.

Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG‑IC‑Notch1 transgenic mice that have a floxed β‑geo/stop signal between a CMV promoter and intracellular domain of Notch1 (IC‑Notch1). Constitutively active IC‑Notch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of IC‑Notch1 in double transgenic ZEG‑IC‑Notch1/Tie2‑Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible IC‑Notch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEG‑IC‑Notch1/Tie2‑tTA/tet‑O‑Cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post‑natal withdrawal of tetracycline induced expression of IC‑Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T‑cell infiltration in multiple organs and T‑cell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphoma‑like neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that IC‑Notch1 might repress ARF‑p53 pathway by a post‑transcriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces T‑cell malignancy.

Developmental changes of BOLD signal correlations with global human EEG power and synchronization during working memory

In humans, theta band (5-7 Hz) power typically increases when performing cognitively demanding working memory (WM) tasks, and simultaneous EEG-fMRI recordings have revealed an inverse relationship between theta power and the BOLD (blood oxygen level dependent) signal in the default mode network during WM. However, synchronization also plays a fundamental role in cognitive processing, and the level of theta and higher frequency band synchronization is modulated during WM. Yet, little is known about the link between BOLD, EEG power, and EEG synchronization during WM, and how these measures develop with human brain maturation or relate to behavioral changes. We examined EEG-BOLD signal correlations from 18 young adults and 15 school-aged children for age-dependent effects during a load-modulated Sternberg WM task. Frontal load (in-)dependent EEG theta power was significantly enhanced in children compared to adults, while adults showed stronger fMRI load effects. Children demonstrated a stronger negative correlation between global theta power and the BOLD signal in the default mode network relative to adults. Therefore, we conclude that theta power mediates the suppression of a task-irrelevant network. We further conclude that children suppress this network even more than adults, probably from an increased level of task-preparedness to compensate for not fully mature cognitive functions, reflected in lower response accuracy and increased reaction time. In contrast to power, correlations between instantaneous theta global field synchronization and the BOLD signal were exclusively positive in both age groups but only significant in adults in the frontal-parietal and posterior cingulate cortices. Furthermore, theta synchronization was weaker in children and was--in contrast to EEG power--positively correlated with response accuracy in both age groups. In summary we conclude that theta EEG-BOLD signal correlations differ between spectral power and synchronization and that these opposite correlations with different distributions undergo similar and significant neuronal developments with brain maturation.

Increased sensitivity in mapping task demand in visuospatial processing using reaction-time-dependent hemodynamic response predictors in rapid event-related fMRI

Searching for the neural correlates of visuospatial processing using functional magnetic resonance imaging (fMRI) is usually done in an event-related framework of cognitive subtraction, applying a paradigm comprising visuospatial cognitive components and a corresponding control task. Besides methodological caveats of the cognitive subtraction approach, the standard general linear model with fixed hemodynamic response predictors bears the risk of being underspecified. It does not take into account the variability of the blood oxygen level-dependent signal response due to variable task demand and performance on the level of each single trial. This underspecification may result in reduced sensitivity regarding the identification of task-related brain regions. In a rapid event-related fMRI study, we used an extended general linear model including single-trial reaction-time-dependent hemodynamic response predictors for the analysis of an angle discrimination task. In addition to the already known regions in superior and inferior parietal lobule, mapping the reaction-time-dependent hemodynamic response predictor revealed a more specific network including task demand-dependent regions not being detectable using the cognitive subtraction method, such as bilateral caudate nucleus and insula, right inferior frontal gyrus and left precentral gyrus.

Time course of blood oxygenation level-dependent signal response after theta burst transcranial magnetic stimulation of the frontal eye field

The aim of the current study was to examine the effect of theta burst repetitive transcranial magnetic stimulation (rTMS) on the blood oxygenation level-dependent (BOLD) activation during repeated functional magnetic resonance imaging (fMRI) measurements. Theta burst rTMS was applied over the right frontal eye field in seven healthy subjects. Subsequently, repeated fMRI measurements were performed during a saccade-fixation task (block design) 5, 20, 35, and 60 min after stimulation. We found that theta burst rTMS induced a strong and long-lasting decrease of the BOLD signal response of the stimulated frontal eye field at 20 and 35 min. Furthermore, less pronounced alterations of the BOLD signal response with different dynamics were found for remote oculomotor areas such as the left frontal eye field, the pre-supplementary eye field, the supplementary eye field, and both parietal eye fields. Recovery of the BOLD signal changes in the anterior remote areas started earlier than in the posterior remote areas. These results show that a) the major inhibitory impact of theta burst rTMS occurs directly in the stimulated area itself, and that b) a lower effect on remote, oculomotor areas can be induced.

Analysis of eye and head coordination in a visual peripheral recognition task

Coordinated eye and head movements simultaneously occur to scan the visual world for relevant targets. However, measuring both eye and head movements in experiments allowing natural head movements may be challenging. This paper provides an approach to study eye-head coordination: First, we demonstra- te the capabilities and limits of the eye-head tracking system used, and compare it to other technologies. Second, a beha- vioral task is introduced to invoke eye-head coordination. Third, a method is introduced to reconstruct signal loss in video- based oculography caused by cornea reflection artifacts in order to extend the tracking range. Finally, parameters of eye- head coordination are identified using EHCA (eye-head co- ordination analyzer), a MATLAB software which was developed to analyze eye-head shifts. To demonstrate the capabilities of the approach, a study with 11 healthy subjects was performed to investigate motion behavior. The approach presented here is discussed as an instrument to explore eye-head coordination, which may lead to further insights into attentional and motor symptoms of certain neurological or psychiatric diseases, e.g., schizophrenia.

Prognostic and diagnostic value of EEG signal coupling measures in coma.

OBJECTIVE Our aim was to assess the diagnostic and predictive value of several quantitative EEG (qEEG) analysis methods in comatose patients. METHODS In 79 patients, coupling between EEG signals on the left-right (inter-hemispheric) axis and on the anterior-posterior (intra-hemispheric) axis was measured with four synchronization measures: relative delta power asymmetry, cross-correlation, symbolic mutual information and transfer entropy directionality. Results were compared with etiology of coma and clinical outcome. Using cross-validation, the predictive value of measure combinations was assessed with a Bayes classifier with mixture of Gaussians. RESULTS Five of eight measures showed a statistically significant difference between patients grouped according to outcome; one measure revealed differences in patients grouped according to the etiology. Interestingly, a high level of synchrony between the left and right hemisphere was associated with mortality on intensive care unit, whereas higher synchrony between anterior and posterior brain regions was associated with survival. The combination with the best predictive value reached an area-under the curve of 0.875 (for patients with post anoxic encephalopathy: 0.946). CONCLUSIONS EEG synchronization measures can contribute to clinical assessment, and provide new approaches for understanding the pathophysiology of coma. SIGNIFICANCE Prognostication in coma remains a challenging task. qEEG could improve current multi-modal approaches.