Neuronal biomarkers of cognitive development in preterm and term born infants: a multidimensional approach combining electrophysiology and peripheral blood biomarkers

Prematurity is a global health problem, affecting about 11% of infants born worldwide. Due to the recent advancements in neonatal medicine the rates of preterm births are increasing and especially the survival of very and extremely preterm. Preterm born infants are at high risk for neurodevelopmental deficits, which have a lifelong impact. Therefore it is of utmost clinical importance to find a screening tool to detect infants at high risk that can possibly benefit from early intervention programs. In the present work we aim at investigating neuronal biomarkers in preterm and term born infants in order to examine their ability to predict neurodevelopmental outcome. Behavioral tests alone are inadequate to assess cognition in early infancy and therefore neuronal biomarkers are considered. Two methods are explored: an electrophysiological approach, using auditory event related potentials (AERPs) and a protein of neuroaxonal injury found in the blood named neurofilament (Nf). Three publications are included. First a systematic review of the literature, examining the association between AERPs and cognitive outcome in preterm born infants. This review is followed by a pilot study, where neonatal AERPs are investigated and correlated with neurodevelopmental outcome at 2 years in healthy very preterm and term born infants. In particular discrimination and habituation are examined as early forms of attention and learning respectively. Finally, we investigated a promising biomarker of neuroaxonal injury Nf light chain (NfL) for the very first time in preterm and term born infants during the first week of life

Habituation as parameter for prediction of mental development in healthy preterm infants : an electrophysiological pilot study

The aim of this prospective pilot study was to evaluate the predictive value of discrimination and habituation, which was measured by mismatch negativity in 17 healthy very preterm (mean gestational age: 27.4 weeks; range 25.0 – 31.3) and 16 term (mean gestational age 40.3 weeks; range 37.9 – 41.7) born infants at term equivalent age. Developmental outcome was measured by Bayley Scales of Infant Development-I in 13 preterm and 13 term born children at a mean age of 21.7 months (±2.18) and 18.5 months (±1.9) respectively. No differences in amplitude and latency of the mismatch negativity were found between both groups at term equivalent age. Within the preterm group habituation capacity was positively correlated with the Mental Developmental Index MDI (r=0.654; p=0.008) and Performance Developmental Index (r=0.482; p=0.048) at 21 months. Early learning capability, as measured by habituation, may be associated with a better prognosis for early mental development in healthy preterm infants

Neurofilament Light Chain: Blood Biomarker of Neonatal Neuronal Injury

Background: Neurofilament light chain (NfL) is a highly promising biomarker of neuroaxonal injury that has mainly been studied in adult neurodegenerative disease. Its involvement in neonatal disease remains largely unknown. Our aim was to establish NfL plasma concentrations in preterm and term infants in the first week of life.Methods: Plasma NfL was measured by single molecule array immunoassay in two neonatal cohorts: cohort 1 contained 203 term and preterm infants, median gestational age (GA) 37.9 weeks (interquartile range [IQR] 31.9–39.4), in whom venous and arterial umbilical cord blood was sampled at birth and venous blood at day of life (DOL) 3; cohort 2 contained 98 preterm infants, median GA 29.3 weeks (IQR 26.9–30.6), in whom venous blood was sampled at DOL 7.Results: Median NfL concentrations in venous blood increased significantly from birth (18.2 pg/mL [IQR 12.8–30.8, cohort 1]) to DOL 3 (50.9 pg/mL [41.3–100, cohort 1]) and DOL 7 (126 pg/mL [78.8–225, cohort 2]) (p < 0.001). In both cohorts NfL correlated inversely with birth weight (BW, Spearman's rho −0.403, p < 0.001, cohort 1; R −0.525, p < 0.001, cohort 2) and GA (R −0.271, p < 0.001, cohort 1; R −0.487, p < 0.001, cohort 2). Additional significant correlations were found for maternal age at delivery, preeclampsia, delivery mode, 5-min Apgar, duration of oxygen supplementation, sepsis, and brain damage (intraventricular hemorrhage or periventricular leukomalacia). Multivariable logistic regression analysis identified the independent predictors of NfL in cohort 1 as BW (beta = −0.297, p = 0.003), delivery mode (beta = 0.237, p = 0.001) and preeclampsia (beta = 0.183, p = 0.022) and in cohort 2 as BW (beta = −0.385, p = 0.001) and brain damage (beta = 0.222, p = 0.015).Conclusion: Neonatal NfL levels correlate inversely with maturity and BW, increase during the first days of life, and relate to brain injury factors such as intraventricular hemorrhage and periventricular leukomalacia, and also to vaginal delivery

Rapid naming and reading skills in school-aged children : a behavioral and ERP approach to the contribution of the lexical-phonological processes

Reading is an important aspect of everyday life, but is at the same time a complex skill to master. There is a high variability in reading skills among normal developing children and one of the phonological processing skills that has a significant influence on reading will be investigated in the current study. Rapid Automatized Naming (RAN) is next to phonological awareness and phonological short term memory an ability that acts on the word identification skills that are necessary for learning to read. The relationship between RAN and reading is well documented in the literature in both typical and disabled readers and across different languages. However there is still a debate concerning the components driving this relationship..

An Electrophysiological Pilot Study

Weber P, Depoorter A, Hetzel P, Lemola S. Habituation as Parameter for Prediction of Mental Development in Healthy Preterm Infants. Journal of Child Neurology. 2016;31(14):1591-1597.The aim of this prospective pilot study was to evaluate the predictive value of discrimination and habituation, which was measured by mismatch negativity in 17 healthy very preterm (mean gestational age 27.4 weeks; range 25.0-31.3) and 16 term (mean gestational age 40.3 weeks; range 37.9-41.7) born infants at term equivalent age. Developmental outcome was measured by Bayley Scales of Infant Development–I in 13 preterm and 13 term-born children at a mean age of 21.7 months (±2.18) and 18.5 months (±1.9), respectively. No differences in amplitude and latency of the mismatch negativity were found between both groups at term equivalent age. Within the preterm group habituation capacity was positively correlated with the Mental Developmental Index ( r = .654, P = .008) and Performance Developmental Index ( r = .482, P = .048) at 21 months. Early learning capability, as measured by habituation, may be associated with a better prognosis for early mental development in healthy preterm infants

The impact of gut hormones on the neural circuit of appetite and satiety : A systematic review

The brain-gut-axis is an interdependent system affecting neural functions and controlling our eating behaviour. In recent decades, neuroimaging techniques have facilitated its investigation. We systematically looked into functional and neurochemical brain imaging studies investigating how key molecules such as ghrelin, glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY), cholecystokinin (CCK), leptin, glucose and insulin influence the function of brain regions regulating appetite and satiety. Of the 349 studies published before July 2016 identified in the database search, 40 were included (27 on healthy and 13 on obese subjects). Our systematic review suggests that the plasma level of ghrelin, the gut hormone promoting appetite, is positively correlated with activation in the pre-frontal cortex (PFC), amygdala and insula and negatively correlated with activation in subcortical areas such as the hypothalamus. In contrast, the plasma levels of glucose, insulin, leptin, PYY, GLP-1 affect the same brain regions conversely. Our study integrates previous investigations of the gut-brain matrix during food-intake and homeostatic regulation and may be of use for future meta-analyses of brain-gut interactions

Decreased Fronto-Parietal and Increased Default Mode Network Activation is Associated with Subtle Cognitive Deficits in Elderly Controls

BACKGROUND: Cognitive functions progressively deteriorate during aging and neurodegenerative diseases. The present study aims at investigating differences in working memory performance as well as functional brain changes during the earliest stages of cognitive decline in health elderly individuals. METHODS: 62 elderly individuals (41 females), including 41 controls (35 females) and 21 middle cognitive impairment subjects (6 females), underwent neuropsychological assessment at baseline and an fMRI examination in a N-back paradigm contrasting 2-back vs. 0-back condition. Upon a 18 months follow-up, we identified stable controls (sCON) with preserved cognition and deteriorating controls (dCON) with -1SD decrease of performances in at least two neuropsychological tests. Data analyses included accuracy and reaction time (RT) for the 2-back condition and general linear model (GLM) for the fMRI sequence. RESULTS: At the behavioral level, sCON and dCON performed better than MCI in terms of accuracy and reaction time. At the brain level, functional differences in regions of the fronto-parietal network (FPN) and of the Default Mode Network (DFM) were observed. Significantly lower neural activations in the bilateral inferior and middle frontal gyri were found in MCI versus both dCON / sCON and for dCON versus sCON. Significantly increased activations in the anterior cingulate cortex and posterior cingulate cortex and bilateral insula were found in MCI versus both dCON / sCON and in dCON versus sCON. CONCLUSION: The present study suggests that brain functional changes in FPN and DMN anticipate differences in cognitive performance in healthy elderly individuals with subsequent subtle cognitive decline

Acute Effects of Glucose and Fructose Administration on the Neural Correlates of Cognitive Functioning in Healthy Subjects: A Pilot Study

The present randomized double-blinded cross-over study aims to extensively study the neural correlates underpinning cognitive functions in healthy subjects after acute glucose and fructose administration, using an integrative multimodal neuroimaging approach. Five minutes after glucose, fructose, or placebo administration through a nasogastric tube, 12 participants underwent 3 complementary neuroimaging techniques: 2 task-based functional magnetic resonance imaging (fMRI) sequences to assess working memory (N-back) and response inhibition (Go/No-Go) and one resting state fMRI sequence to address the cognition-related fronto-parietal network (FPN) and salience network (SN). During working memory processing, glucose intake decreased activation in the anterior cingulate cortex (ACC) relative to placebo, while fructose decreased activation in the ACC and sensory cortex relative to placebo and glucose. During response inhibition, glucose and fructose decreased activation in the ACC, insula and visual cortex relative to placebo. Resting state fMRI indicated increased global connectivity strength of the FPN and the SN during glucose and fructose intake. The results demonstrate that glucose and fructose lead to partially different partially overlapping changes in regional brain activities that underpin cognitive performance in different tasks

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<p>The present randomized double-blinded cross-over study aims to extensively study the neural correlates underpinning cognitive functions in healthy subjects after acute glucose and fructose administration, using an integrative multimodal neuroimaging approach. Five minutes after glucose, fructose, or placebo administration through a nasogastric tube, 12 participants underwent 3 complementary neuroimaging techniques: 2 task-based functional magnetic resonance imaging (fMRI) sequences to assess working memory (N-back) and response inhibition (Go/No-Go) and one resting state fMRI sequence to address the cognition-related fronto-parietal network (FPN) and salience network (SN). During working memory processing, glucose intake decreased activation in the anterior cingulate cortex (ACC) relative to placebo, while fructose decreased activation in the ACC and sensory cortex relative to placebo and glucose. During response inhibition, glucose and fructose decreased activation in the ACC, insula and visual cortex relative to placebo. Resting state fMRI indicated increased global connectivity strength of the FPN and the SN during glucose and fructose intake. The results demonstrate that glucose and fructose lead to partially different partially overlapping changes in regional brain activities that underpin cognitive performance in different tasks.</p