Mismatch response in preterm and asphyxic neonates: a functional electrophysiological investigation of attention and habituation.

BACKGROUND AND AIM: There is a lack of diagnostic tools for early risk stratification of cognitive outcome in infants born preterm and infants with asphyxia. Using auditory event-related potentials and mismatch response, we aimed to assess possible differences in early attention and learning, as a marker for brain maturation to subsequently improve the allocation of early neurodevelopmental support. STUDY DESIGN AND METHODS: This cross-sectional study included 22 very preterm infants (gestational age (GA) < 32 weeks), eight term infants with asphyxia and 35 healthy term infants. An auditory oddball-paradigm with three consecutive stimulation blocks, separated by a two-minute break, was used as a cognitive discrimination task to assess attention and habituation. RESULTS: The peak-to-peak analysis in the group comparisons showed no significant differences for the first stimulation block. In term healthy infants and term infants after asphyxia, no significant differences were found in amplitudes between block one and three. Preterm infants showed significantly (p = .007) lower amplitudes in the third block for F7 congruent to a positive habituation. The amplitude of the grouped electrodes correlated positively with GA for frontal (R = .271, p= .029) and parietal electrodes (R =.275, p = .027). CONCLUSION: We found no differences in the auditory attention paradigm between preterm or term asphyxic and control infants when they were evaluated at term corrected age. Most infants did not show any electrophysiologically measurable learning effect indicating habituation or dishabituation. The small sample size of this study is a clear limitation. Therefore, the results must be evaluated with caution, especially regarding their potential predictive value for future cognitive development of infants with a developmental risk. However, our study underlines the possibility of an electrophysiological evaluation as a feasible tool to assess very early cognition in infants.

Birth experience in newborn infants is associated with changes in nociceptive sensitivity.

Vaginal birth prepares the fetus for postnatal life. It confers respiratory, cardiovascular and homeostatic advantages to the newborn infant compared with elective cesarean section, and is reported to provide neonatal analgesia. We hypothesize that infants born by vaginal delivery will show lower noxious-evoked brain activity a few hours after birth compared to those born by elective cesarean section. In the first few hours of neonatal life, we record electrophysiological measures of noxious-evoked brain activity following the application of a mildly noxious experimental stimulus in 41 infants born by either vaginal delivery or by elective cesarean section. We demonstrate that noxious-evoked brain activity is related to the mode of delivery and significantly lower in infants born by vaginal delivery compared with those born by elective cesarean section. Furthermore, we found that the magnitude of noxious-evoked brain activity is inversely correlated with fetal copeptin production, a surrogate marker of vasopressin, and dependent on the experience of birth-related distress. This suggests that nociceptive sensitivity in the first few hours of postnatal life is influenced by birth experience and endogenous hormonal production.

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.

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.

Predicting neurodevelopmental outcome in preterm born infants using auditory event-related potentials: A systematic review.

Prematurity is a known risk factor for later cognitive deficits. At present there are neither behavioral nor neurological tests available to detect those preterm infants who would benefit most from early interventions. Neurophysiologic methods, and more specifically, auditory event-related potentials (AERPs) are convenient tools to investigate early cognitive functioning. However, the capability of AERPs as a prognostic factor for mental development in preterm infants remains unclear. The present systematic search of the literature yielded 1016 articles, out of which 13 were included. Both prospective and cross-sectional studies reported a relationship between AERPs and cognitive outcome. Our results show that larger amplitudes and shorter latencies of late AERPs are related to better cognitive outcomes. Additional studies are needed to corroborate our findings regarding this potential use of AERPs in the individual evaluation of preterm born infants.

Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography.

Pain is an unpleasant sensory and emotional experience. In non-verbal patients, it is very difficult to measure pain, even with pain assessment tools. Those tools are subjective or determine secondary physiological indicators which also have certain limitations particularly when exploring the effectiveness of analgesia. As cortical processing is essential for pain perception, brain activity measures may provide a useful approach to assess pain in infants. Here we present a method to assess nociception with electrophysiological brain activity recordings optimized for the use in newborn infants. To produce highly standardized and reproducible noxious stimuli we applied mechanical stimulation with a flat-tip probe, e.g., PinPrick, which is not skin-breaking and does not cause behavioral distress. The noxious-evoked potential allows the objective measurement of nociception in non-verbal patients. This method can be used in newborn infants as early as 34 weeks of gestational age. Moreover, it could be applied in different situations such as measuring the efficacy of analgesic or anesthetic drugs.

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.

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.

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 (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.