Electroencephalographic functional connectivity in extreme prematurity: a pilot study based on graph theory

Background: Connectivity studies based on functional magnetic resonance imaging (MRI) provided new insights in neonatal brain development but cannot be performed at bedside in the clinical setting. The electroencephalogram (EEG) connectivity has been less studied, particularly using the new approach based on graph theory. This study aimed to explore the functional EEG connectivity using graph theory analysis at an early post-conception age in extremely premature and late-preterm babies free of medical complications and overt brain damage. Methods: Sixteen neonates (8 extremely low gestational age (ELGA) and 8 late-preterm infants), both groups having performed multichannel EEG recordings at 35 weeks’ post-conception, were recruited in a single tertiary-level neonatal intensive care unit and well-baby nursery, respectively. Global (i.e., small-worldness) and local (i.e., clustering and strength) connectivity measures were calculated on a single-subject connectivity matrix of EEG data. Results: Both ELGA and late-preterm infants showed small-worldness organization at 35 weeks’ post-conception. The ELGA group had the strength parameter of the theta frequency band lower in the right than in the left hemisphere. This asymmetry did not emerge in the late-preterm group. Moreover, the mean strength parameter was significantly greater in the right hemisphere in the late preterms than in the ELGA group. Conclusion: EEG connectivity measures could represent an index of left-to-right maturation and developmental disadvantage in extremely preterm infants

Early development of sleep and brain functional connectivity in term-born and preterm infants

The proper development of sleep and sleep-wake rhythms during early neonatal life is crucial to lifelong neurological well-being. Recent data suggests that infants who have poor quality sleep demonstrate a risk for impaired neurocognitive outcomes. Sleep ontogenesis is a complex process, whereby alternations between rudimentary brain states-active vs. wake and active sleep vs. quiet sleep-mature during the last trimester of pregnancy. If the infant is born preterm, much of this process occurs in the neonatal intensive care unit, where environmental conditions might interfere with sleep. Functional brain connectivity (FC), which reflects the brain's ability to process and integrate information, may become impaired, with ensuing risks of compromised neurodevelopment. However, the specific mechanisms linking sleep ontogenesis to the emergence of FC are poorly understood and have received little investigation, mainly due to the challenges of studying causal links between developmental phenomena and assessing FC in newborn infants. Recent advancements in infant neuromonitoring and neuroimaging strategies will allow for the design of interventions to improve infant sleep quality and quantity. This review discusses how sleep and FC develop in early life, the dynamic relationship between sleep, preterm birth, and FC, and the challenges associated with understanding these processes. Impact Sleep in early life is essential for proper functional brain development, which is essential for the brain to integrate and process information. This process may be impaired in infants born preterm. The connection between preterm birth, early development of brain functional connectivity, and sleep is poorly understood. This review discusses how sleep and brain functional connectivity develop in early life, how these processes might become impaired, and the challenges associated with understanding these processes. Potential solutions to these challenges are presented to provide direction for future research.Peer reviewe

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

Early brain activity : Translations between bedside and laboratory

Neural activity is both a driver of brain development and a readout of developmental processes. Changes in neuronal activity are therefore both the cause and consequence of neurodevelopmental compromises. Here, we review the assessment of neuronal activities in both preclinical models and clinical situations. We focus on issues that require urgent translational research, the challenges and bottlenecks preventing translation of biomedical research into new clinical diagnostics or treatments, and possibilities to overcome these barriers. The key questions are (i) what can be measured in clinical settings versus animal experiments, (ii) how do measurements relate to particular stages of development, and (iii) how can we balance practical and ethical realities with methodological compromises in measurements and treatments.Peer reviewe

Clinical value of cortical bursting in preterm infants with intraventricular haemorrhage

Background: In healthy preterm infants, cortical burst rate and temporal dynamics predict important measures such as brain growth. We hypothesised that in preterm infants with germinal matrix-intraventricular haemorrhage (GM-IVH), cortical bursting could provide prognostic information. / Aims: We determined how cortical bursting was influenced by the injury, and whether this was related to developmental outcome. / Study design: Single-centre retrospective cohort study at University College London Hospitals, UK. / Subjects: 33 infants with GM-IVH ≥ grade II (median gestational age: 25 weeks). / Outcome measures: We identified 47 EEGs acquired between 24 and 40 weeks corrected gestational age as part of routine clinical care. In a subset of 33 EEGs from 25 infants with asymmetric injury, we used the least-affected hemisphere as an internal comparison. We tested whether cortical burst rate predicted survival without severe impairment (median 2 years follow-up). / Results: In asymmetric injury, cortical burst rate was lower over the worst- than least-affected hemisphere, and bursts over the worst-affected hemisphere were less likely to immediately follow bursts over the least-affected hemisphere than vice versa. Overall, burst rate was lower in cases of GM-IVH with parenchymal involvement, relative to milder structural injury grades. Higher burst rate modestly predicted survival without severe language (AUC 0.673) or motor impairment (AUC 0.667), which was partly mediated by structural injury grade. / Conclusions: Cortical bursting can index the functional injury after GM-IVH: perturbed burst initiation (rate) and propagation (inter-hemispheric dynamics) likely reflect associated grey matter and white matter damage. Higher cortical burst rate is reassuring for a positive outcome

Characterisation of the Haemodynamic Response Function (HRF) in the neonatal brain using functional MRI

Background: Preterm birth is associated with a marked increase in the risk of later neurodevelopmental impairment. With the incidence rising, novel tools are needed to provide an improved understanding of the underlying pathology and better prognostic information. Functional Magnetic Resonance Imaging (fMRI) with Blood Oxygen Level Dependent (BOLD) contrast has the potential to add greatly to the knowledge gained through traditional MRI techniques. However, it has been rarely used with neonatal subjects due to difficulties in application and inconsistent results. Central to this is uncertainity regarding the effects of early brain development on the Haemodynamic Response Function (HRF), knowledge of which is fundamental to fMRI methodology and analysis. Hypotheses: (1) Well localised and positive BOLD functional responses can be identified in the neonatal brain. (2) The morphology of the neonatal HRF differs significantly during early human development. (3) The application of an age-appropriate HRF will improve the identification of functional responses in neonatal fMRI studies. Methods: To test these hypotheses, a systematic fMRI study of neonatal subjects was carried out using a custom made somatosensory stimulus, and an adapted study design and analysis pipeline. The neonatal HRF was then characterised using an event related study design. The potential future application of the findings was then tested in a series of small experiments. Results: Well localised and positive BOLD functional responses were identified in neonatal subjects, with a maturational tendency towards an increasingly complex pattern of activation. A positive amplitude HRF was identified in neonatal subjects, with a maturational trend of a decreasing time-to-peak and increasing positive peak amplitude. Application of the empirical HRF significantly improved the precision of analysis in further fMRI studies. Conclusions: fMRI can be used to study functional activity in the neonatal brain, and may provide vital new information about both development and pathology

Towards Patient-Specific Brain Networks Using Functional Magnetic Resonance Imaging

fMRI applications are rare in translational medicine and clinical practice. What can be inferred from a single fMRI scan is often unreliable due to the relative low signal-to-noise ratio compared to other neuroimaging modalities. However, the potential of fMRI is promising. It is one of the few neuroimaging modalities to obtain functional brain organisation of an individual during task engagement and rest. This work extends on current fMRI image processing approaches to obtain robust estimates of functional brain organisation in two resting-state fMRI cohorts. The first cohort comprises of young adults who were born at extremely low gestations and age-matched healthy controls. Group analysis between term- and preterm-born adults revealed differences in functional organisation, which were discovered to be predominantly caused by underlying structural and physiological differences. The second cohort comprises of elderly adults with young onset Alzheimer’s disease and age-matched controls. Their corresponding resting-state fMRI scans are short in scanning time resulting in unreliable spatial estimates with conventional dual regression analysis. This problem was addressed by the development of an ensemble averaging of matrix factorisations approach to compute single subject spatial maps characterised by improved spatial reproducibility compared to maps obtained by dual regression. The approach was extended with a haemodynamic forward model to obtain surrogate neural activations to examine the subject’s task behaviour. This approach applied to two task-fMRI cohorts showed that these surrogate neural activations matched with original task timings in most of the examined fMRI scans but also revealed subjects with task behaviour different than intended by the researcher. It is hoped that both the findings in this work and the novel matrix factorisation approach itself will benefit the fMRI community. To this end, the derived tools are made available online to aid development and validation of methods for resting-state and task fMRI experiments