Measurement of Neurovascular Coupling in Neonates

Neurovascular coupling refers to the mechanism that links the transient neural activity to the subsequent change in cerebral blood flow, which is regulated by both chemical signals and mechanical effects. Recent studies suggest that neurovascular coupling in neonates and preterm born infants is different compared to adults. The hemodynamic response after a stimulus is later and less pronounced and the stimulus might even result in a negative (hypoxic) signal. In addition, studies both in animals and neonates confirm the presence of a short hypoxic period after a stimulus in preterm infants. In clinical practice, different methodologies exist to study neurovascular coupling. The combination of functional magnetic resonance imaging or functional near-infrared spectroscopy (brain hemodynamics) with EEG (brain function) is most commonly used in neonates. Especially near-infrared spectroscopy is of interest, since it is a non-invasive method that can be integrated easily in clinical care and is able to provide results concerning longer periods of time. Therefore, near-infrared spectroscopy can be used to develop a continuous non-invasive measurement system, that could be used to study neonates in different clinical settings, or neonates with different pathologies. The main challenge for the development of a continuous marker for neurovascular coupling is how the coupling between the signals can be described. In practice, a wide range of signal interaction measures exist. Moreover, biomedical signals often operate on different time scales. In a more general setting, other variables also have to be taken into account, such as oxygen saturation, carbon dioxide and blood pressure in order to describe neurovascular coupling in a concise manner. Recently, new mathematical techniques were developed to give an answer to these questions. This review discusses these recent developments

Translating the hemodynamic response: why focused interdisciplinary integration should matter for the future of functional neuroimaging

The amount of information acquired with functional neuroimaging techniques, particularly fNIRS and fMRI, is rapidly growing and has enormous potential for studying human brain functioning. Therefore, many scientists focus on solving computational neuroimaging and Big Data issues to advance the discipline. However, the main obstacle—the accurate translation of the hemodynamic response (HR) by the investigation of a physiological phenomenon called neurovascular coupling—is still not fully overcome and, more importantly, often overlooked in this context. This article provides a brief and critical overview of significant findings from cellular biology and in vivo brain physiology with a focus on advancing existing HR modelling paradigms. A brief historical timeline of these disciplines of neuroscience is presented for readers to grasp the concept better, and some possible solutions for further scientific discussion are provided

Development of simultaneous electroencephalography and near-infrared optical topography for applications to neurovascular coupling and neonatal seizures

This thesis describes the development and preliminary application of methods for performing simultaneous electroencephalography (EEG) and near-infrared (NIR) imaging of the brain. The simultaneous application of EEG and NIR imaging has many benefits because of the complementary nature of the two modalities, and has significant potential in the study of the relationship between neuronal activity and cerebral haemodynamics. This work goes beyond previous experiments which have combined EEG and limited-channel near-infrared spectroscopy by designing and implementing an arrangement which allows dense near-infrared optical topography and EEG to be performed over the same cortical area, with as simple an application method as possible. These application methods are described in detail, as is their extensive testing using novel dual-modality phantoms and an in-vivo EEG-NIR imaging experiment in a healthy adult. These methods are subsequently applied to the study of neonates in the clinical environment. An intricate EEG-NIR imaging experiment is designed and implemented in an investigation of functional activation in the healthy neonatal visual cortex. This series of experiments also acts as a further test of the suitability of our EEG-NIR imaging methods for clinical application. The results of these experiments are presented. The EEG-NIR imaging arrangement is then applied to four neurologically damaged infants in the neonatal intensive care unit, each of whom had been diagnosed with seizures. The results of these studies are presented, and a potentially significant haemodynamic feature, which is not present in agematched controls, is identified. The importance and physiological implications of our findings are discussed, as is the suitability of a combined EEG and NIR imaging approach to the study and monitoring of neonatal brain injury

Existence of Initial Dip for BCI: An Illusion or Reality

A tight coupling between the neuronal activity and the cerebral blood flow (CBF) is the motivation of many hemodynamic response (HR)-based neuroimaging modalities. The increase in neuronal activity causes the increase in CBF that is indirectly measured by HR modalities. Upon functional stimulation, the HR is mainly categorized in three durations: (i) initial dip, (ii) conventional HR (i.e., positive increase in HR caused by an increase in the CBF), and (iii) undershoot. The initial dip is a change in oxygenation prior to any subsequent increase in CBF and spatially more specific to the site of neuronal activity. Despite additional evidence from various HR modalities on the presence of initial dip in human and animal species (i.e., cat, rat, and monkey); the existence/occurrence of an initial dip in HR is still under debate. This article reviews the existence and elusive nature of the initial dip duration of HR in intrinsic signal optical imaging (ISOI), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIRS). The advent of initial dip and its elusiveness factors in ISOI and fMRI studies are briefly discussed. Furthermore, the detection of initial dip and its role in brain-computer interface using fNIRS is examined in detail. The best possible application for the initial dip utilization and its future implications using fNIRS are provided

Study of the Term Neonatal Brain Injury with combined Diffuse Optical Tomography and Electroencephalography

This thesis describes the application of combined diffuse optical tomography (DOT) and electroencephalography (EEG) in the investigation of neonatal term brain injury. With hypoxic ischaemic encephalopathy (HIE) and perinatal stroke being the most frequent contributors to brain injury in the term neonatal population, the first part of the thesis focuses on the description and ongoing requirement for their further investigation. In continuation to that, the characteristics and unique properties of both DOT and EEG are described and explored. The combination of these two modalities was utilised in elucidating the relationship between neuronal activity and cerebral haemodynamics both in physiological processes as well as in disease, by the infant’s cot side. This work differs to previous studies using near-infrared technologies and EEG, as a denser whole head array was used, offering the potential of 3-dimensional image reconstruction of the cortical haemodynamic events in relation to electro-cortical activity. These methods were applied in the study of critically ill infants presenting with seizures in the first few days of life. The relevant results are presented in three separate chapters of the thesis. Distinct neurophysiological phenomena such as seizures and burst suppression were detected and studied in association to underlying HIE. On the grounds of a pre-existing pilot study of our research group, distinct prolonged de-oxygenated cortical areas were identified following electrical seizure activity. Further exploration of infants with seizures provided limited supporting evidence. The investigation of burst suppression in HIE led to the first ever identification of repeated, waveform, cortical haemodynamic events in response to bursts of electrical activity with some spatial correlation to regions of brain injury. Further analysis of the low frequencies within the diffuse optical signal in cases of perinatal stroke, showed a consistent interhemispheric difference between the healthy and stroke-affected brain regions. The limitations, prospects and conclusions are presented in the final chapter. The use of simultaneous DOT and EEG offers a unique neuro-monitoring and neuro-investigating tool in the neonatal intensive care environment, which is safe, portable, and cost-effective, Ongoing research is required for the exploration and development of the methodology and its potential diagnostic properties

Effects of exposure to colored light on cerebral and systemic physiology in humans

Humans in industrialized societies have become independent of the natural day and night cycle due to the invention and use of artificial light. Colored light is an element of everyday life, which affects various human functions. The main aim of this PhD thesis is to comprehensively investigate the effects of exposure to colored light on cerebral and human physiology. To achieve this goal, 201 healthy right-handed adults were recruited for 20 different colored light conditions. By using systemic physiology augmented functional near-infrared spectroscopy (SPA-fNIRS) neuroimaging, each subject was measured 2-4 times on different days resulting in 676 single measurements. The SPA-fNIRS approach combines the measurement of brain activity and systemic physiological changes. fNIRS is a non-invasive neuroimaging technique employed to measure changes in cerebral hemodynamics and oxygenation. There is an interaction between these and changes in systemic physiology: consequently, the SPA-fNIRS generally enables us to identify and understand these interactions. We simultaneously assessed the effects of colored light exposure (CLE) in the visual cortex (VC), prefrontal cortex (PFC) and systemic physiology. Such a comprehensive study has not been carried out yet, and an integrative view of how the color of light affects the brain and systemic physiology is lacking. In general, CLE has relatively long-lasting effects on cerebral and systemic physiology in humans, and yellow light leads to higher brain activation in the PFC than the other colored lights. Yellow CLE is associated with more active and positive emotions, including happiness, joy, hope, and cheerfulness. We also show that long-term colored light exposures induce wavelength-dependent modulations of brain responses in the VC. Violet and blue lights elicit higher changes in cerebral parameters compared to the other colored lights during the CLE and recovery phase. Our results show that CLE affects individual humans differently. In particular, blue light leads to eight different hemodynamic response patterns, while the typical hemodynamic response pattern (increase in oxygenated ([O2Hb]) and decrease in deoxygenated ([HHb]) hemoglobin) is still observed and valid at the group-level analysis. The SPA-fNIRS approach is able to show that systemic and cerebral physiology interact. Experimental findings in most parts of this research display that inter-subject variability of hemodynamic responses is partially explained by systemic physiological changes. The finding of this research that blue light has an activating effect in the VC should be taken into consideration when assessing the impact of modern light sources such as screens and light-emitting diodes (LEDs) on the human body. Our findings that yellow light leads to higher PFC activation be tested as a potentially beneficial tool in chromotherapy, i.e., a complementary medicine method, to balance “energy” lacking in physical, emotional, and mental levels. Although yellow light, i.e., CLE in general term, influences humans in several positive ways, it should be noted that each individual reacts differently to the CLE, implying that colored light therapy has to be also adjusted to each individual. Therefore, further research should clarify which color in CLE benefits whom. In a civilization that is rapidly exposed to new and increasing lighting, the findings of this research are relevant for the scientific community, medical professionals, and society

Functional Electrical Impedance Tomography of adult and neonatal brain function.

Electrical Impedance Tomography (EIT) is a fast, portable imaging technique that produces tomographic images of the internal impedance of an object from surface electrode measurements. This thesis reports the first use of EIT to image evoked brain activity in adults and neonates and determines whether accurate EIT images could be obtained from the adult and neonatal brain. In addition, a realistic head-tank phantom was developed to test the performance of EIT with known impedance changes placed within a real human skull. Two EIT systems were used. Images were obtained using 31 or 21 Ag/AgCl EEG scalp electrodes in adults and neonates, respectively, with either 256 or 187 individual impedance measurements from different electrode combinations: 2 applied a safe, alternating current and 2 measured the resultant scalp voltage. Imaging was performed using a block design with 6-15 stimulation periods of between 10-75s during either: 1) Visual, 2) Somatosensory or 3) Motor stimuli. Impedance changes were detected in 38/39 adults and 9/9 neonates within 0.6-5.8s after stimulus onset, and returned to baseline 7.6-36s after stimulus cessation. Reconstructed images were noisy: -20-70% images showed correct localisation to the expected area of cortex stimulated by the visual, motor or somatosensory paradigms. As EIT images from the head-tank localised changes within 10% of the impedance perturbation, this indicated that poor localisation in humans was not due to the head-shape or the skull, but may be related to unknown physiological factors. An improved EIT reconstruction algorithm, using a computerised finite-element model of the head, showed improved localisation for the adult images. This is the first demonstration that EIT can detect and image impedance changes in the head, probably due to increased regional cerebral blood volume in the activated cortex. Improvements may enable more accurate neuroimaging of the adult and neonatal brain for use in clinical practice

Functional MRI of focal and generalised interictal epileptiform discharges.

Localizing the source of epileptic discharges is important in gaining a greater understanding of the disease, classifying epilepsy, and identifying areas suitable for potentially curable surgical resection. Functional imaging measures haemodynamic, metabolic or neurochemical correlates to localise neural activity. Combining EEG with functional MRI (EEG-fMRI) allows the localisation of haemodynamic correlates of neuronal events recorded on surface EEG. The work in this thesis aims to identify the spatial haemodynamic correlates of interictal epileptiform discharges (IED) in patients with epilepsy using EEG-fMRI. Five studies form the main body of this thesis. In the first study, 46 patients with frequent generalised spike wave activity (GSW) were studied with EEG-fMRI on a 1.5 Tesla scanner. The main finding was of a characteristic pattern of fMRI signal decrease in frontal, parietal and posterior cingulate cortex, areas of association cortex, during GSW. In the second study, 4 patients from this first series were re-studied with a 3 Tesla scanner. A high degree of reproducibility was seen in the spatial distribution of fMRI changes. Perfusion MRI with an arterial spin label sequence was used that showed a decrease in blood flow to these areas during GSW. In the third study, a novel method for the analysis of fMRI data in epilepsy, temporal clustering analysis (TCA) was assessed. The technique was confounded by subject motion, and we were unable to reliably detect correlates of IED. The fourth study moves away from correlating visually identified IEDs on the EEG, and correlates power fluctuations in the delta frequency band with simultaneously acquired fMRI. Finally a combination of EEG-fMRI and MR tractography were used to study a patient with temporal lobe epilepsy. The issues surrounding potential use of EEG-fMRI as a clinical tool are discussed

Dynamic Assessment of Cerebral Metabolic Rate of Oxygen (cmro2) With Magnetic Resonance Imaging

The brain is almost entirely dependent on oxidative metabolism to meet its energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) is a direct measure of brain energy use. CMRO2 provides insight into brain functional architecture and has demonstrated potential as a clinical tool for assessing many common neurological disorders. Recent developments in magnetic resonance imaging (MRI)-based CMRO2 quantification have shown promise in spatially resolving CMRO2 in clinically feasible scan times. However, brain energy requirements are both spatially heterogeneous and temporally dynamic, responding to rapid changes in oxygen supply and demand in response to physiologic stimuli and neuronal activation. Methods for dynamic quantification of CMRO2 are lacking, and this dissertation aims to address this gap. Given the fundamental tradeoff between spatial and temporal resolution in MRI, we focus initially on the latter. Central to each proposed method is a model-based approach for deriving venous oxygen saturation (Yv) – the critical parameter for CMRO2 quantification – from MRI signal phase using susceptometry-based oximetry (SBO). First, a three-second-temporal-resolution technique for whole-brain quantification of Yv and CMRO2 is presented. This OxFlow method is applied to measure a small but highly significant increase in CMRO2 in response to volitional apnea. Next, OxFlow is combined with a competing approach for Yv quantification based on blood T2 relaxometry (TRUST). The resulting interleaved-TRUST (iTRUST) pulse sequence greatly improves T2-based CMRO2 quantification, while allowing direct, simultaneous comparison of SBO- and T2-based Yv. iTRUST is applied to assess the CMRO2 response to hypercapnia – a topic of great interest in functional neuroimaging – demonstrating significant biases between SBO- and T2-derived Yv and CMRO2. To address the need for dynamic and spatially resolved CMRO2 quantification, we explore blood-oxygen-level-dependent (BOLD) calibration, introducing a new calibration model and hybrid pulse sequence combining OxFlow with standard BOLD/CBF measurement. Preliminary results suggest Ox-BOLD provides improved calibration “M-maps” for converting BOLD signal to CMRO2. Finally, OxFlow is applied clinically to patients with obstructive sleep apnea (OSA). A small clinical pilot study demonstrates OSA-associated reductions in CMRO2 at baseline and in response to apnea, highlighting the potential utility of dynamic CMRO2 quantification in assessing neuropathology