Cortical pain processing in the infant brain.

Premature infants are exposed to multiple invasive procedures as part of their essential medical care. It is not known, however, if nociceptive information is processed by the cortex at this age. The fundamental question to be addressed by this thesis is whether premature infants display cortical responses to noxious stimulation. This thesis describes a series of studies where the question of cortical pain processing is addressed by directly measuring cortical responses to noxious stimulation using near-infrared spectroscopy (NIRS) and electroencephalography (EEG). The NIRS results show that, following an acute noxious event, the contralateral somatosensory cortex is functionally activated in infants from 25 weeks postmenstrual age (PMA). Awake infants have a larger cortical response than asleep infants and, in the awake group, the size of the response increases with PMA. The magnitude of the haemodynamic response correlates with pain scores calculated using the premature infant pain profile (PIPP), although infants who do not display a change in facial expression can still process noxious stimuli at the cortical level. Latency to response is longest in the youngest infants using either the haemodynamic response or change in facial expression as an output measure. The underlying pain-related neuronal activity in the cortex has been investigated using EEG. Nociceptive-specific event related potentials have been observed in infants from 31-42 weeks PMA, with a recognisable N-P complex visible in the contralateral somatosensory cortex in 82% of studies. Noxious stimulation can evoke specific patterns of neural activity within the cortex of preterm and term infants that can be observed on a single-trial basis. The studies represent the first measurements of cortical activation in the immature preterm cortex following a noxious event. The fact that noxious information is transmitted to higher levels of the central nervous system highlights the importance of developing a systematic approach to reduce pain and improve analgesic strategies in this vulnerable population

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

Diffuse optical tomography to investigate the newborn brain

Over the past 15 years, functional near-infrared spectroscopy (fNIRS) has emerged as a powerful technology for studying the developing brain. Diffuse optical tomography (DOT) is an extension of fNIRS that combines hemodynamic information from dense optical sensor arrays over a wide field of view. Using image reconstruction techniques, DOT can provide images of the hemodynamic correlates to neural function that are comparable to those produced by functional magnetic resonance imaging. This review article explains the principles of DOT, and highlights the growing literature on the use of DOT in the study of healthy development of the infant brain, and the study of novel pathophysiology in infants with brain injury. Current challenges, particularly around instrumentation and image reconstruction, will be discussed, as will the future of this growing field, with particular focus on whole-brain, time-resolved DOT

Development of a portable multi-channel broadband near infrared spectroscopy instrument to measure brain tissue oxygenation and metabolism during functional activation and seizures

Epilepsy is a common neurological disorder often developed during childhood, characterised by abnormal neuronal discharges. These spontaneous recurrent seizures can be associated with poor long-term neurological development. Near-infrared spectroscopy (NIRS) is a non-invasive tech- nique able to monitor cerebral concentration changes in oxygenated- (∆[HbO2]) and deoxygenated- (∆[HHb]) haemoglobin. However, current commercial NIRS systems use only a few wavelengths, limiting their use to haemodynamic monitoring. Broadband NIRS (bNIRS) systems use a larger number of wavelengths enabling changes in concentration of the oxidation state of cytochrome-c- oxidase (∆[oxCCO]) to be determined, a marker of cellular metabolism. This thesis describes the development and miniaturisation of an existing bNIRS system to monitor haemodynamic and metabolic changes in children with epilepsy. Using the latest technological advancements, the bulk and complexity of the system was reduced while increasing the number of measurement channels. Two miniature tungsten halogen light sources were utilised with time- multiplexing capabilities implemented (0.5Hz). Bifurcated optical fibre bundles (2.8mm diameter) connected to each light source and twelve detector fibre bundles (1mm diameter) arranged linearly into a ferrule (25mm diameter); modification of the interface between the detectors and lens-based spectrograph ensured compatibility with the increased detector number. Light was collimated to a diffraction grating with a wider 308nm bandwidth and the largest CCD image sensor available (1340x1300 array, 26.8x26mm) was integrated into the system. LabVIEW software was updated to enable simultaneous, real-time collection and display of intensity and concentration changes. Extensive testing of the system was performed; in-vivo testing in healthy adults using a Stroop task demonstrated a typical haemodynamic response with regional variation in metabolism. Si- multaneous bNIRS and electroencephalography data were collected from 12 children with epilepsy in the Neurology Unit. One patient case study is presented in detail, with temporal data from 17 seizures collected. A large decrease in metabolism was observed in the left posterior region, corresponding to a region of cortical malformation, suggesting an energetic deficiency in this re- gion. This indicates the potential for ∆[oxCCO] as an investigative marker in monitoring seizures, providing localised information about cellular oxygen utilisation

Advanced Signal Processing and Control in Anaesthesia

This thesis comprises three major stages: classification of depth of anaesthesia (DOA); modelling a typical patient’s behaviour during a surgical procedure; and control of DOAwith simultaneous administration of propofol and remifentanil. Clinical data gathered in theoperating theatre was used in this project. Multiresolution wavelet analysis was used to extract meaningful features from the auditory evoked potentials (AEP). These features were classified into different DOA levels using a fuzzy relational classifier (FRC). The FRC uses fuzzy clustering and fuzzy relational composition. The FRC had a good performance and was able to distinguish between the DOA levels. A hybrid patient model was developed for the induction and maintenance phase of anaesthesia. An adaptive network-based fuzzy inference system was used to adapt Takagi-Sugeno-Kang (TSK) fuzzy models relating systolic arterial pressure (SAP), heart rate (HR), and the wavelet extracted AEP features with the effect concentrations of propofol and remifentanil. The effect of surgical stimuli on SAP and HR, and the analgesic properties of remifentanil were described by Mamdani fuzzy models, constructed with anaesthetist cooperation. The model proved to be adequate, reflecting the effect of drugs and surgical stimuli. A multivariable fuzzy controller was developed for the simultaneous administration of propofol and remifentanil. The controller is based on linguistic rules that interact with three decision tables, one of which represents a fuzzy PI controller. The infusion rates of the two drugs are determined according to the DOA level and surgical stimulus. Remifentanil is titrated according to the required analgesia level and its synergistic interaction with propofol. The controller was able to adequately achieve and maintain the target DOA level, under different conditions. Overall, it was possible to model the interaction between propofol and remifentanil, and to successfully use this model to develop a closed-loop system in anaesthesia

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

Investigating the role of Gamma-aminobutyric acid (GABA) in sedation: a combinedelectrophysiological, haemodynamicand spectroscopic study in humans

A better understanding of the mechanisms of anaesthesia and sedation are expected not only to improve the understanding of the neural correlates of consciousness but also to help improve safety from the complications of anaesthesia/ sedation and develop safer drugs and objective brain function monitoring systems. Neuroimaging modalities such as functional MRI, magnetoencephalography and MR spectroscopy provide complimentary information about brain functions and can help interrogate brain activity in a living human brain. Most anaesthetic drugs act by enhancing the inhibitory actions of GABA in the brain. Most neuroimaging research has focused on anaesthetic-induced unconsciousness, with only few investigating the earliest levels of sedation-induced altered consciousness. The work in this thesis used a range of advanced neuroimaging modalities to investigate the role of GABA (through a GABA-ergic drug, propofol), during mild sedation, in humans. This was performed as a series of experiments within two, sequential, scanning sessions, MEG followed by fMRI, in the same participants. Propofol resulted in a dissociation of the visual gamma band response (decreased evoked, increased induced power). This was related to a reduced BOLD fMRI response but there were no changes in MRS detectable GABA concentration. Response to multisensory stimulation also revealed interesting changes with MEG and fMRI. Functional connectivity analyses showed changes in connectivities of the posterior cingulate cortex (key hub of default-mode network) and thalamus with each other and other key brain regions. Resting state networks were identified with MEG too, which revealed interesting increases in connectivity in certain band- limited networks while motor networks showed no change. Perfusion fMRI using arterial spin labelling revealed a global and regional reduction in perfusion, highlighting some of the key regions (frontal cortex, precuenus, PCC and thalamus) involved in sedation

Near Infrared Spectroscopy and Electroencephalography For an Assessment of Brain Function in patients with Disorders of Consciousness

There is growing evidence that some of the patients presenting with the Vegetative State (VS), also known as Unresponsive Wakefulness State, can respond to environmental stimuli. This response can be detected by using functional brain imaging, including electroencephalography (EEG) or Near Infrared Spectroscopy (NIRS). By definition, the VS patients are awake but not aware, unlike the patients in the Minimally Conscious State (MCS), who have some fluctuating awareness. Since consciousness is impaired in both conditions, these states are also referred as Disorders of Consciousness (DOC) or prolonged Disorders of Consciousness (pDOC) This thesis aims to develop a bedside applicable tool using the EEG and NIRS for brain function assessment in VS and MCS patients. In this study, two experimental protocols have been developed and validated on healthy subjects. The results showed that using the motor imagery and own subject name stimuli, some of the VS patients were able to wilfully modulate their brain activity in response to those stimuli. The results presented in this thesis can be implemented as a part of a protocol for brain function assessment in pDOC patients and can be used for the further studies for better understanding of the brain function in these patients