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Electrophysiological responses to noxious stimuli in the anaesthetised child
Get PDFIn the UK, more than 235,000 children admitted to hospital each year receive an operation or investigation under general anaesthesia. It is not known whether nociceptive stimulation evokes a change in cortical brain activity in the anaesthetised child. The aim of this thesis is to determine whether noxious stimulation administered to anaesthetised children results in a measurable change in brain activity and whether this evoked activity is altered in children who have been born prematurely and experienced a high level of pain in early life. Changing patterns of neuronal activity evoked by noxious and non-noxious stimuli were 'time locked' to electrophysiological recordings by means of a novel high-speed camera and an event detection interface developed during this thesis. Changes in band power were examined pre- and post-stimuli and across the different stimulus modalities. In all children, background EEG activity was dominated by delta (<3 Hz) and alpha (8-12 Hz) band frequencies, consistent with previously reported anaesthetic literature. Clinical and experimental noxious stimulation, and tactile stimulation evoked a significant increase in delta activity (p<0.05) with no changes in average heart rate or ipsilateral EMG activity observed between pre- and post-stimulus. The application of local anaesthetic to the stimulation site diminished the evoked increase in delta activity. The response to noxious stimulation in the children born prematurely was not significantly different from the age-matched control group (p>0.05) but they had striking differences in their background EEG activity. Prematurely born children had significantly lower alpha and beta band activity. The electrophysiological recordings we have obtained show that it is possible to measure evoked brain activity following a variety of noxious and non-noxious stimuli to investigate how the paediatric human brain processes sensory information under anaesthesia. The EEG measures were more sensitive to nociception than changes in autonomic activity and reflex withdrawal activity. Noxious stimulation caused a significant increase in delta activity, representing an increase in cortical synchronisation. While the children who were born prematurely did not respond differently to the noxious stimulation they had dramatically different background activity, which could have clinical relevance when using brain-derived patterns of EEG activity to help establish anaesthetic depth
Investigating pain in the developing human brain
Get PDFInfants born prematurely or critically ill require a plethora of painful procedures during a period of extensive structural and functional neurodevelopment. Pain is however inconsistently and inadequately managed in neonatal care due to the inherent challenges of pain assessment and a lack of evidence-based analgesics. Noxious stimuli provoke behavioural and cardiorespiratory responses, which are valuable indicators of pain in the absence of verbal report. These measures can however be subjective and limited in specificity and sensitivity. EEG and fMRI can provide objective measures of noxious-evoked brain activity with which to investigate the development of nociceptive processing, its modulation in early life, and efficacy of analgesics.
In this thesis, I used electrophysiological measures to characterise the development of noxious-evoked brain and spinal reflex activity in the preterm period. Nociceptive-specific brain activity increased in magnitude with gestational age, whereas reflex withdrawal activity decreased in amplitude, duration, and latency. The relative proportion of these responses was strongly correlated with gestational age, suggesting a developmental relationship between spinal and supraspinal maturation. FMRI was subsequently used to investigate the relationship between noxious-evoked brain activity and connectivity of the periaqueductal grey (PAG), a core region of endogenous pain modulation and common target of analgesics. Functional connectivity of the PAG to the middle frontal gyrus and anterior cingulate cortex was negatively correlated with noxious-evoked BOLD activity. Developing connectivity of the PAG may begin to influence noxious-evoked brain activity in term neonates and influence the developmental relationship between electrophysiological measures.
Many external and internal factors influence pain. Sex differences in pain sensitivity and nociceptive processing are extensively reported in adults and animals. I therefore used electrophysiology and fMRI to investigate sex differences in nociceptive processing in healthy term infants. Noxious stimulation evoked greater magnitude of electrophysiological activity and greater BOLD activity across multiple brain regions in female compared to male infants.
Morphine is a commonly used analgesic in neonates despite inconclusive evidence of its efficacy. In my final study, noxious-evoked brain activity was employed as a co-primary outcome with clinical pain scoring to investigate the efficacy of oral morphine for procedural pain relief in infants born prematurely. The placebo-controlled trial was terminated early due to safety concerns. Despite significant cardiorespiratory effects, morphine did not attenuate multimodal measures of pain, raising questions concerning the balance of safety and efficacy of this drug.
In summary, this thesis demonstrates that age, connectivity of endogenous pain modulatory brain regions, and sex affect noxious-evoked brain activity, and this valuable biomarker of pain can be used alongside multimodal outcome measures and rigorous physiological monitoring to assess the efficacy of analgesic agents in neonates
Measuring pain in the newborn infant
Get PDFHospitalised infants require multiple painful procedures a day as part of their essential medical care. However, identifying and managing pain in non-verbal populations is challenging – the gold standard in adults is self-report of pain, but in infants we must rely on surrogate measures. In this thesis, electroencephalography (EEG), behavioural measures and physiological changes are used to investigate infant pain responses, exploring how responses to noxious stimulation are modulated by analgesics, age and pathology. It is essential to validate measures of pain in infants. As pain is both an emotional and sensory experience, noxious-evoked brain activity likely provides an important surrogate pain measure. An EEG template of noxious-evoked brain activity was validated for use in an independent group of infants: the noxiousevoked brain activity was only elicited in response to noxious stimulation and not in response to stimulation of other sensory modalities; was correlated with pain-related behaviour; and was sensitive to analgesic modulation by the use of topical local anaesthetic. This provides a novel approach, which can be used to test analgesic efficacy in infants. Behavioural responses form the cornerstone of clinical infant pain assessment. However, it is not clear whether the youngest, most premature infants are able to mount behavioural responses that can discriminate between noxious and innocuous stimulation. In this thesis, I have investigated the behavioural response to noxious and tactile stimulation in infants from 28-41 weeks corrected gestational age (CGA). The youngest infants demonstrated a lack of behavioural discrimination, being equally likely to mount a behavioural response to a tactile or a noxious stimulus. Responses diverged with increasing age, such that from approximately 32 weeks’ gestation, infants were significantly more likely to display facial grimacing to noxious stimulation. Finally, the impact of pathology on pain experience has not been well studied. I have investigated how early life infection impacts pain-related responses and demonstrate, using a multidimensional approach, that infants with infection display significantly greater noxious-evoked brain activity and are more likely to mount a behavioural response compared with non-infected infants. In summary, this thesis demonstrates that responses to pain are altered by age and pathology, and provides a novel brain-derived approach to testing the efficacy of analgesic interventions in infants
Sensory development in the newborn infant: modulation by early life experience and the impact of brain injury
Get PDFNeurological examination in newborn infants is challenging and novel methods of evaluating how multiple sensory systems are affected are needed to compliment developmental care interventions and treatments in the neonatal intensive care (NICU) setting. Infants who are born prematurely and those who are born with a perinatal complication are most vulnerable to debilitating neurocognitive dysfunction. Even though in some cases the problems may arise from clearly identifiable brain lesions routinely captured by brain ultrasound, more subtle changes in brain development may not be identified until school age. Bedside neuroimaging techniques such as the recording of evoked potentials (EP) can provide information regarding the functional integrity of sensory pathways, yet due to the technical challenges of performing them and interpretational issues, they are not widely used in neonatal care. In this thesis, electroencephalography (EEG) was recorded in infants born between 27 – 42 weeks gestational age (GA) and evoked responses to different types of sensory stimulation were analysed using advanced data driven analysis techniques. The spatial and temporal aspects of evoked activity in response to visual, tactile, and noxious stimulation in healthy term infants were characterised, and morphological templates were constructed for each stimulus modality. These templates were designed such that they could be projected onto data collected in independent infant cohorts to evaluate the early maturation of visual and somatosensory processing in prematurely-born infants and to establish how brain activity is altered by brain damage and hypothermia.
Using this data-driven analytical approach, the normative development of stimulus evoked activity was studied longitudinally in infants between 28-36 weeks post menstrual age (PMA). This study demonstrated the refinement of the spatial organisation of the stimulus-evoked activity with age and show how the developmental trajectory of these responses differs with the stimulus modality. Comparisons with cross sectional data recorded from a near-term control group of prematurely-born infants shows how specific components of the tactile and visual evoked response are altered by premature exposure to the ex-utero environment. In addition, similar methods were applied to a cohort of infants with neonatal hypoxic ischaemic encephalopathy (HIE) which were compared to a healthy term control group. Tactile and noxious stimulation in infants with HIE evokes significantly reduced magnitude EP responses compared with healthy term infants.
This thesis demonstrates how novel methods of evoked potential analysis can be used to evaluate evoked brain activity in newborn infants to address clinically relevant questions across various infant cohorts. In this thesis, I show how normal ex-utero sensory development is potentially affected by early exposure to the ex-utero environment. This supports the importance of developmental care interventions in the NICU. I also show the significant impact of neonatal HIE on somatosensory processing, highlighting the important effects of sedation on the interpretation of evoked potentials in this cohort of infants
Improving the measurement and treatment of infant pain
Get PDFInfants undergo numerous medically necessary painful procedures while in hospital, and this early life pain can lead to adverse effects. A range of pain relief interventions are available for use in neonatal units, including pharmacological analgesics, and non- pharmacological comfort measures. However, the literature regarding the efficacy of many of these pain relief interventions is inconclusive and inconsistent, and infant pain is consequently undertreated.
To assess infant pain, behavioural and physiological surrogate measures are utilised in the absence of verbal report. However, as these measures are not direct measures of pain, and can be influenced by other factors such as procedure-related distress, their use can lead to inconsistent conclusions regarding the efficacy of pain relief interventions. The perception of pain manifests in the brain, therefore it is plausible that measures of brain activity can provide specific and objective indications of the infant pain experience, and that these measures can be used to assess the efficacy of pain relief interventions. In this thesis, noxious-evoked brain activity is measured and used to investigate the effect of a pharmacological analgesic, paracetamol, and a non- pharmacological pain relief intervention, gentle touch targeted towards C-tactile (CT) fibres.
Noxious-evoked brain activity has been well characterised following medically required heel lances and experimental noxious stimuli, but brain activity evoked by alternative clinically relevant stimuli must also be characterised to assess the efficacy of a wider range of pain relief interventions for these procedures. In this thesis, brain activity evoked by immunisation is characterised, enabling the analgesic efficacy of paracetamol to be tested during routine infant immunisations.
Between-subject comparisons are often necessary when investigating the efficacy of pain relief interventions for medical procedures. However, there is great individual variability in nociceptive sensitivity, and controlling for this variability could enable better between-group comparisons. In the last section of this thesis, infant nociceptive sensitivity is measured and accounted for, in order to explore how this approach can be used to assess intervention efficacy, using the example of gentle touch targeted towards CT fibres.
Overall, the aims of the research described in this thesis are to advance knowledge regarding how infants respond to noxious clinical procedures, how pain relief interventions can modulate these responses, and how individual variability can be accounted for to enable better assessment of intervention efficacy. Research in the area of infant pain management is critical to inform clinical practise and improve the treatment of infant pain.</p
Developing neuroimaging methods for clinical translation and better understanding neonatal brain development
Get PDFUnderstanding and measuring pain and brain development in neonates is essential to be able to provide the best care for this vulnerable population. This is particularly important for premature infants, for whom early life is filled with more painful procedures, and earlier exposure to extrauterine stimuli, which can adversely affect development. Infant pain assessments combine behavioural and physiological measures such as facial expression, crying, and heart rate. However, these metrics are not specific to pain experience, nor sensitive enough to provide reliable outcome measures for clinical trials to validate pain treatments in infants. Neuroimaging techniques provide means to study brain health, development and function. EEG and fMRI measurements of noxious-evoked brain activity could be used to develop more objective and specific pain assessment tools. This thesis focusses on using EEG and MRI to measure infant pain and its relation to overall brain development.
First, I present tests of the validity of an EEG template measure of noxious response in infants recruited at multiple hospital sites. EEG has been used to quantify noxious-evoked activity and study pain interventions in infants, but a standard generalisable approach needs to be established. I tested whether the EEG template discriminates between noxious and non-noxious stimuli, whether the scale of noxious response is equivalent across different hospital sites, and whether noxious response increases with age in premature infants. I found that noxious-evoked responses are significantly greater than non-noxious responses, but that the scale is not equivalent across study sites, and there was no significant age correlation. This suggests that the EEG template can be reliably used as a surrogate measure of pain, with promise for clinical trials. Additionally, data collection site should be accounted for as a confounding factor as needed.
Then, I focus on how MRI can aid our understanding of infant pain and the underlying neurophysiology behind differences in noxious-evoked activity. I present a machine learning model that I developed to predict the magnitude of noxious-evoked responses from resting- state brain activity in infants, using fMRI data. By applying this model to data from the independent Developing Human Connectome Project, I explore how predicted noxious- evoked responses relate to development metrics, including resting-state cortical function and microstructure, as well as prematurity, and assessments of infant cognitive and motor ability at 2-year follow up. I found that prematurity is associated with accelerated development of the nociceptive system, but disrupted neurodevelopment overall.
In summary, this thesis demonstrates the potential for neuroimaging techniques to improve our understanding of infant brain development, and improve clinical assessment and treatment of infant pain
Multimodal assessment of neonatal pain
Get PDFPain assessment is critical to prevent suffering and harm in infants admitted to the neonatal care unit. As pain is a subjective experience, its assessment in nonverbal infants relies on surrogate measures. Current infant pain assessment tools that are based on behaviour and autonomic nervous system measurements lack face validity — they are unlikely to reflect pain in all its dimensions. In recent years, EEG-derived measures of pain have been developed in late preterm and term infants. Multimodal tools which include these cerebral measurements are conceptually more appropriate to measure pain. Yet, their use is still limited to specific research applications. This thesis focuses on outstanding questions that need to be addressed in order to advance the development of multimodal pain assessment tools that incorporate cerebral measurements.
In the first part of this thesis, I focus on the characterisation of preterm infants’ noxious-evoked responses and their development. Across several modalities, premature infants have dampened or altered responsiveness compared to term infants, and it is uncertain if these responses can be reliably discriminated from tactile-evoked responses. In particular, a discriminative pattern of noxious-evoked EEG activity that is present in term infants, is unlikely to be present in preterm infants. In addition, it is unclear how noxious-evoked responses, especially brainderived responses, change with age. In this thesis, I use a classification model to show that infants aged 28–40 weeks postmenstrual age display discriminable multimodal responses to a noxious clinical procedure and a tactile control procedure, and I provide examples of how a such a model could be used in clinical trials of analgesics. I show that noxious-evoked responses change magnitude and morphology across this age range, and that discriminative brain activity emerges in early prematurity. In the second part of this thesis, I focus on improving the neuroscientific validity of a noxious-evoked EEG response measured at the cot-side, as the spatial neural correlates of these responses are still poorly understood. I present an EEG-fMRI pilot study to investigate the spatial neural correlates of inter-individual differences in noxious-evoked EEG responses and provide recommendations for a larger follow-up study.
Overall, this thesis provides a characterisation of infants’ noxious-evoked responses and their development across multiple modalities, a crucial next step in improving multimodal neonatal pain assessment
Developing translational tools for measuring pain in neonates
Get PDFDespite the high burden of pain experienced by hospitalised neonates, there are few analgesics with proven efficacy. In part, this is due to the lack of a gold standard to measure pain in neonates. Assessing a complex experience like pain is challenging and, in the absence of self-report, all indicators of pain are surrogate measures. Clinicians often rely on behavioural and autonomic physiological responses which can be subjective and have limited sensitivity and specificity to detect pain. The pain experience requires the nociceptive signal to be processed in the brain. From a very young age, infants have the basic neural functional connectivity for pain perception. Thus, brain activity may provide a quantitative and objective measure of nociceptive processing in the infant brain.
Noxious-evoked brain activity using electroencephalography (EEG) has been previously characterised following experimental noxious stimuli and heel lances. In this thesis, I assessed the generalisability of a brain-derived surrogate measure of pain across various body locations and stimulus modalities. The morphology and latency of the evoked potentials were characterised following clinically-required injections applied to the thigh, and the efficacy of paracetamol during routine immunisations was evaluated in a pilot study.
The magnitude of the brain activity response to the same stimulus intensity can be highly variable between infants. As a result, large sample sizes are often required in studies of analgesic efficacy to account for inter-individual variability. In the second study, I developed an EEG-based paradigm that can be used to determine the baseline sensitivity of individual infants to noxious stimuli and I demonstrated that this paradigm can help to reduce sample sizes in analgesic clinical trials in infants.
The normal development of the nervous system is vulnerable to alterations by multiple factors, with the potential for long-term structural and functional detrimental outcomes. Immune function and sensitivity to pain are closely related, but the impact of early life inflammation on sensory nervous system development is poorly understood. In the final study, I used electrophysiological measures to investigate this relationship. I demonstrated in a cohort of term neonates that inflammation is associated with increased spinal cord excitability and hyperalgesia.
In summary, this thesis advances our understanding of the processing of nociceptive information in the infant brain and demonstrates how the use of brain-derived measures of pain can improve the evaluation of analgesic interventions
Translational neuroimaging for infant pain
Get PDFMany newborns are hospitalised, where they undergo clinically essential, noxious procedures. Exposure to these noxious stimuli is known to have harmful effects on infants in both the short-term and the long-term, and there are analgesic and other non-pharmacological interventions which might mitigate these. Despite this, pain is often undertreated in infants. This is partly because of the difficulty in identifying and measuring pain in this population. Our inability to accurately identify and measure pain in this population makes it difficult to evaluate the effect of interventions, and difficult to identify which hospitalised infants would benefit from them.
Neuroimaging measures of nociception have the advantage that they directly measure the brain. They can avoid many of the external confounding factors which are inherent to other methods, such as those based on physiology or behaviour. One particularly promising neuroimaging method is electroencephalography, which can be used to measure noxious evoked potentials (electroencephalographic signals caused by noxious stimuli). In this thesis I address two limitations of noxious evoked potential measurement; I do so by developing new methods for analysis.
The first topic is artefact and I address this in Chapter 4. Artefact in neuroimaging is measurement noise due to non-neural signals. I develop an automated, reproducible artefact detection algorithm. This algorithm uses machine learning techniques to distinguish between ‘clean’ epochs and those containing artefact. It performs as well as experienced raters in a fraction of the time.
The second topic is clinical utility and I address this in Chapter 5. A measurement for research settings does not necessarily translate well into clinical settings. For best clinical utility it is important for a measurement to be easily interpretable. I explore methods for combining individual neuroimaging and physiological metrics into a single, easily interpretable measure.
The overall intention of this thesis is to improve the EEG analysis methodology used both in neuroimaging research of neonatal pain, and in clinical practice
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