CLOSED-LOOP CONTROLLED TOTAL INTRA VENOUS ANAESTHESIA

Anaesthesia is important for both surgery and intensive care and intravenous anaesthetics are widely used to provide rapid onset, stable maintenance, and rapid recovery compared with inhaled anaesthetics. The aim of the project on which this thesis is based was to investigate a reliable and safe methodology for delivering total intravenous anaesthesia using closed-loop control technology and bispectral analysis of human electroencephalogram (EEG) waveform. In comparison with Target Controlled Infusion (TCI), drug effect is measured during drug infusion in closed loop anaesthesia (CLAN). This may provide superior safety, better patient care, and better quality of anaesthesia whilst relieving the clinician of the need to make recurrent and minor alterations to drug administration. However, the development of a CLAN system has been hindered by the Jack of a 'gold standard' for anaesthetic states and difficulties with patient variability in pharmacokinetic and pharmacodynamic modelling, and a new and generic mathematical model of a closed-loop anaesthesia system was developed for this investigation. By using this CLAN model, investigations on pharmacokinetic and pharmacodynamic variability existing in patients were carried out. A new control strategy that combines a Proportional, Integral, Derivative (PID) controller, bispectral analysis of EEG waveform and pharmacokinetic/ pharmacodynamic models was investigated. Based on the mathematical model, a prototype CLAN system, the first CLAN system capable of delivering both hypnotics and analgesics simultaneously for total intravenous anaesthesia, was developed. A Bispectral Index (BIS), derived from power spectral and bispectral analysis on EEG waveform, is used to measure depth of anaesthesia. A supervision system with built-in digital signal processing techniques was developed to compensate the non-linear characteristics inherent in the system while providing a comprehensive protection mechanism for patient safety. The CLAN system was tested in 78125 virtual patients modelled using published data. Investigations on intravenous anaesthesia induction and maintenance with the CLAN system were carried out in various clinical settings on 21 healthy volunteers and 15 patients undergoing surgery. Anaesthesia targets were achieved quickly and well maintained in all volunteers/patients except for 2 patients with clinically satisfactory anaesthesia quality.Derriford Hospita

Spatiotemporal brain dynamics induced by propofol and ketamine in humans

Human brain dynamics are radically altered under the influence of anaesthetics. However, despite their widespread clinical use, the whole-brain mechanisms by which anaesthetics alter consciousness are still not fully understood and clinical translation of existing insights is limited. This thesis presents several lines of investigation aimed to improve our understanding of spatiotemporal brain states under the anaesthetics propofol and ketamine. First, slow-wave activity saturation (SWAS) was studied across the brain and in relation to existing depth of anaesthesia markers. Local propofol concentration needed to achieve SWAS in healthy volunteers correlated with GABA-A receptor density (Spearman ρ=-0.69, P=0.0018), providing more evidence for the importance of the neurophysiological state of SWAS. The average Bispectral Index at SWAS across volunteers was 49±4, but its value varied significantly over time. Second, relevant cortico-cardiac interactions were studied. A slow propofol infusion increased heart rate in a dose-dependent manner (increase of +4.2±1.5 bpm / (μg ml-1), P<0.001). Individual cortical slow waves were coupled to the heartbeat (P<0.001), with heartbeat incidence peaking about 450ms before slow-wave onset. A ketamine case study showed decreased amplitude of heartbeat-evoked potentials, suggesting impaired interoceptive signalling may have a part in dissociative phenomenology. Third, novel methodology was developed, validated, and applied throughout the thesis. Iterated Masking Empirical Mode Decomposition was used to identify three types of low-frequency propofol waves with different spatiotemporal maps and dose-responses. Hidden Markov Modelling of propofol showed a shift to anterior alpha states and a reduced switching rate (P<0.01); with ketamine states exhibiting low alpha power and decreased connectivity became more prominent (P<0.001). Fourth, the potential of translating electroencephalographic markers from high- to low- density montages was studied. Posterior montages were best at capturing the reduced state switching under propofol. A patient study of antidepressant ketamine treatment demonstrated reduced temporal lobe alpha and theta power were associated with dissociation (P=0.0109)

Quantification of inter-brain coupling: A review of current methods used in haemodynamic and electrophysiological hyperscanning studies

Hyperscanning is a form of neuroimaging experiment where the brains of two or more participants are imaged simultaneously whilst they interact. Within the domain of social neuroscience, hyperscanning is increasingly used to measure inter-brain coupling (IBC) and explore how brain responses change in tandem during social interaction. In addition to cognitive research, some have suggested that quantification of the interplay between interacting participants can be used as a biomarker for a variety of cognitive mechanisms aswell as to investigate mental health and developmental conditions including schizophrenia, social anxiety and autism. However, many different methods have been used to quantify brain coupling and this can lead to questions about comparability across studies and reduce research reproducibility. Here, we review methods for quantifying IBC, and suggest some ways moving forward. Following the PRISMA guidelines, we reviewed 215 hyperscanning studies, across four different brain imaging modalities: functional near-infrared spectroscopy (fNIRS), functional magnetic resonance (fMRI), electroencephalography (EEG) and magnetoencephalography (MEG). Overall, the review identified a total of 27 different methods used to compute IBC. The most common hyperscanning modality is fNIRS, used by 119 studies, 89 of which adopted wavelet coherence. Based on the results of this literature survey, we first report summary statistics of the hyperscanning field, followed by a brief overview of each signal that is obtained from each neuroimaging modality used in hyperscanning. We then discuss the rationale, assumptions and suitability of each method to different modalities which can be used to investigate IBC. Finally, we discuss issues surrounding the interpretation of each method

Imaging the spatial-temporal neuronal dynamics using dynamic causal modelling

Oscillatory brain activity is a ubiquitous feature of neuronal dynamics and the synchronous discharge of neurons is believed to facilitate integration both within functionally segregated brain areas and between areas engaged by the same task. There is growing interest in investigating the neural oscillatory networks in vivo. The aims of this thesis are to (1) develop an advanced method, Dynamic Causal Modelling for Induced Responses (DCM for IR), for modelling the brain network functions and (2) apply it to exploit the nonlinear coupling in the motor system during hand grips and the functional asymmetries during face perception. DCM for IR models the time-varying power over a range of frequencies of coupled electromagnetic sources. The model parameters encode coupling strength among areas and allows the differentiations between linear (within frequency) and nonlinear (between-frequency) coupling. I applied DCM for IR to show that, during hand grips, the nonlinear interactions among neuronal sources in motor system are essential while intrinsic coupling (within source) is very likely to be linear. Furthermore, the normal aging process alters both the network architecture and the frequency contents in the motor network. I then use the bilinear form of DCM for IR to model the experimental manipulations as the modulatory effects. I use MEG data to demonstrate functional asymmetries between forward and backward connections during face perception: Specifically, high (gamma) frequencies in higher cortical areas suppressed low (alpha) frequencies in lower areas. This finding provides direct evidence for functional asymmetries that is consistent with anatomical and physiological evidence from animal studies. Lastly, I generalize the bilinear form of DCM for IR to dissociate the induced responses from evoked ones in terms of their functional role. The backward modulatory effect is expressed as induced, but not evoked responses

Nociception level during anaesthesia : analysis and control

Tese de Programa Doutoral. Engenharia Biomédica. Universidade do Porto. Faculdade de Engenharia. 201

Understanding loss of consciousness under general anaesthesia using multimodal neuroimaging

Despite major advancements in consciousness science over the past few decades, how anaesthesia causes loss of consciousness remains incompletely understood and the translation from basic science to clinical practice has been limited. Recent concurrent electroencephalography (EEG) and functional magnetic resonance imaging (FMRI) evidence indicates that a state of complete perception loss is achieved under general anaesthesia when slow wave activity in the brain reaches saturation. Slow wave activity saturation (SWAS) is therefore a potentially clinically relevant end point for titration of anaesthesia. We have developed a prototype system for titrating anaesthesia to SWAS within an individual. The system features EEG and anaesthesia data input, modelling of slow wave power and detection of SWAS, and visualisation of the model output in a graphical user interface. The prototype system was applied in a patient pre-surgery study (Study 1) which focused on clinical translation of SWAS, and a healthy volunteer EEG-MRI study (Study 2) which focused on experimental validation of SWAS. We successfully applied the prototype SWAS system in twelve patients (Study 1) and twenty-three healthy volunteers (Study 2). No subjects in either Study 1 or Study 2 were behaviourally responsive when held at SWAS and none had recall of events from when they were held at SWAS. In Study 2, we also acquired measures of cerebral blood flow (CBF), and resting and task-related FMRI data during wakefulness and when held at SWAS. When held at the SWAS state, CBF was significantly elevated compared to wakefulness. Furthermore, we found that the brain was unresponsive to external stimulation when held at SWAS even when controlling for the observed CBF changes. Finally, we found that this was accompanied by disruption of functional connectivity in the thalamocortical system and in known resting state networks. Our findings provide further evidence that SWAS is a state of perception loss and a clinically relevant target for surgical anaesthesia

Characterisation of awakening from anaesthesia in infants

There is uncertainty about the doses of anaesthetic drugs required for unconsciousness in infants. It is important to both avoid inadequate doses leading to intraoperative awareness and also excess doses that may harm the developing brain. Depth of anaesthesia monitoring has been developed in adults based upon electroencephalography (EEG). The EEG of infants is different and few data are available. Heart rate variability (HRV) using the ECG is another non-invasive tool that could be used in infants. The hypothesis of this thesis is that EEG and HRV could help predict or warn of awakening after anaesthesia. Awakening was defined by a panel of experts as at least 2 of crying, coughing, vigorous limb movements, eyes open or looking around. A suitable clinical model of awakening from anaesthesia was determined in a series of pilot studies. Intubated infants anaesthetised with sevoflurane were studied after surgery. Tickling the foot proved a reliable stimulus to cause awakening. EEG and HRV were monitored at the end of surgery during emergence. Events and behaviour were videoed and characteristics of EEG and HRV were identified. After awakening began EMG and other interference made signals difficult to interpret. In all infants there was negligible EEG power in frequencies higher than 20Hz and most power was in frequencies less than 5Hz. Infants older than 52 weeks post menstrual age (PMA) had an oscillatory characteristic within the 5 to 20 Hz range during anaesthesia that reduced in power appreciably as sevoflurane levels decreased; power in 5-20 Hz reduced to less than 100 μV2 before awakening began which may provide a potential warning of awakening. Infants less than 52 weeks PMA had low EEG power in 5-20 Hz throughout. EEG power in this frequency band during anaesthesia increases with age. HRV was low during anaesthesia but increased before awakening began. HRV low frequency power increased in bursts as anaesthesia levels decreased. A case report demonstrated the potential value of P5-20Hz and LF HRV band power in the development of intraoperative depth of anaesthesia monitoring in infants older than 52 weeks PMA