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

Imaging physiological brain activity and epilepsy with Electrical Impedance Tomography

Electrical Impedance Tomography (EIT) allows reconstructing conductivity changes into images. EIT detects fast impedance changes occurring over milliseconds, due to ion channel opening, and slow impedance changes, appearing in seconds, due to cell swelling/increased blood flow. The purpose of this work was to examine the feasibility of using EIT for imaging a gyrencephalic brain with implanted depth electrodes during seizures. Chapter 1 summarises the principles of EIT. In Chapter 2, it is investigated whether recent technical improvements could enable EIT to image slow impedance changes upon visual stimulation non-invasively. This was unsuccessful so the remaining studies were undertaken on intracranial recordings. Chapter 3 presents a computer modelling study using data from patients, for whom the detection of simulated seizure-onset perturbations for both, fast and slow impedance changes, were improved with EIT compared to stereotactic electroencephalography (SEEG) detection or EEG inverse-source modelling. Chapter 4 describes the development of a portable EIT system that could be used on patients. The system does not require averaging and post-hoc signal processing to remove switching artefacts, which was the case previously. Chapter 5 describes the use of the optimised method in chemically-induced focal epilepsy in anaesthetised pigs implanted with depth electrodes. This shows for the first time EIT was capable of producing reproducible images of the onset and spread of seizure-related slow impedance changes in real-time. Chapter 6 presents a study on imaging ictal/interictal-related fast impedance changes. The feasibility of reconstructing ictal-related impedance changes is demonstrated for one pig and interictal-related impedance changes were recorded for the first time in humans. Chapter 7 summarises all work and future directions. Overall, this work suggests EIT in combination with SEEG has a potential to improve the diagnostic yield in epilepsy and demonstrates EIT can be performed safely and ethically creating a foundation for further clinical trials

Imaging fast neural activity in the brain during epilepsy with electrical impedance tomography

Electrical impedance tomography (EIT) is a medical imaging technique which reconstructs images of the internal conductivity of an object using boundary measurements obtained by applying current through pairs of non-penetrating surface electrodes. EIT is able to image impedance changes which arise during neural activity at a high spatiotemporal resolution through the rat cerebral cortex and therefore represents a novel method for understanding neuronal network dynamics in epilepsy. Additionally, it holds therapeutic potential for improving the presurgical localisation of epileptogenic foci in individuals with drug-resistant epilepsy. This thesis was aimed at developing EIT for imaging epileptiform activity in vivo and assessing its potential for clinical use. Chapter 1 is a review of existing functional neuroimaging modalities, the principles of EIT and previous studies that have used EIT for imaging epileptic events. In Chapter 2, the safety of continuous current application to the rat cortical surface at 10-100 μA and 1725 Hz, parameters that are representative of fast neural EIT protocols, was verified by histological evaluation. Chapter 3 details the development of two acute rat models of focal epilepsy, the cortical and hippocampal epileptic afterdischarges models, for assessing the feasibility of imaging epileptiform activity with fast neural EIT using epicortical electrode arrays. In Chapter 4, EIT was used to image the propagation of ictal spike-and-wave activity through the cerebral cortex at a resolution of 2 ms and ≤300 µm. In order to enable imaging of epileptiform discharges in deeper subcortical structures, the optimal carrier frequency for current application was determined in Chapter 5. Results demonstrated that the maximal signal-to-noise ratio of fast neural impedance changes during ictal discharges is obtained at 1355 Hz. Finally, in Chapter 6, epileptiform activity in the hippocampus was imaged, with a localisation accuracy of ≤400 µm, using epicortical impedance measurements obtained at this optimised carrier frequency

Pharmacodynamics of the Glutamate Receptor Antagonists in the Rat Barrel Cortex

Epipial application is one of the approaches for drug delivery into the cortex. However, passive diffusion of epipially applied drugs through the cortical depth may be slow, and different drug concentrations may be achieved at different rates across the cortical depth. Here, we explored the pharmacodynamics of the inhibitory effects of epipially applied ionotropic glutamate receptor antagonists CNQX and dAPV on sensory-evoked and spontaneous activity across layers of the cortical barrel column in urethane-anesthetized rats. The inhibitory effects of CNQX and dAPV were observed at concentrations that were an order higher than in slices in vitro, and they slowly developed from the cortical surface to depth after epipial application. The level of the inhibitory effects also followed the surface-to-depth gradient, with full inhibition of sensory evoked potentials (SEPs) in the supragranular layers and L4 and only partial inhibition in L5 and L6. During epipial CNQX and dAPV application, spontaneous activity and the late component of multiple unit activity (MUA) during sensory-evoked responses were suppressed faster than the short-latency MUA component. Despite complete suppression of SEPs in L4, sensory-evoked short-latency multiunit responses in L4 persisted, and they were suppressed by further addition of lidocaine suggesting that spikes in thalamocortical axons contribute ∼20% to early multiunit responses. Epipial CNQX and dAPV also completely suppressed sensory-evoked very fast (∼500 Hz) oscillations and spontaneous slow wave activity in L2/3 and L4. However, delta oscillations persisted in L5/6. Thus, CNQX and dAPV exert inhibitory actions on cortical activity during epipial application at much higher concentrations than in vitro, and the pharmacodynamics of their inhibitory effects is characterized by the surface-to-depth gradients in the rate of development and the level of inhibition of sensory-evoked and spontaneous cortical activity

Direction-Dependent Responses To Traumatic Brain Injury In Pediatric Pigs

Traumatic brain injury (TBI) in children is a costly and alarmingly prevalent public health concern. Children (4-11 years of age) in the US have the highest rate of TBI-related emergency department visits. The plane of head rotation significantly affects neurocognitive deficits and pathophysiological responses such as axonal injury, but is largely ignored in TBI literature. In Chapter 1, an outline of existing research is provided, including the lack of attention to diagnosis, treatment, and prevention in children, who exhibit distinct biomechanical and neuropathological responses to TBI. Additionally, we hypothesize that the plane of head rotation in TBI induces a) region-specific changes in axonal injury, which lead to acute and chronic changes in electrophysiological responses; b) changes to event-related potentials and resting state electroencephalography (EEG) and c) tract-oriented strain and strain rate alterations in the white matter. All work in this dissertation is based on a well-established piglet model of TBI. In Chapter 2, we assess a novel rotational head kinematic metric, rotational work (RotWork), which incorporates head rotation rate, direction, and brain shape, as a predictor of acute axonal injury. This metric provides an improvement over existing metrics and could be useful in the development of effective child safety equipment used in recreation or transportation. In Chapter 3, we generate functional networks from auditory event-related potentials and use the patterns of change to distinguish injured brains from non-injured; the resulting algorithm showed an 82% predictive accuracy. In Chapter 4, we find elevations in network nodal strength, modularity and clustering coefficient after TBI across all frequency bands relative to baseline, whereas both metrics were reduced in shams. We report the first study using resting state EEG to create functional networks in relation to pediatric TBI, noting that this work may assist in the development of TBI biomarkers. In Chapter 5, we use a high-resolution finite element model to examine the effects of head rotation plane on the distribution of regional strains and strain rates. Sagittal rapid head rotations induced significantly larger volume fraction of damaged brainstem than axial and coronal rotations. We also found that local tissue deformation and histopathology were head direction- and region- dependent but poorly correlated at a local scale. Finally, in Chapter 6, we conclude that the work presented in this dissertation is novel and contributes valuable knowledge to the study of pediatric TBI, and that consideration of the plane of head rotation is critical to the understanding and accurate prediction of pediatric functional and region-dependent responses to TBI

Imaging Physiological and Pathological Activity in the Brain using Electric Impedance Tomography

Electric Impedance Tomography (EIT) is a promising medical imaging technique that reconstructs the internal conductivity of an object from boundary measurements. EIT is currently being used to monitor the lung during ventilation clinically. Amongst other suggested uses for imaging it can also be used to image neuronal function. There are different ways on how EIT can image neuronal function and two of these are tested in this thesis. The overall aim of our work was to advance imaging of physiological and pathological neuronal activity using EIT and assess its potential for future clinical use. In Chapter 1, a general introduction into brain imaging techniques and EIT is given. In Chapter 2, the effect of different anaesthetics on the neuronal signal was assessed to prepare for EIT recordings under anaesthesia. In Chapter 3, we assessed the validity of two biophysical models regarding the behaviour of the impedance in response to alterations in the carrier frequency experimentally. This allowed an assessment of the ideal carrier frequency to image physiological neuronal activity. In Chapter 4, the source of the fast neural signal in EIT is discussed further. In Chapter 5, the possibility of imaging physiological neuronal activity throughout the brain is tested and its limitations are discussed. In Chapter 6, the impedance response to epileptiform activity is characterized and the potential use of EIT in imaging epileptic foci in epilepsy patients is discussed. In Chapter 7, imaging of epileptic foci in subcortical structures is tested using two different ways of imaging with EIT

Combined measures of oxygenation, haemodynamics and metabolism to understand neural responses in infants

fNIRS is an established research tool used to investigate typical and atypical brain development.Primarily, it provides measures of haemodynamic changes that are used to indirectly infer neural activity. Broadband NIRS provides a more direct marker of neuronal activation through measurement of changes in cytochrome-c-oxidase (CCO). As a cellular measure, CCO can be used as a bridge to improve our understanding of the link between neural and haemodynamic activity or “neurovascular coupling”. Study 1 demonstrated that changes in mitochondrial activity could be measured alongside haemodynamics during functional activation, over the temporal cortex, using a miniature system in four-to-six-month-old infants. In order to investigate the spatial specificity of CCO, its relation to haemodynamics and to build upon our understanding of neurovascular coupling mechanisms, multi-channel broadband NIRS was used alongside EEG in Study 2 where responses were measured over the visual cortex. Study 2 was performed in adults as the development of a concurrent NIRS and EEG protocol was methodologically challenging. Following this, Study 3 extended on experimental paradigms from Studies 1 and 2 to measure changes in metabolic activity and haemodynamics over the temporal and visual cortices, in four-to-seven-month-old infants. This study demonstrated simultaneous broadband NIRS and EEG use in infants for the first time. The results provided evidence of underdeveloped coupling of cerebral blood flow changes and mitochondrial activity in early infancy. Finally, Study 4 extended the protocol to investigate underlying biological mechanisms that may be altered in neurovascular coupling in autism, by studying infants at high familial risk for the disorder. The findings demonstrated that the combined protocol was not only feasible for use to study atypical brain development but also provided preliminary evidence of altered coupling between cerebral energy metabolism and haemodynamics.Taken together, this work illuminates hitherto undocumented evidence of neurovascular coupling during brain development and highlights the potential of using broadband NIRS with EEG for future neurodevelopmental research in typical and atypical populations

Combined measures of oxygenation, haemodynamics and metabolism to understand neural responses in infants

fNIRS is an established research tool used to investigate typical and atypical brain development.Primarily, it provides measures of haemodynamic changes that are used to indirectly infer neural activity. Broadband NIRS provides a more direct marker of neuronal activation through measurement of changes in cytochrome-c-oxidase (CCO). As a cellular measure, CCO can be used as a bridge to improve our understanding of the link between neural and haemodynamic activity or “neurovascular coupling”. Study 1 demonstrated that changes in mitochondrial activity could be measured alongside haemodynamics during functional activation, over the temporal cortex, using a miniature system in four-to-six-month-old infants. In order to investigate the spatial specificity of CCO, its relation to haemodynamics and to build upon our understanding of neurovascular coupling mechanisms, multi-channel broadband NIRS was used alongside EEG in Study 2 where responses were measured over the visual cortex. Study 2 was performed in adults as the development of a concurrent NIRS and EEG protocol was methodologically challenging. Following this, Study 3 extended on experimental paradigms from Studies 1 and 2 to measure changes in metabolic activity and haemodynamics over the temporal and visual cortices, in four-to-seven-month-old infants. This study demonstrated simultaneous broadband NIRS and EEG use in infants for the first time. The results provided evidence of underdeveloped coupling of cerebral blood flow changes and mitochondrial activity in early infancy. Finally, Study 4 extended the protocol to investigate underlying biological mechanisms that may be altered in neurovascular coupling in autism, by studying infants at high familial risk for the disorder. The findings demonstrated that the combined protocol was not only feasible for use to study atypical brain development but also provided preliminary evidence of altered coupling between cerebral energy metabolism and haemodynamics.Taken together, this work illuminates hitherto undocumented evidence of neurovascular coupling during brain development and highlights the potential of using broadband NIRS with EEG for future neurodevelopmental research in typical and atypical populations