The epileptology of William Aldren Turner

William Aldren Turner (1864-1945), in his day Physician to the National Hospital, Queen Square, and to King's College Hospital, London, was one of the major figures in the world of epileptology in the period between Hughlings Jackson in the latter part of the 19th century and the advent of electroencephalography in the 1930s. Although he also made contributions to knowledge in other areas of neurology, and with Grainger Stewart wrote a competent textbook on that subject, Turner's main professional interest throughout his career seems to have been epilepsy. On the basis of a series of earlier, rather heavily statistical, personal publications dealing with various aspects of the disorder, he authored what became a well-accepted monograph entitled Epilepsy-a study of the idiopathic disorder, which appeared in 1907, and he also gave the 1910 Morison lectures in Edinburgh on the topic. His writings on epilepsy over a period of three decades consolidated knowledge rather than led to significant advances, but helped maintain interest in the disorder during a rather long fallow phase in the development of the understanding of its nature. (C) 2005 Elsevier Ltd. All rights reserved.

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy (n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses > 1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.

Monitoring Infants By Automatic Video Processing

This work has, as its objective, the development of non-invasive and low-cost systems for monitoring and automatic diagnosing specific neonatal diseases by means of the analysis of suitable video signals. We focus on monitoring infants potentially at risk of diseases characterized by the presence or absence of rhythmic movements of one or more body parts. Seizures and respiratory diseases are specifically considered, but the approach is general. Seizures are defined as sudden neurological and behavioural alterations. They are age-dependent phenomena and the most common sign of central nervous system dysfunction. Neonatal seizures have onset within the 28th day of life in newborns at term and within the 44th week of conceptional age in preterm infants. Their main causes are hypoxic-ischaemic encephalopathy, intracranial haemorrhage, and sepsis. Studies indicate an incidence rate of neonatal seizures of 0.2% live births, 1.1% for preterm neonates, and 1.3% for infants weighing less than 2500 g at birth. Neonatal seizures can be classified into four main categories: clonic, tonic, myoclonic, and subtle. Seizures in newborns have to be promptly and accurately recognized in order to establish timely treatments that could avoid an increase of the underlying brain damage. Respiratory diseases related to the occurrence of apnoea episodes may be caused by cerebrovascular events. Among the wide range of causes of apnoea, besides seizures, a relevant one is Congenital Central Hypoventilation Syndrome (CCHS) \cite{Healy}. With a reported prevalence of 1 in 200,000 live births, CCHS, formerly known as Ondine's curse, is a rare life-threatening disorder characterized by a failure of the automatic control of breathing, caused by mutations in a gene classified as PHOX2B. CCHS manifests itself, in the neonatal period, with episodes of cyanosis or apnoea, especially during quiet sleep. The reported mortality rates range from 8% to 38% of newborn with genetically confirmed CCHS. Nowadays, CCHS is considered a disorder of autonomic regulation, with related risk of sudden infant death syndrome (SIDS). Currently, the standard method of diagnosis, for both diseases, is based on polysomnography, a set of sensors such as ElectroEncephaloGram (EEG) sensors, ElectroMyoGraphy (EMG) sensors, ElectroCardioGraphy (ECG) sensors, elastic belt sensors, pulse-oximeter and nasal flow-meters. This monitoring system is very expensive, time-consuming, moderately invasive and requires particularly skilled medical personnel, not always available in a Neonatal Intensive Care Unit (NICU). Therefore, automatic, real-time and non-invasive monitoring equipments able to reliably recognize these diseases would be of significant value in the NICU. A very appealing monitoring tool to automatically detect neonatal seizures or breathing disorders may be based on acquiring, through a network of sensors, e.g., a set of video cameras, the movements of the newborn's body (e.g., limbs, chest) and properly processing the relevant signals. An automatic multi-sensor system could be used to permanently monitor every patient in the NICU or specific patients at home. Furthermore, a wire-free technique may be more user-friendly and highly desirable when used with infants, in particular with newborns. This work has focused on a reliable method to estimate the periodicity in pathological movements based on the use of the Maximum Likelihood (ML) criterion. In particular, average differential luminance signals from multiple Red, Green and Blue (RGB) cameras or depth-sensor devices are extracted and the presence or absence of a significant periodicity is analysed in order to detect possible pathological conditions. The efficacy of this monitoring system has been measured on the basis of video recordings provided by the Department of Neurosciences of the University of Parma. Concerning clonic seizures, a kinematic analysis was performed to establish a relationship between neonatal seizures and human inborn pattern of quadrupedal locomotion. Moreover, we have decided to realize simulators able to replicate the symptomatic movements characteristic of the diseases under consideration. The reasons is, essentially, the opportunity to have, at any time, a 'subject' on which to test the continuously evolving detection algorithms. Finally, we have developed a smartphone App, called 'Smartphone based contactless epilepsy detector' (SmartCED), able to detect neonatal clonic seizures and warn the user about the occurrence in real-time.

Induced visual illusions and gamma oscillations in human primary visual cortex

Using magnetoencephalography, we studied the spatiotemporal properties of cortical responses in terms of event-related synchronization and event-related desynchronization to a range of stripe patterns in subjects with no neurological disorders. These stripes are known for their tendency to induce a range of abnormal sensations, such as illusions, nausea, dizziness, headache and attacks of pattern-sensitive epilepsy. The optimal stimulus must have specific physical properties, and maximum abnormalities occur at specific spatial frequency and contrast. Despite individual differences in the severity of discomfort experienced, psychophysical studies have shown that most observers experience some degree of visual anomaly on viewing such patterns. In a separate experiment, subjects reported the incidence of illusions and discomfort to each pattern. We found maximal cortical power in the gamma range (30-60 Hz) confined to the region of the primary visual cortex in response to patterns of 2-4 cycles per degree, peaking at 3 cycles per degree. This coincides with the peak of mean illusions and discomfort, also maximal for patterns of 2-4 cycles per degree. We show that gamma band activity in V1 is a narrow band function of spatial frequency. We hypothesize that the intrinsic properties of gamma oscillations may underlie visual discomfort and play a role in the onset of seizures.

Causality and synchronisation in complex systems with applications to neuroscience

This thesis presents an investigation, of synchronisation and causality, motivated by problems in computational neuroscience. The thesis addresses both theoretical and practical signal processing issues regarding the estimation of interdependence from a set of multivariate data generated by a complex underlying dynamical system. This topic is driven by a series of problems in neuroscience, which represents the principal background motive behind the material in this work. The underlying system is the human brain and the generative process of the data is based on modern electromagnetic neuroimaging methods . In this thesis, the underlying functional of the brain mechanisms are derived from the recent mathematical formalism of dynamical systems in complex networks. This is justified principally on the grounds of the complex hierarchical and multiscale nature of the brain and it offers new methods of analysis to model its emergent phenomena. A fundamental approach to study the neural activity is to investigate the connectivity pattern developed by the brain’s complex network. Three types of connectivity are important to study: 1) anatomical connectivity refering to the physical links forming the topology of the brain network; 2) effective connectivity concerning with the way the neural elements communicate with each other using the brain’s anatomical structure, through phenomena of synchronisation and information transfer; 3) functional connectivity, presenting an epistemic concept which alludes to the interdependence between data measured from the brain network. The main contribution of this thesis is to present, apply and discuss novel algorithms of functional connectivities, which are designed to extract different specific aspects of interaction between the underlying generators of the data. Firstly, a univariate statistic is developed to allow for indirect assessment of synchronisation in the local network from a single time series. This approach is useful in inferring the coupling as in a local cortical area as observed by a single measurement electrode. Secondly, different existing methods of phase synchronisation are considered from the perspective of experimental data analysis and inference of coupling from observed data. These methods are designed to address the estimation of medium to long range connectivity and their differences are particularly relevant in the context of volume conduction, that is known to produce spurious detections of connectivity. Finally, an asymmetric temporal metric is introduced in order to detect the direction of the coupling between different regions of the brain. The method developed in this thesis is based on a machine learning extensions of the well known concept of Granger causality. The thesis discussion is developed alongside examples of synthetic and experimental real data. The synthetic data are simulations of complex dynamical systems with the intention to mimic the behaviour of simple cortical neural assemblies. They are helpful to test the techniques developed in this thesis. The real datasets are provided to illustrate the problem of brain connectivity in the case of important neurological disorders such as Epilepsy and Parkinson’s disease. The methods of functional connectivity in this thesis are applied to intracranial EEG recordings in order to extract features, which characterize underlying spatiotemporal dynamics before during and after an epileptic seizure and predict seizure location and onset prior to conventional electrographic signs. The methodology is also applied to a MEG dataset containing healthy, Parkinson’s and dementia subjects with the scope of distinguishing patterns of pathological from physiological connectivity.

Do tinted spectacle lens wearers have a different personality?

The wearing of tinted spectacle lenses is considered by some health care workers to be a marker of psychopathology or a hypochondriacal personality type. The purpose of this study was to determine whether there is a relationship between the wearing of tinted spectacle lenses and personality type in physically healthy subjects. The Sixteen Personality Factor Questionnaire 5th Edition, a multidimensional standardized self-report inventory, was used to determine the personality type of 98 participants. Twenty currently wore tinted spectacle lenses for reasons other than ocular disease, sun protection, outdoor or indoor glare reduction, pattern sensitive epilepsy, migraines, reading difficulties or fashion. The remainder did not wear tinted spectacle lenses for any purpose other than sun protection. Tinted lens wear and no tinted lens wear groups were age and gender matched. There was no statistically significant difference in five global personality factors between the no-tint and tint groups: extraversion (p = 0.31), anxiety (p = 0.75), tough-mindedness (p = 0.96), independence (p = 0.63), and self-control (p = 0.87). This suggests that the use of tinted lenses by physically healthy people is unlikely to be an indicator of personality type. © 2007 The Author.

Interhemispheric differences of spectral power in expressive language:a MEG study with clinical applications

In the last decade we have seen an exponential growth of functional imaging studies investigating multiple aspects of language processing. These studies have sparked an interest in applying some of the paradigms to various clinically relevant questions, such as the identification of the cortical regions mediating language function in surgical candidates for refractory epilepsy. Here we present data from a group of adult control participants in order to investigate the potential of using frequency specific spectral power changes in MEG activation patterns to establish lateralisation of language function using expressive language tasks. In addition, we report on a paediatric patient whose language function was assessed before and after a left hemisphere amygdalo-hippocampectomy. Our verb generation task produced left hemisphere decreases in beta-band power accompanied by right hemisphere increases in low beta-band power in the majority of the control group, a previously unreported phenomenon. This pattern of spectral power was also found in the patient's post-surgery data, though not her pre-surgery data. Comparison of pre and post-operative results also provided some evidence of reorganisation in language related cortex both inter- and intra-hemispherically following surgery. The differences were not limited to changes in localisation of language specific cortex but also changes in the spectral and temporal profile of frontal brain regions during verb generation. While further investigation is required to establish concordance with invasive measures, our data suggest that the methods described may serve as a reliable lateralisation marker for clinical assessment. Furthermore, our findings highlight the potential utility of MEG for the investigation of cortical language functioning in both healthy development and pathology.

Ethical issues in neuroimaging health research:an IPA study with research participants

Neuroimaging is increasingly used to understand conditions like stroke and epilepsy. However, there is growing recognition that neuroimaging can raise ethical issues. We used interpretative phenomenological analysis to analyse interview data pre-and post-scan to explore these ethical issues. Findings show participants can become anxious prior to scanning and the protocol for managing incidental findings is unclear. Participants lacked a frame of reference to contextualize their expectations and often drew on medical narratives. Recommendations to reduce anxiety include dialogue between researcher and participant to clarify understanding during consent and the use of a `virtual tour' of the neuroimaging experience.

Meta-analysis of the population and phenotypic expression of CYP2C9/2C19 polymorphism on drug metabolism in different ethnicities

The term "pharmacogenetics" has been defined as the scientific study of inherited factors that affect the human drug response. Many pharmacogenetie studies have been published since 1995 and have focussed on the principal enzyme family involved in drug metabolism, the cytochrome P450 family, particularly cytochrome P4502C9 and 2C19. In order to investigate the pharmacogenetic aspect of pharmacotherapy, the relevant studies describing the association of pharmacogenetic factor(s) in drug responses must be retrieved from existing literature using a systematic review approach. In addition, the estimation of variant allele prevalence for the gene under study between different ethnic populations is important for pharmacogenetic studies. In this thesis, the prevalence of CYP2C9/2C19 alleles between different ethnicities has been estimated through meta-analysis and the population genetic principle. The clinical outcome of CYP2C9/2C19 allelic variation on the pharmacotherapy of epilepsy has been investigated; although many new antiepileptic drugs have been launched into the market, carbamazepine, phenobarbital and phenytoin are still the major agents in the pharmacotherapy of epilepsy. Therefore, phenytoin was chosen as a model AED and the effect of CYP2C9/2C19 genetic polymorphism on phenytoin metabolism was further examined.An estimation of the allele prevalence was undertaken for three CYP2C9/2C19 alleles respectively using a meta-analysis of studies that fit the Hardy-Weinberg equilibrium. The prevalence of CYP2C9*1 is approximately 81%, 96%, 97% and 94% in Caucasian, Chinese, Japanese, African populations respectively; the pooled prevalence of CYP2C19*1 is about 86%, 57%, 58% and 85% in these ethnic populations respectively. However, the studies of association between CYP2C9/2C19 polymorphism and phenytoin metabolism failed to achieve any qualitative or quantitative conclusion. Therefore, mephenytoin metabolism was examined as a probe drug for association between CYP2C19 polymorphism and mephenytoin metabolic ratio. Similarly, analysis of association between CYP2C9 polymorphism and warfarin dose requirement was undertaken.It was confirmed that subjects carrying two mutated CYP2C19 alleles have higher S/R mephenytoin ratio due to deficient CYP2C19 enzyme activity. The studies of warfarin and CYP2C9 polymorphism did not provide a conclusive result due to poor comparability between studies.The genetic polymorphism of drug metabolism enzymes has been studied extensively, however other genetic factors, such as multiple drug resistance genes (MDR) and genes encoding ion channels, which may contribute to variability in function of drug transporters and targets, require more attention in future pharmacogenetic studies of antiepileptic drugs.

Functional localisation of human sensory-motor cortex using magnetoencephalography

The 19 channel Neuromagnetometer system in the Clinical Neurophysiology Unit at Aston University is a multi-channel system, unique in the United Kingdom. A bite bar head localisation and MRI co-registration strategy which enabled accurate and reproducible localisation of MEG data into cortical space was developed. This afforded the opportunity to study magnetic fields of the human cortex generated by stimulation of peripheral nerve, by stimulation of visceral sensory receptors and by those evoked through voluntary finger movement. Initially, a study of sensory-motor evoked data was performed in a healthy control population. The techniques developed were then applied to patients who were to undergo neurosurgical intervention for the treatment of epilepsy and I or space occupying lesions. This enabled both validation of the effective accuracy of source localisation using MEG as well as to determine the clinical value of MEG in presurgical assessment of functional localisation in human cortex. The studies in this thesis have demonstrated that MEG can repeatedly and reliably locate sources contained within a single gyrus and thus potentially differentiate between disparate gyral activation. This ability is critical in the clinical application of any functional imaging technique; which is yet to be fully validated by any other 'non-invasive' functional imaging methodology. The technique was also applied to the study of visceral sensory representation in the cortex which yielded important data about the multiple cortical representation of visceral sensory function.

Migraine, A study of environmental and intrapersonal factors

A study was carried out of 45 migrainous patients with visually induced migraine (VIM), and 25 migrainous students, each having an age and sex matched control. The study utilised questionnaires, interviews, electroencephalography (EEG) and visual evoked potentials (VEP). The experimental work and analysis was carried out in the Neuropsychology Unit in collaboration with the Birmingham Migraine Clinic, over a period of five years. The study suggests: 1. The literature on a possible relationship between migraine and epilepsy hitherto published is unreliable (supporting evidence is given). 2. That a much greater precision is needed in defining migraine for research purposes. 3. A revised methodology for the selection of controls is needed and this is proposed. 4. That despite what are now seen to be superficial similarities, there are clear distinctions of a fundamental nature between photo-sensitive epilepsy (PSE) and VIM. 5. Caution be used when taking headache as a symptom, since many of the precipitants of migrainous headache can also precipitate non-migrainous headache (NMH). 6. The list of visual precipitants of migraine is expanded (particularly flicker and pattern). 7. That colour (principally red) is a previously unreported precipitant of migraine. 8. The extended range of responses to flicker (the 'H' response) has no significant difference in its frequency of occurrence in patients and normal controls, which contradicts previous literature. 9. The mechanisms thought to underlie migraine serve to explain previously unexplained EEG findings. 10. Further research is needed and proposed.

Infraslow (<0.1 Hz) oscillations in thalamic relay nuclei basic mechanisms and significance to health and disease states

In the absence of external stimuli, the mammalian brain continues to display a rich variety of spontaneous activity. Such activity is often highly stereotypical, is invariably rhythmic, and can occur with periodicities ranging from a few milliseconds to several minutes. Recently, there has been a particular resurgence of interest in fluctuations in brain activity occurring at <0.1 Hz, commonly referred to as very slow or infraslow oscillations (ISOs). Whilst this is primarily due to the emergence of functional magnetic resonance imaging (fMRI) as a technique which has revolutionized the study of human brain dynamics, it is also a consequence of the application of full band electroencephalography (fbEEG). Despite these technical advances, the precise mechanisms which lead to ISOs in the brain remain unclear. In a host of animal studies, one brain region that consistently shows oscillations at <0.1 Hz is the thalamus. Importantly, similar oscillations can also be observed in slices of isolated thalamic relay nuclei maintained in vitro. Here, we discuss the nature and mechanisms of these oscillations, paying particular attention to a potential role for astrocytes in their genesis. We also highlight the relationship between this activity and ongoing local network oscillations in the alpha (a; ~8-13 Hz) band, drawing clear parallels with observations made in vivo. Last, we consider the relevance of these thalamic ISOs to the pathological activity that occurs in certain types of epilepsy.

Methodology of photic stimulation revisited:updated European algorithm for visual stimulation in the EEG laboratory

Intermittent photic stimulation (IPS) is a common procedure performed in the electroencephalography (EEG) laboratory in children and adults to detect abnormal epileptogenic sensitivity to flickering light (i.e., photosensitivity). In practice, substantial variability in outcome is anecdotally found due to the many different methods used per laboratory and country. We believe that standardization of procedure, based on scientific and clinical data, should permit reproducible identification and quantification of photosensitivity. We hope that the use of our new algorithm will help in standardizing the IPS procedure, which in turn may more clearly identify and assist monitoring of patients with epilepsy and photosensitivity. Our algorithm goes far beyond that published in 1999 (Epilepsia, 1999a, 40, 75; Neurophysiol Clin, 1999b, 29, 318): it has substantially increased content, detailing technical and logistical aspects of IPS testing and the rationale for many of the steps in the IPS procedure. Furthermore, our latest algorithm incorporates the consensus of repeated scientific meetings of European experts in this field over a period of 6 years with feedback from general neurologists and epileptologists to improve its validity and utility. Accordingly, our European group has provided herein updated algorithms for two different levels of methodology: (1) requirements for defining photosensitivity in patients and in family members of known photosensitive patients and (2) requirements for tailored studies in patients with a clear history of visually induced seizures or complaints, and in those already known to be photosensitive.

Preterm infants with video-EEG confirmed seizures:outcome at 30 months of age

Our aim was to identify early predictors of poor neurodevelopmental outcome and of subsequent epilepsy in very early preterm and late preterm newborns with neonatal seizures.