Evaluation and implementation of functional cerebral biomarkers in Alzheimer’s disease

The aim of this thesis was to evaluate and implement functional cerebral biomarkers in Alzheimer’s disease (AD) with respect to pathophysiology, disease severity, prognosis and treatment effect in medical trials. We focused on functional cerebral biomarkers that assess synaptic activity and functional connectivity using electroencephalography (EEG), magnetoencephalography (MEG) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In the different chapters a broad range of challenges associated with this topic was covered. We started by using FDG- PET to observe the effects of the experimental treatment of AD patients with the medical food Souvenaid, followed by EEG as treatment outcome measure in a trial with the drug PQ912. Next to the primary outcomes, the results of these studies revealed that more research was needed to observe which markers could observe reliable, reproducible and valid results and what the factors were that could influence their ability to do this. The EEG markers, rather than the FDG- PET markers, showed promising results. Therefore, we aimed to investigate the effects of sensitivity, reproducibility, heterogeneity of the population and treatment efficacy, while maintaining a well-defined study population and study design, on EEG biomarkers. We first investigated the reproducibility of AD related changes in functional connectivity captured by different measures in electroencephalography (EEG) and magnetoencephalography (MEG). Second, we evaluated the influence of subtypes of AD on various EEG measures and, on the other hand, we used EEG to find heterogeneity and to predict clinical progression

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques

Physiological regulation of chronic tinnitus: A new methodological approach

Decrease of auditory alpha-rhythm might lead to tinnitus which it calls a rehabilitation strategy using training to increase auditory alpha in chronic tinnitus patients. A novel auditory alpha monitoring method was devised to circumvent the inverse problem of standard EEG source localization methods. To prevent projection of alpha from somatosensory and occipital cortex, alpha-blockade of these two regions using tactile and visual stimulations is integrated in an EEG neurofeedback set-up. The monitoring online source method’s results showed rigorous tracking of auditory alpha activity purely from the sensor-level while the up-regulation of auditory alpha activity was very difficult for tinnitus patients. Therefore, only contingent feedback was applied instead of using a control condition or control group. Although the neurofeedback training exerted a positive effect on the tinnitus symptoms, this effect was not a consequence of neurophysiological changes, but it was probably the effect of positive expectancy and the reduction of cognitive dissonance related to the attribution of concentration and effort. Different reasons could be responsible for this lack of covariation between neurophysiology and behavior like short training time for up-regulation of alpha activity or permanent neuronal reorganization. However, the developed on-line neurofeedback of localized alpha allows systematic replication and variation of the determining variables of neurofeedback training in tinnitus in future larger clinical trials

A critical analysis of the present neuropsychological and neuroanatomical theories and knowledge of art perception and artistic production taking creativity into account

The present paper analyses the neuroanatomical and neuropsychological backgrounds of art reception and art creation in modern visual art and creative processes. It critically presents two models of aesthetic experience to provide a comprehensive theoretical basis for the discussion. The research purpose is to show that with increasing experience and expertise the referential frame of the aesthetic judgment is changing and that neural processes involved in object recognition provide a starting point for visual aesthetics. Thus, the investigation focuses on constructing and testing neuropsychological theories that fall in the domain called 'neuroaesthetics'. These theories, in turn, serve as a starting point to formulate neural laws of art and aesthetics and aesthetic experience. Some artistic styles, such as expressionism, reflect specific neural processes. Various studies indicate correlations between hemispheric specialisation and art or creativity and show the right hemisphere plays a particular role in it. However, studies exploring the neural correlates of aesthetic preference have yielded mixed results. Furthermore, neuroimaging studies have proved that different categories of modern artworks are processed in different areas of the brain. These diverging results will be discussed in a critical assessment of the two models of aesthetic experience. Besides, the question of identifying exclusive neural correlates of aesthetic preference will be raised. Comparing amateurs and experts has revealed the more reduced the cortical activation, the more efficiently it works. Biological and neuropsychological factors of creativity point out the meaning of the activation level, cognitive inhibition and prefrontal cortex. Divergent thinking differs from convergent thinking in terms of the neural level. Neurodegenerative processes and brain injuries sometimes influence the artistic output surprisingly or even launch it. Lesion studies contributing to understanding art experience will be explained.PsychologyM.A. (Psychology

In a network state of mind

Scheltens, P. [Promotor]Stam, C.J. [Promotor]Flier, W.M. van der [Copromotor

Variability of head tissues’ conductivities and their impact in electrical brain activity research

The presented thesis endeavoured to establish the impact that the variability in electrical conductivity of human head tissues has on electrical brain imaging research, particularly transcranial direct current stimulation (tDCS) and electroencephalography (EEG). A systematic meta-analysis was firstly conducted to determine the consistency of reported measurements, revealing significant deviations in electrical conductivity measurements predominantly for the scalp, skull, GM, and WM. Found to be of particular importance was the variability of skull conductivity, which consists of multiple layers and bone compositions, each with differing conductivity. Moreover, the conductivity of the skull was suggested to decline with participant age and hypothesised to correspondingly impact tDCS induced fields. As expected, the propositioned decline in the equivalent (homogeneous) skull conductivity as a function of age resulted in reduced tDCS fields. A further EEG analysis also revealed, neglecting the presence of adult sutures and deviation in proportion of spongiform and compact bone distribution throughout the skull, ensued significant errors in EEG forward and inverse solutions. Thus, incorporating geometrically accurate and precise volume conductors of the skull was considered as essential for EEG forward analysis and source localisation and tDCS application. This was an overarching conclusion of the presented thesis. Individualised head models, particularly of the skull, accounting for participant age, the presence of sutures and deviation in bone composition distribution are imperative for electrical brain imaging. Additionally, it was shown that in vivo, individualised measurements of skull conductivity are further required to fully understand the relationship between conductivity and participant demographics, suture closure, bone compositions, skull thickness and additional factors

Functional neuroimaging in subjects at high genetic risk of schizophrenia

Schizophrenia is an incapacitating psychiatric disorder characterized by hallucinations and delusions with a lifetime risk of around 1% worldwide. It is a highly heritable disorder which generally becomes manifest in early adult life. The established condition has been associated with structural and functional brain abnormalities, principally in prefrontal and temporal lobes, but it is unclear whether such abnormalities are related to inherited vulnerability, medication effects, or the presence of symptoms. Furthermore, the mechanisms by which the pre-morbid state switches into florid psychosis are unknown. The Edinburgh High Risk Study is designed to address these issues. The first phase (1994-1999) employed repeated clinical, neuropsychological assessments and structural imaging. In the current phase (1999-2004) functional magnetic resonance imaging (fMRI) has been added to the tests used previously.As part of the Edinburgh High Risk Study, this study used a covert verbal initiation fMRI task (the Hayling Sentence Completion Test) known to elicit frontal and temporal activation, to examine a large number of young participants at high risk of developing schizophrenia for genetic reasons, in comparison with a matched group of healthy controls. Subjects were scanned at baseline, and after approximately one year. At the time of the baseline scan none of the participants met criteria for any psychiatric disorder, however, a number of subjects reported isolated psychotic symptoms on direct questioning. Over the course of the entire study (1994-2004), 21 individuals developed schizophrenia according to standard diagnostic criteria. Four of these subjects made the transition over the course of the current study (1999-2004), i.e. subsequent to the baseline functional scanThere were three main aims of the current study (i) to use fMRI to identify the neural correlates of state and trait effects in high risk individuals, (ii) to determine ifit is possible to distinguish those who subsequently become ill from those who remain well using functional imaging, and (iii) to determine if patterns of brain activity change with the transition to illness, or vary with changes in symptomatic status of these individuals.Regarding the first aim, group differences of apparent genetic origin were found in prefrontal, thalamic, cerebellar regions, and differences in activation in those with symptoms were found in the parietal lobe. Functional connectivity analysis examining interactions between these regions also indicated similar abnormalities. These results may therefore reflect inherited deficits, and the earliest changes associated with the psychotic state, respectively. Although only a small number of subjects became ill over the course of the current study («=4), initial findings suggested abnormalities in medial prefrontal and medial temporal regions (with an indication of parietal lobe dysfunction) were able to distinguish those who later became ill versus those that remained well. Finally, there were also indications of changes in activation patterns over time in a subgroup of subjects with varying symptomatic status.To conclude, these results are consistent with previous findings in the Edinburgh High Risk Study - what is inherited by the high risk individuals is a state of heightened vulnerability manifesting, in the case of functional imaging, as abnormalities in activation and/or connectivity in preffontal-thalamiccerebellar and prefrontal-parietal regions. These finding also suggest that there are additional differences seen in those with psychotic symptoms, and to some extent in those who subsequently go on to develop the disorder. These results are not confounded by anti-psychotic medication since all subjects were anti-psychotic naive at the time of assessment. The lack of findings traditionally associated with the established illness (dorsolateral prefrontal cortex and lateral temporal lobe) indicate these may be specifically associated with the established state, or when performance differences become manifest. Overall therefore these findings reveal information regarding the pathophysiology of the state of vulnerability to the disorder and about the mechanisms involved in the development of schizophrenia or schizophrenic symptomatology

Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors

A dramatic increase in knowledge regarding the molecular biology of brain tumors has been established over the past few years, and this has lead to the development of novel therapeutic strategies for these patients. In this book a review of the options available for the clinical management of patients with these tumors are outlined. In addition advances in radiology both for pre-operative diagnostic purposes along with surgical planning are described. Furthermore a review of newer developments in chemotherapy along with the evolving field of photodynamic therapy both for intra-operative management and subsequent therapy is provided. A discussion of certain surgical management issues along with tumor induced epilepsy is included. Finally a discussion of the management of certain unique problems including brain metastases, brainstem glioma, central nervous system lymphoma along with issues involving patients with a brain tumor and pregnancy is provided