Small-World Network Analysis of Cortical Connectivity in Chronic Fatigue Syndrome using EEG

The primary aim of this thesis was to explore the relationship between electroencephalography (qEEG) and brain system dysregulation in people with Chronic Fatigue Syndrome (CFS). EEG recordings were taken from an archival dataset of 30 subjects, 15 people with CFS and 15 healthy controls (HCs), evaluated during an eye-closed resting state condition. Exact low resolution electromagnetic tomography (eLORETA) was applied to the qEEG data to estimate cortical sources and perform functional connectivity analysis assessing the strength of time-varying signals between all pairwise cortical regions of interest. To obtain a comprehensive view of local and global processing, eLORETA lagged coherence was computed on 84 regions of interest representing 42 Brodmann areas for the left and right hemispheres of the cortex, for the delta (1-3 Hz) and alpha-1 (8-10 Hz) and alpha-2 (10-12 Hz) frequency bands. Graph theory analysis of eLORETA coherence matrices for each participant was conducted to derive the “small-worldness” index, a measure of the optimal balance between the functional integration (global) and segregation (local) properties known to be present in brain networks. The data were also associated with the cognitive impairment composite score on the DePaul Symptom Questionnaire (DSQ), a patient-reported symptom outcome measure of frequency and severity of cognitive symptoms. Results showed that small-worldness for the delta band was significantly lower for patients with CFS compared to HCs. Small-worldness for delta, alpha-1, and alpha-2 were associated with higher cognitive composite scores on the DSQ. Finally, small-worldness in all 3 frequency bands correctly distinguished those with CFS from HCS with a classification rate of nearly 87 percent. These preliminary findings suggest disease processes in CFS may be functionally disruptive to small-world characteristics, especially in the delta frequency band, resulting in cognitive impairments. In turn, these findings may help to confirm a biological basis for cognitive symptoms, providing clinically relevant diagnostic indicators, and characterizing the neurophysiological status of people with CFS

Feasibility of using Arterial Spin Labeling for Detecting Longitudinal Changes in Cerebral Blood Flow

The ability of the perfusion MRI technique, arterial spin labeling (ASL), to quantify cerebral blood flow (CBF) makes it attractive for longitudinal studies of changes in brain function, such as those related to chronic pain. However, ASL\u27s poor spatial resolution makes image alignment between sessions difficult, leading to increased variance and greater Type-I errors. In addition, variability due to differences in basal blood flow between sessions and confounding effects such as the arterial transit time (ATT) have the potential to reduce reproducibility over time. The focus of this thesis is to investigate the ability of ASL to detect long-term changes in regional CBF within an individual on a voxel-wise level. It is hypothesized that ASL has the sensitivity to detect activation-induced CBF changes over periods as long as a month if the sources of variance that degrade between-session comparisons are minimized. To test this hypothesis rest and activation (motor task) CBF images were acquired from healthy subjects on three separate imaging sessions. Registration errors were minimized by using individual head molds to replicate the head position in successive sessions. Variations in resting CBF were controlled for by performing the imaging during the same time of day, and subjects were asked to refrain from using common substances, such as caffeine, that are known to affect CBF. Finally, ATT maps were generated on each session to investigate its stability. From these data sets, the within- and between-session variability in CBF was determined and motor-related activation maps were generated from rest and activation data acquired on from the same session and from sessions separated by a week and a month. The results demonstrated excellent reliability (intraclass correlation coefficients greater than 0.75) both within- (0.89 ± 0.2) and between-session (0.84 ± 0.15), and high reproducibility (within subject coefficient of variation, wsCV, greater than 20%) within- (wsCV = 4.7 ± 4.5%) and between-session (wsCV = 5.7 ± 4.4%). Between-session reproducibility of the ATT was high (wsCV = 5.0 ± 2.7%), suggesting that the confounding effect of ATT over a month was minimal. The similarity in within- and between-session variability and their activation maps indicated that registration errors between sessions were minimal. Measures of precision of activation demonstrated that less than ~20% of between-session activation were false positives. These results demonstrate the feasibility of conducting voxel-wise analysis of CBF images acquired on different days and highlight the potential of this technique for longitudinal studies

ADVANCEMENTS IN QUANTITATIVE PERFUSION MAGNETIC RESONANCE IMAGING (MRI) OF DEMENTIA

Alzheimer's disease (AD) affects a considerable, and increasing, part of the population. Early diagnosis of AD is very important to permit effective therapy, and minimize AD's social and economic burden. The goal of our research is to evaluate the changes of cerebral perfusion (i.e., blood flow) in the early stages of AD and the effects from hypertension.We studied volunteers with Mild Cognitive Impairment (MCI) and early AD from the Pittsburgh cohort of the Cardiovascular Health Study (CHS) Cognitive Study during a four-year follow-up. Previously, studies used referral patients who typically have more advanced AD. No perfusion data concerning the early and transitional disease stages are currently available from population studies (i.e., subjects who have been monitored longitudinally in time). There are no common techniques for perfusion quantification and image analysis so that inconsistencies are observed between/within studies, modalities, and researchers. Several advancements were achieved in preparation for the cohort study. First, we improved the accuracy and speed of brain perfusion quantification. Second, we improved the accuracy of image registration to a reference brain using quantitative validation of a registration method and performance comparison with a popular registration method. Third, we improved the method of statistical analysis for evaluating the changes of perfusion between groups. Fourth, we evaluated the changes of cerebral perfusion between cognitive groups (controls, MCIs, ADs), and hypertension and normo-tensive subgroups.Individual perfusion maps were improved by measuring and incorporating individual arrival time, saturation effects, and individual inversion efficiency. A fully deformable registration technique was shown to be more accurate than standard techniques like statistical parametric mapping to detect local perfusion changes. All of the published literature for perfusion up-to-date reported decreased perfusion in AD, but we found hyperperfusion in some regions. The regional findings imply that a hemodynamic process, at the capillary level, accompanied the neurodegenerative process. Hypertensive normal cognitive controls demonstrated hypoperfusion in regions usually involved in AD pathology. However, the effect of hypertension was attenuated after the onset of the pathological cognitive process

A Longitudinal Study of Closed Head Injury: Neuropsychological Outcome and Structural Analysis using Region of Interest Measurements and Voxel-Based Morphometry

Background: The hippocampus and corpus callosum have been shown to be vulnerable in head injury. Various neuroimaging modalities and quantitative measurement techniques have been employed to investigate pathological changes in these structures. Cognitive and behavioural deficiencies have also been well documented in head injury. Aims: The aim of this research project was to investigate structural changes in the hippocampus and corpus callosum. Two different quantitative methods were used to measure physical changes and neuropsychological assessment was performed to determine cognitive and behavioural deficit. It was also intended to investigate the relationship between structural change and neuropsychology at 1 and 6 months post injury. Method: Forty-seven patients with head injury (ranging from mild to severe) had undergone a battery of neuropsychological tests and an MRI scan at 1 and 6 months post injury. T1-weighted MRI scans were obtained and analysis of hippocampus and corpus callosum was performed using region-of-interest techniques and voxel-based morphometry which also included comparison to 18 healthy volunteers. The patients completed neuropsychological assessment at 1 and 6 months post injury and data obtained was analysed with respect to each assessment and with structural data to determine cognitive decline and correlation with neuroanatomy. Results: Voxel-based morphometry illustrated reduced whole scan signal differences between patients and controls and changes in patients between 1 and 6 months post injury. Reduced grey matter concentration was also found using voxel-based morphometry and segmented images between patients and controls. A number of neuropsychological aspects were related to injury severity and correlations with neuroanatomy were present. Voxel-based morphometry provided a greater number of associations than region-of-interest analysis. No longitudinal changes were found in the hippocampus or corpus callosum using region-of-interest methodology or voxel-based morphometry. Conclusions: Decreased grey matter concentration identified with voxel-based morphometry illustrated that structural deficit was present in the head injured patients and does not change between 1 and 6 months. Voxel-based morphometry appears more sensitive for detecting structural changes after head injury than region- of-interest methods. Although the majority of patients had suffered mild head injury, cognitive and neurobehavioural deficits were evidenced by a substantial number of patients reporting increased anxiety and depression levels. Also, the findings of relationships between reduced grey matter concentration and cognitive test scores are indicative of the effects of diffuse brain damage in the patient group

Use of functional neuroimaging and optogenetics to explore deep brain stimulation targets for the treatment of Parkinson's disease and epilepsy

Deep brain stimulation (DBS) is a neurosurgical therapy for Parkinson’s disease and epilepsy. In DBS, an electrode is stereotactically implanted in a specific region of the brain and electrical pulses are delivered using a subcutaneous pacemaker-like stimulator. DBS-therapy has proven to effectively suppress tremor or seizures in pharmaco-resistant Parkinson’s disease and epilepsy patients respectively. It is most commonly applied in the subthalamic nucleus for Parkinson’s disease, or in the anterior thalamic nucleus for epilepsy. Despite the rapidly growing use of DBS at these classic brain structures, there are still non-responders to the treatment. This creates a need to explore other brain structures as potential DBS-targets. However, research in patients is restricted mainly because of ethical reasons. Therefore, in order to search for potential new DBS targets, animal research is indispensable. Previous animal studies of DBS-relevant circuitry largely relied on electrophysiological recordings at predefined brain areas with assumed relevance to DBS therapy. Due to their inherent regional biases, such experimental techniques prevent the identification of less recognized brain structures that might be suitable DBS targets. Therefore, functional neuroimaging techniques, such as functional Magnetic Resonance Imaging and Positron Emission Tomography, were used in this thesis because they allow to visualize and to analyze the whole brain during DBS. Additionally, optogenetics, a new technique that uses light instead of electricity, was employed to manipulate brain cells with unprecedented selectivity

Exploring the combined use of electrical and hemodynamic brain activity to investigate brain function

This thesis explored the relationship between electrical and metabolic aspects of brain functioning in health and disease, measured with QEEG and NIRS, in order to evaluate its clinical potential. First the limitations of NIRS were investigated, depicting its susceptibility to different types of motion artefacts and the inability of the CBSI-method to remove them from resting state data. Furthermore, the quality of the NIRS signals was poor in a significant portion of the investigated sample, reducing clinical potential. Different analysis methods were used to explore both EEG and NIRS, and their coupling in an eyes open eyes closed paradigm in healthy participants. It could be reproduced that during eyes closed blocks less HbO2 (p = 0.000), more Hbb (p = 0.008), and more alpha activity (p = 0.000) was present compared to eyes open blocks. Furthermore, dynamic cross correlation analysis reproduced a positive correlation between alpha and Hbb (r: 0.457 and 0.337) and a negative correlation between alpha and HbO2 (r: -0.380 and -0.366) with a delayed hemodynamic response (7 to 8s). This was only possible when removing all questionable and physiological illogical data, suggesting that an 8s hemodynamic delay might not be the golden standard. Also the inability of the cross correlation to take non-linear relationships into account may distort outcomes. Therefore, In chapter 5 non-linear aspects of the relationship were evaluated by introducing the measure of relative cross mutual information. A newly suggested approach and the most valuable contribution of the thesis since it broadens knowledge in the fields of EEG, NIRS and general time series analysis. Data of two stroke patients then showed differences from the healthy group between the coupling of EEG and NIRS. The differences in long range temporal correlations (p= 0.000 for both cases), entropy (p< 0.040 and p =0.000), and relative cross mutual information (p < 0.003 and p < 0.013) provide the proof of principle that these measures may have clinical utility. Even though more research is necessary before widespread clinical use becomes possible