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Graph analysis was used to study the effects of accelerated intermittent theta burst stimulation (aiTBS) on the brain's network topology in medication-resistant depressed patients. Anatomical and resting-state functional MRI (rs-fMRI) was recorded at baseline and after sham and verum stimulation. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS). Using various graph measures, the different effects of sham and verum aiTBS were calculated. It was also investigated whether changes in graph measures were correlated to clinical responses. Furthermore, by correlating baseline graph measures with the changes in HDRS in terms of percentage, the potential of graph measures as biomarker was studied. Although no differences were observed between the effects of verum and sham stimulation on whole-brain graph measures and changes in graph measures did not correlate with clinical response, the baseline values of clustering coefficient and global efficiency showed to be predictive of the clinical response to verum aiTBS. Nodal effects were found throughout the whole brain. The distribution of these effects could not be linked to the strength of the functional connectivity between the stimulation site and the node. This study showed that the effects of aiTBS on graph measures distribute beyond the actual stimulation site. However, additional research into the complex interactions between different areas in the brain is necessary to understand the effects of aiTBS in more detail.

Contains fulltext : 170424.pdf (Publisher’s version ) (Closed access) Cerebral small vessel disease (cSVD) and amyloid-beta (Abeta) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Abeta have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Abeta pathology was assessed as cerebrospinal fluid-derived Abeta1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Abeta on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Abeta and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Abeta and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Abeta42 levels, but not in individuals with normal CSF Abeta42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Abeta levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

Purpose: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. Methods: Thirty-two children aged 8–13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired Key Findings: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. Significance: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.

Epilepsy is a chronic brain disorder characterized by unprovoked recurrent seizures that give rise to episodes of abnormal neuronal activity in the central nervous system. The most common application of magnetic resonance imaging (MRI) techniques in the epileptic brain is the identification of the underlying cause for a person’s epilepsy, and possibly the localization of the epileptic focus. In addition, quantitative magnetic resonance (MR) techniques enable examining certain relatively subtle aspects of epilepsy within the brain that go beyond the identification of seizure focus within the brain. In this thesis a number of studies are presented that investigate the application of quantitative MR techniques to epilepsy-related abnormalities of metabolism, microstructures and brain function. The research project was aimed at developing and validating quantitative MR techniques (spectroscopy, diffusion, T2 relaxometry, and functional magnetic resonance imaging) with clinical diagnostic potential. The main focus was on data acquisition and processing, and the application of this multi-modal MR approach in both patients with epilepsy and an animal model of epileptogenesis. We explored in a clinical setting how the cognitive consequences of epilepsy (either due to medication or due to seizures) may be reflected in altered MR tissue characteristics. Furthermore, using an experimental model of febrile convulsions, it was investigated whether neurological abnormalities, possibly linked with epileptogenesis and thus with epilepsy, could be detected by quantitative MR. A general introduction into quantitative MR techniques and epilepsy is given in Chapter 1. Chapter 2 describes a thorough review on absolute quantification of metabolites using spectroscopy, which can substantially improve the diagnostic utility of spectroscopy. Absolute quantification requires more time and expertise than relative quantification, as additional calibrations for concentration determination and spectrum analyses have to be performed. One can only benefit from absolute quantification if all additional reference steps are executed properly; otherwise unwanted additional errors may be introduced. Chapter 3 concerns a clinically relevant reproducibility study of several quantitative MR techniques which was performed on a 3.0 Tesla MR system. Repeated measurements in 10 healthy volunteers were used to establish the reproducibility of quantitative measures derived from different quantitative MR techniques, namely the T2 relaxation time, the apparent diffusion coefficient (ADC), the fractional anisotropy (FA), and metabolite concentrations of N-acetyl-aspartate (NAA), total creatine (tCr), choline (Cho) and myo-inositol (mI). The reproducibility of quantitative brain MR at 3.0 T appeared to be better than, or at least comparable to the reproducibility at 1.5 T. A newly developed statistical image analysis method, which offers considerably increased sensitivity for the detection of subtle signal changes in images of several neurological MR applications, is described in Chapter 4. This method, the regional false discovery rate (FDR) control, increases sensitivity by exploiting the spatially clustered nature of neuroimaging effects. The method was validated, characterized, and compared to some other commonly used methods (uncorrected thresholding, Bonferroni correction, and conventional FDR-control). It was found that the new method showed considerably higher sensitivity as compared to conventional FDR-control. Application of the method to two different neuroimaging applications, revealed substantial improvements compared to the other methods. Quantitative MR (T2 relaxation, diffusion, spectroscopy, and functional MRI) at 1.5 T and neuropsychological assessment was performed in a group of patients with localization related epilepsy and secondarily generalized tonicoclonic seizures (SGTCS) to study cognitive deterioration. Chapter 5 relates to the investigation of the effect of these seizures on microstructural and metabolic changes in brain tissue characteristics. Frontal, but not temporal, MR abnormalities were found to be related to SGTCS. These findings confirm that SGTCS do have a substantial effect on frontal brain function and on the microstructural brain tissue characteristics. This knowledge may help to obtain a better understanding and anticipatory treatment of SGTCS-related cognitive deterioration. In Chapter 6 it was investigated using functional MRI whether a higher number of SGCTS were associated with a functional reorganization of working memory. It was found that high numbers of SGTCS resulted in a decrease in intelligence scores and altered prefrontal brain activation. A shift from frontotemporal to prefrontal activation seemed to have occurred, suggesting that a functional reorganization of working memory is induced by a high number of SGTCS. It remains uncertain if this reorganization reflected compensatory mechanisms, or the underlying pathological processes of cognitive deterioration. In the same patient group it was found in Chapter 7 that the presence of a certain marker for neuronal damage in blood serum (telencephalin) correlates with a decreased frontotemporal activity during an functional MRI memory task.