Measuring decline in white matter integrity after systemic treatment for breast cancer:Omitting skeletonization enhances sensitivity

Chemotherapy for non-central nervous system cancers is associated with abnormalities in brain structure and function. Diffusion tensor imaging (DTI) allows for studying in vivo microstructural changes in brain white matter. Tract-based spatial statistics (TBSS) is a widely used processing pipeline in which DTI data are typically normalized to a generic DTI template and then ‘skeletonized’ to compensate for misregistration effects. However, this approach greatly reduces the overall white matter volume that is subjected to statistical analysis, leading to information loss. Here, we present a re-analysis of longitudinal data previously analyzed with standard TBSS (Menning et al., BIB 2018, 324–334). For our current approach, we constructed a pipeline with an optimized registration method in Advanced Normalization Tools (ANTs) where DTI data are registered to a study-specific, high-resolution T1 template and the skeletonization step is omitted. In a head to head comparison, we show that with our novel approach breast cancer survivors who had received chemotherapy plus or minus endocrine therapy (BC + SYST, n = 26) showed a global decline in overall FA that was not present in breast cancer survivors who did not receive systemic therapy (BC-SYST, n = 23) or women without a cancer diagnosis (no cancer controls, NC, n = 30). With the standard TBSS approach we did not find any group differences. Moreover, voxel-based analysis for our novel pipeline showed a widespread decline in FA in the BC + SYST compared to the NC group. Interestingly, the BC-SYST group also showed a decline in FA compared to the NC group, although in much less voxels. These results were not found with the standard TBSS approach. We demonstrate that a modified processing pipeline makes DTI data more sensitive to detecting changes in white matter integrity in non-CNS cancer patients after treatment, particularly chemotherapy

A CAD system for early diagnosis of autism using different imaging modalities.

The term “autism spectrum disorder” (ASD) refers to a collection of neuro-developmental disorders that affect linguistic, behavioral, and social skills. Autism has many symptoms, most prominently, social impairment and repetitive behaviors. It is crucial to diagnose autism at an early stage for better assessment and investigation of this complex syndrome. There have been a lot of efforts to diagnose ASD using different techniques, such as imaging modalities, genetic techniques, and behavior reports. Imaging modalities have been extensively exploited for ASD diagnosis, and one of the most successful ones is Magnetic resonance imaging(MRI),where it has shown promise for the early diagnosis of the ASD related abnormalities in particular. Magnetic resonance imaging (MRI) modalities have emerged as powerful means that facilitate non-invasive clinical diagnostics of various diseases and abnormalities since their inception in the 1980s. After the advent in the nineteen eighties, MRI soon became one of the most promising non- invasive modalities for visualization and diagnostics of ASD-related abnormalities. Along with its main advantage of no exposure to radiation, high contrast, and spatial resolution, the recent advances to MRI modalities have notably increased diagnostic certainty. Multiple MRI modalities, such as different types of structural MRI (sMRI) that examines anatomical changes, and functional MRI (fMRI) that examines brain activity by monitoring blood flow changes,have been employed to investigate facets of ASD in order to better understand this complex syndrome. This work aims at developing a new computer-aided diagnostic (CAD) system for autism diagnosis using different imaging modalities. It mainly relies on making use of structural magnetic resonance images for extracting notable shape features from parts of the brainthat proved to correlate with ASD from previous neuropathological studies. Shape features from both the cerebral cortex (Cx) and cerebral white matter(CWM)are extracted. Fusion of features from these two structures is conducted based on the recent findings suggesting that Cx changes in autism are related to CWM abnormalities. Also, when fusing features from more than one structure, this would increase the robustness of the CAD system. Moreover, fMRI experiments are done and analyzed to find areas of activation in the brains of autistic and typically developing individuals that are related to a specific task. All sMRI findings are fused with those of fMRI to better understand ASD in terms of both anatomy and functionality,and thus better classify the two groups. This is one aspect of the novelty of this CAD system, where sMRI and fMRI studies are both applied on subjects from different ages to diagnose ASD. In order to build such a CAD system, three main blocks are required. First, 3D brain segmentation is applied using a novel hybrid model that combines shape, intensity, and spatial information. Second, shape features from both Cx and CWM are extracted and anf MRI reward experiment is conducted from which areas of activation that are related to the task of this experiment are identified. Those features were extracted from local areas of the brain to provide an accurate analysis of ASD and correlate it with certain anatomical areas. Third and last, fusion of all the extracted features is done using a deep-fusion classification network to perform classification and obtain the diagnosis report. Fusing features from all modalities achieved a classification accuracy of 94.7%, which emphasizes the significance of combining structures/modalities for ASD diagnosis. To conclude, this work could pave the pathway for better understanding of the autism spectrum by finding local areas that correlate to the disease. The idea of personalized medicine is emphasized in this work, where the proposed CAD system holds the promise to resolve autism endophenotypes and help clinicians deliver personalized treatment to individuals affected with this complex syndrome

Innovations in Metastatic Brain Tumor Treatment

Metastatic brain tumors (MBTs) are the most common intracranial tumor and occur in up to 40% of patients with certain cancer diagnoses. The most common and frequent primary locations are cancers originating from the lung, breast, kidney, gastrointestinal tract or skin, and also may arising from any part of the body. Treatment for brain metastasis management includes surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Standard treatment for MBTs includes surgery and SRS which offer the best outcomes, while the WBRT is still an important treatment option for patients who cannot tolerate surgery and SRS or patients with multiple brain metastases. Newer approaches such as immunotherapy and molecularly targeted therapy (e.g., small molecules and monoclonal antibodies) are currently being evaluated for the treatment of MBTs. In this chapter, we will review current available treatments for MBTs and discuss treatments that are undergoing active investigation

Concurrent whole brain radiotherapy and bortezomib for brain metastasis

Abstract Background Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis. Methods A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects. Results Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023). Conclusions Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.http://deepblue.lib.umich.edu/bitstream/2027.42/112849/1/13014_2013_Article_928.pd

Neurocognitive function in patients undergoing stereotactic radiosurgery for brain metastases

National Institute of Clinical Excellence (NICE) recommends Stereotactic radiosurgery (SRS) as the treatment of choice for patients with limited brain metastases, which is defined as volume <20 cc, with performance status 0-2, controlled or controllable extracranial disease and expected prognosis of greater than 6 months. Despite its precision, studies have reported 24-60% of patients can develop neurocognitive impairment following SRS alone. Dose to the hippocampus is thought to be related to development of neurocognitive impairment following fractionated radiotherapy for primary brain tumours and whole brain radiotherapy for brain metastases. However, this has not been studied in patients undergoing SRS. This thesis investigates the importance of hippocampus delineation and dose delivered to this organ in patients undergoing SRS and its impact on neurocognitive decline following treatment. Multi-parametric MRI imaging identifies changes in the hippocampus structure, blood flow, metabolites, and diffusion tensor imaging of the tracts involved in the limbic system. We utilised this opportunity to perform novel microstructure MRI imaging of the metastases to understand the tumour microenvironment and oxygenation

Fast and Robust Automatic Segmentation Methods for MR Images of Injured and Cancerous Tissues

Magnetic Resonance Imaging: MRI) is a key medical imaging technology. Through in vivo soft tissue imaging, MRI allows clinicians and researchers to make diagnoses and evaluations that were previously possible only through biopsy or autopsy. However, analysis of MR images by domain experts can be time-consuming, complex, and subject to bias. The development of automatic segmentation techniques that make use of robust statistical methods allows for fast and unbiased analysis of MR images. In this dissertation, I propose segmentation methods that fall into two classes---(a) segmentation via optimization of a parametric boundary, and: b) segmentation via multistep, spatially constrained intensity classification. These two approaches are applicable in different segmentation scenarios. Parametric boundary segmentation is useful and necessary for segmentation of noisy images where the tissue of interest has predictable shape but poor boundary delineation, as in the case of lung with heavy or diffuse tumor. Spatially constrained intensity classification is appropriate for segmentation of noisy images with moderate contrast between tissue regions, where the areas of interest have unpredictable shapes, as is the case in spinal injury and brain tumor. The proposed automated segmentation techniques address the need for MR image analysis in three specific applications:: 1) preclinical rodent studies of primary and metastatic lung cancer: approach: a)),: 2) preclinical rodent studies of spinal cord lesion: approach: b)), and: 3) postclinical analysis of human brain cancer: approach: b)). In preclinical rodent studies of primary and metastatic lung cancer, respiratory-gated MRI is used to quantitatively measure lung-tumor burden and monitor the time-course progression of individual tumors. I validate a method for measuring tumor burden based upon average lung-image intensity. The method requires accurate lung segmentation; toward this end, I propose an automated lung segmentation method that works for varying tumor burden levels. The method includes development of a novel, two-dimensional parametric model of the mouse lungs and a multifaceted cost function to optimally fit the model parameters to each image. Results demonstrate a strong correlation: 0.93), comparable with that of fully manual expert segmentation, between the automated method\u27s tumor-burden metric and the tumor burden measured by lung weight. In preclinical rodent studies of spinal cord lesion, MRI is used to quantify tissues in control and injured mouse spinal cords. For this application, I propose a novel, multistep, multidimensional approach, utilizing the Classification Expectation Maximization: CEM) algorithm, for automatic segmentation of spinal cord tissues. In contrast to previous methods, my proposed method incorporates prior knowledge of cord geometry and the distinct information contained in the different MR images gathered. Unlike previous approaches, the algorithm is shown to remain accurate for whole spinal cord, white matter, and hemorrhage segmentation, even in the presence of significant injury. The results of the method are shown to be on par with expert manual segmentation. In postclinical analysis of human brain cancer, access to large collections of MRI data enables scientifically rigorous study of cancers like glioblastoma multiforme, the most common form of malignant primary brain tumor. For this application, I propose an efficient and effective automated segmentation method, the Enhanced Classification Expectation Maximization: ECEM) algorithm. The ECEM algorithm is novel in that it introduces spatial information directly into the classical CEM algorithm, which is otherwise spatially unaware, with low additional computational complexity. I compare the ECEM\u27s performance on simulated data to the standard finite Gaussian mixture EM algorithm, which is not spatially aware, and to the hidden-Markov random field EM algorithm, a commonly-used spatially aware automated segmentation method for MR brain images. I also show sample results demonstrating the ECEM algorithm\u27s ability to segment MR images of glioblastoma

Quantitative Magnetic Resonance Imaging of Tissue Microvasculature and Microstructure in Selected Clinical Applications

This thesis is based on four papers and aims to establish perfusion and diffusion measurements with magnetic resonance imaging (MRI) in selected clinical applications. While structural imaging provides invaluable geometric and anatomical information, new disease relevant information can be obtained from measures of physiological processes inferred from advanced modelling. This study is motivated by clinical questions pertaining to diagnosis and treatment effects in particular patient groups where inflammatory processes are involved in the disease. Paper 1 investigates acquisition parameters in dynamic contrast enhanced (DCE)-MRI of the temporomandibular joint (TMJ) with possible involvement of juvenile idiopathic arthritis. High level elastic motion correction should be applied to DCE data from the TMJ, and the DCE data should be acquired with a sample rate of at least 4 s. Paper 2 investigates choices of arterial input functions (AIFs) in dynamic susceptibility contrast (DSC)-MRI in brain metastases. AIF shapes differed across patients. Relative cerebral blood volume estimates differentiated better between perfusion in white matter and grey matter when scan-specific AIFs were used than when patient-specific AIFs and population-based AIFs were used. Paper 3 investigates DSC-MRI perfusion parameters in relation to outcome after stereotactic radiosurgery (SRS) in brain metastases. Low perfusion prior to SRS may be related to unfavourable outcome. Paper 4 applies free water (FW) corrected diffusion MRI to characterise glioma. Fractional anisotropy maps of the tumour region were significantly impacted by FW correction. The estimated FW maps may also contribute to a better description of the tumour. Although there are challenges related to post-processing of MRI data, it was shown that the advanced MRI methods applied can add to a more accurate description of the TMJ and of brain lesions.Doktorgradsavhandlin

The Effects of Daytime Melatonin Administration on Sleep, Higher Cognitive Function, and Changes in the Brain

This study investigated the effects of exogenous melatonin on people’s sleep, ability to perform an emotional Stroop task, and underlying brain architecture. 10 healthy adults (age = 26.8 ± 6.25 years) underwent a baseline period followed by an experimental period whereby melatonin was administered at inappropriate times, with daily activity logs kept throughout. The emotional Stroop task was performed four times during each period, followed by an MRI scan. Following melatonin administration, sleep and wake times were significantly shifted and sleep quality ratings were significantly decreased compared to baseline values. Additionally, processing of emotional words but not faces was negatively affected by the melatonin treatment. Fractional anisotropy and mean diffusivity values were also significantly altered in the inferior frontal gyrus. It is inferred that the melatonin treatment induced circadian desynchronization, resulting in behavioural changes and structural alterations in brain regions involved in performance of the emotional Stroop task

The impact of aerobic exercise on brain's white matter integrity in the Alzheimer's disease and the aging population

The brain is the most complex organ in the body. Currently, its complicated functionality has not been fully understood. However, in the last decades an exponential growth on research publications emerged thanks to the use of in-vivo brain imaging techniques. One of these techniques pioneered for medical use in the early 1970s was known as nuclear magnetic resonance imaging based (now called magnetic resonance imaging [MRI]). Nowadays, the advances of MRI technology not only allowed us to characterize volumetric changes in specific brain structures but now we could identify different patterns of activation (e.g. functional MRI) or changes in structural brain connectivity (e.g. diffusion MRI). One of the benefits of using these techniques is that we could investigate changes that occur in disease-specific cohorts such as in the case of Alzheimer’s disease (AD), a neurodegenerative disease that affects mainly older populations. This disease has been known for over a century and even though great advances in technology and pharmacology have occurred, currently there is no cure for the disease. Hence, in this work I decided to investigate whether aerobic exercise, an emerging alternative method to pharmacological treatments, might provide neuroprotective effects to slow down the evident brain deterioration of AD using novel in-vivo diffusion imaging techniques. Previous reports in animal and human studies have supported these exercise-related neuro-protective mechanisms. Concurrently in AD participants, increased brain volumes have been positively associated with higher cardiorespiratory fitness levels, a direct marker of sustained physical activity and increased exercise. Thus, the goal of this work is to investigate further whether exercise influences the brain using structural connectivity analyses and novel diffusion imaging techniques that go beyond volumetric characterization. The approach I chose to present this work combined two important aspects of the investigation. First, I introduced important concepts based on the neuro-scientific work in relation to Alzheimer’s diseases, in-vivo imaging, and exercise physiology (Chapter 1). Secondly, I tried to describe in simple mathematics the physics of this novel diffusion imaging technique (Chapter 2) and supported a tract-specific diffusion imaging processing methodology (Chapter 3 and 4). Consequently, the later chapters combined both aspects of this investigation in a manuscript format (Chapter 5-8). Finally, I summarized my findings, include recommendations for similar studies, described future work, and stated a final conclusion of this work (Chapter 9)