| 1. |
- Blystad, Ida, 1972-
(författare)
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Clinical Applications of Synthetic MRI of the Brain
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Magnetic Resonance Imaging (MRI) has a high soft-tissue contrast with a high sensitivity for detecting pathological changes in the brain. Conventional MRI is a time-consuming method with multiple scans that relies on the visual assessment of the neuroradiologist. Synthetic MRI uses one scan to produce conventional images, but also quantitative maps based on relaxometry, that can be used to quantitatively analyse tissue properties and pathological changes. The studies presented here apply the use of synthetic MRI of the brain in different clinical settings.In the first study, synthetic MR images were compared to conventional MR images in 22 patients. The contrast, the contrast-to-noise ratio, and the diagnostic quality were assessed. Image quality was perceived to be inferior in the synthetic images, but synthetic images agreed with the clinical diagnoses to the same extent as the conventional images.Patients with early multiple sclerosis were analysed in the second study. In patients with multiple sclerosis, contrast-enhancing white matter lesions are a sign of active disease and can indicate a need for a change in therapy. Gadolinium-based contrast agents are used to detect active lesions, but concern has been raised regarding the long-term effects of repeated use of gadolinium. In this study, relaxometry was used to evaluate whether pre-contrast injection tissue-relaxation rates and proton density can identify active lesions without gadolinium. The findings suggest that active lesions often have relaxation times and proton density that differ from non-enhancing lesions, but with some overlap. This makes it difficult to replace gadolinium-based contrast agent injection with synthetic MRI in the monitoring of MS patients.Malignant gliomas are primary brain tumours with contrast enhancement due to a defective blood-brain barrier. However, they also grow in an infiltrative, diffuse manner, making it difficult to clearly delineate them from surrounding normal brain tissue in the diagnostic workup, at surgery, and during follow-up. The contrast-enhancing part of the tumour is easily visualised, but not the diffuse infiltration. In studies three and four, synthetic MRI was used to analyse the peritumoral area of malignant gliomas, and revealed quantitative findings regarding peritumoral relaxation changes and non-visible contrast enhancement suggestive of non-visible infiltrative tumour growth.In conclusion, synthetic MRI provides quantitative information about the brain tissue and this could improve the diagnosis and treatment for patients.
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| 2. |
- Lilja, Johan, 1977-
(författare)
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[18F]Flutemetamol PET image processing, visualization and quantification targeting clinical routine
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the leading cause of dementia and is alone responsible for 60-70% of all cases of dementia. Though sharing clinical symptoms with other types of dementia, the hallmarks of AD are the abundance of extracellular depositions of β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles of hyper phosphorylated tau proteins and synaptic depletion. The onset of the physiological hallmarks may precede clinical symptoms with a decade or more, and once clinical symptoms occur it may be difficult to separate AD from other types of dementia based on clinical symptoms alone. Since the introduction of radiolabeled Aβ tracer substances for positron emission tomography (PET) imaging it is possible to image the Aβ depositions in-vivo, strengthening the confidence in the diagnosis. Because the accumulation of Aβ may occur years before the first clinical symptoms are shown and even reach a plateau, Aβ PET imaging may not be feasible for disease progress monitoring. However, a negative scan may be used to rule out AD as the underlying cause to the clinical symptoms. It may also be used as a predictor to evaluate the risk of developing AD in patients with mild cognitive impairment (MCI) as well as monitoring potential effects of anti-amyloid drugs.Though currently validated for dichotomous visual assessment only, there is evidence to suggest that quantification of Aβ PET images may reduce inter-reader variability and aid in the monitoring of treatment effects from anti-amyloid drugs.The aim of this thesis was to refine existing methods and develop new ones for processing, quantification and visualization of Aβ PET images to aid in the diagnosis and monitoring of potential treatment of AD in clinical routine. Specifically, the focus for this thesis has been to find a way to fully automatically quantify and visualize a patient’s Aβ PET image in such way that it is presented in a uniform way and show how it relates to what is considered normal. To achieve the aim of the thesis registration algorithms, providing the means to register a patient’s Aβ PET image to a common stereotactic space avoiding the bias of different uptake patterns for Aβ- and Aβ+ images, a suitable region atlas and a 3-dimensional stereotactic surface projections (3D SSP) method, capable of projecting cortical activity onto the surface of a 3D model of the brain without sampling white matter, were developed and evaluated.The material for development and testing comprised 724 individual amyloid PET brain images from six distinct cohorts, ranging from healthy volunteers to definite AD. The new methods could be implemented in a fully automated workflow and were found to be highly accurate, when tested by comparisons to Standards of Truth, such as defining regional uptake from PET images co-registered to magnetic resonance images, post-mortem histopathology and the visual consensus diagnosis of imaging experts.
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| 3. |
- Nordanskog, Pia, 1971-
(författare)
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On electroconvulsive therapy in depression : Clinical, cognitive and neurobiological aspects
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Electroconvulsive therapy (ECT) is used worldwide to treat severe mental disorders. The most common mental disorder, and the third leading cause of disease burden in the world is depression. The clinical efficacy of ECT for severe depression is well-established. However, both the pathophysiology of depression and the mechanism of action of ECT remain elusive.The main aims of this thesis are to address the following issues: 1) the use and practice of ECT in Sweden has not been systematically evaluated since 1975, 2) cognitive side-effects (memory disturbances) are a major concern with ECT and 3) the mechanism of action of ECT remain elusive. The neurobiological aspects of ECT focus on two hypotheses. First, the recent years´ preclinical studies that have provided evidence that ECT induces hippocampal cell proliferation, including neurogenesis. Second, that enhanced functional inhibition of neuronal activity is a key feature.Current use and practice of ECT in Sweden (paper I) is based on data from the national quality register for ECT, the mandatory patient register of the National Board of Health and Welfare and a survey. Treated person rate (TPR) in Sweden 2013 was found to be 41 individuals / 100 000, and thus unchanged since the latest systematic investigation in Sweden 1975. In more than 70% of treatment series the indication was a depressive episode. The selection of patients for ECT and treatment technique in Sweden was similar to that in other western countries, but the consent procedure and the involvement of nurses and nursing assistants in the delivery of ECT differ. Data also shows that there is room for improvement in both the specificity of use and availability of ECT.The second study in this thesis is a longitudinal observational trial where 12 (paper II and III) and 14 (paper IV) patients with depression referred for ECT were investigated. Patients underwent a 3 T MRI structural scanning and DSC-MRI perfusion, a neuropsychological test battery and clinical ratings before ECT, within one to two weeks after ECT and after 6 and 12 months. In line with preclinical findings and the plasticity hypothesis of mechanism of action of ECT, the hippocampal volume increased after ECT in patients with depression. However, this increase was transient and returned to baseline levels within 6 months. No correlation was found between volumetric changes and clinical effect or cognitive outcome. Instead our results suggested an association to the number of treatments, without relation to the side of stimulation. A right-sided decrease in frontal blood flow distinguished remission from non-remission after ECT. There were significant impairments in verbal episodic memory and verbal fluency within one week after ending the ECT course, but these impairments were transient and no persistent cognitive impairments were seen during the follow-up.In summary, this thesis present the first update on the use and practice of ECT in Sweden in the last 40 years as well as a pioneering MRI-study on the hippocampal volume increase in the treatment of depression with ECT. Supportive to earlier findings we also found the cognitive side-effects that are measurable after ECT to be transient. Furthermore, we found that a decreased frontal blood flow is of importance for the anti-depressive response to ECT.
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| 4. |
- Kockum, Karin, 1981-
(författare)
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Imaging in Idiopathic Normal Pressure Hydrocephalus : The value of structured radiological evaluation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Idiopathic normal pressure hydrocephalus (iNPH) is a neurological condition where the symptoms include disturbed gait, balance, cognition and continence. The diagnostic guidelines are based on typical symptoms combined with imaging showing enlarged ventricles. Several scales for evaluating symptoms exist, but no corresponding tool is in use for imaging. The aim of this thesis was to construct a radiological scoring system, the iNPH Radscale, to facilitate radiological evaluation and systematic reporting of changes. Further, to test the reliability and accuracy of the scale and evaluate the usefulness for longitudinal monitoring.Methods: In paper I 168 individuals over 65 years of age from the general population underwent computed tomography (CT) of the brain and a neurological examination, and the same cohort was followed up 2 years later in paper IV. The iNPH Radscale was developed in these papers and further validated in papers II and III. Papers II and III included surgically treated iNPH patients with preoperative imaging of the brain. Thirty-five patients were included in paper II comparing preoperative CT and magnetic resonance imaging (MRI) using the iNPH Radscale. Paper III included 75 shunt responsive patients and 55 asymptomatic controls to evaluate the accuracy of the iNPH Radscale.Results: In paper I, seven parameters summarized as a total iNPH Radscale score were significantly associated with clinical iNPH symptoms (r = 0.55, p < 0.001). In paper II, the agreement between CT and MRI was substantial to almost perfect (kappa and intraclass correlation, 0.60–0.91, p < 0.001) for all parameters except periventricular white matter changes. In paper III the iNPH Radscale score was significantly higher in the iNPH group than the control group (p <0.001). Receiver operating characteristics analysis yielded an area under the curve of 99.7 %, and an iNPH Radscale score £ 4 identified those without iNPH (sensitivity 100 %, specificity 96 % and overall accuracy 98.5 %). In paper IV, symptomatic participants had significantly higher iNPH Radscale scores at baseline and follow-up.Conclusions: The iNPH Radscale summarizes seven imaging features from the diagnostic guidelines and is applicable to both CT and MRI. INPH is very likely in patients with an iNPH Radscale score ³ 8 and corresponding clinical symptoms. On the other hand, the diagnosis should be questioned when the iNPH Radscale score is less than the cut-off of 4. In summary, the iNPH Radscale may become a relevant diagnostic tool for standardized evaluation in the workup of patients with suspected iNPH, as a diagnostic checklist and as a screening tool for detection with the potential for ruling out the disease.
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| 5. |
- Velickaite, Vilma
(författare)
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Analysis of regional atrophy on brain imaging compared with cognitive function in the elderly and in patients with dementia – cross-sectional and longitudinal evaluation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During aging, brain changes are not homogeneous throughout the entire brain, but are related to changes in the morphology of neurons, as well as to changes in the tissue density, and are specific to each region of the brain. Dementia is a broad category of brain disorders with a set of symptoms including memory, visual-spatial and language problems. Most types of dementia are slowly progressing, and by the time the person shows signs of the disorder, processes in the brain are already advanced. Dementia reduces not only the person’s ability to perform everyday activities, it also increases mortality rates significantly. Because of the increasing incidence of dementia, possible prevention and treatment of dementia as early as possible are essential.The aim of the PhD project is to compare a quantitative and qualitative image analysis of regional cerebral atrophy with cognitive function in the elderly persons.In paper I, 58 persons participated (84–88 years old) from the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort. They underwent CT of the brain, cognitive testing and LP. This study showed that AD biomarkers seem to be less informative in subjects with an advanced age.In papers II–IV, the cohort included subjects from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study.Paper II showed that at age 75, gender and education are confounders for MTA rating. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later.Paper III showed that automated rating of MTA could be used in clinical practice to support the radiological evaluation. Automated rating of PA and F-GCA should be tested in future studies.In paper IV, we found a mild age-associated decrease in regional brain volumes in this healthy cohort with well-preserved cognitive and executive functions.In conclusion, the included studies in this thesis compare regional atrophy grades in the brain on CT and MRI and clinical data and provide knowledge that may be used in future investigations that aim to detect dementia in its early stages.
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| 6. |
- Fällmar, David, 1980-
(författare)
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Visual assessment of perfusion and metabolism in neurodegenerative dementia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A worldwide demographic shift is currently occurring, with rapidly increasing numbers of elderly individuals. Since the incidence of neurodegenerative disease generally increases with age, this entails an increase in dementia prevalence. There are several strong incentives for establishing robust and widely available imaging methods for the early diagnosis of these diseases. Atrophy patterns are evident only late in the disease process, and the distinction from healthy ageing can often be elusive. For early diagnosis, physiologic parameters such as perfusion or metabolism must be assessed. The available modalities all have restricted clinical usefulness. The main aim of this thesis was to advance the clinical usefulness of perfusion and metabolism imaging in patients with neurodegenerative dementia, with a focus on visual assessment.A cohort of patients with neurodegenerative dementia was included, along with an age-matched control group. All subjects underwent MRI, including a pseudocontinuous ASL sequence and FDG-PET. In papers II and III, a subgroup containing both patients and controls underwent a second FDG-PET with reduced dose. In paper IV, the material was combined with a similar cohort from Amsterdam.Paper I showed that spatial smoothing increased the correlation between visually assessed perfusion and metabolism levels as displayed with FDG-PET. However, the distinction between patients and healthy controls was less satisfactory due to false positives.Paper II showed that differences in regional standard uptake value ratios between normal- and low-dose FDG-PET were small and without clinically significant bias.Paper III showed that the diagnostic performance of Z-score maps showing regions of significant deficits in metabolism was highly similar in normal- and low-dose FDG-PET images. Paper IV showed that ASL perfusion-based Z-score maps can be used for diagnostic purposes with high specificity, but inferior sensitivity, compared to FDG-PET.In conclusion, the included studies address aspects of the visual assessment of perfusion and metabolism neuroimaging, with a focus on clinical usefulness in diagnosing neurodegenerative dementia.
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| 7. |
- Georgiopoulos, Charalampos, 1984-
(författare)
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Imaging Studies of Olfaction in Health and Parkinsonism
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Olfactory loss is a common non-motor symptom of Parkinson’s disease (PD), often preceding the cardinal motor symptoms of the disease. The aim of this thesis was to: (a) evaluate whether olfactory examination can increase diagnostic accuracy, and (b) study the structural and functional neural basis of olfactory dysfunction in PD with different applications of Magnetic Resonance Imaging (MRI).Paper I was a comparison of the diagnostic accuracy between a simple smell identification test and DaTSCAN Single Photon Emission Computerized Tomography (SPECT), a nuclear medicine tomographic imaging technique that is commonly used in patients with suspected parkinsonism. The results indicate that smell test is inferior to DaTSCAN SPECT, but the combination of these two methods can lead to improved diagnostic accuracy.Paper II showed that diffusion MRI could detect discrete microstructural changes in the white matter of brain areas that participate in higher order olfactory neurotransmission, whereas MRI with Magnetization Transfer contrast could not.Paper III was a methodological study on how two different acquisition parameters can affect the activation pattern of olfactory brain areas, as observed with functional MRI (fMRI). The results indicate that brief olfactory stimulation and fast sampling rate should be preferred on olfactory fMRI studies.Paper IV used olfactory fMRI and resting-state fMRI in order to elucidate potentially altered activation patterns and functional connectivity within olfactory brain areas, between PD patients and healthy controls. Olfactory fMRI showed that olfactory impairment in PD is associated with significantly lower recruitment of the olfactory network. Resting-state fMRI did not detect any significant changes in the functional connectivity within the olfactory network of PD patients.In conclusion, the included studies provide evidence of: (a) disease-related structural and functional changes in olfactory brain areas, and (b) beneficial addition of olfactory tests in the clinical work-up of patients with parkinsonism.
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| 8. |
- Mårtensson, Johanna
(författare)
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Diffusion tensor magnetic resonance imaging of the brain : Tractography analysis with application in healthy individuals and patients
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In study 1, thirty-eight healthy controls were used for optimization of the method. Fifteen patients with progressive supranuclear palsy and an equal number of age-matched healthy controls underwent diffusion tensor MRI and were then investigated and compared groupwise.It was shown that tractography analyses may preferably be performed regionally, such as along the tracts or in different segments of the tracts. Normalization of white matter tracts can be performed using anatomical landmarks.In study 2, 104 males and 153 females in the age interval 13 to 84 years of age participated as healthy individuals in order to investigate age-related changes with diffusion tensor MRI.It was shown that spatially differences in age-related changes exist between subdivided segments within white matter tracts. The aging processes within the CB and the IFO vary regionally.In study 3, 38 human brains were used for investigation of the white matter tract inferior longitudinal fasciculus (ILF) and its subcomponents. Of these, white matter anatomical dissection was performed in 14 post-mortem normal human brains. The remaining 24 brains were investigated in vivo with diffusion tensor MRI in healthy individuals.It was validated that fibers of the ILF in the occipito-temporal region have a clear, constant and detailed organisation. The anatomical connectivity pattern, and quantitative differences between the ILF subcomponents, confirmed a pivotal role of the ILF.In study 4, 12 patients with iNPH were included in the study and examined with diffusion tensor at three time points. For comparison, 12 healthy controls, matched by gender and age were also included. Controls were examined with MRI only once.It was shown that DTI measures differ significantly between patients with iNPH and healthy controls. DTI measures of the CC, the CST and the SLF, correlated to changes in clinical symptoms after shunt surgery.Deeper knowledge about functions of the brain increases possibilities to take advantages from DTI analyses with tractography.
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| 9. |
- Nylander, Ruta
(författare)
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Magnetic resonance imaging markers of cerebral small vessel disease in an elderly population – association with cardiovascular disease and cognitive function
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cerebral small vessel disease (SVD) is identifiable by clinical, neuroimaging, neuropathological and cognitive findings.The aim of this thesis was to assess SVD and cerebral perfusion on magnetic resonance imaging (MRI) in a 75-year-old population and compare the findings with scars of myocardial infarctions, cardiovascular risk markers and cognitive function. In addition, the evolution of SVD over 5 years was studied.The study population included subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The subjects had been chosen in a randomized manner from the register of the municipality. MRI of the brain and the heart, cognitive tests and blood tests for cardiovascular risk factors were performed in 406 subjects at age 75 years and 250 of them were re-examined 5 years later at the age of 80.Paper 1 showed that unrecognized myocardial infarctions (UMIs) were found in 120 subjects (30%) and recognized myocardial infarctions (RMIs) in 21 (5%). Men with RMIs displayed an increased prevalence of cortical and lacunar cerebral infarctions, whereas women with UMIs more frequently had cortical cerebral infarctions.Paper 2 showed that one or more brain infarcts were seen in 23% of the subjects (20% had only lacunar infarcts, 1% had only cortical infarcts and 2% had both). Hypertension and obesity were significantly associated with an increased risk of infarction. The newer risk markers investigated were not significantly associated with brain infarcts.Paper 3 showed that MRI manifestations of SVD progressed over 5 years. Relative cerebral blood flow (rCBF) was not associated with WMH volume or progression of WMH volume.Paper 4 showed that moderate to severe WMHs and incident lacunar infarcts on brain MRI were associated with a mild impairment of executive function.In conclusion, this longitudinal population based study compares MRI manifestations of SVD with clinical data, providing knowledge that may be used in further investigations of preventive interventions and for identification of disease in early stages.
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| 10. |
- Roodakker, Kenney Roy, 1989-
(författare)
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Towards new tools for clinical evaluation and visualization of tumor growth in patients with glioma
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gliomas are derived from glial cells and are the most common type of primary brain tumors in adults. Gliomas are classified by the World Health Organization (WHO) according to their malignancy grade and histological and molecular features. Malignancy grades range from I to IV. WHO grade I tumors are benign tumors, mostly occurring in childhood. High-grade gliomas (WHO grades III and IV) are undifferentiated and fast-growing tumors, with glioblastoma being the most common and malignant form. Patients with glioblastomas have a median survival of only 15 months. Clinical outcomes vary, however, and markers are needed to assist in the decision-making process and management of these patients. PROX1 is a transcription factor critical for embryonic development, with a role in cell cycle control and progenitor cell differentiation. Apart from its role in normal central nervous system development, PROX1 has been ascribed both tumor suppressive and oncogenic roles in several human cancers. The role of PROX1 as a prognostic factor for survival in patients with glioblastomas was the focus of paper I.Gliomas WHO grade II, also called diffuse low-grade gliomas (DLGGs), are well-differentiated tumors that occur mainly in adult life, with a peak incidence at around 30–35 years of age and a median survival of 5–10 years. DLGGs grow continuously at a rate of a few mm per year and have a strong tendency to infiltrate the white matter tracts surrounding the tumor. Eventually these tumors transform into high-grade gliomas, but, as is the case with glioblastomas, there is a large variety of clinical outcomes. For radiological diagnosis, magnetic resonance imaging (MRI) is routinely used, often in combination with advanced MRI. Positron emission tomography with amino acid tracers provides additional diagnostic accuracy. From a histological as well as imaging point of view, DLGGs are heterogeneous tumors. The heterogeneity of DLGGs, in particular the correlation between radiological and histological tumor features, was the focus of paper II & paper III.Seizures are amongst the most common presenting symptoms of patients with gliomas. Seizure semiology in patients with brain tumors and other structural brain lesions is closely related to the anatomical location of the lesion and the involvement of functional networks. A possible dynamic interplay between the anatomical region of seizure onset and connected target areas within the network was the focus of paper IV.
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