Development of Diffusion MRI Methodology to Quantify White Matter Integrity Underlying Post-Stroke Anomia

In 1909 German neurologist Korbinian Brodmann wrote “functional localization of the cerebral cortex without the lead of anatomy is impossible... In all domains, physiology has its firmest foundations in anatomy [1”. While histology is the current gold standard for studying brain microstructure, it is primarily a post-mortem technique that has an average resolution of one micrometer making it impractical for studying the entire brain. Diffusion Magnetic Resonance Imaging (dMRI) is ideally suited to study whole-brain tissue microstructure by sensitizing the MRI contrast to water diffusion, which has a length scale on the order of micrometers. Even though dMRI is applied clinically for the detection of acute ischemia, the relation between tissue microstructure and the dMRI signal is complex and not fully understood. The focus of this dissertation was the validation and development of a new biophysical model of the dMRI signal. Notwithstanding, it is important to keep in mind the potential clinical applications of these models, so in parallel we studied the relationship between white matter integrity and language impairments in post-stroke anomia. This application is of interest since response to language treatment is variable and it is currently difficult to predict which patients will benefit. A better understanding of the underlying brain damage could help inform on functionality and recovery potential. Our work resulted in 9 peer-reviewed papers in international journals and 13 abstracts in proceedings at national and international conferences. Using data collected from 32 chronic stroke patients with language impairments, we studied the relation between baseline naming impairments and microstructural integrity of the residual white matter. An existing dMRI technique, Diffusional Kurtosis Imaging (DKI), was used to assess the tissue microstructure along the length of two major white matter bundles: the Inferior Longitudinal Fasciculus (ILF) and the Superior Longitudinal Fasciculus (SLF). The frequency of semantic paraphasias was strongly associated with ILF axonal loss, whereas phonemic paraphasias were strongly associated with SLF axonal loss. This double dissociation between semantic and phonological processing is in agreement with the dual stream model of language processing and corroborates the concept that, during speech production, knowledge association (semantics) depends on the integrity of ventral pathways (ILF), whereas form encoding (phonological encoding) is more localized to dorsal pathways (SLF). Using a smaller dataset of 8 chronic stroke subjects whom underwent speech entrainment therapy, we assessed if naming improvements were supported by underlying changes in microstructure. Remarkably, we saw that a decrease in semantic errors during confrontational naming was related to a renormalization of the microstructure of the ILF. Together, these two studies support the idea that white matter integrity (in addition to regional gray matter damage) impacts baseline stroke impairments and disease progression. Acquiring accurate information about a patient’s linguistic disorder and the underlying neuropathology is often an integral part to developing an appropriate intervention strategy. However, DKI metrics describe the general physical process of diffusion, which can be difficult to interpret biologically. Different pathological processes could lead to similar DKI changes further complicating interpretation and possibly decreasing its specificity to disease. A multitude of biophysical models have been developed to improve the specificity of dMRI. Due to the complexity of biological tissue, assumptions are necessary, which can differ in stringency depending on the dMRI data at hand. One such assumption is that axons can be approximated by water confined to impermeable thin cylinders. In this dissertation, we provide evidence for this “stick model”. Using data from 2 healthy controls we show that the dMRI signal decay behaves as predicted from theory, particularly at strong diffusion weightings. This work validated the foundation of a biophysical model known as Fiber Ball Imaging (FBI), which allows for the calculation of the angular dependence of fiber bundles. Here, we extend FBI by introducing the technique Fiber Ball White Matter (FBWM) modeling that in addition provides estimations for the Axonal Water Fraction (AWF) and compartmental diffusivities. The ability to accurately estimate compartment specific diffusion dynamics could provide the opportunity to distinguish between different disease processes that affect axons differently than the extra-axonal environment (e.g. gliosis). Lastly, we were able to show that FBI data can also be used to calculate compartmental transverse relaxation times (T2). These metrics can be used as biomarkers, aid in the calculation of the myelin content, or be used to reduce bias in diffusion modeling metrics. Future work should focus on the application of FBI and FBWM to the study of white matter in post-stroke anomia. Since FBWM offers the advantage of isolating the diffusion dynamics of the intra- and extra- axonal environments, it could be used to distinguish between pathological processes such as glial cell infiltration and axonal degeneration. A more specific assessment of the structural integrity underlying anomia could provide information on an individual’s recovery potential and could pave the way for more targeted treatment strategies. The isolation of intra-axonal water is also beneficial for a technique known as dMRI tractography, which delineates the pathway of fiber bundles in the brain. dMRI tractography is a popular research tool for studying brain networks but it is notoriously challenging to do in post-stroke brains. In damaged brain tissue, the high extra-cellular water content masks the directionality of fibers; however, since FBI provides the orientational dependence of solely intra-axonal water, it is not affected by this phenomenon. It is important to understand that caution should be taken when applying biophysical models (FBWM/FBI vs. DKI) to the diseased brain as the validation we provided in this work was only for healthy white matter and these experiments should be repeated in pathological white matter

Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and data processing, including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Biogeochemical and ecological impacts of boundary currents in the Indian Ocean

Monsoon forcing and the unique geomorphology of the Indian Ocean basin result in complex boundary currents, which are unique in many respects. In the northern Indian Ocean, several boundary current systems reverse seasonally. For example, upwelling coincident with northward-flowing currents along the coast of Oman during the Southwest Monsoon gives rise to high productivity which also alters nutrient stoichiometry and therefore, the species composition of the resulting phytoplankton blooms. During the Northeast Monsoon most of the northern Indian Ocean boundary currents reverse and favor downwelling. Higher trophic level species have evolved behavioral responses to these seasonally changing conditions. Examples from the western Arabian Sea include vertical feeding migrations of a copepod (Calanoides carinatus) and the reproductive cycle of a large pelagic fish (Scomberomorus commerson). The impacts of these seasonal current reversals and changes in upwelling and downwelling circulations are also manifested in West Indian coastal waters, where they influence dissolved oxygen concentrations and have been implicated in massive fish kills. The winds and boundary currents reverse seasonally in the Bay of Bengal, though the associated changes in upwelling and productivity are less pronounced. Nonetheless, their effects are observed on the East Indian shelf as, for example, seasonal changes in copepod abundance and zooplankton community structure. In contrast, south of Sri Lanka seasonal reversals in the boundary currents are associated with dramatic changes in the intensity of coastal upwelling, chlorophyll concentration, and catch per unit effort of fishes. Off the coast of Java, monsoon-driven changes in the currents and upwelling strongly impact chlorophyll concentrations, seasonal vertical migrations of zooplankton, and sardine catch in Bali Strait. In the southern hemisphere the Leeuwin is a downwelling-favorable current that flows southward along western Australia, though local wind forcing can lead to transient near shore current reversals and localized coastal upwelling. The poleward direction of this eastern boundary current is unique. Due to its high kinetic energy the Leeuwin Current sheds anomalous, relatively high chlorophyll, warm-core, downwelling eddies that transport coastal diatom communities westward into open ocean waters. Variations in the Leeuwin transport and eddy generation impact many higher trophic level species including the recruitment and fate of rock lobster (Panulirus cygnus) larvae. In contrast, the transport of the Agulhas Current is very large, with sources derived from the Mozambique Channel, the East Madagascar Current and the southwest Indian Ocean sub-gyre. Dynamically, the Agulhas Current is upwelling favorable; however, the spatial distribution of prominent surface manifestations of upwelling is controlled by local wind and topographic forcing. Meanders and eddies in the Agulhas Current propagate alongshore and interact with seasonal changes in the winds and topographic features. These give rise to seasonally variable localized upwelling and downwelling circulations with commensurate changes in primary production and higher trophic level responses. Due to the strong influence of the Agulhas Current, many neritic fish species in southeast Africa coastal waters have evolved highly selective behaviors and reproductive patterns for successful retention of planktonic eggs and larvae. For example, part of the Southern African sardine (Sardinops sagax) stock undergoes a remarkable northward migration enhanced by transient cyclonic eddies in the shoreward boundary of the Agulhas Current. There is evidence from the paleoceanographic record that these currents and their biogeochemical and ecological impacts have changed significantly over glacial to interglacial timescales. These changes are explored as a means of providing insight into the potential impacts of climate change in the Indian Ocean

A systematic map of evidence on the contribution of forests to poverty alleviation

Abstract Background Forests provide an essential resource to the livelihoods of an estimated 20% of the global population. The contribution of forest ecosystems and forest-based resources to poverty reduction is increasingly emphasized in international policy discourse and conservation and development investments. However, evidence measuring the effect of forest-based activities on poverty outcomes remains scattered and unclear. Lack of systematic understanding of forest-poverty relationships, in turn, inhibits research, policymaking, and efficient financial resource allocation. Methods To identify relevant studies for inclusion in this systematic map we searched six bibliographic databases, 15 organizational websites, eight systematic evidence syntheses (reviews and maps), and solicited information from key informants. Search results were screened for relevance against predefined inclusion criteria at title, abstract, and full text levels, according to a published protocol. Included articles were coded using a predefined framework. Trends in the evidence, knowledge gaps and relatively well-researched sub-topics are reported in a narrative synthesis. Occurrence and extent of existing evidence about links between interventions and outcomes are presented in a visual heatmap. Data are available through the open access Evidence for Nature and People Data Portal (http://www.natureandpeopleevidence.org). Results A total of 242 articles were included in the systematic map database. Included articles measured effects of 14 forest-based intervention types on 11 poverty dimensions. The majority of the evidence base (72%) examined links between productivity-enhancement strategies (e.g. forest management, agroforestry, and habitat management) and monetary income and/or social capital outcomes. Other areas with high occurrence of articles include linkages between interventions involving governance, individual rights/empowerment or linked enterprises/livelihood alternatives with impacts on monetary income from direct sale of goods. A key knowledge gap was on the impacts of investment-based interventions (i.e. enhancing produced, human, and social capitals). Another was the impacts of forest-based interventions on financial capital (savings, debt), non-monetary benefits, and health. Conclusions The evidence base on forest-based productive activities and poverty alleviation is growing but displays a number of biases in the distribution of articles on key linkages. Priorities for future systematic reviews and evaluations include in-depth examinations into the impacts of rights-based activities (e.g. governance, empowerment) on poverty dimensions; and productivity-enhancing activities on social capital. More comprehensive and robust evidence is needed to better understand the synergies and trade-offs among the different objectives of forest conservation and management and variation in outcomes for different social groups in different social-ecological contexts

Dual Receptor-Targeted Theranostic Nanoparticles for Localized Delivery and Activation of Photodynamic Therapy Drug in Glioblastomas

Targeting gold nanoparticles (AuNPs) with two or more receptor binding peptides has been proposed to address intratumoral heterogeneity of glioblastomas that overexpress multiple cell surface receptors to ultimately improve therapeutic efficacy. AuNPs conjugated with peptides against both the epidermal growth factor and transferrin receptors and loaded with the photosensitizer phthalocyanine 4 (Pc 4) have been designed and compared with monotargeted AuNPs for <i>in vitro</i> and <i>in vivo</i> studies. The (EGF_pep+Tf_pep)-AuNPs-Pc 4 with a particle size of ∼41 nm improved both specificity and worked synergistically to decrease time of maximal accumulation in human glioma cells that overexpressed two cell surface receptors as compared to cells that overexpressed only one. Enhanced cellular association and increased cytotoxicity were achieved. <i>In vivo</i> studies show notable accumulation of these agents in the brain tumor regions