Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references. / A key requirement from cognitive models of language comprehension is that they specify the distinct computational mechanisms that are engaged in language processing and the division of linguistic labor across them. Here, I address this requirement from a cognitive neuroscience perspective by employing functional MRI to study the neural implementation of comprehension processes. My experimental approach, unprecedented in studies of language, combines available methods to simultaneously achieve (i) increased functional resolution, via localization of functional brain regions at the single-participant level; (ii) ecological validity, through datadriven, model-free paradigms using naturalistic stimuli; and (iii) statistical rigor, by explicit comparison of functional profiles across regions. Using this approach, I first contrast two cortical networks engaged in comprehension: one, the "high-level language network", is selectively recruited by linguistic processing but not by other cognitive functions; another, the "multiple-demand network", is recruited across diverse cognitive tasks, both linguistic and non-linguistic. I show that, during naturalistic cognition, each network shows high synchronization amongst its constituent regions, whereas regions across the two networks are functionally dissociated. Thus, these two systems likely play distinct roles in comprehension, which I then characterize by demonstrating that the language network closely tracks linguistic input whereas the multiple-demand network does not. This finding critically constrains the possible contributions of the multiple-demand system to comprehension. Next, I focus on the high-level language network and examine two current hypotheses about its internal structure. In one study, I find that activity elicited by syntactic processing is not localized to focal language regions but is instead distributed throughout the network, suggesting that syntax is cognitively inseparable from other aspects of language. In another study, I estimate the timescales over which different language regions integrate linguistic information and find that they share a common profile of temporal integration. Therefore, the topographic division of linguistic labor across this network is not organized along distinct integration timescales. Collectively, these results account for crucial inconsistencies in the literature and challenge common theoretical views. By characterizing the fundamental functional architecture of comprehension mechanisms, these results provide novel insights into the ontology of linguistic mechanisms that give rise to human language. / by Idan Blank. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2003. / Includes bibliographical references. / The cognitive and neural processes underlying memory formation may differ depending on the vividness, or detail, of information encoded. In Chapter 1, a divided attention paradigm was used to examine memory formation when resources are (a) devoted primarily to encoding and (b) directed away from encoding, and toward a secondary task. In condition (b) the memories formed often lacked vividness. The formation of these less detailed memories recruited right inferior prefrontal cortex (PFC) and left parahippocampal gyrus. The left inferior PFC and left anterior hippocampus were additionally recruited in condition (a) when vivid memories could be formed. Investigations of memories' vividness have typically included only neutral information. The studies in Chapter 2 revealed that emotional information is vividly remembered more frequently than information lacking emotional import. This enhancement occurred for words with valence only (i.e., negative words that did not elicit physiological arousal) as well as for arousing ("taboo") words, but was stronger for the arousing words. In Chapter 3 a divided attention paradigm was employed to investigate the contributions of automatic and controlled processing to the recollective enhancement for the emotional words. Automatic processes (unaffected by task manipulation) drove the enhancement for arousing words, whereas controlled processes (disrupted by task manipulation) supported the enhancement for words with valence only. Thus, dissociable cognitive processes contributed to the enhancement for the two types of emotional words. In Chapter 4, fMRI was used to examine whether distinct encoding processes underlie enhanced memory for words with valence only versus words with arousal. / (cont.) Successful encoding of words with valence only was via a PFC-hippocampal network associated with controlled encoding processes (e.g., elaboration and rehearsal), whereas successful encoding of arousing words was mediated by an amygdalar-hippocampal network that may be important for automatic processing of emotional content. In conclusion, distinct neural processes appear to support the ability to form vivid memories as compared to less detailed ones. The specific cognitive and neural processes depended on the emotional nature of the stimuli. Vividly-remembered neutral words, and words with valence only, relied on similar encoding processes. In contrast, dissociable processes mediated successful encoding of vividly-remembered arousing words. / by Elizabeth A. Kensinger. / Ph.D.

Thesis: S.M. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (page 16). / The ventral pre-arcuate area (VPA) in the primate prefrontal cortex has recently been found to play an important role in feature-based selection of visual targets in the context of a naturalistic free-gaze visual search task. While VPA neuronal activation was found to be necessary for behavioral performance as well as target selection in the FEF, its role in the broader context of the visual system remains to be addressed. To this end, we have interrogated the role of the VPA in mediating the effects of feature attention in the macaque visual area V4 by recording in V4 with and without muscimol inactivation in the VPA. We report here that neuronal activation in the VPA is necessary for firing rate increases related to target selection in V4. KEYWORDS: feature attention, visual search, muscimol, neurophysiology / by Azriel Ghadooshahy. / S.M. in Neuroscience

Salt-sensitive hypertension, a key component of essential hypertension, affects approximately 50% of hypertensive patients and dramatically increases the risk of adverse cardiovascular events. Excess dietary sodium intake is an established cause of hypertension, but there remains no clear understanding of the central molecular pathways acting to facilitate sodium homeostasis and normotension in salt-resistant phenotypes, or potential derangements in these antihypertensive systems in salt-sensitive hypertension. Therefore, there exists a critical need to elucidate the neural mechanisms that account for the phenotypic difference between salt-resistance and salt-sensitivity. The current studies hypothesize that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the central responses activated to counter the development of salt-sensitive hypertension. Salt-resistant (Sprague-Dawley, Dahl salt-resistant, Brown Norway) and salt-sensitive (Dahl salt-sensitive, 8-congenic Dahl salt-sensitive) rat phenotypes were utilized to investigate the role of central Gαi2 proteins in the physiological regulation of blood pressure in response to acute and chronic challenges to sodium homeostasis. Salt-resistant animals remain normotensive following chronic high salt intake and exhibit an endogenous site-specific increase in PVN Gαi2 proteins. Exogenous oligodeoxynucleotide-mediated downregulation of Gαi2 proteins throughout the brain evokes rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation in animals typically salt-resistant. In salt-sensitive animals, Gαi2 protein downregulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Central Gαi2 protein downregulation also resulted in prolonged elevated blood pressure mediated by an attenuated activation of parvocellular PVN neurons. The PVN is the critical brain site at which the antihypertensive compensatory action of Gαi2 protein mediated signal transduction influences blood pressure regulation. PVN Gαi2 protein-mediated signal transduction represents a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. This also differentially influences PVN parvocellular neuronal activation, sympathetic outflow, and arterial pressure in response to sodium challenges, independently of actions on magnocellular neurons and vasopressin release. Impairment of this signaling mechanism contributes to the development of salt-sensitive hypertension. Collectively, this work highlights the complex interaction between the CNS and kidney, and the role of the sympathetic nervous system, in the short and long-term regulation of blood pressure.

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Glioblastoma is the most common primary malignant brain tumour in the adult population. Despite multimodality treatment with surgery, radiotherapy and chemotherapy, outcomes are very poor, with less than 15% of patients alive after two years. Increasing evidence suggests that glioblastoma stem cells (GSCs) are likely to play an important role in the biology of this disease and are involved in treatment resistance and tumour recurrence following standard therapy. My thesis aims to address two main aspects of this research area: 1) optimization of methods to evaluate treatment responses of GSCs and their differentiated counterparts (non-GSCs), with a particular focus on a tissue culture model that resembles more closely the tumoral niche; 2) characterization of cell division and centrosome cycle of GSCs, investigating possible differences between these cells and non-GSCs, that would allow the identification of targets for new therapeutic strategies against glioblastomas. In the first part of my project, I optimized a clonogenic survival assay, to compare sensitivity of GSCs and non-GSCs to various treatments, and I developed the use of a 3-dimentional tissue culture system, that allows analysis of features and radiation responses of these two subpopulations in the presence of specific microenvironmental factors from the tumoral niche. In the second part, I show that GSCs display mitotic spindle abnormalities more frequently than non-GSCs and that they have distinctive features with regards to the centrosome cycle. I also demonstrate that GSCs are more sensitive than non-GSCs to subtle changes in Aurora kinase A activity, which result in a rapid increase in polyploidy and subsequently in senescence, with a consistent reduction in clonogenic survival. Based on these findings, I propose that kinases involved in the centrosome cycle need to be explored as a novel strategy to target GSCs effectively and improve outcomes of glioblastoma patients.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2009. / "September 2009." Cataloged from PDF version of thesis. / Includes bibliographical references (p. 191-201). / What do words and phrases mean? How do we infer their meaning in a given context? How do we know which sets of words have sensible meanings when combined, as opposed to being nonsense? As language learners and speakers, we can solve these problems starting at a young age, but as scientists, our understanding of these processes is limited. This thesis seeks to address these questions using a computational approach. Bayesian modeling provides a method of combining categories and logical constraints with probabilistic inference, yielding word and phrase meanings that involve graded category memberships and are governed by probabilistically inferred structures. The Bayesian approach also allows an investigation to separately identify the prior beliefs a language user brings to a particular situation involving meaning-based inference (e.g., learning a word meaning or identifying which objects an adjective applies to within a given context), and to identify what the language user can infer from the context. This approach therefore provides the foundation also for investigations of how different prior beliefs affect what a language user infers in a given situation, and how prior beliefs can develop over time. Using a computational approach, I address the following questions: (1) How do people generalize about a word's meaning from limited evidence? (2) How do people understand and use phrases, particularly when some of the words in those phrases depend on context for interpretation? (3) How do people know and learn which combinations of predicates and noun phrases can sensibly be combined and which are nonsensical? / (cont.) I show how each of these topics involves the probabilistic induction of categories, and I examine the constraints on inference in each domain. I also explore which of these constraints may themselves be learned. / by Lauren A. Schmidt. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, September 2011. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / "September, 2011." Cataloged from student submitted PDF version of thesis. / Includes bibliographical references. / This dissertation documents how healthy aging and Parkinson's disease (PD) affect brain anatomy and physiology and how these neural changes relate to measures of cognition and perception. While healthy aging and PD are both accompanied by a wide-range of cognitive impairments, the neural underpinnings of cognitive decline in each is likely mediated by deterioration of different systems. The four chapters of this dissertation address specific aspects of how healthy aging and PD affect the neural circuits that support sensory processes and high-level cognition. The experiments in Chapters 2 and 3 examine the effects of healthy aging on the integrity of neural circuits that modulate cognitive control processes. In Chapter 2, we test the hypothesis that the patterns of age-related change differ between white matter and gray matter regions, and that changes in the integrity of anterior regions correlate most strongly with performance on cognitive control tasks. In Chapter 3, we build upon the structural findings by examining the hypothesis that age-related changes in white matter integrity are associated with disrupted oscillatory dynamics observed during a visual search task. Chapter 4 investigates healthy age-related changes in somatosensory mu rhythms and evoked responses and uses a computational model of primary somatosensory cortex to predict the underlying cellular and neurophysiolgical bases of these alterations. In contrast to the widespread cortical changes seen in healthy OA, the cardinal motor symptoms of PD are largely explained by degeneration of the dopaminergic substantia nigra, pars compacta (SNc). Cognitive sequelae of PD, however, likely result from disruptions in multiple neurotransmitter systems, including nondopaminergic nuclei, but research on these aspects of the disease has been hindered by a lack of sensitive MRI biomarkers for the affected structures. Chapter 5 presents new multispectral MRI tools that visualize the SNc and the cholinergic basal forebrain (BF). We applied these methods to test the hypothesis that degenerative processes in PD affect the SNc before the BF. This experiment lays important groundwork for future studies that will examine the relative contribution of the SNc and BF to cognitive impairments in PD. / by David A. Ziegler. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 112-126). / Human language is notable for its expressivity; syntax is powerful and allows for potentially unlimited new sentences. But even simple transitive sentences like "I broke the lamp" provide a sophisticated tool for communication, capture the basic building blocks of syntax and semantics that are widely agreed to be part of our linguistic capacity like agent or subject. With this relatively simple machinery, we are able to move a cognitive representation of an event from one person's head to another. How is this possible? In this dissertation, I examine both adult and child language to understand this capacity. Paper 1 examines the link between non-linguistic cognition and preschoolers' expectations about the meaning of novel verbs. We find that even though transitive verbs can refer to many event types, 3- and 4-year-olds are more likely to associate them with scenes with spatiotemporal features indicating causation. Papers 2 and 3 ask a second question: how do people organize language to facilitate communication? Paper 2 probes how adults order the basic elements (Subject, Verb, Object) in a task that appears to be independent of native language constraints, and tests whether the content of the message leads gesturers to reorganize their utterances. Paper 3 asks whether adults and children are aware that the relative informativity of arguments depends on context, and whether they can successfully make decisions in a novel communication task. By limiting the expression of transitive sentences to just two words (e.g. MONKEY EAT), we discover which elements people consider to be most informative. Both adults and children flexibly adjust their expectations about informative sentences according to which arguments are the most ambiguous in context. Together, these case studies help us understand how human language accomplishes its communicative goals, both in terms of the cognitive representations recruited for processing complex events in language, and the strategies used for expressing them. Whatever the formal nature of the representations involved in syntax and semantics, they must ultimately allow us to form predicates over nonlinguistic representations of the world, and they must support the kinds of pragmatic inferences that we know people can make. / by Melissa Kline. / Ph. D.