Behavioural and neural characteristics of navigation impairments in preclinical Alzheimer’s disease

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk preclinical individuals. This thesis focuses on spatial navigation deficits, which are increasingly shown to be present in atrisk individuals, because the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Experimental chapters 2 and 3, show that a novel test battery captures navigation deficits that precede the onset of verbal and non-verbal episodic memory deficits in preclinical disease and that resting-state functional connectivity between the EC and the PCC underpins such deficits. Evidence for moderate test re-test reliability in the same non-clinical sample is presented in chapter 4. Moving beyond detection of preclinical disease, and towards prevention, in chapter 5 we examined whether marine fish oils help preserve the volume of AD vulnerable brain regions and found that low circulating DHA blood concentration predicts preservation of hippocampal and entorhinal volume in preclinical AD. This is potentially due to increased DHA uptake from the blood to the brain due to preclinical disease. Taken together, the research advances our conceptual understanding of the pathological and compensatory changes that characterise preclinical AD and offers important information toward generating more accurate risk profiles for AD vulnerable adults

The Aging Navigational System

The discovery of neuronal systems dedicated to computing spatial information, composed of functionally distinct cell types such as place and grid cells, combined with an extensive body of human-based behavioral and neuroimaging research has provided us with a detailed understanding of the brain's navigation circuit. In this review, we discuss emerging evidence from rodents, non-human primates, and humans that demonstrates how cognitive aging affects the navigational computations supported by these systems. Critically, we show 1) that navigational deficits cannot solely be explained by general deficits in learning and memory, 2) that there is no uniform decline across different navigational computations, and 3) that navigational deficits might be sensitive markers for impending pathological decline. Following an introduction to the mechanisms underlying spatial navigation and how they relate to general processes of learning and memory, the review discusses how aging affects the perception and integration of spatial information, the creation and storage of memory traces for spatial information, and the use of spatial information during navigational behavior. The closing section highlights the clinical potential of behavioral and neural markers of spatial navigation, with a particular emphasis on neurodegenerative disorders

Understanding space by moving through it: neural networks of motion- and space processing in humans

Humans explore the world by moving in it, whether moving their whole body as during walking or driving a car, or moving their arm to explore the immediate environment. During movement, self-motion cues arise from the sensorimotor system comprising vestibular, proprioceptive, visual and motor cues, which provide information about direction and speed of the movement. Such cues allow the body to keep track of its location while it moves through space. Sensorimotor signals providing self-motion information can therefore serve as a source for spatial processing in the brain. This thesis is an inquiry into human brain systems of movement and motion processing in a number of different sensory and motor modalities using functional magnetic resonance imaging (fMRI). By characterizing connections between these systems and the spatial representation system in the brain, this thesis investigated how humans understand space by moving through it. In the first study of this thesis, the recollection networks of whole-body movement were explored. Brain activation was measured during the retrieval of active and passive self-motion and retrieval of observing another person performing these tasks. Primary sensorimotor areas dominated the recollection network of active movement, while higher association areas in parietal and mid-occipital cortex were recruited during the recollection of passive transport. Common to both self-motion conditions were bilateral activations in the posterior medial temporal lobe (MTL). No MTL activations were observed during recollection of movement observation. Considering that on a behavioral level, both active and passive self-motion provide sufficient information for spatial estimations, the common activation in MTL might represent the common physiological substrate for such estimations. The second study investigated processing in the 'parahippocampal place area' (PPA), a region in the posterior MTL, during haptic exploration of spatial layout. The PPA in known to respond strongly to visuo-spatial layout. The study explored if this region is processing visuo-spatial layout specifically or spatial layout in general, independent from the encoding sensory modality. In both a cohort of sighted and blind participants, activation patterns in PPA were measured while participants haptically explored the spatial layout of model scenes or the shape of information-matched objects. Both in sighted and blind individuals, PPA activity was greater during layout exploration than during object-shape exploration. While PPA activity in the sighted could also be caused by a transformation of haptic information into a mental visual image of the layout, two points speak against this: Firstly, no increase in connectivity between the visual cortex and the PPA were observed, which would be expected if visual imagery took place. Secondly, blind participates, who cannot resort to visual imagery, showed the same pattern of PPA activity. Together, these results suggest that the PPA processes spatial layout information independent from the encoding modality. The third and last study addressed error accumulation in motion processing on different levels of the visual system. Using novel analysis methods of fMRI data, possible links between physiological properties in hMT+ and V1 and inter-individual differences in perceptual performance were explored. A correlation between noise characteristics and performance score was found in hMT+ but not V1. Better performance correlated with greater signal variability in hMT+. Though neurophysiological variability is traditionally seen as detrimental for behavioral accuracy, the results of this thesis contribute to the increasing evidence which suggests the opposite: that more efficient processing under certain circumstances can be related to more noise in neurophysiological signals. In summary, the results of this doctoral thesis contribute to our current understanding of motion and movement processing in the brain and its interface with spatial processing networks. The posterior MTL appears to be a key region for both self-motion and spatial processing. The results further indicate that physiological characteristics on the level of category-specific processing but not primary encoding reflect behavioral judgments on motion. This thesis also makes methodological contributions to the field of neuroimaging: it was found that the analysis of signal variability is a good gauge for analysing inter-individual physiological differences, while superior head-movement correction techniques have to be developed before pattern classification can be used to this end

Testing Spatial Cognition in Mild Cognitive Impairment Using Immersive Virtual Reality

The prodromal stage of dementia is known as mild cognitive impairment (MCI). Currently, cognitive tests are unable to correctly characterize the MCI type, and specifically, whether it will develop into Alzheimer's disease (AD). This means that cognitive deficits are detected long after the onset of pathological changes. More sensitive and specific tests, which can non-invasively detect the subtle, early signs of AD in MCI, would facilitate investigation of its early development and potentially permit early treatments. This thesis aims to develop a diagnostic tool to target the cognitive functions – and engage the corresponding brain regions – typically affected during the prodromal stages of AD. Pathological changes start in the hippocampal formation, a critical area for episodic memory and navigation. The tasks are developed from previous work demonstrating hippocampal dependence and make use of recent advances in immersive virtual reality, providing an ecologically valid improvement on standard tests of cognitive function. The first experimental chapter presents a test of navigation by path integration, a function specifically associated with processing by grid cells in the medial entorhinal cortex (mEC). The second experiment presents a test of object-location memory, believed to involve place cells in the hippocampus proper, combining inputs from mEC and object-identity information from the lateral entorhinal cortex (lEC). The third experiment tests object-location memory in a way that enables the contribution of self-motion to be assessed. Results show that the immersive virtual reality paradigms developed to test spatial cognition in prodromal AD are able to differentiate MCI patients from healthy age-matched older controls. Additionally, in combination with CSF biomarkers, navigation testing has proven the ability to stratify between MCI with different levels of biomarkers, identifying the patients who are most likely going to develop the disease. Finally, the last experiment, in an attempt to summarize different aspects of spatial cognition tested in the previous experiments, can detect subtle changes starting from ageing that may further decline with the onset of cognitive decline due to AD neuropathology. In conclusion within this thesis, we demonstrated the use of immersive virtual reality tests as an ecological valid tool for assessing the behavioural changes associated with the early progression of AD

Cognitive and Neuroimaging Markers of Vascular Cognitive Impairment

Detection of incipient cognitive impairment and dementia pathophysiology is critical to identifying preclinical populations and target potentially disease modifying interventions towards them. There are currently concerted efforts for such detection in Alzheimer’s disease (AD). By contrast, the examination of cognitive markers and their relationship to biomarkers for vascular cognitive impairment (VCI) is far less established, despite VCI being highly prevalent and often concomitantly presenting with AD. Critically, vascular risk factors are currently associated with the most viable treatment options via pharmacological and non-pharmacological intervention, hence developing selective and sensitive methods for the identification of vascular factors have important implications for modifying dementia disease trajectories. As outlined in Chapter one, this thesis focuses on uncovering spatial navigation deficits in established and preclinical VCI and investigates potential brain dysconnectivity in the frontoparietal regions and overlapping navigation systems. Chapter two reveals egocentric orientation deficits in established VCI to distinguish it from AD. In Chapter three, the VCI case study, RK, who previously displayed spatial navigation deficits is followed up three years after initial diagnosis. Results suggest an ongoing egocentric orientation deficit whilst there are improvements in cognitive scores assessed using conventional neuropsychological assessments. Diffusion tensor imaging (DTI) analysis suggests reduced superior longitudinal fasciculus (SLF) integrity to parietal segments. Chapter four shows that a novel test battery of navigation and ERP components capture deficits that precede the onset of general cognitive decline assessed by typical neuropsychological assessment in preclinical VCI. Taken together, this research advances our conceptual understanding of the pathological changes to cognition that characterise VCI and at-risk individuals

The functional anatomy of white matter pathways for visual configuration learning

The role of the medial temporal lobes (MTL) in visuo-spatial learning has been extensively studied and documented in the neuroscientific literature. Numerous animal and human studies have demonstrated that the parahippocampal place area (PPA), which sits at the confluence of the parahippocampal and lingual gyri, is particularly important for learning the spatial configuration of objects in visually presented scenes. In current visuo-spatial processing models, the PPA sits downstream from the parietal lobes which are involved in multiple facets of spatial processing. Yet, direct input to the PPA from early visual cortex (EVC) is rarely discussed and poorly understood. This thesis adopted a multimodal neuroimaging analysis approach to study the functional anatomy of these connections. First, the pattern of structural connectivity between EVC and the MTL was explored by means of surface-based ‘connectomes’ constructed from diffusion MRI tractography in a cohort of 200 healthy young adults from the Human Connectome Project. Through this analysis, the PPA emerged as a primary recipient of EVC connections within the MTL. Second, a data-driven clustering analysis of the PPA’s connectivity to an extended cortical region (including EVC, retrosplenial cortex, and other areas) revealed multiple clusters with different connectivity profiles within the PPA. The two main clusters were located in the posterior and anterior portions of the PPA, with the posterior cluster preferentially connected to EVC. Motivated by this result, virtual tractography dissections were used to delineate the medial occipital longitudinal tract (MOLT), the white matter bundle connecting the PPA with EVC. The properties of this bundle and its relation to visual configuration learning were verified in a different, cross-sectional adult cohort of 90 subjects. Finally, the role of the MOLT in the visuo-spatial learning domain was further confirmed in the case of a stroke patient who, after bilateral occipital injury, exhibited deficits confined to this domain. The results presented in this work suggest that the MOLT should be included in current visuo-spatial processing models as it offers additional insight into how the MTL acquires and processes information for spatial learning

What is the function of the human retrosplenial cortex?

The retrosplenial cortex (RSC) comprises Brodmann areas 29/30 and is an integral part of a brain system that is engaged by spatial navigation, scene processing, recollection of the past and imagining the future. Damage involving the RSC in humans can result in significant memory and navigation deficits, while the earliest metabolic decline in Alzheimer's disease is centred upon this region. The precise function of the RSC, however, remains elusive. In this thesis I sought to determine the key contribution of the RSC in a series of six studies that each comprised behavioural and functional magnetic resonance imaging (fMRI) experiments. Specifically, I discovered that the RSC is acutely responsive to landmarks in the environment that maintain a fixed, permanent location in space, and moreover is sensitive to the exact number of permanent landmarks in view. Using a virtual reality environment populated with entirely novel ‘alien’ landmarks I then tracked the de novo acquisition of landmark knowledge and observed the selective engagement of the RSC as information about landmark permanence accrued. In three further studies I established the parameters within which the RSC operates by contrasting permanent landmarks in large- and small-scale space, by comparing landmark permanence with orientation value, and by investigating permanence in non-spatial domains. In parallel lines of inquiry, I uncovered evidence that a fully functional RSC may be a prerequisite for successful navigation, while also characterising RSC interactions with other brain regions, such as the hippocampus, that could have importance for constructing reliable representations of the world. Together my findings provide new insights into the role of the RSC in a range of cognitive functions. The RSC’s processing of permanent predictable features may represent a key building block for spatial and scene representations that are central to navigation, recalling past experiences and imagining the future

Hippocampal Influences on Movements, Sensory, and Language Processing: A Role in Cognitive Control?

Beyond its established role in declarative memory function, the hippocampus has been implicated in varied roles in sensory processing and cognition, particularly those requiring temporal or spatial context. Disentangling its known role in memory from other cognitive functions can be challenging, as memory is directly or indirectly involved in most conscious activities, including tasks that underlie most experimental investigations. Recent work from this lab has examined the directional influence from the hippocampus on cortical areas involved in task performance, including tasks requiring movements, sensory processing, or language judgments. The hippocampus shows preferential connectivity with relevant cortical areas, typically the region critically involved in task performance, raising the possibility that the hippocampus plays a role in cognitive control. Minimal criteria for a role in cognitive control are proposed, and hippocampal connectivity with sensorimotor cortex during a non-mnemonic motor task is shown to meet this standard. Future directions for exploration are discussed

Gender differences in spatial ability within virtual reality

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