Multimodal neuroimaging of vestibular and postural networks: Investigating the pathophysiology of idiopathic dizziness in older adults

Successful ageing - the preservation of good performance into old age, is an aspiration for many and a challenge for society. Modifiable factors which account for ageing-related functional decline should thus be identified and reduced. As life expectancy increases, brain ageing and its functional consequences become an increasingly important target for research and intervention. Cerebral small vessel disease, largely driven by vascular risk factors, has emerged as a strong contributor to cognitive and balance decline in late life. Though the early effects of cerebral small vessel disease on cognition are increasingly better understood, its symptomatic effects on other functional systems are not well characterised. In this thesis, I investigated the long recognised, but pathophysiologically enigmatic syndrome of dizziness in older adults, not accounted for by neurological disease or vestibular dysfunction. I considered the hypothesis that this ‘idiopathic dizziness’ is secondary to cerebral small vessel disease through its deleterious effects on white matter networks which subserve vestibular perceptual processes and/or the control of balance. I first defined the functional anatomy of the core human vestibular cortex by its functional connectivity (Chapter 3). I related the resulting anatomical subregions to behavioural and task neuroimaging data to define a vestibular network involved in self-motion perception. I proceeded to characterise the syndrome of idiopathic dizziness using clinical, cognitive and behavioural (vestibular function, balance and gait) data from patients and controls (Chapter 4). I combined this data with structural and diffusion magnetic resonance imaging data to investigate the pathophysiology of idiopathic dizziness. I found that frontal white matter tracts relevant to the control of balance had lower integrity in patients with idiopathic dizziness than controls. These findings occurred in the context of excess vascular risk, and markers of cerebral small vessel disease. Additionally, I found vestibular function and perception were normal in patients with idiopathic dizziness. The results suggest disrupted balance control may underpin idiopathic dizziness in cerebral small vessel disease. I proceeded to investigate whether neural correlates of balance control were altered in idiopathic dizziness as a model for mild balance impairment in cerebral small vessel disease (Chapter 5). To do this, I applied electroencephalography during quiet standing and related brain activity to spontaneous sway. I showed idiopathic dizziness was linked to altered cortical activity in relation to balance control, and this cortical activity was influenced by the burden of cerebral small vessel disease. Additionally, patients with idiopathic dizziness uniquely engaged a low frequency postural connectivity network, consistent with a different mode of postural control. Overall, the results within this thesis show a relationship between idiopathic dizziness and vascular injury to frontal tracts involved in the control of balance in cerebral small vessel disease. Small vessel disease may disrupt the cortical control of balance as a basis for symptoms in this syndrome.Open Acces

The impact of vestibular modulations on whole brain structure and function in humans

The vestibular system is a sensory system that monitors active and passive headmovements while at the same time permanently sensing gravity. Vestibular information is important for maintaining balance and stabilisation of vision and ultimately for general orientation in space. A distributed set of cortical vestibular regions process vestibular sensory information, together with other sensory and motor signals. How these brain regions are influenced by or interact with each other, and how this depends on the context in which the system is acting is not well understood. In my research I investigated the whole brain consequences of different vestibular sensory contexts by means of structural and functional magnetic resonance (MR) imaging on three different time scales (long-term, short-term, and medium-term). For the long-term time scale, I investigated functional brain connectivity in individuals experiencing a type of chronic dizziness that cannot be explained by structural damage within the nervous system. These patients exhibit chronic or long-term alterations in their processing of vestibular information, which leads to dizziness and vertigo. I found altered sensory and cerebellar network connectivity when they experience a dizziness-provoking stimulus. These two networks contain, but are not limited to, vestibular processing regions, demonstrating the importance of a whole-brain approach. The alterations correspond the notion that these patients have dysfunctional stimulus expectations. The short-term vestibular processing I investigated was the effect of artificial vestibular stimulation, which is frequently used in vestibular research and treatment. For this, I analysed functional network connectivity in healthy participants. I found that short-term vestibular stimulation does not cause a cortical functional reorganisation, although a nociceptive stimulus, which was matched for the somatosensory component of this stimulation, led to a reorganisation. The fact that cortical reorganisation does not occur during exclusively vestibular stimulation may reflect subconscious nature of vestibular processing in that it does not induce a different internal brain state. On the medium-term time scale, I investigated whole-brain structural changes as a result of gravity. Astronauts that travel to space for extended periods of time experience several physiological symptoms also affecting the fluid exchange of the brain. To characterise if these fluid exchanges also affect size of the spaces around brain blood vessels (perivascular spaces), I developed a semi-automatic detection pipeline which requires only one type of structural MR image. I found that space travellers have enlarged perivascular spaces even before their mission, when compared to a control population. These spaces were to a small extend further increased shortly after a long duration space flight of 6 months. Astronaut training thus contributes to structural changes in the whole brain in combination with long-duration space flight. This further suggests that additional contextual factors such as sleep quality should be considered in the future. Overall, in my thesis I show that investigating the whole brain during different vestibular modulations provides additional and novel insights about the underlying neural processes. I found that long-term vestibular states have an impact on functional networks, whilst short-term vestibular modulations do not seem to impact functional network organisation. In addition, I quantified the structural impact of microgravity and astronaut training in the whole brain using a new analysis pipeline. In the future, I expect that new advancements in the field of neuroimaging analysis, such as high sampling of individuals and dynamic network analysis will advance the field. This will potentially also provide new means to monitor disease progression or intervention success

The human posterior cingulate, retrosplenial, and medial parietal cortex effective connectome, and implications for memory and navigation

The human posterior cingulate, retrosplenial, and medial parietal cortex are involved in memory and navigation. The functional anatomy underlying these cognitive functions was investigated by measuring the effective connectivity of these Posterior Cingulate Division (PCD) regions in the Human Connectome Project-MMP1 atlas in 171 HCP participants, and complemented with functional connectivity and diffusion tractography. First, the postero-ventral parts of the PCD (31pd, 31pv, 7m, d23ab, and v23ab) have effective connectivity with the temporal pole, inferior temporal visual cortex, cortex in the superior temporal sulcus implicated in auditory and semantic processing, with the reward-related vmPFC and pregenual anterior cingulate cortex, with the inferior parietal cortex, and with the hippocampal system. This connectivity implicates it in hippocampal episodic memory, providing routes for “what,” reward and semantic schema-related information to access the hippocampus. Second, the antero-dorsal parts of the PCD (especially 31a and 23d, PCV, and also RSC) have connectivity with early visual cortical areas including those that represent spatial scenes, with the superior parietal cortex, with the pregenual anterior cingulate cortex, and with the hippocampal system. This connectivity implicates it in the “where” component for hippocampal episodic memory and for spatial navigation. The dorsal–transitional–visual (DVT) and ProStriate regions where the retrosplenial scene area is located have connectivity from early visual cortical areas to the parahippocampal scene area, providing a ventromedial route for spatial scene information to reach the hippocampus. These connectivities provide important routes for “what,” reward, and “where” scene-related information for human hippocampal episodic memory and navigation. The midcingulate cortex provides a route from the anterior dorsal parts of the PCD and the supracallosal part of the anterior cingulate cortex to premotor regions

A common neural substrate for processing scenes and egomotion-compatible visual motion

Neuroimaging studies have revealed two separate classes of category-selective regions specialized in optic flow (egomotion-compatible) processing and in scene/place perception. Despite the importance of both optic flow and scene/place recognition to estimate changes in position and orientation within the environment during self-motion, the possible functional link between egomotion- and scene-selective regions has not yet been established. Here we reanalyzed functional magnetic resonance images from a large sample of participants performing two well-known \u201clocalizer\u201d fMRI experiments, consisting in passive viewing of navigationally relevant stimuli such as buildings and places (scene/place stimulus) and coherently moving fields of dots simulating the visual stimulation during self-motion (flow fields). After interrogating the egomotion-selective areas with respect to the scene/place stimulus and the scene-selective areas with respect to flow fields, we found that the egomotion-selective areas V6+ and pIPS/V3A responded bilaterally more to scenes/places compared to faces, and all the scene-selective areas (parahippocampal place area or PPA, retrosplenial complex or RSC, and occipital place area or OPA) responded more to egomotion-compatible optic flow compared to random motion. The conjunction analysis between scene/place and flow field stimuli revealed that the most important focus of common activation was found in the dorsolateral parieto-occipital cortex, spanning the scene-selective OPA and the egomotion-selective pIPS/V3A. Individual inspection of the relative locations of these two regions revealed a partial overlap and a similar response profile to an independent low-level visual motion stimulus, suggesting that OPA and pIPS/V3A may be part of a unique motion-selective complex specialized in encoding both egomotion- and scene-relevant information, likely for the control of navigation in a structured environment

Altered resting-state functional connectivity in patients with chronic bilateral vestibular failure

AbstractPatients with bilateral vestibular failure (BVF) suffer from gait unsteadiness, oscillopsia and impaired spatial orientation. Brain imaging studies applying caloric irrigation to patients with BVF have shown altered neural activity of cortical visual–vestibular interaction: decreased bilateral neural activity in the posterior insula and parietal operculum and decreased deactivations in the visual cortex. It is unknown how this affects functional connectivity in the resting brain and how changes in connectivity are related to vestibular impairment.We applied a novel data driven approach based on graph theory to investigate altered whole-brain resting-state functional connectivity in BVF patients (n= 22) compared to age- and gender-matched healthy controls (n= 25) using resting-state fMRI. Changes in functional connectivity were related to subjective (vestibular scores) and objective functional parameters of vestibular impairment, specifically, the adaptive changes during active (self-guided) and passive (investigator driven) head impulse test (HIT) which reflects the integrity of the vestibulo-ocular reflex (VOR).BVF patients showed lower bilateral connectivity in the posterior insula and parietal operculum but higher connectivity in the posterior cerebellum compared to controls. Seed-based analysis revealed stronger connectivity from the right posterior insula to the precuneus, anterior insula, anterior cingulate cortex and the middle frontal gyrus. Excitingly, functional connectivity in the supramarginal gyrus (SMG) of the inferior parietal lobe and posterior cerebellum correlated with the increase of VOR gain during active as compared to passive HIT, i.e., the larger the adaptive VOR changes the larger was the increase in regional functional connectivity.Using whole brain resting-state connectivity analysis in BVF patients we show that enduring bilateral deficient or missing vestibular input leads to changes in resting-state connectivity of the brain. These changes in the resting brain are robust and task-independent as they were found in the absence of sensory stimulation and without a region-related a priori hypothesis. Therefore they may indicate a fundamental disease-related change in the resting brain. They may account for the patients' persistent deficits in visuo-spatial attention, spatial orientation and unsteadiness. The relation of increasing connectivity in the inferior parietal lobe, specifically SMG, to improvement of VOR during active head movements reflects cortical plasticity in BVF and may play a clinical role in vestibular rehabilitation

Cortico-spinal modularity in the parieto-frontal system: a new perspective on action control

: Classical neurophysiology suggests that the motor cortex (MI) has a unique role in action control. In contrast, this review presents evidence for multiple parieto-frontal spinal command modules that can bypass MI. Five observations support this modular perspective: (i) the statistics of cortical connectivity demonstrate functionally-related clusters of cortical areas, defining functional modules in the premotor, cingulate, and parietal cortices; (ii) different corticospinal pathways originate from the above areas, each with a distinct range of conduction velocities; (iii) the activation time of each module varies depending on task, and different modules can be activated simultaneously; (iv) a modular architecture with direct motor output is faster and less metabolically expensive than an architecture that relies on MI, given the slow connections between MI and other cortical areas; (v) lesions of the areas composing parieto-frontal modules have different effects from lesions of MI. Here we provide examples of six cortico-spinal modules and functions they subserve: module 1) arm reaching, tool use and object construction; module 2) spatial navigation and locomotion; module 3) grasping and observation of hand and mouth actions; module 4) action initiation, motor sequences, time encoding; module 5) conditional motor association and learning, action plan switching and action inhibition; module 6) planning defensive actions. These modules can serve as a library of tools to be recombined when faced with novel tasks, and MI might serve as a recombinatory hub. In conclusion, the availability of locally-stored information and multiple outflow paths supports the physiological plausibility of the proposed modular perspective

Reverse-Engineering the brain: The parts are as complex as the whole.

The purpose of this paper is to review the current state of neuroscience research with a focus on what has been achieved to date in unraveling the mysteries of brain operations, major research initiatives, fundamental challenges, and potentially realizable objectives. General research approaches aimed at constructing a wiring diagram of the brain (i.e., connectome), determining how the brain encodes and computes information, and whole brain simulation attempts are reviewed in terms of strategies employed and difficulties encountered. While promising advances have been made during the past 50 years due to electron microscopy, the development of new experimental methods, and the availability of computer-enabled high throughput imaging systems, brain research is still greatly encumbered by inadequate monitoring and recording capabilities. Four hypotheses relating to comprehension through the assembly of parts, formation of memories, influence of genes, and synapse formation are described as plausible explanations even though they cannot be validated at this time. By assessing the feasibility of overcoming the principal problems that beleaguer brain research in comparison with the potential benefits that can be derived from even partial achievement of the goals the author concludes that the significant investment of government funding is justified

Age-Related Differences in Functional and Structural Connectivity in the Spatial Navigation Brain Network

International audienceSpatial navigation involves multiple cognitive processes including multisensory integration, visuospatial coding, memory, and decision-making. These functions are mediated by the interplay of cerebral structures that can be broadly separated into a posterior network (subserving visual and spatial processing) and an anterior network (dedicated to memory and navigation planning). Within these networks, areas such as the hippocampus (HC) are known to be affected by aging and to be associated with cognitive decline and navigation impairments. However, age-related changes in brain connectivity within the spatial navigation network remain to be investigated. For this purpose, we performed a neuroimaging study combining functional and structural connectivity analyses between cerebral regions involved in spatial navigation. Nineteen young (μ = 27 years, σ = 4.3; 10 F) and 22 older (μ = 73 years, σ = 4.1; 10 F) participants were examined in this study. Our analyses focused on the parahippocampal place area (PPA), the retrosplenial cortex (RSC), the occipital place area (OPA), and the projections into the visual cortex of central and peripheral visual fields, delineated from independent functional localizers. In addition, we segmented the HC and the medial prefrontal cortex (mPFC) from anatomical images. Our results show an age-related decrease in functional connectivity between low-visual areas and the HC, associated with an increase in functional connectivity between OPA and PPA in older participants compared to young subjects. Concerning the structural connectivity, we found age-related differences in white matter integrity within the navigation brain network, with the exception of the OPA. The OPA is known to be involved in egocentric navigation, as opposed to allocentric strategies which are more related to the hippocampal region. The increase in functional connectivity between the OPA and PPA may thus reflect a compensatory mechanism for the age-related alterations around the HC, favoring the use of the preserved structural network mediating egocentric navigation. Overall, these findings on age-related differences of functional and structural connectivity may help to elucidate the cerebral bases of spatial navigation deficits in healthy and pathological aging

Investigating the interplay of the human attentional and vestibular systems using transcranial magnetic stimulation

The aim of this doctoral thesis was to investigate the relationship between the processing of vestibular information, on the one hand, and higher cognitive functions such as visual (spatial) attention and perceptual decision making, on the other. In order to draw causal inference about the role of specific cortical regions in this interplay, two experimental studies were conducted which combined psychophysical task designs using verticality judgment tasks with transcranial magnetic stimulation (TMS). The first study employed a simultaneous TMS-EEG approach to examine the role of the right intraparietal sulcus (IPS) within the dorsal parietal cortex in verticality judgments – a cortical area that has repeatedly been associated with both the visual attention and vestibular systems. Facilitatory effects of right IPS TMS on the bias of verticality perception were reported and mirrored by EEG results, which pointed to a normalization of individual perceptual biases reflected in a fronto-central ERP component following the stimulation. In contrast, no effects of left IPS TMS on either behavioural or electrophysiological measures were observed and right IPS TMS did not modulate performance in a control task that used the same set of stimuli (vertical Landmark task). These findings point to a causal role of the right IPS in the neuronal implementation of upright perception and strengthen the notion of vestibular-attentional coupling. In the second study verticality judgments had to be made under different levels of perceptual demand to address the question of how perceptual decision making interacts with vestibular processing. Stimuli adapted from those used in the first study were presented in a visual search setting, which required perceptual and response switches, in a way that varied attentional demands. This task was combined with offline theta-burst TMS applied to the dorsal medial frontal cortex (dMFC). The dMFC has been found to crucially contribute to perceptual decision making and is connected to core parts of the vestibular cortical network. Analysis of distinct features of behavioural performance before as compared to following dMFC TMS revealed a specific involvement of the dMFC in establishing the precision and accuracy of verticality judgments, particularly under conditions of high perceptual load. In summary, the results of the two studies support the idea of a functional link between the processing of vestibular information, (spatial) attention, and perceptual decision making, giving rise to higher vestibular cognition. Moreover, they suggest that on a cortical level this interplay is achieved within a network of multimodal processing regions such as the parietal and frontal cortices

The Value of Seizure Semiology in Epilepsy Surgery: Epileptogenic-Zone Localisation in Presurgical Patients using Machine Learning and Semiology Visualisation Tool

Background Eight million individuals have focal drug resistant epilepsy worldwide. If their epileptogenic focus is identified and resected, they may become seizure-free and experience significant improvements in quality of life. However, seizure-freedom occurs in less than half of surgical resections. Seizure semiology - the signs and symptoms during a seizure - along with brain imaging and electroencephalography (EEG) are amongst the mainstays of seizure localisation. Although there have been advances in algorithmic identification of abnormalities on EEG and imaging, semiological analysis has remained more subjective. The primary objective of this research was to investigate the localising value of clinician-identified semiology, and secondarily to improve personalised prognostication for epilepsy surgery. Methods I data mined retrospective hospital records to link semiology to outcomes. I trained machine learning models to predict temporal lobe epilepsy (TLE) and determine the value of semiology compared to a benchmark of hippocampal sclerosis (HS). Due to the hospital dataset being relatively small, we also collected data from a systematic review of the literature to curate an open-access Semio2Brain database. We built the Semiology-to-Brain Visualisation Tool (SVT) on this database and retrospectively validated SVT in two separate groups of randomly selected patients and individuals with frontal lobe epilepsy. Separately, a systematic review of multimodal prognostic features of epilepsy surgery was undertaken. The concept of a semiological connectome was devised and compared to structural connectivity to investigate probabilistic propagation and semiology generation. Results Although a (non-chronological) list of patients’ semiologies did not improve localisation beyond the initial semiology, the list of semiology added value when combined with an imaging feature. The absolute added value of semiology in a support vector classifier in diagnosing TLE, compared to HS, was 25%. Semiology was however unable to predict postsurgical outcomes. To help future prognostic models, a list of essential multimodal prognostic features for epilepsy surgery were extracted from meta-analyses and a structural causal model proposed. Semio2Brain consists of over 13000 semiological datapoints from 4643 patients across 309 studies and uniquely enabled a Bayesian approach to localisation to mitigate TLE publication bias. SVT performed well in a retrospective validation, matching the best expert clinician’s localisation scores and exceeding them for lateralisation, and showed modest value in localisation in individuals with frontal lobe epilepsy (FLE). There was a significant correlation between the number of connecting fibres between brain regions and the seizure semiologies that can arise from these regions. Conclusions Semiology is valuable in localisation, but multimodal concordance is more valuable and highly prognostic. SVT could be suitable for use in multimodal models to predict the seizure focus