The Structural Basis for Brain Health

Cardiovascular disease (CVD) remains the leading cause of mortality in the United States. Stroke and dementia are the leading causes of adult disability worldwide, and the 5th and 6th leading causes of mortality respectively in the United States. Furthermore, CVD annually accounts for approximately $330 billion in direct and indirect costs in the United States: approximately one in seven health care dollars is spent on CVD. While these diseases have different etiologies, and present with different clinical manifestations and prognosis, converging evidence increasingly supports the idea of CVD as a common pathophysiological origin of cerebrovascular disease, potentially indicating a complex interplay between brain health and cardiovascular health. In this thesis, we leverage methodological advancements in systems and computational neurosciences related to the human brain connectome to assess individual topological network organization and integrity in acute and chronic stroke cohorts, and in a non-stroke cohort with varying CV risk factor burden, using graph theory and network analysis. We propose measures that underly neuroanatomical mechanisms that constitute efficient transfer of information and brain health. We demonstrate the impact of cardiovascular risk factors on brain health, even before overt clinical manifestation, and the resulting impact on cognitive performance, and further determine the underlying pathophysiology relating white matter disease and post-stroke outcomes

Neurocognitive screening following acquired brain injury: an adaptation of the Birmingham Cognitive Screen for Zimbabwe (Zim-BCoS)

Neuropsychology as a discipline has not taken root in low- and middle-income countries. Most neurocognitive tests used in these countries were developed and normed in high-income, mostly western countries. The psychometric robustness of these tests is often weak when they are used on low to middle-income clinical populations. The objectives of this study were to select, adapt and generate normative data for a suitable neurocognitive screen for use in Zimbabwe. To achieve these objectives, we divided the study into 4 phases. In Phase 1 of the study, we did a systematic review that identified 83 neurocognitive assessment instruments commonly used in low- and middle-income countries on patients who have suffered a stroke. From these instruments, we selected, adapted and normed the Birmingham Cognitive Screen (BCoS; Humphreys al., 2012) through phases 2 to 4 of this study. The screen offers a robust and sufficiently broad but shallow assessment tool for cognitive deficits across key cognitive domains commonly impaired following a stroke. In particular, in Phase 2 of the study, we evaluated the cross-cultural sensitivity of BCoS on healthy participants (N=105). We then performed surveys using the Delphi method on a panel of experts to culturally adapt BCoS for use in Zimbabwe (Zim-BCoS). We evaluated the inter-rater and test-retest reliability of the translated and validated Zim-BCoS and also compared its agreement with the original BCoS version to determine its robustness. In Phase 3, we evaluated the effects of demographic variables on performance on the cognitive domains assessed by Zim-BCoS. To do this, we performed multiple linear regression analyses to calculate regression-based norms using scores from a sample of healthy participants (N=412). From these analyses, participants' age, level of education and sex had significant effects, mainly on subtests in the language cognitive domain (Picture Naming, Sentence/Word Reading/Writing and Instruction Comprehension). In Phase 4 of the study, we performed neurocognitive assessments using Zim-BCoS (and other tests) to assess and determine the frequency of specific neurocognitive deficits in patients who had suffered a stroke and were attending two major hospitals in Harare, Zimbabwe's capital city (N=103). We also compared the performance of these patients to a matched control sample (N=103). To determine the psychometric stability of Zim-BCoS we determined its validity and reliability by comparing scores on its subtests to parallel neurocognitive tests that assess similar cognitive domains. We also assessed the predictive value of Zim-BCoS on patients' neuropsychiatric and functional outcomes. We evaluated the convergence and predictive validity as well as the inclusivity of Zim-BCoS to assess patients with aphasia. We used the Zim-BCoS test scores to establish prevalence rates of cognitive deficits and other post-stroke sequelae in the sample of patients with stroke. We also assessed the predictive value of ZimBCoS subtests on patients' neuropsychiatric and functional outcomes. All comparisons of ZimBCoS against standard cognitive tests and post-stroke sequelae measures had statistically significant convergence, predictive validity and inclusivity. In this study, we demonstrated the utility of Zim-BCoS for assessing cognitive impairment in patients who have suffered a stroke, particularly in resource poor contexts typical of low-income countries. We concluded that ZimBCoS is a robust neuropsychological screen suitable for research and clinical use in Zimbabwe. The screen has the potential to offer a cost effective and easy to use neurocognitive screen for patients with acquired neurological changes in low-income countries in Southern Africa

Aggregation studies on the transactive response DNA binding protein of 43 KDA (TDP-43)

The pathological deposition of the transactive response DNA-binding protein of 43 kDa (TDP-43) occurs in the majority (\uf07e97%) of amyotrophic lateral sclerosis (ALS) and in around 45% of frontotemporal lobar degeneration cases (FTLD). ALS and FTLD clinically overlap, presenting a continuum of phenotypes. Both ALS and FTLD lack treatments able to interfere with the underlying pathological process and early detection of TDP-43 pathology would facilitate the development of disease modifying drugs. The Real Time Quaking Induced Conversion reaction (RT-QuIC) showed the ability to detect prions in several peripheral tissues of patients with different forms of prion and prion-like diseases. Despite TDP-43 displays prion-like properties, to date the RT-QuIC technology has not yet been adapted to this protein. The main aim of this study was to adapt the RT-QuIC technique for the TDP-43 substrate and to exploit the intrinsic ability of this technology to amplify minutes amount of misfolded proteins for the detection of pathological TDP-43 species in the CSF of ALS and FTLD patients. As a second objective, we aimed at performing a preliminary evaluation of the seeding properties of the in vitro obtained TDP-43 synthetic aggregates, in order to evaluate their ability to recapitulate ALS/FTD TDP-43 pathology. First, we adapted the RT-QuIC technique for the aggregation of the TDP-43 substrate and then we optimized it with synthetic TDP-43 preformed aggregates and with autopsy-verified brain homogenate samples. After this optimization, we analyzed CSF samples from ALS and FTLD patients and controls. TDP-43 RT-QuIC was able to detect as little as 15 picograms of TDP-43 aggregates, discriminating between a cohort of subjects affected by ALS and FTLD and age-matched controls, with a total sensitivity of 94% and a specificity of 85%. Our preliminary analysis of HuTDP-43(263-414) fibrils showed that they were readily internalized and actively phosphorylated in SH-SY5Y cells. Furthermore, they were able to recruit the full-length endogenous protein in the formation of intra-cellular aggregates composed of hyperphosphorylated forms of the protein. We observed that the formation of TDP-43 intra-cellular aggregates resulted in a severe reduction of cell vitality which was not linked to a TDP-43 loss of function, but potentially related to a maintained RNA-binding capacity of TDP-43 aggregates. In conclusion, our data represent a proof-of-concept of TDP-43 RT-QuIC potential for the detection of TDP-43 pathological aggregates. Together with prion, amyloid beta, tau and \u3b1-syn RT-QuIC assays, a further optimization of the presented TDP-43 RT-QuIC protocol, would increase the opportunity to perform the earliest and most accurate diagnosis at a single patient level. Furthermore, we show that CSF detection of TDP-43 pathological aggregates may be exploited as a disease biomarker for ALS and FTLD. Our preliminary results regarding the seeding properties of TDP-43 synthetic aggregates suggest that TDP-43 RT-QuIC could be exploited not only as a powerful drug screening and diagnostic tool but could also serve as a very helpful instrument to further elucidate TDP-43 prion-like features

An integrated theory of language production and comprehension

Currently, production and comprehension are regarded as quite distinct in accounts of language processing. In rejecting this dichotomy, we instead assert that producing and understanding are interwoven, and that this interweaving is what enables people to predict themselves and each other. We start by noting that production and comprehension are forms of action and action perception. We then consider the evidence for interweaving in action, action perception, and joint action, and explain such evidence in terms of prediction. Specifically, we assume that actors construct forward models of their actions before they execute those actions, and that perceivers of others' actions covertly imitate those actions, then construct forward models of those actions. We use these accounts of action, action perception, and joint action to develop accounts of production, comprehension, and interactive language. Importantly, they incorporate well-defined levels of linguistic representation (such as semantics, syntax, and phonology). We show (a) how speakers and comprehenders use covert imitation and forward modeling to make predictions at these levels of representation, (b) how they interweave production and comprehension processes, and (c) how they use these predictions to monitor the upcoming utterances. We show how these accounts explain a range of behavioral and neuroscientific data on language processing and discuss some of the implications of our proposal

Towards a complete multiple-mechanism account of predictive language processing [Commentary on Pickering & Garrod]

Although we agree with Pickering & Garrod (P&G) that prediction-by-simulation and prediction-by-association are important mechanisms of anticipatory language processing, this commentary suggests that they: (1) overlook other potential mechanisms that might underlie prediction in language processing, (2) overestimate the importance of prediction-by-association in early childhood, and (3) underestimate the complexity and significance of several factors that might mediate prediction during language processing

Collaborative capacity development to complement stroke rehabilitation in Africa

This scholarly book focuses on stroke in Africa. Stroke is a leading cause of disability among adults of all ages, contributing significantly to health care costs related to long term implications, particularly if rehabilitation is sub-optimal. Given the burden of stroke in Africa, there is a need for a book that focuses on functioning African stroke survivors and the implications for rehabilitation within the African context. In addition, there is a need to progress with contextualised, person-centred, evidence-based guidance for the rehabilitation of people with stroke in Africa, thereby enabling them to lead socially and economically meaningful lives. The research incorporated in the book used a range of primary and secondary methodological approaches (scoping reviews, systematic reviews, meta-analyses, descriptive studies, surveys, health economics, and clinical practice guideline methodology) to shed new insights into African-centred issues and strategies to optimise function post-stroke

Scale-free amplitude modulation of neuronal oscillations tracks comprehension of accelerated speech

Speech comprehension is preserved up to a threefold acceleration, but deteriorates rapidly at higher speeds. Current models posit that perceptual resilience to accelerated speech is limited by the brain's ability to parse speech into syllabic units using δ/θ oscillations. Here, we investigated whether the involvement of neuronal oscillations in processing accelerated speech also relates to their scale-free amplitude modulation as indexed by the strength of long-range temporal correlations (LRTC). We recorded MEG while 24 human subjects (12 females) listened to radio news uttered at different comprehensible rates, at a mostly unintelligible rate and at this same speed interleaved with silence gaps. δ, θ, and low-γ oscillations followed the nonlinear variation of comprehension, with LRTC rising only at the highest speed. In contrast, increasing the rate was associated with a monotonic increase in LRTC in high-γ activity. When intelligibility was restored with the insertion of silence gaps, LRTC in the δ, θ, and low-γ oscillations resumed the low levels observed for intelligible speech. Remarkably, the lower the individual subject scaling exponents of δ/θ oscillations, the greater the comprehension of the fastest speech rate. Moreover, the strength of LRTC of the speech envelope decreased at the maximal rate, suggesting an inverse relationship with the LRTC of brain dynamics when comprehension halts. Our findings show that scale-free amplitude modulation of cortical oscillations and speech signals are tightly coupled to speech uptake capacity.SIGNIFICANCE STATEMENT One may read this statement in 20-30 s, but reading it in less than five leaves us clueless. Our minds limit how much information we grasp in an instant. Understanding the neural constraints on our capacity for sensory uptake is a fundamental question in neuroscience. Here, MEG was used to investigate neuronal activity while subjects listened to radio news played faster and faster until becoming unintelligible. We found that speech comprehension is related to the scale-free dynamics of δ and θ bands, whereas this property in high-γ fluctuations mirrors speech rate. We propose that successful speech processing imposes constraints on the self-organization of synchronous cell assemblies and their scale-free dynamics adjusts to the temporal properties of spoken language