Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments

Background Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. Methods DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. Results 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study

Relationship between white matter alteration and encoding related brain activation in connected brain regions

Background: Aging is associated with alterations of white matter and brain activation. Functional MRI studies in elderly subjects showed changes in encoding related brain activation such as hyperactivation in frontal areas and hypoactivation in occipital gyrus in comparison to a younger control group. A contributing factor could be alterations of white matter integrity, resulting from age-related small vessel disease (SVD), a pathology that effects the small vessels of the brain or Wallerian Degeneration (WD) that explains axonal degeneration distal of an injury. These processes lead to changes such as white matter hyperintensities (WMH) detected by MRI or microstructural change assessed by the diffusion tensor imaging (DTI), marker mean diffusivity (MD) or peak width (PW). It was hypothesized that the directionality of the structure-function relationship of the brain is dependent on the investigated brain region. We aim to verify this assumption. Other studies focused on frontal brain regions. Instead we implemented a whole-brain analysis of the structure-function relationship. Therefore, the goal of this study was to investigate changes in white matter as a predictor of changed encoding-related brain activation in anatomically connected brain regions in cognitively normal performing older subjects. Furthermore, there are different theories that try to explain the changed brain activation in association with white matter change, such as compensatory mechanisms, dedifferentiation theory or inefficient neuronal processes. To gain a better understanding we examined the association between decreased brain activation respectively increased white matter changes in relation to cognitive performance of the subjects. Methods: Cognitively healthy elderly subjects (N = 35) performed a face-name matching paradigm within the fMRI scanner with the encoding phase being relevant in the present study. The integrity of white matter was determined with measurement of WMH volume and DTI based markers such as MD and PW. We performed ANOVAs with DTI-markers as dependent and activation as the independent variable. Furthermore, we performed ANOVAs with white matter change or brain activation as dependent variable and cognitive performance as independent variable. Since we assumed that there are local differences of white matter change we created boxplots for the chosen MD, PW and WMH-ratio within the chosen fiber tracts and global MD, PW and WMH-ratio. Additionally, we computed a correlation matrix between tract-specific MD or PW for a comparison of these two markers. Results: We could demonstrate a significant positive association between PW in the inferior fronto-occipital fasciculus left (IFOF L) and the activation in the left frontal gyrus as well as PW in the inferior longitudinal fasciculus right (ILF R) and activation in the occipital gyrus. Furthermore, the data revealed no significant result for the relationship between white matter change and cognition or brain activation and cognition. The boxplot showed a significant difference between the white matter tracts when using MD and PW as marker. Because of its low burden we had to exclude WMH-ratio as a marker for white matter change. The correlation-matrix revealed that PW within the tracts correlated less with each other than MD. Conclusion: These results suggest that microstructural changes lead to increased brain activation due to decreased white matter connectivity and reduced fidelity of data transmission. Additionally, the subjects' cognitive performance appears not to benefit from the increased brain activation. Thus, the negative structure-function relationship seems not to be based on a compensatory mechanism or dedifferentiation theory but most likely on an inefficient neuronal response. White matter change can be considered as regionally variable as revealed by the boxplots and the correlation matrix. However, the structure-function relation seems not be dependent on brain region, because the whole brain analysis showed a consistent directionality of the structure-function relationship

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

Dissociable roles of the inferior longitudinal fasciculus and fornix in face and place perception

We tested a novel hypothesis, generated from representational accounts of medial temporal lobe (MTL) function, that the major white matter tracts converging on perirhinal cortex (PrC) and hippocampus (HC) would be differentially involved in face and scene perception, respectively. Diffusion tensor imaging was applied in healthy participants alongside an odd-one-out paradigm sensitive to PrC and HC lesions in animals and humans. Microstructure of inferior longitudinal fasciculus (ILF, connecting occipital and ventro-anterior temporal lobe, including PrC) and fornix (the main HC input/output pathway) correlated with accuracy on odd-one-out judgements involving faces and scenes, respectively. Similarly, blood oxygen level-dependent (BOLD) response in PrC and HC, elicited during oddity judgements, was correlated with face and scene oddity performance, respectively. We also observed associations between ILF and fornix microstructure and category-selective BOLD response in PrC and HC, respectively. These striking three-way associations highlight functionally dissociable, structurally instantiated MTL neurocognitive networks for complex face and scene perception

MEG coherence imaging in dyslexia: Activation of working memory pathways

The aims of this dissertation are to 1) review the genetic, neurodevelopmental, structural, and functional brain imaging studies that are the foundations of our understanding of dyslexia and 2) investigate the pattern of activation and functional connectivity of neuronal networks critical in working memory in dyslexics by means of magnetoenchephalographic (MEG) coherence imaging. Dyslexics showed an early onset of activation in the precentral gyrus and the superior frontal gyrus, which differed from controls where activation was initiated in posterior cortical regions (supramarginal gyrus and superior temporal gyrus). Further, dyslexics showed lower normalized amplitudes of activation in the right superior temporal gyrus and right middle temporal gyrus than controls during a spatial working memory (SWM) task. In contrast, during a verbal working memory (VWM) task, dyslexics showed lower normalized amplitudes in the right insular cortex and right superior temporal gyrus and higher, likely compensatory, activation in the right fusiform gyrus, left parahippocampal gyrus, and left precentral gyrus. Dyslexics performing a SWM task showed significantly reduced MEG coherence and lower 1) right frontal connectivity, 2) right fronto-temporal connectivity, 3) left and right frontal connectivity, 4) left temporal and right frontal connectivity, and 5) left occipital and right frontal connectivity. MEG coherence by frequency band showed lower mean coherences in dyslexics than in controls at each frequency range and when the bands were combined during the SWM task. In contrast, during the VWM task, dyslexics showed a higher coherence in the low frequency range (1-15 Hz) and lower coherence in the high gamma frequency range (30-45 Hz) than controls. Logistic regression of the coherence by group membership was significant, with an overall predictive success of 84.4% (88.9% for controls and 77.8% for dyslexics). Coherence between the right lateral orbitofrontal gyrus and right middle orbitofrontal gyrus paired region substantially contributed to group membership. These findings deepen our understanding of the underlying pathophysiology of dyslexia, highlighting the importance of working memory circuits and prefrontal cortical dysregulation in this disorder. These results have far-reaching ramifications not only for prevention and early diagnosis, but also for the development of effective, evidence-based treatments and interventions

Protracted development of brain systems underlying working memory in adolescence: a longitudinal study

Working memory (WM), the ability to hold information on line to guide planned behavior, continues to improve through adolescence in parallel with brain maturational processes of systems known to support it. Initial studies have only examined individuals once or twice, limiting our understanding of developmental trajectories, leading to sparse and conflicting results. Further, it is unclear how age-related changes in WM performance and neural processes are associated, and what mechanisms might underlie these changes. In this study, we report on developmental improvements of WM performance and changes in brain function and connectivity of systems underlying WM using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), in a large longitudinal sample in which participants were followed annually for up to nine years. First, results confirmed that WM performance continues to improve into the early 20's. Alongside these refinements, brain activity in the frontal eye fields (FEF) and parietal cortex continue to change during this time; age-related changes in prefrontal regions were specifically associated with WM performance, suggesting a primary role in WM improvements. Supporting these changes, task-related functional connectivity from dorsolateral prefrontal cortex (DLPFC) to FEF, visual association cortex (VAC), and cingulate regions continued to change during adolescence and were related to WM development. Greater connectivity was associated with less mature behavior, suggesting a decreased reliance on top-down communication to support WM with development. DTI results indicated robust increases in white matter integrity across the brain with the several tracts connecting prefrontal and posterior systems, continuing to mature into early adulthood. Further, white matter measures were correlated with behavior, functional activity, and functional connectivity, suggesting that the development of structural connections may provide a scaffold on which cognitive and functional brain development can specialize. Taken together, these results suggest that while regional prefrontal function supports the transition from childhood to adolescence, the period of transition to adult level WM performance is characterized, by enhancements in prefrontal functional and structural connectivity to posterior regions supporting mnemonic aspects of working memory residing in attention and visual association regions

Visual brain areas in obsessive compulsive disorder : a diffusion tensor imaging approach

Dissertação de mestrado integrado em Psicologia (área de especialização em Psicologia Clínica)A Perturbação Obsessivo-Compulsiva (POC) é uma condição psiquiátrica pertencente ao espectro das perturbações de ansiedade, sendo caracterizada por obsessões e compulsões. Obsessões são definidas como pensamentos, imagens, ideias ou impulsos recorrentes cujo conteúdo causam um elevado grau de ansiedade no indivíduo, levando-o a executar ações especificas ou rituais mentais de modo a reduzir a ansiedade, i.e. compulsões, (DSM-IV-TR, APA, 2000). A POC é uma psicopatologia bastante debilitante com uma taxa de prevalência de 1 a 2,5% na população adulta, com diversas facetas no que diz respeito às suas características clínicas: comportamentais, emocionais e neurocognitivas. Com especial atenção, défices ao nível do processamento visual e um viés atencional são descritos como uma significante manifestação desta perturbação, desempenhando um papel importante na ineficiente apreensão de estímulos sociais, um importante característica desta perturbação. Em concordância, alterações cerebrais estruturais e funcionais têm sido associadas a este fenótipo. Deste modo, o principal objectivo é analisar a integridade da microestrutura de substância branca em pacientes com POC, através de técnicas de Imagiologia por Tensor de Difusão (do inglês Diffusion Tensor Imaging), usando uma metodologia baseada na segmentação e tractografia, de modo a estabelecer uma relação entre estes padrões de conexão cerebral e a sua sintomatologia clínica. Considerando os défices cognitivos e alterações cerebrais da POC, nomeadamente ao nível das áreas frontais (orbitofrontal e dorsolateral) e occipitais, pretendemos continuar investigações prévias da nossa equipa de investigação e examinar a integridade da substância branca dos feixes da circunvolução frontal inferior (CFI), lobo occipital e área V1, regiões cerebrais relacionadas com o processamento visuo-perceptivo, que hipotetizamos estarem alteradas na população com POC (Gonçalves et al., 2010). Recorrendo a uma inovadora técnica de imagiologia (DTI), foram avaliadas as medidas de integridade dos feixes de substância branca (FA, MD, AD e RD) das áreas da CFI, lobo occipital e V1 devido ao seu papel no processamento visual e perceptivo. Catorze pacientes com POC (idade média,M=32,64±11,41) e dez participantes no grupo controlo (idade média M=30,70±9,73), emparelhados em idade, sexo e lateralidade, participaram neste estudo. Os nosso resultados demonstraram diferenças entre pacientes e controlos em três medidas de DTI nas regiões occipitais e V1. Especificamente, o grupo com POC apresentou menor integridade dos feixes de substância branca nestas áreas cerebrais que estão estritamente relacionadas com o processamento visual. No entanto, não foram encontradas diferenças de grupo no que diz respeito às medidas de integridade da matéria branca no feixe da CFI. Os resultados sugerem que feixes de substância branca envolvidas no processamento precoce de estímulos visuais podem estar associadas às manifestações clínicas da POC, nomeadamente o viés de processamento de estímulos emocionais.Obsessive Compulsive Disorder (OCD) is a psychiatric disorder classified within the spectrum of anxiety disorders, being characterized by obsessions and compulsions. Obsessions are defined as thoughts, images, ideas or recurrent impulses which content causes an elevated degree of anxiety on the individual, impelling him to execute specific actions or mental rituals in order to reduce anxiety, i.e. compulsions, (DSM-IV-TR, APA, 2000). OCD is a very disabling psychopathology with a prevalence rate of 1 to 2,5% in the adult population, with several facets concerning its clinical features: behavioral, emotional and neurocognitive. Of special note, visual processing deficits and an attentional bias has been described as a significant manifestation of this disorder, playing an important role in their inefficient social stimuli aprehension, a important characteristic of this disorder. In agreement, structural and functional brain alterations in the occipital, parietal and other visual areas have been associated with this phenotype. Therefore, the main objective of the present study is to analyze white matter microstructure in OCD patients through the use of Diffusion Tensor Imaging (DTI) techniques, using a segmentation and tractography based approach, in order to establish a relation between connectivity patterns of these visual brain and OCD’ clinical symptomatology. Considering their neurocognitive phenotype and specific brain abnormalities in OCD, namely in frontal (orbitofrontal and dorsolateral) and occipital areas, we now aim to follow our team previous research and investigate the integrity of the Inferior Frontal Gyrus (IFG), occipital lobe and V1 area, as are related with visuo-perceptive processing, which we hypothesize to be abnormal in OCD population (Gonçalves et al., 2010). Using this innovative imaging technique (DTI) we evaluated white matter DTI-derived measures (FA, MD, AD and RD) of the IFG, occipital and V1 areas taking into account their role on visual processing and perception. Fourteen patients with OCD (Mean age=32,64 ± 11,41) and ten comparison controls (Mean age=30,70 ± 9,73), matched on age, sex and handedness, participated in this study. Our results reported group differences in three DTI indexes (MD, AD and RD) in occipital and V1. Specifically, OCD group displayed decreased integrity of these white matter tracts which are strictly related with visual processing. Nevertheless, we did not find group differences regarding the integrity of the IFG white matter tract. Results suggest that brain fiber tracts enrolled in early steges of visual processing may be associated with the clinical features of OCD, specifically the bias in processing for emotional stimuli

Examining Brain Connectivity and Reading Ability in Children

In this thesis, I investigated the relationship between functional and structural connectivity and reading ability in children. Prior research has tended to use single word reading measures or composite measures, however this is problematic as reading is a complex skill relying on multiple subskills, such as decoding efficiency, sight word reading efficiency, reading comprehension, and rapid automatized naming. As a result, the multi-faceted relationship between brain connectivity and reading ability is not well understood. I aimed to address this issue by considering multiple reading subskills while examining the neural substrates of reading. In Chapter 2, I examined how individual differences in decoding efficiency, sight word reading efficiency, reading comprehension, and rapid automatized naming relate to resting-state functional connectivity from regions of the brain’s reading network. I found that distinct functional networks in both hemispheres of the brain support different components of reading in children. In Chapter 3, I built on these findings to examine how individual differences in the same reading subskills are associated with structural connectivity in reading-related white matter tracts, as measured by diffusion tensor imaging. Similar to Chapter 2, the results of Chapter 3 suggested that different components of reading ability are supported by structural characteristics in distinct bilateral tracts of the brain. Importantly, many of the effects observed in Chapters 2 and 3 were found to be specific to reading subskills and were not associated with more general cognitive abilities. In Chapter 4, I examined how improvements in reading ability are related to changes in structural and functional connectivity, by measuring brain connectivity pre- and post-intervention in a group of children with reading disability. I also investigated whether individual differences in the amount of improvement in reading ability post-intervention was predicted by pre-intervention brain connectivity. I found that gains in reading ability were associated with changes in resting-state functional connectivity, particularly between reading-related regions and frontal regions as well as regions of the default mode network. Changes in white matter microstructure of the right arcuate fasciculus were strongly associated with gains in single word reading abilities. Additionally, results showed that distinct pre-intervention characteristics of resting-state functional connectivity and white matter integrity predicted the magnitude of subsequent gains in reading ability following the reading intervention. Chapter 5 summarizes the findings of this thesis in relation to the current literature and presents recommendations for future research on reading ability and brain connectivity

Brain anatomical correlates of perceptual phonological proficiency and language learning aptitude

The present dissertation concerns how brain tissue properties reflect proficiency in two aspects of language use: the ability to use tonal cues on word stems to predict how words will end and the aptitude for learning foreign languages. While it is known that people differ in their language abilities and that damage to brain tissue cause loss of cognitive functions, it is largely unknown if differences in language proficiencies correlate with differences in brain structure. The first two studies examine correlations between cortical morphometry, i.e. the thickness and surface area of the cortex, and the degree of dependency on word accents for processing upcoming suffixes in Swedish native speakers. Word accents in Swedish facilitate speech processing by having predictive associations to specific suffixes, (e.g. fläckaccent1+en ‘spot+singular’, fläckaccent2+ar ‘spot+plural’). This use of word accents, as phonological cues to inflectional suffixes, is relatively unique among the world’s languages. How much a speaker depends on word accents in speech processing can be measured as the difference in response time (RT) between valid and invalid word accent-suffix combinations when asked to identify the inflected form of a word. This can be thought of as a measure of perceptual phonological proficiency in native speakers. Perceptual phonological proficiency is otherwise very difficult to study, as most phonological contrasts are mandatory to properly interpret the meaning of utterances. Study I compares the cortical morphometrical correlates in the planum temporale and inferior frontal gyrus pars opercularis in relation to RT differences in tasks involving real words and pseudowords. We found that thickness of the left planum temporale correlates with perceptual phonological proficiency in lexical words but not pseudowords. This could implicate that word accents are part of full-form representations of familiar words. Moreover, for pseudowords but not lexical words, the thickness of the inferior frontal gyrus pars opercularis correlates with perceptual phonological proficiency. This association could reflect a greater importance for decompositional analysis in which word accents are part of a set of rules listeners need to rely on during processing of novel words. In study II, the investigation of the association between perceptual phonological proficiency in real words with cortical morphometry is expanded to the entire brain. Results show that cortical thickness and surface area of anterior temporal lobe areas, known constituents of a ventral sound-to-meaning language-processing stream is associated with greater perceptual phonological proficiency. This is consistent with a role for word accents in aiding putting together the meaning of or accessing a whole word representation of an inflected word form. Studies III and IV investigate the cortical morphometric associations with language learning aptitude. Findings in study III suggest that aptitude for grammatical inferencing, i.e. the ability to analytically discern the rules of a language, is associated with cortical thickness in the left inferior frontal gyrus pars triangularis. Furthermore, pitch discrimination proficiency, a skill related to language learning ability, correlates negatively with cortical thickness in the right homologue area. Moreover, study IV, using improved imaging techniques, reports on a correlation between vocabulary learning aptitude and cortical surface area in the left inferior precuneus as well as a negative correlation between diffusional axial kurtosis and phonetic memory in the left arcuate fasciculus and subsegment III of the superior longitudinal fasciculus. However, the finding correlation between cortical thickness and grammatical inferencing skill from study III was not replicated in study IV.Taken together, the present dissertation shows that differences in some language proficiencies are associated with regionally thicker or larger cortex and more coherent white matter tracts, the nature and spatial locus of which depend on the proficiency studied. The studies add to our understanding of how language proficiencies are represented in the brain’s anatomy