Modeling spatial, developmental, physiological, and topological constraints on human brain connectivity.

The complex connectivity of nervous systems is thought to have been shaped by competitive selection pressures to minimize wiring costs and support adaptive function. Accordingly, recent modeling work indicates that stochastic processes, shaped by putative trade-offs between the cost and value of each connection, can successfully reproduce many topological properties of macroscale human connectomes measured with diffusion magnetic resonance imaging. Here, we derive a new formalism that more accurately captures the competing pressures of wiring cost minimization and topological complexity. We further show that model performance can be improved by accounting for developmental changes in brain geometry and associated wiring costs, and by using interregional transcriptional or microstructural similarity rather than topological wiring rules. However, all models struggled to capture topographical (i.e., spatial) network properties. Our findings highlight an important role for genetics in shaping macroscale brain connectivity and indicate that stochastic models offer an incomplete account of connectome organization.

Global and local shape features of the hippocampus based on Laplace-Beltrami eigenvalues and eigenfunctions: a potential application in the lateralization of temporal lobe epilepsy.

Using magnetic resonance (MR) images to evaluate changes in the shape of the hippocampus has been an active research topic. This paper presents a new shape analysis approach to quantify and visualize deformations of the hippocampus in epilepsy. The proposed method is based on Laplace-Beltrami (LB) eigenvalues and eigenfunctions as isometric invariant shape features, and thus, the procedure does not require any image registration. In addition to the LB-based shape features, total hippocampal volume and surface area are calculated using manually segmented images. Theses shape and volumetric descriptors are used to distinguish the patients with temporal lobe epilepsy (TLE) (N = 55) from healthy control subjects (N = 12, age = 32.2 ± 9.1, sex (M/F) = 6/6) and patients with right TLE (N = 26, age = 45.1 ± 11.0, sex (M/F) = 9/17) from left TLE (N = 29, age = 45.4 ± 11.9, sex (M/F) = 10/19). Experimental results illustrate the usefulness of the proposed approach for the diagnosis and lateralization of TLE with 93.0% and 86.4% of the cases, respectively. Moreover, the proposed method outperforms the volumetric analysis in terms of both sensitivity (94.9% vs. 88.1%) and specificity (83.3% vs. 50.0%) of the lateralization. The analysis of local hippocampal thickness variations suggests significant deformation in both ipsilateral and contralateral hippocampi of epileptic patients, while there were no differences between right and left hippocampi in controls. It is anticipated that the proposed method could be advantageous in the presurgical evaluation of patients with drug-resistant epilepsy; however, further validation of the method using a larger dataset is required.

Investigating longitudinal changes to frontal cortico-striatal tracts in Huntington's disease: the IMAGE-HD study.

The striatum is the principal site of disease pathology in Huntington's disease and contains neural connections to numerous cortical brain regions. Studies examining abnormalities to neural connections find that white matter integrity is compromised in HD; however, further regional, and longitudinal investigation is required. This paper is the first longitudinal investigation into region-based white-matter integrity changes in Huntington's Disease. The aim of this study was to better understand how disease progression impacts white matter tracts connecting the striatum to the prefrontal and motor cortical regions in HD. We used existing neuroimaging data from IMAGE-HD, comprised of 25 pre-symptomatic, 27 symptomatic, and 25 healthy controls at three separate time points (baseline, 18-months, 30-months). Fractional anisotropy, axial diffusivity and radial diffusivity were derived as measures of white matter microstructure. The anatomical regions of interest were identified using the Desikan-Killiany brain atlas. A Group by Time repeated measures ANCOVA was conducted for each tract of interest and for each measure. We found significantly lower fractional anisotropy and significantly higher radial diffusivity in the symptomatic group, compared to both the pre-symptomatic group and controls (the latter two groups did not differ from each other), in the rostral middle frontal and superior frontal tracts; as well as significantly higher axial diffusivity in the rostral middle tracts only. We did not find a Group by Time interaction for any of the white matter integrity measures. These findings demonstrate that whilst the microstructure of white matter tracts, extending from the striatum to these regions of interest, are compromised during the symptomatic stages of Huntington's disease, 36-month follow-up did not show progressive changes in these measures. Additionally, no correlations were found between clinical measures and tractography changes, indicating further investigations into the relationship between tractography changes and clinical symptoms in Huntington's disease are required.

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume.

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-ß PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-ß positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-ß burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.

Longitudinal mapping of cortical surface changes in Huntington's Disease.

This paper investigated cortical folding in Huntington's disease to understand how disease progression impacts the surface of the cortex. Cortical morphometry changes in eight gyral based regions of interest (i.e. the left and right hemispheres of the lateral occipital, precentral, superior frontal and rostral middle gyri) were examined. We used existing neuroimaging data from IMAGE-HD, comprising 26 pre-symptomatic, 26 symptomatic and 24 healthy control individuals at three separate time points (baseline, 18-month, 30-month). Local gyrification index and cortical thickness were derived as the measures of cortical morphometry using FreeSurfer 6.0's longitudinal pipeline. The gyral based regions of interest were identified using the Desikan-Killiany Atlas. A Group by Time repeated measures ANCOVA was conducted for each region of interest. We found significantly lower LGI at a group level in the right hemisphere lateral occipital region and both hemispheres of the precentral region; as well as significantly reduced cortical thickness at a group level in both hemispheres of the lateral occipital and precentral regions and the right hemisphere of the superior frontal region. We also found a Group by Time interaction for Local gyrification index in the right hemisphere lateral occipital region. This change was largely driven by a significant decrease in the symptomatic group between baseline and 18-months. Additionally, lower local gyrification index and cortical thickness were associated with higher disease burden score. These findings demonstrate that significant longitudinal decline in right hemisphere local gyrification index is evident during manifest disease in lateral occipital cortex and that these changes are more profound in individuals with greater disease burden score.

Longitudinal investigation of brain activation during motor tasks in Friedreich ataxia: 24-month data from IMAGE-FRDA.

Friedreich ataxia (FRDA) is a progressive autosomal recessive disease. While motor dysfunction is the primary neurological hallmark, little is known about the underlying neurobiological changes associated with motor deficits over the course of disease. We investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. Twenty-two individuals with FRDA and 28 controls participated over 24 months. The longitudinal investigation included finger tapping tasks with different levels of complexity (i.e., visually cued, multi-finger; self-paced, single finger), performed in conjunction with fMRI acquisitions, to interrogate changes in the neurobiology of motor and attentional brain networks including the cerebellum and cerebrum. We demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus. Importantly, longitudinal decreased activity was associated with more severe disease status at baseline, higher GAA1 repeat length and earlier age of onset. These findings suggest a dynamic pattern of neuronal activity in motor, attention and executive control networks over time in individuals with FRDA, which is associated with increased disease severity at baseline, increased GAA1 repeat length and earlier age at onset.

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI.

To improve understanding of Alzheimer's disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-ß in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses.

Longitudinal structural brain changes in Friedreich ataxia depend on disease severity: the IMAGE-FRDA study.

BACKGROUND: Friedreich ataxia is an inherited neurodegenerative disease, with cerebral and cerebellar pathology evident. Despite an increased understanding of its neuropathology, disease progression in this disease remains poorly understood. This study aimed to characterise longitudinal change in brain structure using a multi-modal approach across cerebral and cerebellar grey and white matter. METHODS: T1-weighted, diffusion-tensor, and magnetisation transfer magnetic resonance images were obtained from 28 individuals with Friedreich ataxia and 29 age- and gender-matched controls at two time-points, 2 years apart. Region-of-interest and exploratory between-group comparisons assessed changes in brain macrostructure (cerebellar lobule volume, cerebral cortical thickness/gyrification, brain white matter volume) and microstructure (white matter fractional anisotropy, mean/axial/radial diffusivity, magnetisation transfer ratio). Rates of change were correlated against change in neurological severity, Time 1 severity, and onset age. RESULTS: Individuals with Friedreich ataxia had a greater rate of white matter volume loss than controls in the superior cerebellar peduncles and right peri-thalamic/posterior cerebral regions, and greater reduction in left primary motor cortex gyrification. Greater cerebellar/brainstem white matter volume loss and right dorsal premotor gyrification loss was observed amongst individuals with less severe neurological symptoms at Time 1. Conversely, cerebral atrophy and changes in axial diffusivity were observed in individuals with more severe Time 1 symptoms. Progression in radial diffusivity was more pronounced amongst individuals with earlier disease onset. Greater right ventral premotor gyrification loss correlated with greater neurological progression. CONCLUSION: Heterogeneity in Friedreich ataxia progression is observed at the neurobiological level, with evidence of earlier cerebellar and later cerebral degeneration.

A gyrification analysis approach based on Laplace Beltrami eigenfunction level sets.

An accurate measure of the complexity of patterns of cortical folding or gyrification is necessary for understanding normal brain development and neurodevelopmental disorders. Conventional gyrification indices (GIs) are calculated based on surface curvature (curvature-based GI) or an outer hull surface of the cortex (outer surface-based GI). The latter is dependent on the definition of the outer hull surface and a corresponding function between surfaces. In the present study, we propose the Laplace Beltrami-based gyrification index (LB-GI). This is a new curvature-based local GI computed using the first three Laplace Beltrami eigenfunction level sets. As with outer surface-based GI methods, this method is based on the hypothesis that gyrification stems from a flat surface during development. However, instead of quantifying gyrification with reference to corresponding points on an outer hull surface, LB-GI quantifies the gyrification at each point on the cortical surface with reference to their surrounding gyral points, overcoming several shortcomings of existing methods. The LB-GI was applied to investigate the cortical maturation profile of the human brain from preschool to early adulthood using the PING database. The results revealed more detail in patterns of cortical folding than conventional curvature-based methods, especially on frontal and posterior tips of the brain, such as the frontal pole, lateral occipital, lateral cuneus, and lingual. Negative associations of cortical folding with age were observed at cortical regions, including bilateral lingual, lateral occipital, precentral gyrus, postcentral gyrus, and superior frontal gyrus. The results also indicated positive significant associations between age and the LB-GI of bilateral insula, the medial orbitofrontal, frontal pole and rostral anterior cingulate regions. It is anticipated that the LB-GI will be advantageous in providing further insights in the understanding of brain development and degeneration in large clinical neuroimaging studies.

Cortical morphometry and neural dysfunction in Huntington's disease: a review.

Numerous neuroimaging techniques have been used to identify biomarkers of disease progression in Huntington's disease (HD). To date, the earliest and most sensitive of these is caudate volume; however, it is becoming increasingly evident that numerous changes to cortical structures, and their interconnected networks, occur throughout the course of the disease. The mechanisms by which atrophy spreads from the caudate to these cortical regions remains unknown. In this review, the neuroimaging literature specific to T1-weighted and diffusion-weighted magnetic resonance imaging is summarized and new strategies for the investigation of cortical morphometry and the network spread of degeneration in HD are proposed. This new avenue of research may enable further characterization of disease pathology and could add to a suite of biomarker/s of disease progression for patient stratification that will help guide future clinical trials.

Longitudinal evaluation of the natural history of amyloid-ß in plasma and brain.

Plasma amyloid-ß peptide concentration has recently been shown to have high accuracy to predict amyloid-ß plaque burden in the brain. These amyloid-ß plasma markers will allow wider screening of the population and simplify and reduce screening costs for therapeutic trials in Alzheimer's disease. The aim of this study was to determine how longitudinal changes in blood amyloid-ß track with changes in brain amyloid-ß. Australian Imaging, Biomarker and Lifestyle study participants with a minimum of two assessments were evaluated (111 cognitively normal, 7 mild cognitively impaired, 15 participants with Alzheimer's disease). Amyloid-ß burden in the brain was evaluated through PET and was expressed in Centiloids. Total protein amyloid-ß 42/40 plasma ratios were determined using ABtest® assays. We applied our method for obtaining natural history trajectories from short term data to measures of total protein amyloid-ß 42/40 plasma ratios and PET amyloid-ß. The natural history trajectory of total protein amyloid-ß 42/40 plasma ratios appears to approximately mirror that of PET amyloid-ß, with both spanning decades. Rates of change of 7.9% and 8.8%, were observed for total protein amyloid-ß 42/40 plasma ratios and PET amyloid-ß, respectively. The trajectory of plasma amyloid-ß preceded that of brain amyloid-ß by a median value of 6 years (significant at 88% confidence interval). These findings, showing the tight association between changes in plasma and brain amyloid-ß, support the use of plasma total protein amyloid-ß 42/40 plasma ratios as a surrogate marker of brain amyloid-ß. Also, that plasma total protein amyloid-ß 42/40 plasma ratios has potential utility in monitoring trial participants, and as an outcome measure.

Longitudinal Increases in Cerebral Brain Activation During Working Memory Performance in Friedreich Ataxia: 24-Month Data from IMAGE-FRDA.

Friedreich ataxia (FRDA) has been associated with functional abnormalities in cerebral and cerebellar networks, particularly in the ventral attention network. However, how functional alterations change with disease progression remains largely unknown. Longitudinal changes in brain activation, associated with working memory performance (N-back task), and grey matter volume were assessed over 24 months in 21 individuals with FRDA and 28 healthy controls using functional and structural magnetic resonance imaging, respectively. Participants also completed a neurocognitive battery assessing working memory (digit span), executive function (Stroop, Haylings), and set-shifting (Trail Making Test). Individuals with FRDA displayed significantly increased brain activation over 24 months in ventral attention brain regions, including bilateral insula and inferior frontal gyrus (pars triangularis and pars opercularis), compared with controls, but there was no difference in working memory (N-back) performance between groups. Moreover, there were no significant differences in grey matter volume changes between groups. Significant correlations between brain activations and both clinical severity and age at disease onset were observed in FRDA individuals only at 24 months. There was significant longitudinal decline in Trail Making Test (TMT) difference score (B-A) in individuals with FRDA, compared with controls. These findings provide the first evidence of increased longitudinal activation over time in the cerebral cortex in FRDA, compared with controls, despite comparable working memory performance. This finding represents a possible compensatory response in the ventral attention network to help sustain working memory performance in individuals with FRDA.

Advanced MRI analysis to detect white matter brain injury in growth restricted newborn lambs.

BACKGROUND: Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased risk of adverse neurodevelopment and neuromorbidity. Current imaging techniques, including conventional magnetic resonance imaging (MRI), are not sensitive enough to detect subtle structural abnormalities in the FGR brain. We examined whether advanced MRI analysis techniques have the capacity to detect brain injury (particularly white matter injury) caused by chronic hypoxia-induced fetal growth restriction in newborn preterm lambs. METHODS: Surgery was undertaken in twin bearing pregnant ewes at 88-90 days gestation (term = 150 days) to induce FGR in one fetus. At 127 days gestation (~32 weeks human brain development), FGR and control (appropriate for gestational age, AGA) lambs were delivered by caesarean section, intubated and ventilated. Conventional and advanced brain imaging was conducted within the first two hours of life using a 3T MRI scanner. T1-weighted (T1w) and T2-weighted (T2w) structural imaging, magnetic resonance spectroscopy (MRS), and diffusion MRI (dMRI) data were acquired. Diffusion tensor imaging (DTI) modelling and analysis of dMRI data included the following regions of interest (ROIs): subcortical white matter, periventricular white matter, cerebellum, hippocampus, corpus callosum and thalamus. Fixel-based analysis of 3-tissue constrained spherical deconvolution (CSD) of the dMRI data was performed and compared between FGR and AGA lambs. Lambs were euthanised immediately after the scans and brain histology performed in the regions of interest to correlate with imaging. RESULTS: FGR and AGA lamb (body weight, mean (SD): 2.2(0.5) vs. 3.3(0.3) kg, p = .002) MRI brain scans were analysed. There were no statistically significant differences observed between the groups in conventional T1w, T2w or MRS brain data. Mean, axial and radial diffusivity, and fractional anisotropy indices obtained from DTI modelling also did not show any statistically significant differences between groups in the ROIs. Fixel-based analysis of 3-tissue CSD, however, did reveal a decrease in fibre cross-section (FC, p < .05) but not in fibre density (FD) or combined fibre density and cross-section (FDC) in FGR vs. AGA lamb brains. The specific tracts that showed a decrease in FC were in the regions of the periventricular white matter, hippocampus and cerebellar white matter, and were supported by histological evidence of white matter hypomyelination and disorganisation in corresponding FGR lamb brain regions. CONCLUSIONS: The neuropathology associated with FGR in neonatal preterm lambs is subtle and imaging detection may require advanced MRI and tract-based analysis techniques. Fixel-based analysis of 3-tissue CSD demonstrates that the preterm neonatal FGR brain shows evidence of macrostructural (cross-sectional) deficits in white matter subsequent to altered antenatal development. These findings can inform analysis of similar brain pathology in neonatal infants.

The Subplate: A Potential Driver of Cortical Folding?

In many species of Mammalia, the surface of the brain develops from a smooth structure to one with many fissures and folds, allowing for vast expansion of the surface area of the cortex. The importance of understanding what drives cortical folding extends beyond mere curiosity, as conditions such as preterm birth, intrauterine growth restriction, and fetal alcohol syndrome are associated with impaired folding in the infant and child. Despite being a key feature of brain development, the mechanisms driving cortical folding remain largely unknown. In this review we discuss the possible role of the subplate, a developmentally transient compartment, in directing region-dependent development leading to sulcal and gyral formation. We discuss the development of the subplate in species with lissencephalic and gyrencephalic cortices, the characteristics of the cells found in the subplate, and the possible presence of molecular cues that guide axons into, and out of, the overlying and multilayered cortex before the appearance of definitive cortical folds. An understanding of what drives cortical folding is likely to help in understanding the origins of abnormal folding patterns in clinical pathologies.

Altered Cortical Morphometry in Pre-manifest Huntington's Disease: Cross-sectional Data from the IMAGE-HD Study.

Huntington's disease (HD) is an inherited progressive neurodegenerative disease mainly associated with subcortical striatal atrophy. There is also strong evidence showing cerebral atrophy and cortical thinning; however, limited research has investigated altered patterns of cortical folding in this disease. Here, we investigated cortical morphometry via both gyrification index (GI, a measure of cortical folding) and cortical thinning. The localized GI was examined using a novel GI, namely LB-GI. As part of a cross-sectional study, pre-manifest (pre-HD) individuals (n = 29) and matched controls (n = 29) underwent T1-MRI using data from the IMAGE-HD study. Compared to controls, pre-HD individuals demonstrated significantly lower GI in the left superior parietal and the right superior temporal regions and greater cortical thinning in the bilateral pre-central and the superior frontal gyri and left caudal middle frontal gyrus, as well as the superior parietal region. For the first time, we report evidence of abnormal localized cortical folding in pre-HD. We also provide evidence that cortical folding impacts different regions of the cortical surface more so than cortical thickness. As a result, we propose a potential new biological marker that may increase our understanding of the neuropathology of HD. Greater understanding of brain changes could inform new therapeutic approaches and target points for clinical trials.

Sulcal curve extraction using Laplace Beltrami eigenfunction level sets.

The complexity of the human cortex is demonstrated in the intricate pattern of gyri and sulci that arise from the cortical folding process during development. Quantitative assessment of cortical folding is important in the definition of normal brain development and provides insight into neurodevelopmental disorders. In this work, a method for sulcal curve extraction is proposed that combines the advantages of previously proposed depth based and curvature based methods. The technique, derived from Laplace Beltrami eigenfunction level sets, maps mean curvature on the level sets, and incorporates depth information using extracted sulci and gyri, a characteristic previously attributed only to depth based methods. The use of Laplace Beltrami eigenfunction level sets requires neither definition of an outer hull surface nor correspondence between the cortical surface and outer hull, both of which are required by depth based methods. The utility of the method for extracting sulcal curves is demonstrated by application to fetal sheep brain MRI data, imaged at key time points during development.

A method for assessing nonlinear growth in the fetal cortex.

The cerebral cortex is folded into gyri and sulci in the brains of higher mammals. Quantitative study of the process by which the cortex folds during brain development is critical to a complete understanding of normal brain development and neuro-developmental disorders. In this work, we propose a new method by which to localise nonlinearities in the cortical folding process, and thereby identify regions of differential growth across the cortex. Our method is based on spherical harmonic (SPHARM) representation of the cortical surface. Linearity is assessed by comparison of each SPHARM reconstructed surface with an artificial surface constructed using a linear combination of SPHARM coefficients from data at adjoining developmental time points. The resultant quantification of cortical folding development is easy to interpret, and the method has low computational cost. We demonstrate application to a set of experimental MRI data of fetal sheep brains, across key developmental timepoints as the cortex first folds during development.