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Cerebral blood flow (CBF) SPECT is an interesting methodology to study brain connectivity in mild cognitive impairment (MCI) since it is accessible worldwide and can be used as a biomarker of neuronal injury in MCI. In CBF SPECT, connectivity is grounded in group-based correlation networks. Therefore, topological metrics derived from the CBF correlation network cannot be used to support diagnosis and prognosis individually. However, methods to extract the individual patient contribution to topological metrics of group-based correlation networks were developed although not yet applied to MCI patients. Here, we investigate whether the episodic memory of 24 amnestic MCI patients correlates with individual patient contributions to topological metrics of the CBF correlation network. We first compared topological metrics of the MCI group network with the network corresponding to 26 controls. Metrics that showed significant differences were then used for the individual patient contribution analysis. We found that the global network modularity was increased while global efficiency decreased in the MCI network compared to the control. Most importantly, we found that episodic memory inversely correlates with the patient contribution to the global network modularity, which highlights the potential of this approach to develop a CBF connectivity-based biomarker at the individual level.

This article provides a brief overview of relevant cerebrovascular mechanisms implicated in late-onset Alzheimer's disease (LOAD) development, and highlights the main reasons for incorporating novel cerebrovascular biomarkers to the models defining a multifactorial LOAD pathogenesis. We also discuss how novel brain mapping techniques and multifactorial data-driven models are having a critical role on understanding LOAD and may be particularly useful for identifying effective therapeutic agents for this disorder.A growing body of evidence supports that LOAD is a complex disorder, causally associated to a high multiplicity of pathologic mechanisms. New experimental and neuroimaging data, in combination with the recent use of integrative multifactorial data-driven models, support the early role of vascular factors in LOAD genesis and development. Among other relevant roles, the cerebrovascular system has a key modulatory effect on prion-like propagation, deposition and toxicity (e.g. Aβ, tau proteins). The early signs of vascular dysregulation during LOAD progression are notable both at the microscopic and the macroscopic scales.We emphasize that LOAD should be studied as a complex multifactorial disorder, not dominated by a dominant biological factor (e.g. Aβ), and without disregarding any relevant pathologic factor, such as vascular dysregulation. Cerebrovascular biomarkers are invaluable for defining multifactorial disease progression models as well as for evaluating the effectiveness of different therapeutic strategies.

Identifying how spatially distributed information becomes integrated in the brain is essential to understanding higher cognitive functions. Previous computational and empirical studies suggest a significant influence of brain network structure on brain network function. However, there have been few analytical approaches to explain the role of network structure in shaping regional activities and directionality patterns. In this study, analytical methods are applied to a coupled oscillator model implemented in inhomogeneous networks. We first derive a mathematical principle that explains the emergence of directionality from the underlying brain network structure. We then apply the analytical methods to the anatomical brain networks of human, macaque, and mouse, successfully predicting simulation and empirical electroencephalographic data. The results demonstrate that the global directionality patterns in resting state brain networks can be predicted solely by their unique network structures. This study forms a foundation for a more comprehensive understanding of how neural information is directed and integrated in complex brain networks.

Resting-state studies conducted with stroke patients are scarce. The study of brain activity and connectivity at rest provides a unique opportunity for the investigation of brain rewiring after stroke and plasticity changes. This study sought to identify dynamic changes in the functional organization of the default mode network (DMN) of stroke patients at three months after stroke. Eleven patients (eight male and three female; age range: 48–72) with right cortical and subcortical ischemic infarctions and 17 controls (eleven males and six females; age range: 57–69) were assessed by neurological and neuropsychological examinations and scanned with resting-state functional magnetic ressonance imaging. First, we explored group differences in functional activity within the DMN by means of probabilistic independent component analysis followed by a dual regression approach. Second, we estimated functional connectivity between 11 DMN nodes both locally by means of seed-based connectivity analysis, as well as globally by means of graph-computation analysis. We found that patients had greater DMN activity in the left precuneus and the left anterior cingulate gyrus when compared with healthy controls (P

Previous behavioral and scanning studies have suggested that handedness is associated with differences in brain morphology as well as in anatomical and functional lateralization. However, little is known about the topological organization of the white matter (WM) structural networks related to handedness. We employed diffusion tensor imaging tractography to investigate handedness- and hemisphere-related differences in the topological organization of the human cortical anatomical network. After constructing left hemispheric/right hemispheric weighted structural networks in 32 right-handed and 24 left-handed healthy individuals, we analyzed the networks by graph theoretic analysis. We found that both the right and left hemispheric WM structural networks in the two groups possessed small-world attributes (high local clustering and short paths between nodes), findings which are consistent with recent results from whole-brain structural networks. In addition, the right hemisphere tended to be more efficient than the left hemisphere, suggesting a high efficiency of general information processing in the right hemisphere. Finally, we found that the right-handed subjects had significant asymmetries in small-world properties (normalized clustering coefficient γ, normalized path length λ, and small-worldness σ), while left-handed subjects had fewer asymmetries. Our findings from large-scale brain networks aid in understanding the structural substrates underlying handedness-related and hemisphere-related differences in cognition and behavior.

How the brain deals with more than one language and whether we need different or extra brain language sub-networks to support more than one language remain unanswered questions. Here, we investigate structural brain network differences between early bilinguals and monolinguals. Using diffusion-weighted MRI (DW-MRI) tractography techniques and a network-based statistic (NBS) procedure, we found two structural sub-networks more connected by white matter (WM) tracts in bilinguals than in monolinguals; confirming WM brain plasticity in bilinguals. One of these sub-networks comprises left frontal and parietal/temporal regions, while the other comprises left occipital and parietal/temporal regions and also the right superior frontal gyrus. Most of these regions have been related to language processing and monitoring; suggesting that bilinguals develop specialized language sub-networks to deal with the two languages. Additionally, a complex network analysis showed that these sub-networks are more graph-efficient in bilinguals than monolinguals and this increase seems to be at the expense of a whole-network graph-efficiency decrease.

The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action. © 2019 the Alzheimer’s Association and the World Stroke Organisation. Published by Elsevier Inc. All rights reserved.

Wavelet-based methods have been developed for statistical analysis of functional MRI and PET data, where the wavelet transformation is employed as a tool for efficient signal representation. A number of studies using these approaches have reported better estimation capabilities, in terms of increased sensitivity and specificity, than the standard statistical analyses in the spatial domain. In line with these previous studies, the present report proposes a statistical analysis in the wavelet domain for the estimation of inter-group differences from structural MRI data. The procedure, called wavelet-based morphometry (WBM), was implemented under a voxel-based morphometry (VBM) style analysis. It was evaluated by comparing the gray-matter images of a group of 32 healthy subjects whose images were artificially altered to induce thinning of the cortex, with a different group of 32 healthy subjects whose images were unaltered. In order to quantify the performance of the reconstruction from a practical perspective, the same comparison was also conducted with standard VBM using SPM's Gaussian random fields and FSL's cluster-based statistics, family-wise error corrected, for datasets spatially-normalized via two different registration methods (i.e., SyN and FNIRT). The effect of using different amounts of smoothing, Battle-Lemarié filters and resolution levels in the wavelet transform was also investigated. Results support the proposed approach as a different and promising methodology to assess the structural morphometric differences between different populations of subjects.

Generative models focused on multifactorial causal mechanisms in brain disorders are scarce and generally based on limited data. Despite the biological importance of the multiple interacting processes, their effects remain poorly characterized from an integrative analytic perspective. Here, we propose a spatiotemporal multifactorial causal model (MCM) of brain (dis)organization and therapeutic intervention that accounts for local causal interactions, effects propagation via physical brain networks, cognitive alterations, and identification of optimum therapeutic interventions. In this article, we focus on describing the model and applying it at the population-based level for studying late onset Alzheimer's disease (LOAD). By interrelating six different neuroimaging modalities and cognitive measurements, this model accurately predicts spatiotemporal alterations in brain amyloid-β (Aβ) burden, glucose metabolism, vascular flow, resting state functional activity, structural properties, and cognitive integrity. The results suggest that a vascular dysregulation may be the most-likely initial pathologic event leading to LOAD. Nevertheless, they also suggest that LOAD it is not caused by a unique dominant biological factor (e.g. vascular or Aβ) but by the complex interplay among multiple relevant direct interactions. Furthermore, using theoretical control analysis of the identified population-based multifactorial causal network, we show the crucial advantage of using combinatorial over single-target treatments, explain why one-target Aβ based therapies might fail to improve clinical outcomes, and propose an efficiency ranking of possible LOAD interventions. Although still requiring further validation at the individual level, this work presents the first analytic framework for dynamic multifactorial brain (dis)organization that may explain both the pathologic evolution of progressive neurological disorders and operationalize the influence of multiple interventional strategies.

Glucose hypometabolism in the pre-clinical stage of Alzheimer’s disease (AD) has been primarily associated with the APOE ɛ4 genotype, rather than fibrillar β-amyloid. In contrast, aberrant patterns of metabolic connectivity are more strongly related to β-amyloid burden than APOE ɛ4 status. A major limitation of previous studies has been the dichotomous classification of subjects as amyloid-positive or amyloid-negative. Dichotomous treatment of a continuous variable, such as β-amyloid, potentially obscures the true relationship with metabolism and reduces the power to detect significant changes in connectivity. In the present work, we assessed alterations of glucose metabolism and metabolic connectivity as continuous function of β-amyloid burden using positron emission tomography scans from the Alzheimer’s Disease Neuroimaging Initiative study. Modeling β-amyloid as a continuous variable resulted in better model fits and improved power compared to the dichotomous model. Using this continuous model, we found that both APOE ɛ4 genotype and β-amyloid burden are strongly associated with glucose hypometabolism at early stages of Alzheimer’s disease. We also determined that the cumulative effects of β-amyloid deposition result in a particular pattern of altered metabolic connectivity, which is characterized by global, synchronized hypometabolism at early stages of the disease process, followed by regionally heterogeneous, progressive hypometabolism.

With the advent of brain imaging techniques, the study of human brain connectivity in vivo becomes possible and has offered new insights into understanding the structural organization and work mechanisms of the human brain. Using different modalities of neuroimaging, both structural and functional brain connectivity can be mapped. The connectivity analysis has been widely applied into investigating the brain mechanisms of cognitive functions and neuropathology of different brain disorders. However, there are still some challenges when mapping, analyzing, and modeling the brain connectivity at different scales. This special issue aims at reflecting the advances in studies of brain connectivity, including both modeling methods and applications. In this special issue, different imaging techniques, such as structural MRI, diffusion MRI, and functional near-infrared spectroscopy (fNIRS), were employed in the studies of brain connectivity. The applications addressed hemispheric asymmetry, primary insomnia, and motor training. Also, the computational modeling methods and analysis toolbox of brain connectivity were introduced. The types of papers include review articles as well as original research. For the modeling methods of brain connectivity, R. C. Sotero (2015) reviews computational models of phase-amplitude coupling (PAC) generation ranging from realistic networks of Hodgkin-Huxley neurons to neural mass models (NMMs) describing only the average activity of the neuronal populations involved and showed that NMMs are rich enough to provide a variety of PAC patterns. For the analysis toolbox of brain connectivity, J. Xu et al. (2015) developed a MATLAB software package that facilitates fNIRS-based human functional connectome data-analysis, which will be useful for the resting-state brain functional connectivity (FC) studies. For the application studies of brain connectivity, N. Shu et al. (2015) investigated the hemispheric asymmetry of brain white matter anatomical network which is constructed by diffusion MRI tractography and demonstrated that the topological asymmetries of the anatomical networks might reflect the functional lateralization of the human brain. L. Zhao et al. (2015) investigated the topological alterations of the structural covariance network for patient with primary insomnia, suggesting that insomnia might be related to underlying increase in brain network integration encompassing the sensory to motor networks, the default mode network, and the salience network and decrease in the integration between the sensory regions and the frontoparietal working memory network. The special issue also contains several review papers: B. Wong et al. (2015) review structural and functional connectivity studies of bilingualism and examined different issues such as whether the language neural network is different for first- (dominant) versus second- (nondominant) language processing; the effects of bilinguals' executive functioning on the structure and function of the “universal” language neural network; the differential effects of bilingualism on phonological, lexical-semantic, and syntactic aspects of language processing on the brain; and the effects of age of acquisition and proficiency of the user's second language in the bilingual brain, and how these have implications for future research in neurolinguistics. T. D. Ben-Soussan et al. (2015) review the connectivity studies of quadrato motor training and proposed a general model tying cerebellar function to cognitive improvement, via neuronal synchronization as well as biochemical and anatomical changes. In summary, the papers collected in this special issue cover a wide range of topics that are on the frontier of the methods and applications of brain connectivity.

Primary patterns in adult brain connectivity are established during development by coordinated networks of transiently expressed genes; however, neural networks remain malleable throughout life. The present study hypothesizes that structural connectivity from key seed regions may induce effects on their connected targets, which are reflected in gene expression at those targeted regions. To test this hypothesis, analyses were performed on data from two brains from the Allen Human Brain Atlas, for which both gene expression and DW‐MRI were available. Structural connectivity was estimated from the DW‐MRI data and an approach motivated by network topology, that is, weighted gene coexpression network analysis (WGCNA), was used to cluster genes with similar patterns of expression across the brain. Group exponential lasso models were then used to predict gene cluster expression summaries as a function of seed region structural connectivity patterns. In several gene clusters, brain regions located in the brain stem, diencephalon, and hippocampal formation were identified that have significant predictive power for these expression summaries. These connectivity‐associated clusters are enriched in genes associated with synaptic signaling and brain plasticity. Furthermore, using seed region based connectivity provides a novel perspective in understanding relationships between gene expression and connectivity. Hum Brain Mapp 38:3126–3140, 2017. © 2017 Wiley Periodicals, Inc.

Evidence for interregional structural asymmetries has been previously reported for brain anatomic regions supporting well-described functional lateralization. Here, we aimed to investigate whether the two brain hemispheres demonstrate dissimilar general structural attributes implying different principles on information flow management. Common left hemisphere/right hemisphere structural network properties are estimated and compared for right-handed healthy human subjects and a nonhuman primate, by means of 3 different diffusion-weighted magnetic resonance imaging fiber tractography algorithms and a graph theory framework. In both the human and the nonhuman primate, the data support the conclusion that, in terms of the graph framework, the right hemisphere is significantly more efficient and interconnected than the left hemisphere, whereas the left hemisphere presents more central or indispensable regions for the whole-brain structural network than the right hemisphere. From our point of view, in terms of functional principles, this pattern could be related with the fact that the left hemisphere has a leading role for highly demanding specific process, such as language and motor actions, which may require dedicated specialized networks, whereas the right hemisphere has a leading role for more general process, such as integration tasks, which may require a more general level of interconnection.

Diffusion spectrum magnetic resonance imaging (DSI) allows the estimation of the displacement probability density function (pdf) of water molecules, which contain valuable information about the microgeometry of the medium where the diffusion process occurs. It provides a more general approach to disentangle complex fiber structures in biological tissues because it does not assume any particular model of diffusion; even so, it has a number of limitations that remain unstudied. For instance, the theoretical model used to compute the displacement pdf is based on a Fourier transformation defined in the whole measurement space; however, in practice, it is computed using discrete signals with a finite support. As a consequence, the displacement pdf obtained from the experiments is the convolution between the true pdf and a point spread function (PSF) that completely depends on the experimental sampling scheme. In this work, a general framework to rectify and decontaminate the displacement pdf reconstructed from DSI is introduced. This framework is based on model-free deconvolution techniques that allow obtaining clearer and sharper DSI estimates. The method was tested in synthetic data as well as in real data measured from a healthy human volunteer. The results demonstrated that the angular resolution of DSI can be increased, potentially revealing new real fiber components and reducing both the artefactual peaks and the uncertainty of the local diffusion orientational distribution. Furthermore, the deconvolution process provides scalar maps of quantities derived from the propagator, such as the zero displacement probability, with higher tissue contrast.

This article reviews progress and challenges in model driven EEG/fMRI fusion with a focus on brain oscillations. Fusion is the combination of both imaging modalities based on a cascade of forward models from ensemble of post‐synaptic potentials (ePSP) to net primary current densities (nPCD) to EEG; and from ePSP to vasomotor feed forward signal (VFFSS) to BOLD. In absence of a model, data driven fusion creates maps of correlations between EEG and BOLD or between estimates of nPCD and VFFS. A consistent finding has been that of positive correlations between EEG alpha power and BOLD in both frontal cortices and thalamus and of negative ones for the occipital region. For model driven fusion we formulate a neural mass EEG/fMRI model coupled to a metabolic hemodynamic model. For exploratory simulations we show that the Local Linearization (LL) method for integrating stochastic differential equations is appropriate for highly nonlinear dynamics. It has been successfully applied to small and medium sized networks, reproducing the described EEG/BOLD correlations. A new LL‐algebraic method allows simulations with hundreds of thousands of neural populations, with connectivities and conduction delays estimated from diffusion weighted MRI. For parameter and state estimation, Kalman filtering combined with the LL method estimates the innovations or prediction errors. From these the likelihood of models given data are obtained. The LL‐innovation estimation method has been already applied to small and medium scale models. With improved Bayesian computations the practical estimation of very large scale EEG/fMRI models shall soon be possible. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

A new methodology based on Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) and Graph Theory is presented for characterizing the anatomical connections between brain gray matter areas. In a first step, brain voxels are modeled as nodes of a non-directed graph in which the weight of an arc linking two neighbor nodes is assumed to be proportional to the probability of being connected by nervous fibers. This probability is estimated by means of probabilistic tissue segmentation and intravoxel white matter orientational distribution function, obtained from anatomical MRI and DW-MRI, respectively. A new tractography algorithm for finding white matter routes is also introduced. This algorithm solves the most probable path problem between any two nodes, leading to the assessment of probabilistic brain anatomical connection maps. In a second step, for assessing anatomical connectivity between K gray matter structures, the previous graph is redefined as a K + 1 partite graph by partitioning the initial nodes set in K non-overlapped gray matter subsets and one subset clustering the remaining nodes. Three different measures are proposed for quantifying anatomical connections between any pair of gray matter subsets: Anatomical Connection Strength (ACS), Anatomical Connection Density (ACD) and Anatomical Connection Probability (ACP). This methodology was applied to both artificial and actual human data. Results show that nervous fiber pathways between some regions of interest were reconstructed correctly. Additionally, mean connectivity maps of ACS, ACD and ACP between 71 gray matter structures for five healthy subjects are presented.

We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled in the “Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease” (PREVENT-AD) Cohort. Subjects with a family history of Alzheimer's disease in first-degree relatives were recruited as part of an on-going double blind randomized clinical trial of Naproxen or placebo. Two pairs of scans were acquired ~3 months apart, allowing the assessment of both intra- and inter-session reliability, with the possible caveat of treatment effects as a source of inter-session variation. Using the NeuroImaging Analysis Kit (NIAK), we report on the standard quality of co-registration and motion parameters of the data, and assess their validity based on the spatial distribution of seed-based connectivity maps as well as intra- and inter-session reliability metrics in the default-mode network. This resource, released publicly as sample UM1 of the Consortium for Reliability and Reproducibility (CoRR), will benefit future studies focusing on the preclinical period preceding the appearance of dementia in Alzheimer's disease.

We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. DOI: http://dx.doi.org/10.7554/eLife.08440.001, eLife digest Although Parkinson's disease is the second most common neurodegenerative disorder, its cause is not known and there is no cure. The symptoms of Parkinson's disease, which include tremor and slowing of voluntary movements, get progressively worse over time. The numbers of neurons in certain brain regions also decrease, causing those parts of the brain to shrink; this is known as ‘atrophy’. However, no conclusive signs of atrophy have been found in the brains of people in the early stages of the disease. One theory suggests that Parkinson's disease is caused by a toxic protein that is able to spread from neuron to neuron. Recent advances in brain imaging have made it possible to map networks in the living human brain—the so-called brain connectome. These networks could form the ‘highways’ through which a disease-causing agent might spread. The Parkinson's Progression Markers Initiative (PPMI) is a large study that collects data from hundreds of people in an effort to identify the causes of Parkinson's disease. Zeighami et al. have now analyzed MRI scans that were collected as part of this initiative, which show the structure of the brains of 230 people in the early stages of Parkinson's disease. Comparing these scans to those from age-matched healthy individuals allowed Zeighami et al. to identify the set of brain regions that show atrophy in the early stages of Parkinson's disease. These regions correspond to a normal brain network, and the relative extent of atrophy in each brain region supports the theory that the disease spreads through the connectome. The patients who were enrolled in this study will continue to be evaluated on a yearly basis. Zeighami et al. plan to continue mapping how the disease progresses throughout the brain and to relate this to the development of new symptoms of Parkinson's disease. DOI: http://dx.doi.org/10.7554/eLife.08440.002

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Increased brain connectivity, in all its variants, is often considered an evolutionary advantage by mediating complex sensorimotor function and higher cognitive faculties. Interaction among components at all spatial scales, including genes, proteins, neurons, local neuronal circuits and macroscopic brain regions, are indispensable for such vital functions. However, a growing body of evidence suggests that, from the microscopic to the macroscopic levels, such connections might also be a conduit for in intra-brain disease spreading. For instance, cell-to-cell misfolded proteins (MP) transmission and neuronal toxicity are prominent connectivity-mediated factors in aging and neurodegeneration. This article offers an overview of connectivity dysfunctions associated with neurodegeneration, with a specific focus on how these may be central to both normal aging and the neuropathologic degenerative progression.

Spherical deconvolution (SD) methods are widely used to estimate the intra-voxel white-matter fiber orientations from diffusion MRI data. However, while some of these methods assume a zero-mean Gaussian distribution for the underlying noise, its real distribution is known to be non-Gaussian and to depend on many factors such as the number of coils and the methodology used to combine multichannel MRI signals. Indeed, the two prevailing methods for multichannel signal combination lead to noise patterns better described by Rician and noncentral Chi distributions. Here we develop a Robust and Unbiased Model-BAsed Spherical Deconvolution (RUMBA-SD) technique, intended to deal with realistic MRI noise, based on a Richardson-Lucy (RL) algorithm adapted to Rician and noncentral Chi likelihood models. To quantify the benefits of using proper noise models, RUMBA-SD was compared with dRL-SD, a well-established method based on the RL algorithm for Gaussian noise. Another aim of the study was to quantify the impact of including a total variation (TV) spatial regularization term in the estimation framework. To do this, we developed TV spatially-regularized versions of both RUMBA-SD and dRL-SD algorithms. The evaluation was performed by comparing various quality metrics on 132 three-dimensional synthetic phantoms involving different inter-fiber angles and volume fractions, which were contaminated with noise mimicking patterns generated by data processing in multichannel scanners. The results demonstrate that the inclusion of proper likelihood models leads to an increased ability to resolve fiber crossings with smaller inter-fiber angles and to better detect non-dominant fibers. The inclusion of TV regularization dramatically improved the resolution power of both techniques. The above findings were also verified in human brain data. This work was supported by the Catalonian Government (2014SGR1573), several grants from the Plan Nacional de I+D+i and co-funded by the Instituto de Salud Carlos III-Subdireccion General de Evaluacion y Fomento de la Investigacion and the European Regional Development Fund (FEDER): Miguel Servet Research Contracts (CP10/00596 to EP-C, CP13/00018 to RS and CP14/00041 to JR) and Research Project Grants (PI14/00292 to JR, PI14/01148 to EP-C and PI14/01151 to RS). The funding organizations played no role in the study design, data collection and analysis, or manuscript approval.

Whether the neural mechanisms that underlie the processing of a second language in highly proficient late bilinguals (L2 late learners) are similar or not to those that underlie the processing of the first language (L1) is still an issue under debate. In this study, a group of late learners of Spanish whose native language is English and a group of Spanish monolinguals were compared while they read sentences, some of which contained syntactic violations. A brain complex network analysis approach was used to assess the time-varying topological properties of the functional networks extracted from the electroencephalography (EEG) recording. Late L2 learners showed a lower degree of parallel information transfer and a slower propagation between regions of the brain functional networks while processing sentences containing a gender mismatch condition as compared with a standard sentence configuration. In contrast, no such differences between these conditions were detected in the Spanish monolinguals. This indicates that when a morphosyntactic language incongruence that does not exist in the native language is presented in the second language, the neural activation pattern is configured differently in highly proficient late bilinguals than in monolinguals.

Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders., Author Summary Misfolded proteins (MP) mechanisms are a characteristic pathogenic feature of most prevalent human neurodegenerative diseases, such as Alzheimer's disease (AD). Characterizing the mechanisms underlying intra-brain MP propagation and deposition still constitutes a major challenge. Here, we hypothesize that these complex mechanisms can be accurately described by epidemic spreading-like interactions between infectious-like agents (MP) and the brain's MP clearance response, which are constrained by the brain's connectional architecture. Consequently, we have developed a stochastic epidemic spreading model (ESM) of MP propagation/deposition that allows for reconstructing individual lifetime histories of intra-brain MP propagation, and the subsequent analysis of factors that promote propagation/deposition (e.g., MP production and clearance). Using 733 individual PET Amyloid-ß (Aß) datasets, we show that ESM explains advanced Aß deposition patterns in healthy and diseased (AD) brains. More importantly, it offers new avenues for our understanding of the mechanisms underlying MP mediated disorders. For instance, the results strongly support the growing body of evidence suggesting the leading role of a reduced Aβ clearance on AD progression and the modulatory impact of Aß mechanisms on tau proteins concentrations, which could imply a turning point for associated therapeutic mitigation strategies.

Background: The prion-like hypothesis predicts disease spread from propagation of pathogenic misfolded proteins along anatomically-connected pathways. The epidemic spreading model (ESM) is a promising method for predicting this propagation, as was recently demonstrated using data from ADNI. It considers there is an As driving region (epicenter) and that interregional deposition patterns are dependent upon a region’s connectivity to this epicenter. The aim of the present study was to further validate ESM in As overexpressingmice using gold-standard, quantitative immunohistochemistry measures. Methods: 3D quantitative IHC volumes from 12 and 19 month-old transgenic mutant human amyloid precursor protein (hAPP) were spatially normalized to an anatomical template (PERMITS , Biospective Inc.), providing extracted mean values of As deposition in 25 gray matter regions, including 14 cortical regions. C onnectivity between the 25 regions was estimated from publicly-available viral tracer studies (http:// connectivity.brain-map.org/). An anatomical effective distances between each of pair regions i and j (Edist i,j) was then calculated as the shortest path distance between them (i.e. the more connected i and j, the lower the Edist i,j value between them). Using an iterative procedure, we then identified the epicenter region i that maximized the non-linear correlation between regional As deposition values and Edist i,j values (j 1⁄4 1 to 25). Results: The validity of an As epidemic spreading-like behavior hypothesis in mouse models was supported by the identification of the posterior cingulate cortex (PCC) as the epicenter region (same epicenter identified previously for the human subjects). The anatomical effective distance to this epicenter predicted As deposition at 12 and 19 months of age, explaining 60% and 61% of the characteristic As patterns, respectively. Conclusions: The observed correlation between connectivity and As deposition pattern supports the networkdriven hypothesis of misfolded proteins propagation. The epicenter region, PCC, is an central node of the default mode network, which, in humans, has been linked to the progression of Alzheimer’s disease. Further modeling analysis will provide us with a better understanding of disease progression, which will significantly advance translational neurodegenerative research.

The aim of this study was to identify differential global and local brain structural patterns in Dravet Syndrome (DS) patients as compared with a control subject group, using brain morphometry techniques which provide a quantitative whole-brain structural analysis that allows for specific patterns to be generalized across series of individuals. Nine patients with the diagnosis of DS that tested positive for mutation in the SCN1A gene and nine well-matched healthy controls were investigated using voxel brain morphometry (VBM), cortical thickness and cortical gyrification measurements. Global volume reductions of gray matter (GM) and white matter (WM) were related to DS. Local volume reductions corresponding to several white matter regions in brainstem, cerebellum, corpus callosum, corticospinal tracts and association fibers (left inferior fronto-occipital fasciculus and left uncinate fasciculus) were also found. Furthermore, DS showed a reduced cortical folding in the right precentral gyrus. The present findings describe DS-related brain structure abnormalities probably linked to the expression of the SCN1A mutation.

Evidence about the striking relation between the geometric features of the cerebral cortex and cognitive/healthy states of corresponding individuals has being widely reported for different mammalian species, including humans. In this study we evaluated four different geometric features (Average Fractal Dimension, Watershed Regions, Gyrification Index and Absolute Mean Curvature) on the cortex of six healthy mouse brains (C3HeB), based on their corresponding high resolution MR images. Each measure was evaluated firstly on the entire individual’s cerebral cortex, latter on both hemispheres and finally on a set of redefined cortical regions (with a similar volume). In all cases was obtained a low variation through subjects, which is expected due to we are working with healthy subjects at a similar age. In addition, we found that different brain regions presents different geometric properties, which is in correspondence with the different local properties of the cerebral cortex, that responds to the main principle of brain segregation. Future works should be focused on the evaluation through these measures of global and local structural brain affectations provoked by pathological states.

Summary Purpose The structural connection patterns of the human brain are the underlying bases for functional connectivity. Although abnormal functional connectivity has been uncovered in childhood absence epilepsy (CAE) in previous electroencephalography and functional magnetic resonance imaging studies, little is known regarding the structural connectivity in CAE. We hypothesized that the structural connectivity would be disrupted in response to the decreased brain function in CAE. Methods Diffusion tensor imaging tractography was utilized to map the white matter (WM) structural network, composed of 90 cortical and sub-cortical regions, in 18 CAE and 18 age- and gender-matched healthy controls. Graph theoretical methods were applied to investigate the alterations in the topological and nodal properties of the networks in these patients. Results Both the CAE and the controls showed small-world properties in their WM networks. However, the network connection strength, absolute clustering coefficient, and global/local efficiency were significantly decreased, but characteristic path length was significantly increased in the CAE compared with the controls. Significantly decreased WM connections, nodal properties, and impaired sub-networks were found in the sub-cortical structures, orbitofrontal area, and limbic cortex in the CAE. Moreover, network connection strength, local efficiency, and nodal features in some regions were significantly negatively correlated with the duration of epilepsy. Conclusions The present study demonstrated, for the first time, the disrupted topological organization of WM networks in CAE. The decreased connectivity and efficiency in the orbitofrontal and sub-cortical regions may serve as anatomical evidence to support the functional abnormalities related to the epileptic discharges observed in CAE. Moreover, the orbitofrontal sub-network may play a key role in CAE. These findings open up new avenues toward the understanding of absence epilepsy.

Summary The aim of this study was to identify differential global and local brain structuralpatterns in Dravet Syndrome (DS) patients as compared with a control subject group, usingbrain morphometrytechniqueswhichprovideaquantitativewhole-brainstructuralanalysisthatallows for specific patterns to be generalized across series of individuals. Nine patients withthe diagnosis of DS that tested positive for mutation in the SCN1A gene and nine well-matchedhealthy controls were investigated using voxel brain morphometry (VBM), cortical thicknessand cortical gyrification measurements. Global volume reductions of gray matter (GM) andwhite matter (WM) were related to DS. Local volume reductions corresponding to several whitematter regions in brainstem, cerebellum, corpus callosum, corticospinal tracts and associationfibers (left inferior fronto-occipital fasciculus and left uncinate fasciculus) were also found.Furthermore, DS showed a reduced cortical folding in the right precentral gyrus. The presentfindings describe DS-related brain structure abnormalities probably linked to the expression ofthe SCN1A mutation.© 2014 Elsevier B.V. All rights reserved.

Over the last decade, several papers have focused on the construction of highly detailed mouse high field MRI templates via nonlinear registration to unbiased reference spaces, allowing for a variety of neuroimaging applications such as robust morphometric analyses. However, work in rats has only provided medium field MRI averages based on linear registration to biased spaces with the sole purpose of approximate fMRI localization. This precludes any morphometric analysis in spite of the need of exploring in detail the neuroanatomical substrates of diseases in a recent advent of rat models. In this paper we present a new in vivo rat T2 MRI template set, comprising average images of both intensity and shape, obtained via nonlinear registration. Also, unlike previous rat template sets, we include white and gray matter probabilistic segmentations, expanding its use to those applications demanding prior-based tissue segmentation, e.g. SPM voxel-based morphometry. We also provide a preliminary digitalization of latest Paxinos & Watson atlas for anatomical and functional interpretations within the cerebral cortex. We confirmed that, like with previous templates, forepaw and hindpaw fMRI activations can be correctly localized in the expected atlas structure. To exemplify the use of our new MRI template set, we reported the volumes of brain tissues and cortical structures and probed their relationships with ontogenetic development. Other in vivo applications in the near future can be tensor-, deformation- or voxel-based morphometry, morphological connectivity and diffusion tensor-based anatomical connectivity. Our template set, freely available through the SPM extension website, could be an important tool for future longitudinal and/or functional extensive preclinical studies.

A theoretical framework is presented for converting Blood Oxygenation Level Dependent (BOLD) images to temperature maps, based on the idea that disproportional local changes in cerebral blood flow (CBF) as compared with cerebral metabolic rate of oxygen consumption (CMRO2) during functional brain activity, lead to both brain temperature changes and the BOLD effect. Using an oxygen limitation model and a BOLD signal model we obtain a transcendental equation relating CBF and CMRO2 changes with the corresponding BOLD signal, which is solved in terms of the Lambert W function. Inserting this result in the dynamic bio-heat equation describing the rate of temperature changes in the brain, we obtain a non autonomous ordinary differential equation that depends on the BOLD response, which is solved numerically for each brain voxel. In order to test the method, temperature maps obtained from a real BOLD dataset are calculated showing temperature variations in the range: (-0.15, 0.1) which is consistent with experimental results. The method could find potential clinical uses as it is an improvement over conventional methods which require invasive probes and can record only few locations simultaneously. Interestingly, the statistical analysis revealed that significant temperature variations are more localized than BOLD activations. This seems to exclude the use of temperature maps for mapping neuronal activity as areas where it is well known that electrical activity occurs (such as V5 bilaterally) are not activated in the obtained maps. But it also opens questions about the nature of the information processing and the underlying vascular network in visual areas that give rise to this result.

Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P=0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders.

Recently, a related morphometry-based connection concept has been introduced using local mean cortical thickness and volume to study the underlying complex architecture of the brain networks. In this article, the surface area is employed as a morphometric descriptor to study the concurrent changes between brain structures and to build binarized connectivity graphs. The statistical similarity in surface area between pair of regions was measured by computing the partial correlation coefficient across 186 normal subjects of the Cuban Human Brain Mapping Project. We demonstrated that connectivity matrices obtained follow a small-world behavior for two different parcellations of the brain gray matter. The properties of the connectivity matrices were compared to the matrices obtained using the mean cortical thickness for the same cortical parcellations. The topology of the cortical thickness and surface area networks were statistically different, demonstrating that both capture distinct properties of the interaction or different aspects of the same interaction (mechanical, anatomical, chemical, etc.) between brain structures. This finding could be explained by the fact that each descriptor is driven by distinct cellular mechanisms as result of a distinct genetic origin. To our knowledge, this is the first time that surface area is used to study the morphological connectivity of brain networks.

Novel methodologies have been recently developed to characterize the microgeometry of neural tissues and porous structures via diffusion MRI data. In line with these previous works, this article provides a detailed mathematical description of q-space in spherical coordinates that helps to highlight the differences and similarities between various related q-space methodologies proposed to date such as q-ball imaging (QBI), diffusion spectrum imaging (DSI), and diffusion orientation transform imaging (DOT). This formulation provides a direct relationship between the orientation distribution function (ODF) and the diffusion data without using any approximation. Under this relationship, the exact ODF can be computed by means of the Radon transform of the radial projection (in q-space) of the diffusion MRI signal. This new methodology, termed exact q-ball imaging (EQBI), was put into practice using an analytical ODF estimation in terms of spherical harmonics that allows obtaining model-free and model-based reconstructions. This work provides a new framework for combining information coming from diffusion data recorded on multiple spherical shells in q-space (hybrid diffusion imaging encoding scheme), which is capable of mapping ODF to a high accuracy. This represents a step toward a more efficient development of diffusion MRI experiments for obtaining better ODF estimates.

A new methodology is introduced that characterizes the intravoxel orientation distribution function (ODF) based on a single-fiber model of the diffusion MRI signal. Using a Bayesian framework the probability of finding a fiber in a specific orientation is obtained. The proposed ODF estimation relies on a cigar-like diffusion tensor model, the methodology is thus denominated Bayesian cigar-like diffusion tensor (BCDT). This work makes two major contributions: 1) the study of single-fiber models in detecting fibers with different volume fractions in a voxel, and 2) the introduction of the Nth-root correction to improve the detection of fibers with smaller volume fractions, where N is the number of diffusion MRI measurements. It is demonstrated that the incomplete signal modeling fails to reconstruct the relative fiber volume fractions, especially when the intravoxel diffusion profiles have dissimilar contributions to the diffusion MRI signal. In this situation the fibers with smaller contributions are hardly detectable. The BCDT method proposed here reduces this effect by introducing the Nth-root correction, making multiple fibers estimable. The performance of the new methodology is illustrated using synthetic and real data, as well as the data from a phantom of intersecting capillaries. Magn Reson Med 60:616–630, 2008. © 2008 Wiley-Liss, Inc.

Our goal is to study the human brain anatomical network. For this, the anatomical connection probabilities (ACP) between 90 cortical and subcortical brain gray matter areas are estimated from diffusion-weighted Magnetic Resonance Imaging (DW-MRI) techniques. The ACP between any two areas gives the probability that those areas are connected at least by a single nervous fiber. Then, the brain is modeled as a non-directed weighted graph with continuous arc weights given by the ACP matrix. Based on this approach, complex networks properties such as small-world attributes, efficiency, degree distribution, vulnerability, betweenness centrality and motifs composition are studied. The analysis was carried out for 20 right-handed healthy subjects (mean age: 31.10, S.D.: 7.43). According to the results, all networks have small-world and broad-scale characteristics. Additionally, human brain anatomical networks present bigger local efficiency and smaller global efficiency than the corresponding random networks. In a vulnerability and betweenness centrality analysis, the most indispensable and critical anatomical areas were identified: putamens, precuneus, insulas, superior parietals and superior frontals. Interestingly, some areas have a negative vulnerability (e.g. superior temporal poles, pallidums, supramarginals and hechls), which suggest that even at the cost of losing in global anatomical efficiency, these structures were maintained through the evolutionary processes due to their important functions. Finally, symmetrical characteristic building blocks (motifs) of size 3 and 4 were calculated, obtaining that motifs of size 4 are the expanded version of motif of size 3. These results are in agreement with previous anatomical studies in the cat and macaque cerebral cortex.

In this paper we introduce a new method to characterize the intravoxel anisotropy based on diffusion-weighted imaging (DWI). The proposed solution, under a fully Bayesian formalism, deals with the problem of joint Bayesian Model selection and parameter estimation to reconstruct the principal diffusion profiles or primary fiber orientations in a voxel. We develop an efficient stochastic algorithm based on the reversible jump Markov chain Monte Carlo (RJMCMC) method in order to perform the Bayesian computation. RJMCMC is a good choice for this problem because of its ability to jump between models of different dimensionality. This methodology provides posterior estimates of the parameters of interest (fiber orientation, diffusivities etc) unconditional of the model assumed. It also gives an empirical posterior distribution of the number of primary nerve fiber orientations given the DWI data. Different probability maps can be assessed using this methodology: 1) the intravoxel fiber orientation map (or orientational distribution function) that gives the probability of finding a fiber in a particular spatial orientation; 2) a three-dimensional map of the probability of finding a particular number of fibers in each voxel; 3) a three-dimensional MaxPro (maximum probability) map that provides the most probable number of fibers for each voxel. In order to study the performance and reliability of the presented approach, we tested it on synthetic data; an ex-vivo phantom of intersecting capillaries; and DWI data from a human subject.

We study the generation of EEG rhythms by means of realistically coupled neural mass models. Previous neural mass models were used to model cortical voxels and the thalamus. Interactions between voxels of the same and other cortical areas and with the thalamus were taken into account. Voxels within the same cortical area were coupled (short-range connections) with both excitatory and inhibitory connections, while coupling between areas (long-range connections) was considered to be excitatory only. Short-range connection strengths were modeled by using a connectivity function depending on the distance between voxels. Coupling strength parameters between areas were defined from empirical anatomical data employing the information obtained from probabilistic paths, which were tracked by water diffusion imaging techniques and used to quantify white matter tracts in the brain. Each cortical voxel was then described by a set of 16 random differential equations, while the thalamus was described by a set of 12 random differential equations. Thus, for analyzing the neuronal dynamics emerging from the interaction of several areas, a large system of differential equations needs to be solved. The sparseness of the estimated anatomical connectivity matrix reduces the number of connection parameters substantially, making the solution of this system faster. Simulations of human brain rhythms were carried out in order to test the model. Physiologically plausible results were obtained based on this anatomically constrained neural mass model.